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Multiple Sclerosis-1
 

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    Multiple Sclerosis-1 Multiple Sclerosis-1 Document Transcript

    • Multiple sclerosis Page 1 of 123 Folder Path Multiple sclerosis Neurology Neuroimmunology Demyelinating dis Contributors Multiple sclerosis Anthony T Reder MD, contributing editor. Dr. Reder of the University of Chicago has served sclerosis on advisory boards and as a consultant for Bayer, Berlex Laboratories, BioMS Medical Corp, Quick Referenc Biogen Idec, Caremark Rx, Lilly, Neurocrine Biosciences, Novartis, Pfizer, Schering, Serono, Sections of Sum and Teva Marion. - Historical note a nomenclature Publication dates - Clinical manifest Originally released June 27, 1994; last updated August 4, 2011; expires August 4, 2014 - Clinical vignette - Etiology Synonyms - Pathogenesis an Disseminated sclerosis pathophysiology - Epidemiology - Prevention Key points - Differential diag - Diagnostic work • Multiple sclerosis is caused by immune attack against brain cells. - Prognosis and • The primary damage is oligodendroglia destruction and demyelination, but axons and complications neurons are also damaged. - Management • The incidence of multiple sclerosis is increasing around the world. - Pregnancy • Multiple sclerosis lesions cause focal neurologic deficits, but also generalized problems - Anesthesia with fatigue, cognition, and bladder control. - ICD codes • Diagnosis is complex and requires neurologic history, clinical and MRI exam, and - OMIM sometimes spinal fluid analysis. Supplemental C • New therapies have dramatically changed the course of multiple sclerosis and survival - Associated disor from the disease, but therapies are still only partially effective. - Related summar - Differential diag - Demographics Historical note and nomenclature References Greek and Roman physicians did not document multiple sclerosis, but it may have been - References cited mentioned in 13th century Icelandic sagas. Saint Lidwina of Holland appears to have Related Items developed multiple sclerosis in 1396 (Medaer 1979). The court physician was not optimistic after examining Lidwina, stating, "Believe me, there is no cure for this illness; it comes - Cervical spinal c directly from God. Even Hippocrates and Gallenus would not be of any help here." The multiple sclerosi clinical description and prognosis of multiple sclerosis have improved in the intervening 500 - Cervical spinal c years, but progress in understanding its etiology is debatable. multiple sclerosi Multiple sclerosis was clearly described in 1822 in the diary of Sir Augustus D Este, - Immune cell pro grandson of King George III of England (Firth 1948). One of his relapses is described as electrical stimula synergize to exh follows: in multiple scler - Multiple sclerosis At Florence, I began to suffer from a confusion of sight. About the 6th of (MRI) November, the malady increased to the extent of my seeing all objects double. - Multiple sclerosis Each eye had its separate visions. Dr. Kissock supposed bile to be the cause. I to Therapy A was twice blooded from the temple by leeches. Purges were administered. One - Multiple sclerosis to Therapy B Vomit and twice I lost blood from the arm. The Malady in my eyes abated, - Oligoclonal band again I saw all object naturally in their single state. I was able to go out and multiple sclerosi walk (Murray 2005). - Periventricular lo plaques in multi Cruveilhier in Paris and Carswell in London published detailed illustrations of central (MRI) nervous system plaques and sclerosis in the 1840s. Charcot published detailed clinical PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 2 of 123 descriptions and detailed the demyelination in plaques, and Rindfleisch described the - Multiple sclerosis vascular disease perivascular inflammatory CNS lesions in the 1860s (Cook 1998). These observers symptoms documented the intermittent and seemingly random neurologic symptoms and the variable - Pathological sub evolution of the disease. The history of multiple sclerosis is extensively reviewed in Murray multiple sclerosi (Murray 2005). - WBC pause betw endothelial cells basement memb Clinical manifestations natalizumab, the effects Multiple sclerosis lesions in the brain and spinal cord can damage every function of the central nervous system. The clinical presentation varies from mild to aggressive symptoms - Intention tremor titubation, and d and from relapsing-remitting to progressive disease, and the presentation changes in type of - Internuclear evolution over time. The protean symptoms include fatigue as well as disturbed function in ophthalmoplegia sensory, motor, bladder, bowel, sexual, cerebellar, brainstem, optic nerve, and cognitive sclerosis realms. Multiple sclerosis symptoms, especially fatigue, limit activity in three fourths of Patient Hando patients. The neuroanatomical location of plaques is not completely random. Lesions have a - Esclerosis múltip predilection for the periventricular white matter, so certain symptoms and signs are (Spanish) common. For instance, the medial longitudinal fasciculus has a periaqueductal location. - Mielitis transver (Spanish) Damage to the medial longitudinal fasciculus causes internuclear ophthalmoplegia, a - Multiple sclerosis frequent sign of multiple sclerosis. - Neuralgia del tri In most patients, symptoms of an exacerbation arise over hours to days, typically last 2 to (Spanish) 6 weeks, and then remit, sometimes completely. Forty percent of these attacks cause long- - Pain lasting deficits (Lublin et al 2003; 2008), but 20% improve. Resolved symptoms can - Transverse mye reappear transiently with infections or heat (“ghost symptoms,” Uhthoff phenomenon). - Tremor Fatigue from central lesions. Generalized physical and mental fatigue is the number one - Trigeminal neura problem in two thirds of patients (Reder and Antel 1983; Noseworthy et al 2000). Patients describe fatigue as “profound”; it “disrupts life” and it is “different from any other Web Resources experiences.” They say that because of the fatigue, “each day of the week at work is Alerts and Advis cumulatively harder,” and it gets “worse with heat.” The motor fatigue that normally follows - FDA: Avoiding muscular exertion is magnified (“fatigability,” in 75%) after sustained or repetitive muscle Cardiotoxicity W Mitoxantrone (2 contractions and after walking; the fatigue often develops rapidly after minimal activity. It is - FDA: Natalizuma distinct from weakness and may not correlate with weakness in individual muscles (Schwid - FDA: Natalizuma et al 1999). Another type of fatigue is sometimes unprovoked (“lassitude,” “asthenia,” or of Healthcare Pr “overwhelming tiredness,” in 20%). Fatigue limits prolonged neuropsychological testing. Information (20 Rating scales of multiple sclerosis fatigue are difficult to design and correlate poorly with - FDA: Update on function because these symptoms are multidimensional. Self-reports often do not correlate Associated with Natalizumab (20 with clinical measurements of muscle and cognitive fatigue. Fatigue is an essential part of the neurologic history. Fatigue can be the only symptom of Guidelines an exacerbation, or one of many. It is least common in primary progressive multiple - AAN: Multiple Sc - AAN: Neutralizin sclerosis. Thirty percent of multiple sclerosis patients report fatigue before the diagnosis of Antibodies to In multiple sclerosis (Berger personal communication 2011). Fatigue does not correlate with beta: Clinical an MRI plaque load, Gd enhancement, depression, or inflammatory markers. Fatigue, however, Radiographic Im defined by the Sickness Impact Profile Sleep and Rest Scale (SIPSR), predicts later brain - NGC: EFNS Guid atrophy (Marrie et al 2005). It is associated with low prefrontal activity on PET, with reduced the Use of Neuro the Managemen event-related potentials, and with low N-acetylaspartate in frontal lobes and basal ganglia Multiple Sclerosi on magnetic resonance spectroscopy. - NICE: Multiple S Fatigue usually is worse in heat, in high humidity, and in the afternoon; body temperature (U.K.) is slightly higher in all these situations. This extreme sensitivity to heat is termed “Uhthoff Google Scholar phenomenon,” wherein a minimal elevation of body temperature interferes with impulse - Other articles on conduction by demyelinated axons because of their lower “safety factor.” Spasticity amplifies PubMed fatigue by creating resistance to movement, complicating routine actions. Central fatigue - Other articles on has been attributed to decreased Na+/K+ ATPase in multiple sclerosis plaques, disruption of Other Related Li the Kv 1.3 potassium channel in mitochondria, serum and spinal fluid neuroelectric blocking - European Charc factors, neuronal dysfunction and exhaustion, axonal injury and poor axonal conduction, Foundation impaired glial function, poor perfusion of deep gray matter area, and the need to use wide - Multiple Sclerosi Association of A areas of the cortex. Functional MRI for physical and cognitive tasks shows compensatory PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 3 of 123 (inefficient) reorganization of the damaged CNS, with increased demand on remaining - Multiple Sclerosi International Fe neurons. “Primary fatigue” is worst at midday. - MS Society of Ca In “non-primary fatigue,” contributors to fatigue and central conduction block are acidosis; - MS Society of G lactate; heat after exercise; the rise in body temperature in the afternoon; and a half- and Northern Ire degree centigrade rise in body temperature during the luteal phase post-ovulation; pain; - National MS Soc poor sleep (daytime fatigue with waking at night, “middle insomnia,” often caused by need Professional Res to urinate, and also spasms and itching and high incidence of sleep-related movement Center disorders); depression; low levels of dehydroepiandrosterone (DHEA) and its sulphated - Video: Patient G Managing MS (A conjugate (DHEAS); inflammatory cytokines in the central nervous system [prostaglandins, Foundation) tumor necrosis factor-alpha, and interferon-gamma (IFN-gamma)]. Insula lesions in stroke - Video: Multiple S can cause underactivity and tiredness; the insular cortex atrophies in secondary progressive Histopathology S multiple sclerosis. Fatigue is associated with restless leg syndrome, circadian rhythm About Links disruption, periodic limb movements, and hypersomnolence on sleep studies. A report of a - About Web Reso specific brain sodium channel blocker (Brinkmeier et al 2000) could not be confirmed (Cummins et al 2003). Medications, hypothyroidism, anemia, and muscle deconditioning can contribute to fatigue. Sleep disorders in multiple sclerosis are heterogeneous, often profound, and unexplained. Patients often complain of insomnia yet still have severe daytime fatigue. In small studies, CSF hypocretin (orexin) is normal in multiple sclerosis, unlike the low levels in narcolepsy. However, the frequent hypothalamic plaques in corticotrophin-releasing factor pathways could damage orexin-containing neurons. This would reduce input to the suprachiasmatic nucleus and disrupt circadian clock genes. Autonomic problems. The hypothalamus controls autonomic functions, temperature, sleep, and sexual activity. Cortical, brainstem, and spinal cord lesions often interrupt the sympathetic nervous system. This causes slow colonic transit, bladder hyperreflexia, and sexual dysfunction. Other less-recognized phenomena from sympathetic nervous system disruption are vasomotor dysregulation (cold, purple feet), cardiovascular changes (orthostatic changes in blood pressure, poor variation of the EKG R-R interval on Valsalva maneuver, possibly increasing risk of surgery), poor pilocarpine-induced sweating, poor sympathetic skin responses—especially in progressive multiple sclerosis (Karaszewski et al 1990; Acevedo et al 2000), pupillary abnormalities, and possibly fatigue. Rarely, plaques in brainstem autonomic pathways cause atrial fibrillation or neurogenic pulmonary edema, sometimes preceded by lesion-induced cardiomyopathy. Sixty percent of patients have pupillary reactions that are abnormal in rate and degree of constriction (de Seze et al 2001). Pupillary defects do not correlate with visual-evoked potentials or history of optic neuritis. Autonomic dysfunction does correlate with axonal loss and spinal cord atrophy yet not with cord MRI lesions. It is possible that plaques in the insular cortex, hypothalamus, and cord all disrupt sympathetic pathways. Parasympathetic and sympathetic dysfunction correlates with duration of multiple sclerosis but not with disability (Gunal et al 2002). Parasympathetic dysfunction (eg, heart rate variation with respiration, abnormal pupillary reactions) is most pronounced in primary progressive disease. Sympathetic dysfunction (blood pressure response to straining) can worsen during exacerbations, and it is possibly tied to dysregulated immunity (Flachenecker et al 2001), less response to the beta-adrenergic agonist, isoproterenol (Giorelli et al 2004), and conversion to progressive multiple sclerosis. Periodic hyperthermia and profound hypothermia (to 28C/79F, authors observation) are occasionally seen. Cognition is surprisingly preserved with hypothermia. These patients are at high risk for infection because immunity is compromised at low temperature. Conversely, worsening hypothermia can forecast an infection. Abnormal temperature regulation is presumably from hypothalamic or thalamic plaques. Cognitive function. Higher cortical functions, language skills, and intellectual function usually appear normal to a casual observer. However, careful clinical observation and sensitive neuropsychological tests find slight to moderate cognitive slowing, slow information processing, word-finding difficulties, poor recent “explicit” memory, poor clock-drawing, and decline in effortful measures of attention in 50% of patients (Rao et al 1991; Beatty 1999; Arnason 2005). Up to half of patients with clinically isolated syndromes are significantly PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 4 of 123 impaired on some tests. Complaints range from “I always forget where I put my keys” and “the lights are off in the factory” to “I am no longer able to perform cube roots in my head.” These subcortical signs often appear during complex tasks (especially with use of affected limbs), with speeded responses, during working memory, and when multiple visual and sensory stimuli confront the patient: “I feel like I live in an IMAX theater.” The simple question, “Do you have trouble walking through a shopping mall?" is often met with an anguished, "Yes, its too overwhelming.” Patients should be screened for cognitive problems at the first exam. Patients with normal cognition tend to maintain cognitive levels, but mild cognitive deterioration predicts progressive decline in cognition over 3 years. The best measure of cognitive slowing (information processing speed, sustained and complex attention, and working memory) appears to be the symbol digit modalities test (SDMT). Mood swings, irritability, and frustration from slow cognition are common. The family may notice impairment before the patient does. When disputed by the family, complaints of cognitive decline suggest depression. Cognitive deficits are most pronounced in secondary progressive disease, but often do not correlate with physical disability. Cognitive decline leads to difficulty with employment and daily life. Patients have more difficulty walking while performing cognitive tasks. Neuropsychological evaluation can review residual strengths and weaknesses for employment, social function, and driving ability; evaluation can also investigate depression and lead to therapy. Decision making is compromised from slower learning plus impaired emotional reactivity. Occasionally, patients go through a phase of wildly illogical thinking that later resolves as the disease progresses. “Low anxiety” leads to inconsistent, risky decisions in a Gambling Task and predominates in early multiple sclerosis (Kleeberg et al 2004). Impulsivity correlates with loss of anterior corpus callosum integrity in cocaine-dependent subjects and possibly also in multiple sclerosis. Some patients have nearly normal neurologic exams yet are unable to walk from poor patterning of leg movement and gait. Electrophysiological tests confirm this apraxia and show impaired input to the motor cortex and to pathways involved in motor planning. Spinal learning may also be impaired (Arnason 2005). Patients with mild cognitive impairment have cortical thinning on MRI. Chronic cases have extensive hippocampal demyelination (Geurts et al 2007), although cognition is less affected in primary progressive multiple sclerosis. T1 brain and corpus callosum atrophy, third ventricular width, and T2 lesion load correlate modestly with poor cognition. Basal ganglia hypointensity and atrophy (brain parenchymal fraction) correlate modestly with decreased memory. Retinal nerve fiber layer thickness, however, correlates quite well with symbol digit modality tests (r=0.754) (Toledo et al 2008). Global N-acetyl aspartate has a moderate correlation with cognitive loss. Decreased attention correlates with lower N-acetylaspartate in the locus ceruleus in relapsing-remitting patients. On functional MRI, decreased activation of the cerebellum correlates with poor motor learning. Excessive activation (poorly focused) in the supramarginal gyrus, insula, and anterior cingulum correlates with poor episodic memory (Rao personal communication 2005). Excess activation also links to less hand dexterity, suggesting greater allocation of cognitive resources. Conventional MRI and functional MRI (fMRI) abnormalities correlate with slow psychomotor speed and increased risk of driving accidents. Positron emission tomography (PET) shows cortical hypometabolism above subcortical plaques. Cognitive impairment in rats with experimental allergic encephalomyelitis lasts long after inflammatory lesions have resolved. Low bone density is associated with cognitive impairment (Weinstock-Guttman personal communication 2011). This may be a consequence of loss in CNS input to bone or to an underlying cytokine abnormality. Exacerbations can reduce cognition, sometimes as the sole symptom. B Arnason argues that memory problems appear during exacerbations in early multiple sclerosis, coincident with T cell inflammation in the CNS. Later in the disease, cognition is increasingly impaired, coincident with greater monocyte and microglial activation and monokine secretion (Arnason PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 5 of 123 2005). Visual memory declines in multiple sclerosis. Visual pathways course from optic nerves, around the ventricles to the occipital cortex, and back around the ventricles to temporal memory areas. Visual pathways are likely to be interrupted by periventricular plaques and inflammatory cytokines. IFN-beta therapy benefits visual memory (below). Aphasia is rare in multiple sclerosis but can arise in acute disseminated encephalomyelitis. Depression. This topic is extensively reviewed by Arnason (Arnason 2005). The incidence of depression is increased 2- to 3-fold in multiple sclerosis patients (>50%) and their families. Severe, short-duration multiple sclerosis is associated with more depression, but primary progression is associated with less depression. Plaques and hypometabolism in the left arcuate fasciculus (supra-insular white matter) (Pujol et al 1997), right temporal (Berg et al 2000), and left temporal and inferior prefrontal areas (Feinstein et al 2004) are associated with depression. However, depression does not correlate with MRI burden of disease or atrophy, disability, or cognitive deficits. The dexamethasone suppression test is a marker of neuroendocrine function in depression. It is abnormal during active multiple sclerosis (Reder et al 1987; Fassbender et al 1998), possibly from chronic inflammation, cytokine stress, and induction of CRH/AVP in hypothalamic neurons. During attacks, depression and cytokine levels are strongly correlated [tumor necrosis factor-alpha, IFN-gamma, and interleukin 10 (IL-10) all rise] (Kahl et al 2002), possibly because IFN-gamma increases serotonin transporter and indoleamine dioxygenase levels, lowering serotonin. Therapy with IFN-beta can occasionally trigger depression, probably because interferon elevates indolamine-2,3-dioxygenase, which lowers levels of tryptophan and serotonin. However, IFN-beta therapy as well as antidepressants could elevate brain serotonin by decreasing IFN-gamma levels. Both agents induce brain-derived neurotrophic factor. Surprisingly, patients taking anti-depressants have lower BDNF levels in circulating immune cells (Hamamcioglu and Reder 2007), possibly because depressed multiple sclerosis patients have low BDNF levels before antidepressant therapy. Suicide is elevated 7-fold in multiple sclerosis. Suicidal patients are more likely to have a family history of mental illness, to abuse alcohol, to be under social stress or be depressed, and to live alone. Confused thoughts and occasionally psychosis can be seen with exacerbations. Pseudobulbar affect (pathological laughing and crying, involuntary emotional expression disorder) can be disabling. Disinhibition is from multiple supratentorial plaques and is occasionally associated with hiccups and paroxysmal dystonia. Euphoria, despite concurrent neurologic problems, was described by Charcot. It is possible the euphoria is cytokine- mediated, akin to “spes phthisica”—a feeling of hopefulness for recovery seen in patients with tuberculosis. Optic neuritis. The optic nerves are frequently involved (approximately 2/3 clinically), especially in younger patients. Thirty-one percent of army recruits with multiple sclerosis have optic signs. “Asymptomatic” patients, free of optic neuritis, frequently have abnormal visual evoked potentials or perimetry. Optic neuritis typically begins with subacute loss of vision in 1 eye. The central scotoma is described as blurring or a dark patch. Color perception and contrast sensitivity are also disturbed. Subjective reduction of light intensity is often associated with an ipsilateral Marcus Gunn hypoactive pupillary response. Ninety-two percent have retro-orbital pain with eye movement. With acute lesions, there may be blurring of the disc margin or florid papillitis. With papillitis (in 5%), inflammation near the nerve head can cause disc-swelling, cells in the vitreous, and deep retinal exudates. When the inflammation is retrobulbar, the fundus is initially normal. After the neuritis resolves, the disc is usually pale ("optic pallor"), commonly in its temporal aspect. Slit-like defects in the peripapillary nerve fiber layer can be seen with red-free (green) light using an ophthalmoscope. This axonal damage in the retina, an area free of central nervous system myelin, suggests that optic nerve pathology extends beyond central nervous system plaques. Retinal nerve fiber layer atrophy and thinning is obvious on PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 6 of 123 optical coherence tomography (OCT). On OCT, the fellow eye is often abnormal, though not as severe. Bilateral simultaneous optic neuritis led to multiple sclerosis in 1 of 11 adults after an interval of up to 30 years. Sequential optic neuritis led to multiple sclerosis in 8 of 20 (Parkin et al 1984). In children, 1 of 17 developed multiple sclerosis after bilateral onset. Visual function usually begins to improve several weeks after the onset of optic neuritis, and resolution continues over several months. Complete recovery of visual acuity is the rule, even after near blindness. Other disturbances of vision, however, often persist, such as visual "blurring" and red or blue desaturation that causes colors to appear drab (“not as vivid”). There is progressive loss of color discrimination with longer duration multiple sclerosis. Bright lights cause a prolonged afterimage, a "flight of colors." Depth perception is impaired and is worse with moving objects (“Pulfrich phenomenon”). Eye movements sometimes cause fleeting flashes of light (“movement phosphenes”). The mechanism corresponds to the fleeting cervical sensory changes of Lhermitte sign (Lhermitte of the eye). Increased body temperature can amplify all of these symptoms and diminish visual acuity (“Uhthoff phenomenon”). Uveitis and pars planitis (peripheral uveitis) are present in 1% of multiple sclerosis patients. Conversely, 20% of patients with pars planitis develop multiple sclerosis or optic neuritis. Some of these patients will develop macular edema, vitreous opacities, papillitis, vasculitis and vitreous hemorrhage, and cataracts. Perivenous sheathing is an inflammatory change of the retina seen in one fourth of multiple sclerosis patients. Cortical lesions can distort vision, eg, visual inversion. Brainstem abnormalities, including diplopia. Lesions in the brainstem disrupt intra- axial nerves, nerve nuclei, internuclear connections, plus autonomic, motor, and sensory long tracts. Sixth or third nerve and rarely fourth nerve lesions cause diplopia. Cerebellar and brainstem lesions cause eye movement abnormalities, usually coinciding with more severe disability. Proton density MRI is the best way to image abnormalities in the brainstem, including plaques in the median longitudinal fasciculus. There are reports of high T2 signal MRI lesions in peripheral third, fifth (in 2% of patients, with two thirds bilateral), and eighth nerves. Medial rectus weakness is usually part of an “internuclear ophthalmoplegia” (INO). In a young patient, INO is nearly pathognomonic of multiple sclerosis. Infarcts, trauma, and disparate other causes are possible, especially in older patients (Keane 2005). Internuclear ophthalmoplegia is paresis or weakness of adduction ipsilateral to a medial longitudinal fasciculus lesion, along with dissociated nystagmus of the abducting eye. Lesions, usually in the pons or midbrain, cause internuclear ophthalmoplegia when they interrupt connections between the pontine paramedian reticular formation that innervates the ipsilateral abducens nucleus and the contralateral third nerve nucleus. This illustrates an important principle: plaques predominate in periventricular regions and cause characteristic signs. Internuclear ophthalmoplegia is subclinical or “latent” in 80% of patients (in this case, it would be termed “internuclear ophthalmoparesis”). Rapid eye movements can bring out this hidden, minimal oculomotor weakness, causing slowing of the early adducting saccades—an adduction lag. demonstrate ataxic eye movements from cerebellar lesions. Convergence may be normal despite an affected medial rectus. Medial longitudinal fasciculus lesions are seen best with proton density MRI but are even more apparent with the clinical exam. Internuclear ophthalmoplegia is often worse with heat and better with cooling (Frohman et al 2008). Nystagmus is common in multiple sclerosis. It is usually inconsequential, but nystagmus and oscillopsia can be severe enough to prevent reading or driving a car. Seventh nerve lesions mimic Bell palsy. Because the lesions are intra-axial, the sixth nerve is often simultaneously disturbed. Facial myokymia is from pontine tegmentum lesions of the facial nerve and can be revered with carbamazepine and possibly botulinum toxin. Hearing loss is relatively rare, but auditory processing could be slowed by brainstem and deep white matter lesions. Central hearing defects could be supported by brainstem auditory evoked potentials. They could also differentiate multiple sclerosis from benign positional PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 7 of 123 vertigo, which has no central defect. Vertigo is common and sometimes so incapacitating that patients are bed-bound. Isolated autoimmune disease of the auditory nerve can also cause hearing loss and vertigo. The relation to multiple sclerosis is unclear. Up to one fourth of patients have problems swallowing. Horner syndrome is occasionally present. Transverse myelitis. The cord symptoms in idiopathic transverse myelitis are generally more severe than in multiple sclerosis. In multiple sclerosis, a complete transverse lesion is less common than a partial cord lesion (ie, a Brown-Séquard syndrome). Cerebellar dysfunction and tremor. The cerebellum or its pathways are damaged in 50% of patients. "Charcots triad" of cerebellar signs is nystagmus, intention tremor, and “scanning” speech (in the sense of examining words carefully, “scandés” from Charcot). In 3% of patients, intention tremor of the limbs, ataxia, head or trunk titubation, and dysarthria can be totally disabling. Surprisingly, patients with severe ataxia are often strong and thin and would otherwise be fully functional. The Stewart-Holmes rebound maneuver to detect cerebellar dyssynergia does not correlate well with kinetic tremor (flex or extend at elbow) and intention tremor (finger-to-nose). This suggests damage to different anatomic pathways (Waubant et al 2003). Poor cerebellar function correlates with loss of cerebellar volume on MRI. Dystonia and parkinsonian symptoms are occasionally caused by a multiple sclerosis plaque. Severe cerebellar signs correlate with poor pulmonary function. Weakness. The long course of axons traveling from the motor cortex through the cord to the lumbar motor neurons increases the likelihood that a random plaque will interrupt motor neuron conduction. Legs are usually affected more than arms. Patients complain of a foot- drop, tripping, or poor stair climbing. The hip flexors are often weak and out of proportion to other leg muscles, likely from multiple cervical cord lesions (D Garwacki). Patients can walk backwards more easily than they walk forward because gluteal muscles are stronger than the iliopsoas. Hyperreflexia, spasticity, and a Babinski sign are common. Rarely, plaques interrupt intra-axial nerve roots, and the deep tendon reflexes disappear and muscles atrophy. Radicular symptoms arising from a posterior cord lesion are often painful, but anterior plaques are not. Some muscle weakness and fatigue can be explained by a shift in myosin heavy chain isoforms and less contractile force, a result of muscle inactivity and deconditioning (Garner and Widrick 2003). Walking ability can be measured with a timed 25- foot walk or the 6 spot step test, which incorporates coordination and balance. Spasticity. Spasticity increases with a full bladder or bowels, pain, exposure to cold, and sometimes on the day after IFN-beta injections (an effect of cytokines or direct modification of neuronal excitability). There is often transient stiffness after physical inactivity. On arising, the first few steps are difficult. Similarly, internuclear ophthalmoplegia is most obvious with the first eye movements of the exam. Painful tonic spasms are common in patients with severe spasticity and are sometimes provoked by exertion or hyperventilation. Extrapyramidal symptoms disappear when the causative plaque resolves (Maimone et al 1991b). Bladder and sexual dysfunction. Bladder dysfunction is common and markedly reduces quality of life. It is the initial symptom in 5% of patients and eventually develops in 90%. Two thirds of patients have bladder hyperreflexia with urgency and frequency. This is complicated by sphincter dyssynergia in half of the patients (Schoenberg 1983; Andrews and Husmann 1997; Betts 1999). Some of these patients are initially areflexic. The other third of symptomatic patients have hyporeflexic bladders. Patients description of residual volume is often unreliable, so volume should be measured with office sonography or catheterization. Detrusor hyporeflexia is linked to pontine lesions; detrusor-sphincter dyssynergia is linked to cervical spinal cord lesions. Both are more common in Japanese populations than in Western populations. Glomerular filtration rate is reduced by 20% (Calabresi et al 2002). This could be from chronic neurogenic bladder, urinary tract infections, antibiotics, ionic contrast agents, non- steroidal anti-inflammatory drug use, and chronic dehydration. Seventy percent of patients complain of sexual problems—orgasmic difficulty, poor PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 8 of 123 erections or lubrication, low pleasure, low libido, poor movement, and genital numbness. Impotence develops in 40% to 70% of male patients. Fifty percent of women with multiple sclerosis have significant sexual problems and complain of loss of libido, orgasms, and genital sensation. Orgasmic dysfunction correlates with loss of clitoral vibratory sensation and cerebellar deficits (Gruenwald et al 2007). Difficult or no orgasm was associated with abnormal or absent (26/28) pudendal somatosensory evoked potential, although desire was normal (Yang et al 2000). Occasionally, women have diffusely felt orgasmic spasms, not in skeletal muscle, that last for up to 5 minutes. Others mention increased vaginal sensation and orgasmic intensity. Sexual problems often follow or coincide with bladder dysfunction. They are often associated with loss of sweating below the waist from lesions of the sympathetic pathway and also with disruption of genital somatosensory pathways. MRI T1 lesions in the pons correlate with sexual dysfunction, far better than other MRI measures, urodynamics, or pudendal and tibial evoked potentials. Other literature varies on anatomical links to plaque location. Constipation. Constipation is experienced by 50% of clinic patients and is more prevalent in progressive than in relapsing forms. Poor voluntary squeeze pressure on manometric testing, combined with little sensation of “fullness” is typical. Insensitivity to rectal filling causes incontinence. This is uncommon but not rare and is usually associated with constipation. Disruption of autonomic pathways in the cord may underlie the constipation. Gut neurons have not been studied as direct targets of the immune system in multiple sclerosis, but enteric glia have more antigenic resemblance to glia in the central nervous system than glia in the peripheral nervous system (Gershon et al 1994). Sensory symptoms. Sensory symptoms are common. Sensations are characteristically hard to describe because they are spontaneous or distorted perceptions of everyday stimuli caused by areas of demyelination and ephaptic connections unique to each patient. Sensory loss ranges from decreased olfaction to marked loss of pain perception in small spots or over the entire body. Poor perception of vibration in the feet, but spared position sense, is present in more than 90% of multiple sclerosis patients. Vibratory loss can be quantified with a tuning fork and sometimes improves with drug therapy. Sensory paths are unable to transmit impulses from the rapidly oscillating tuning fork, a combination of demyelination and cytokines that interfere with axonal conduction (Smith et al 2001). symptoms are also common. Tingling, numbness, a tight band (usually at T6-T10, the “multiple sclerosis hug”), pins and needles, a dead feeling, “ice” inside the leg, standing on broken glass, and something "not right" are common descriptions. Paresthesias typically begin in a band (a “multiple sclerosis hug”) around the trunk at T6-T9 (often from a cervical plaque). They sometimes start in a hand or foot and progress over several days to involve the entire limb. The sensations then resolve over several weeks. Lhermitte sign. In 1924, Lhermitte described an electric discharge following flexion of the neck in multiple sclerosis. Forty percent of multiple sclerosis patients have Lhermitte sign (symptom, phenomenon). This is rapid, brief "electric shock" or "vibration" running from the neck down the spine, similar to when trauma to the ulnar nerve triggers the “funny bone.” The intensity of the pain is directly related to the amplitude and rapidity of neck flexion. In an instinctive protective reflex, the patient may straighten her neck. This sign is from mechanical stimulation of irritable demyelinated axons. Ninety-five percent of patients with this sign have cervical cord MRI lesions. Cord compression can also generate the sign and must be ruled out. Pain. Up to two thirds of patients with multiple sclerosis have pain at some time during the course of their disease (Clifford and Trotter 1984; Moulin et al 1988; Stenager et al 1991), although pain was regarded as rare in much of the older literature. The pain is chronic most of the time, but acute or intermittent pain also occurs. Legs are affected in 90%, and arms in 31%, of patients complaining of pain. Pain is more common in older women with spasticity or myelopathy, and in multiple sclerosis of long duration (Moulin et al 1988; Stenager et al 1991). It is often worse at night and when the ambient temperature changes suddenly. PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 9 of 123 The spectrum of pain includes central neuropathic pain from focal demyelination (eg, trigeminal neuralgia, dysesthesias, and nonspecific pain) to pain and dysesthesias from ephaptic transmission (Lhermitte symptom, radicular pain, tonic seizures), inflammation or swelling (optic neuritis, headaches), visceral pain from chronic constipation or painful bladder spasms, abnormal motor activity (tonic seizures, spasms, clonus), or simple orthopedic musculoskeletal pain. Lesions in pain inhibitory pathways, abnormal sodium channel redistribution, or maladaptive neural plasticity during plaque repair may cause the central pain. Chronic back pain can arise as a consequence of multiple sclerosis, causing unilateral weakness or spasticity, poor posture, and accelerated degenerative disc disease. Pain is common in optic neuritis. A swollen, inflamed optic nerve puts pressure on the dural sheath. Pain in or behind the eye sometimes precedes the visual loss. The pain in optic neuritis can be present at rest, on voluntary eye movement, and with pressure on the globe. Vasoactive amines, prostaglandins, and kinins released by inflammatory cells may magnify the pain in optic neuritis and in trigeminal neuralgia. Trigeminal neuralgia. Trigeminal neuralgia is relatively rare in multiple sclerosis (occurring in 0.5% to 1% of patients) (Rushton and Olafson 1965). Bilateral trigeminal neuralgia has been described as pathognomonic of multiple sclerosis (Jensen et al 1982). However, it can be caused by vascular lesions (Meaney et al 1995) when arteries compress the trigeminal nerve at the junction of the central and peripheral nervous system (root entry zone). Vascular compression causes demyelination and remyelination, sometimes aberrant, allowing ephaptic conduction between active and silent nerve fibers, and between light touch and pain fibers (Love and Coakham 2001). The trigeminal neuralgia of multiple sclerosis is from a plaque in the fifth nerve nucleus (Olafson et al 1966) or the brainstem entry zone of nerve fibers (Gass et al 1997). After facial nerve injury, IFN-gamma increases, but pituitary adenylyl cyclase-activating polypeptide recruits anti-inflammatory Th2 cells. Radicular pains in multiple sclerosis, especially if lancinating, may have a similar mechanism. The cisternal (peripheral) fifth nerve enhances on MRI in 3% of patients, but this is usually clinically silent. Brainstem plaques can cause glossopharyngeal neuralgia. Headaches. Headaches are more common in multiple sclerosis (27%) than in matched controls (12%) (Watkins and Espir 1969). They can herald exacerbations. Seizures and paroxysmal symptoms. Epileptic seizures double in incidence in multiple sclerosis and are more common in later stages. They seem to result from new or enhancing lesions in the cortex or subcortical areas. They can be triggered by 4-amino pyridine or rapid reductions in baclofen. Other paroxysmal symptoms last seconds to minutes and are triggered by hyperventilation (eg, 20 deep breaths), stress, cold, touch, metabolic abnormalities, exercise, or acute exacerbations. Paroxysms include visual complaints, diplopia, vertigo, dysarthria, facial and limb myokymia, tonic motor seizures, spasms, dystonia, restless legs, akinesia, kinesigenic choreoathetosis, hyperekplexia, rapid eye movement sleep disorders, ataxia, itching, and pain and paresthesias (eg, trigeminal neuralgia, Lhermitte sign). Transverse spread between demyelinated axons (ephaptic transmission) is a likely cause. It is probably amplified by cytokines, extracellular potassium, dysfunction of ion channels, and heterogeneity of new sodium channels. Associated diseases. In multiple sclerosis, there are links between inflammatory bowel disease and thyroiditis, and bone mass is low. Other autoimmune diseases are not associated with multiple sclerosis—and may be less prevalent than in the general population. Many reported associations are likely from the strong autoimmune proclivity in Devic disease or CNS Sjögren disease, variants that comprise 5% of “multiple sclerosis” patients. Cancer incidence is likely reduced. Natural history. The course of multiple sclerosis varies. Heterogeneity over time complicates the use of stage-specific therapies. Classification is important because no therapies are effective in the primary progressive forms. At onset, at an average of 28 years old, multiple sclerosis is relapsing-remitting 85% of the time. This form predominates in young women. Attacks typically occur once every 2 years. PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 10 of 123 Survival is decreased by 10 years. Fifty percent of relapsing-remitting patients become progressive after 10 years, and 89% by 26 years; this is termed "secondary progressive” multiple sclerosis. The number of neurologic systems in the initial attack, and not recovery from the attacks, predicts the chance of developing progressive disease. Once progression appears, the rate of decline is constant. About 10% to 15% are progressive from onset, at an average of 38 years old, with continuing deterioration for a year or more, without obvious exacerbations or remissions, although the rate of decline fluctuates. Compared to age 10 to 19 years, the relative risk of primary progression is 2.3 at age 25, 8.1 at 35, 19 at 45, and 47-fold higher at age 50 to 59 years (Stankoff et al 2007). These categories are not immutable; patients frequently drift from one type of multiple sclerosis to another, become stable, or suddenly develop active disease (Goodkin et al 1989). Primary progression is considered a unique form of multiple sclerosis, but 28% of these patients will eventually have exacerbations (Kremenchutzky et al 1999), sometimes after 20 years of pure progression. The progressive form affects the spinal cord predominantly (in 90%), begins at a later age (40 years) than the relapsing form, and is approximately as common in men as in women. These patients have progressive paraparesis and loss of vibration and pinprick sensation in the legs, and they typically develop a small, spastic neurogenic bladder. Cerebral MRI lesions are 6 times less frequent in the primary progressive group compared to relapsing- remitting patients who become progressive later on (Thompson et al 1991). However, in white matter that appears normal on conventional MRI, low N-acetyl aspartate levels are low (reflecting widespread neuronal loss or dysfunction), and the magnetization transfer ratio is low (Filippi et al 1999). Relapses in the first 2 years predict earlier onset of progression. Relapses after the first 2 years are linked to lower chance of becoming progressive (Scalfari et al 2010), suggesting that evolution of immune dysregulation modifies the course of multiple sclerosis. Progression has features of an age-dependent degenerative process (Kremenchutzky et al 2006). Age at onset of multiple sclerosis is 30 years for secondary progressive disease but 39 years for primary progressive multiple sclerosis. Age at beginning of progression is 39 in both groups. Exacerbations contribute to disability. Forty-two percent to 49% have residual loss of 0.5 EDSS points at 2 to 4 months, and 28% to 33% have a loss of 1 or more EDSS point (Lublin et al 2003; Hirst et al 2008). Some improve; however, 19% have a 0.5 point decrease and 10% have a 1 point decrease (Lublin et al 2003). In 700 placebo-treated patients from 11 clinical trials, worsening after exacerbations was nearly equivalent to improvement (Ebers et al 2008). The authors conclude that disability could not be used as an outcome measure in most (short-term) clinical trials. Occasionally, patients have acute fulminant multiple sclerosis (Marburg variant). This malignant form of multiple sclerosis is possibly associated with developmentally immature myelin basic protein (Wood et al 1996). Twenty percent of patients have “benign multiple sclerosis,” defined as a Kurtzke disability score of 3/10 or lower. After 20 years, 6% of the overall population is still benign—largely comprised of those who scored 2 or lower at 10 years (Hawkins and McDonnell 1999). Some patients with benign multiple sclerosis have surprisingly large lesion loads on MRI (Strasser- Fuchs et al 2008). Clinical/MRI dissociation is also seen in correlating MRI with clinical activity (r is only 0.25). Predictors include young onset, monosymptomatic, no cord symptoms, and few attacks or MRI lesions. Cognitive function, fatigue, and pain should be included in assessment of a propitious course. Autopsy studies indicate that there is a large reservoir of undetected and, therefore, benign multiple sclerosis. Unsuspected and asymptomatic cases. Multiple sclerosis is sometimes unsuspected during life, yet found at autopsy. Twelve unsuspected cases of multiple sclerosis were found in 15,644 autopsies in Switzerland. Only 2 had no reported neurologic signs during life (Georgi 1961). There were 5 diagnosed cases of multiple sclerosis in 2450 autopsies in London and Ontario (Gilbert and Sadler 1983). In autopsy studies, the calculated prevalence of unsuspected multiple sclerosis would be about 31 in 100,000 in Paris (3 in 9300) PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 11 of 123 (Castaigne et al 1981); 90 to 128 in 100,000 in Switzerland (Georgi 1961); and 204 in 100,000 in Ontario (Gilbert and Sadler 1983). This suggests that the number of undiagnosed "normal" people with multiple sclerosis approximates the number of patients diagnosed with multiple sclerosis. Of asymptomatic “normal” first degree relatives, 4% to 10% have MRI lesions indistinguishable from multiple sclerosis (De Stefano et al 2006). This suggests that “benign” multiple sclerosis is itself a spectrum, and sometimes should not be treated with immunomodulators. Clinically isolated syndromes. “Clinically isolated syndromes” include optic neuritis, transverse myelitis, and solitary brainstem lesions. They evolve into multiple sclerosis most often when the MRI T2 lesion load is high and when the CSF reflects inflammation. When clinically isolated symptoms appear in parallel with non-enhancing MRI lesions plus at least 1 enhancing lesion, 70% to 80% of patients will have another gadolinium-positive lesion within 6 months. A positive spinal tap further increases the chance that multiple sclerosis will develop. Partial cervical myelopathy, without brain MRI lesions, often evolves into clinically definite multiple sclerosis if evoked potentials and CSF are abnormal (Bashir and Whitaker 2000). Childhood multiple sclerosis. An attack before the age of 16 happens in 3% to 5% of all patients. A family history (8%) is more common than in adult forms. Sensory symptoms and optic neuritis are common (approximately 50%, even though these symptoms may sometimes not be reported by children). Brainstem and cerebellar symptoms, polysymptomatic disease, and seizures are more frequent than in adult onset multiple sclerosis, but recovery from exacerbations is better (Duquette et al 1987; Selcen et al 1996; Ghezzi et al 1999; Ruggieri et al 1999). One third of patients have cognitive problems. As in adult forms, sphincter involvement and a progressive course have a poor prognosis. Boys predominate over girls between 8 and 10 years of age, but the girl-to-boy ratio is 2:1 after 10 years. Relapses are a bit more frequent in childhood (every 1.6 years versus every 2 years in adults) but are only 4 weeks long versus 7 weeks in adults (Ness et al 2007). The course is slower than in adult-onset multiple sclerosis (Simone et al 2002), and the median time from onset to secondary progression is 28 years. Nonetheless, with continuous exacerbations they become disabled at a younger age than adult-onset patients. Primary progression is exceptionally rare (2% of an already uncommon event). MRI, EEG, and visual-evoked potentials are each abnormal in 80% of patients, and CSF is abnormal in 66% of patients (CSF IgG levels are lower in children, so this is probably an underestimate) (Duquette et al 1987; Banwell 2004). Oligoclonal bands are uncommon in acute disseminated encephalomyelitis, a disorder sometimes difficult to separate from the first attack of multiple sclerosis. Bands are positive in 29% of acute disseminated encephalomyelitis, 64% of acute multiple sclerosis, and 82% of multiple sclerosis at later times in a medium-sized series (Dale et al 2000). Serum antibodies to myelin oligodendrocyte glycoprotein are increased in frequency in children versus adults. The prolonged relapsing-remitting course suggests therapies may be more effective in children than in adults. [Neurology 2007;68(16, Suppl 2) is devoted to pediatric multiple sclerosis.] Geographic variation. The incidence and symptoms of multiple sclerosis are different around the globe. It is uncommon at the equator (prevalence 2 to 10 per 100,000), and increases with distance from the equator (up to 200 per 100,000). This suggests environmental factors influence the incidence, but emigrating northern Europeans tended to stay in temperate climates, suggesting genetic influence. Multiple sclerosis is rare in Asia (4 per 100,000) (Kurtzke 1975). Multiple sclerosis in Japan, China, Malaysia, in black Africans, and in some groups of Canadian Aboriginals often resembles Devic disease because it typically affects the optic nerves and spinal cord and occurs at an earlier age than the Western form of multiple sclerosis (Cosnett 1981; Phadke 1990). Quality of Life (QOL) and clinical scales. Responses by 433 patients were used to generate the 59-question Functional Assessment of Multiple Sclerosis quality of life scale (Cella et al 1996). A factor analysis demonstrated that multiple sclerosis had independent effects on several important factors that impact patients lives. Separate axes with little overlap included the following: PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 12 of 123 (1) Mobility. This correlated highly with the neurologic exam (Kurtzke Expanded Disability Status Score, Scripps Numerical Rating Scale, and Ambulation Index) but not with the other subscales. (2) “Emotional well-being” and “general contentment,” which negatively correlated with psychiatric measures of anxiety and depression. (3) “Symptoms.” (4) Family and social well-being. (5) “Fatigue” plus “thinking,” an indicator of cognitive function. Fatigue is highly prevalent; cognitive loss has the most important impact on quality of life. Neurologic and social function, fatigue, mood, and cognition are important components of clinical multiple sclerosis that are often more disabling than inability to walk. Because these factors do not correlate, different pathogenic mechanisms are likely. For example, difficulty walking could arise from damage to long tracts or oligodendroglia, and fatigue may be caused by inflammatory cytokines in the CNS. Different pathological causes may also vary in responses to drugs; they should all be evaluated in therapeutic trials. Patient-rated scales provide important information about independent factors that are missed when exams are limited to assessment of mobility. Telephone and self-administered scales correlate well (r=0.9) with physician exams. The Kurtzke Extended Disability Status Score (EDSS) is a central clinical measure in most trials. It is based on the neurologic exam and ranges from 0 to 10, where 0 = normal, 4 = walks unaided for greater than 500 meters, 5 = walks unaided for greater than 100 meters, 6 = needs a cane to walk 100 meters, 7 = walks less than 20 meters with aid, 8 = perambulated in wheelchair, and 10 = death. Cognitive problems, fatigue, sexual function, job capabilities, and social factors do not weigh heavily in this scale. This scale is not linear, and transition between stages 4 and 6 is fastest. The Multiple Sclerosis Functional Composite Scale (MSFC) evaluates motor function of legs and arms and cognition. It adds information to the Kurtzke Expanded Disability Status Score and was used in a phase 3 clinical trial of intramuscular IFN-beta-1a (Cohen et al 2001). Correlation between the Kurtzke scale and the Multiple Sclerosis Functional Composite scale is only r = -0.15. The global Multiple Sclerosis Severity Scale (MSSS) combines disease duration with the Kurtzke score to combine rate and severity (Roxburgh et al 2005). Many of the patients who defined the MSSS were on therapy, so untreated progression rates are probably even higher than the table indicates. Clinical vignette A 28-year-old woman began to stumble when walking. Her right leg was slightly stiff and weak, especially after exercise and hot showers. These symptoms developed over 3 days and gradually disappeared over 4 weeks. She was on the college swim team before these symptoms arose. There, when she was 21 years old, she developed a unique and extreme type of fatigue that differed from the usual fatigue after intense swimming workouts. This disappeared after several weeks, but reappeared again when she was 28 years of age. One maternal aunt had multiple sclerosis. An MRI scan showed multiple periventricular lesions. Her spinal fluid had elevated IgG levels and 3 oligoclonal bands (normal, less than 2). One year later, 10 days after a “cold,” she developed blurred vision in her right eye and her visual acuity dropped to 20/200. She had moderate pain behind her eye when she looked to either side. The pain and visual loss gradually disappeared over 6 weeks. Two years later, she noticed that both legs were becoming gradually weaker and spastic and she needed to run to the bathroom nearly every hour to urinate. These symptoms slowly progressed over the next 10 years, with occasional exacerbations affecting other areas of the brain. IFN-beta was begun in the middle of the relapsing and progressive phase and the frequency of attacks and rate of progression slowed. She is now walking with the help of bilateral ankle and foot orthoses. She has been aided by minor modifications of her PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 13 of 123 workplace and by treatment of multiple sclerosis symptoms, and she continues to work as a business executive. Etiology Although there appears to be an "autoimmune" attack against myelin and myelin-forming cells in the brain and spinal cord, multiple sclerosis cannot be called a true autoimmune disease. T cell and antibody reactivity have been tested against numerous virus and brain antigens, but no target antigen has been clearly demonstrated. The antigen-induced animal model, experimental allergic encephalomyelitis, does not appear spontaneously in wild mice. HLA types are associated, but the mechanism is unclear. There are surprisingly few links to autoimmune disease, except Crohn disease and possibly thyroid disease. Systemic lupus erythematosus is underrepresented in multiple sclerosis and is linked to opposite responses to type I interferons (Javed and Reder 2006). Specific antigenic targets for inflammation in multiple sclerosis. Candidate central nervous system antigens and targets include: • Proteins from infectious agents (viruses, chlamydia) that match brain antigens. • Proteins from neurons (synapsin). • Myelin (eg, myelin oligodendrocyte glycoprotein, myelin basic protein, proteolipid protein, and myelin-associated glycoprotein) and glycolipids (ganglioside GD1a). Antibodies to MOG may cross react with Epstein-Barr virus nuclear antigen. Heat shock protein-65 is highly conserved between bacteria and man, and it is cross-reactive with the myelin antigen cyclic nucleotide phosphohydrolase (Birnbaum et al 1996). • Proteins from glia (astrocyte alpha-B crystallin, S100-beta, and arrestin; plus oligodendroglial 2,3 cyclic nucleotide 3 phosphodiesterase, alpha-B crystallin, and transaldolase) (Schmidt 1998) and oligodendrocyte-specific protein (Cross et al 2001). Alpha-B crystallin may bind immunoglobulin and not vice versa, but these proteins could trigger antigen-specific responses or be involved in a gradual evolution in immune reactivity over time, ie, "epitope spreading" to related antigens. The antibody response to central nervous system antigens varies between patients. Anti- myelin basic protein responses are weak in multiple sclerosis, differing from the strong responses in animal models. However, pro-inflammatory cells recognizing myelin basic protein are increased when low concentrations of myelin basic protein are used to detect high avidity human T cell clones (Bielekova et al 2004). Anti-proteolipid antibodies in CSF are more common in women than men, in patients with later onset of multiple sclerosis, in patients without a family history of multiple sclerosis, and in those who have low levels of CSF immunoglobulin and oligoclonal bands (Warren et al 1994). Antibodies to myelin oligodendrocyte protein are debatably elevated in all forms of multiple sclerosis (and other inflammatory brain diseases). Antibodies to myelin basic protein are low in early multiple sclerosis and increase over time (Reindl et al 1999), but detection is erratic between laboratories. Even if antibodies to brain antigens do not cause multiple sclerosis, they could modify disease course. Arguments are made against the presence of a “multiple sclerosis antigen.” For instance, 1 in 220 people vaccinated with the Semple rabies vaccine—which contains central nervous system tissue—develop autoimmune encephalitis (similar to EAE). Patients susceptible to this encephalitis, however, have a human leukocyte antigen (HLA) makeup that is distinct from multiple sclerosis patients (Piyasirisilp et al 1999). The lack of a causative antigen suggests that fundamental control of immune responses may be abnormal and that oligodendroglia are innocent bystanders damaged by unregulated inflammation. Activated lymphocytes and monocytes might enter the central nervous system because of nonspecific adhesion to endothelial cells, become activated within the central nervous system, stay longer during trafficking through the central nervous system, and escape from the normal CNS suppression of the immune response. Putative antigen-specific responses are described below. Non-antigen-specific immunity for inflammation in multiple sclerosis. Etiologies PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 14 of 123 that do not invoke specific target antigens are possible in multiple sclerosis. Viruses. Through direct damage to oligodendroglia, by retrovirus incorporation into oligodendroglia and T cells, and from immune reactivity to shared determinants between oligodendroglia and viruses. The role of human herpes virus-6 and endogenous retroviruses awaits confirmation in multiple sclerosis. Human endogenous retroviruses, HERV, which make up 10% to 30% of the human genome correlate with a more progressive course. However, detection of these viruses is possibly a byproduct of immune activation of viruses and not the cause of the disease. Activated astrocytes produce retrovirus-encoded syncytin, which is toxic to oligodendrocytes. Antibodies to Epstein-Barr virus correlate with brain atrophy and are elevated early in the course of multiple sclerosis. This may simply reflect multiple sclerosis-characteristic high titers to many antigens and many viruses, possible because HLA-DR2 is over-represented in multiple sclerosis and because DR2-positive people have higher antibody titers to Epstein- Barr virus, measles, and rubella (Compston et al 1986). Anti-Epstein-Barr virus antibodies could arise from persistent infection of astrocytes or B cells, causing costimulatory molecule expression, IL-6 secretion, and immune activation. Epstein-Barr virus infects B cells and could generate an autoreactive B cell population resistant to apoptosis and immune control. Antibodies to cytomegalovirus, in contrast, correlate with better outcome (Zivadinov et al 2006). Varicella-zoster virus DNA increases briefly in mononuclear cells during relapses, but this virus does not increase the risk of multiple sclerosis. Report of varicella-zoster virus particles in multiple sclerosis brains has not been confirmed (Burgoon et al 2009). In children, Epstein-Barr virus NA-1 seropositivity increases the risk of multiple sclerosis 3.8-fold. Cytomegalovirus positive serum confers a lower risk of multiple sclerosis in children 0.27-fold (Waubant et al 2011). Bacteria and chlamydia. Through cross-reactive antigens, superantigen activation of pathogenic T cells, responses to induced heat shock proteins (all trigger cytokine release), and release of bacterial toxins, possibly from posterior sinuses and submucosa (Gay 2007). Conversely, parasite infestation could be protective. Oligodendroglia. Defective function or repair. Diet. Affects immunity through oral tolerance and shapes the microbiome. Diet can modify macrophage function, membrane composition of immune cells, and prostaglandin synthesis. Genetic. Predisposition to respond to brain antigens, altered control of the immune response to brain antigens, lack of neurotrophic proteins, or poor ability to repair CNS damage. Other mechanisms. Toxins, microchimerism of circulating blood cells, and endocrine, catecholamine, and stress interrelations with immunity have been proposed. In the 1950s, anticoagulants failed to significantly impact the course of multiple sclerosis based on a theory that CNS microvessels had poor blood flow. Recent use of venous stenting to reverse putative cerebral venous outflow problems (CCSVI) has not been beneficial in controlled studies, although anecdotes of benefit are common. Tens of millions of dollars in research money and medical costs, huge amounts of investigators intellectual energy, and misplaced hope by patients are being directed at this questionable therapy. Pathogenesis and pathophysiology Multiple sclerosis is a demyelinating disease, but brain parenchymal and meningeal inflammation and chronic cytokine exposure also affect neuronal metabolism and survival. This leads to brain atrophy, fatigue, cognitive loss, and neurologic abnormalities. The course of multiple sclerosis can be broken down into 3 phases: (1) The initiating event (inflammation, viruses, hypothalamic damage). (2) Recovery from relapses. (3) Chronic progression. Immunity underlying the CNS pathology. The initiating event for the first attack of multiple sclerosis is unknown. Genetics and environment both play a role (Page et al 1993). Multiple sclerosis plaques are formed after invasion of inflammatory T cells and monocytes. PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 15 of 123 Immune activation is a multi-step process. Primed T cells may be alerted to a CNS antigen and then “licensed” by the innate immune system exposed to viral or microbial antigens through CpG oligonucleotides and toll receptor-9 (TLR-9) or pertussis toxin in experimental allergic encephalomyelitis (Darabi et al 2004) before they are activated by brain antigens. During development, it is possible that thymic presentation of alternately-spliced golli- myelin basic protein in the context of abnormal costimulatory molecules (Maimone and Reder 1991), or later exposure to a viral antigen, starts an autoimmune cascade. Following peripheral activation, circulating T cells adhere to post-capillary venules in the brain and spinal cord. The T cells pass through the endothelial cells and migrate into perivascular brain parenchyma. Note that an equivalent number of monocytes and T cells are present in plaques at early stages. Brain dendritic cells can emigrate to the periphery and educate T cells, and these T cells may then home back to the brain. In the plaque, the cellular infiltrate is associated with destruction of the inner myelin lamellae and dysfunction of oligodendroglia, possibly with diffuse effects such as fatigue and slowed cognition. Early on, gemistocytic astrocytes have high levels of GFAP and also trophic factors, BDNF, TrK receptors, and VEGF (Ludwin 2006). Astrocytes stimulated by IL-9 produce CCL20, which attracts Th17 cells. Inflammation, based on the presence of Gd-enhancing MRI lesions, resolves in 2 to 8 weeks. However, immune cells in plaques are poised for activation, and there is continued low-grade inflammation as well as chronic axonal loss and demyelination. Immune activation and dysregulation. Immune activation in peripheral blood precedes neurologic problems and MRI activity. Several weeks before attacks, there are increases in Concanavalin A-stimulated IFN-gamma and tumor necrosis factor-alpha production (Beck et al 1988), IFN-gamma levels in serum (Dettke et al 1997), IFN-gamma-induced [Ca++] influx in T cells (Martino et al 1995), and secretion of prostaglandins by monocytes (Dore- Duffy et al 1986). Excessive numbers of cytokine-secreting cells are seen early in multiple sclerosis, even in acute monosymptomatic optic neuritis. Cytokines such as IFN-gamma, osteopontin, and IL-2 activate immune cells, Th17 cells, and endothelial cells, and induce costimulatory molecules that further enhance T cell proliferation and activation (Prat et al 2000a). During active multiple sclerosis, Th1 cell-mediated inflammation increases. Lymphocytes express excessive levels of the activating zeta chain of the T cell receptor on CD4 T cells (Khatibi and Reder 2008), activation proteins (HLA-DR and CD71), costimulatory molecules on B cells (CD80, also called B7-1) (Genc et al 1997a), and Th1 cell chemokine receptors (CCR5 and CXCR3) (Balashov et al 1999). Inflammatory cytokines and cytokine-secreting cells (eg, IL-2, IL-15, IL-17, IL-23, and IFN-gamma) are elevated (Trotter et al 1991; Lu et al 1993). Messenger ribonucleic acid for inflammatory cytokines is elevated in white blood cells (Rieckmann et al 1994; Byskosh and Reder 1996). IL-1, IL-6, and IL-15 and tumor necrosis factor-alpha are present in the CSF (Maimone et al 1991a; Kivisakk 1998). These Th1-like cytokines and monokines amplify immune responses. In support, IFN-gamma "therapy" and granulocyte colony-stimulating factor (G-CSF) infusions trigger attacks of multiple sclerosis, though they both prevent experimental allergic encephalomyelitis. IFN- gamma, a proinflammatory cytokine, is toxic to actively remyelinating oligodendroglia, and it activates monocytes and microglia. However, it inhibits proliferation of Th1 cells (it downregulates the IFN-gamma receptor-beta chain), can cause apoptosis of activated T cells (Ahn et al 2004), and is protective for mature oligodendroglia (Lin et al 2007). Thus, timing, location, and degree of inflammation are all affected by cytokines. During attacks of multiple sclerosis, concanavalin A-induced suppressor cell function drops (Antel et al 1986). During progressive multiple sclerosis, excessive IL-12 production induces IFN-gamma (Balashov et al 1997). Low production of IL-10 removes another brake on Th1 cells (Soldan et al 2004). IL-15 (related to IL-2) levels rise in blood > CSF monocytes, especially during attacks and progression. These changes could lead to delayed-type hypersensitivity (Th1-type) immune reactions. The Th1/Th2 dichotomy is too simplistic, however: (1) Both types of cytokines rise in blood cells before attacks—a “cytokine storm” (Link PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 16 of 123 1998). Both Th1 and Th2 cytokines are present in CNS immune cells (Cannella and Raine 1995) and also in peripheral immune cells following IFN-beta therapy (Byskosh and Reder 1996; Wandinger et al 2001). (2) Therapy with anti-CD52 (alemtuzumab) depletes Th1 cells, potentially causing a Th1 to Th2 shift, but does not stop progression or MRI activity. (3) Th2 cytokines can potentially cause damage. A Th2-driven form of myelin- oligodendrocyte-glycoprotein-induced experimental allergic encephalomyelitis causes lethal demyelination. (4) Monokines are increased in CSF (Maimone et al 1991a). Families with high IL-1/IL-1Ra plus high TNF-alpha/IL-10 ratios have a 6-fold increased risk of having a family member with multiple sclerosis (de Jong et al 2002). (5) Microarrays of immune cell RNA show the IFN-alpha/beta pathway is more dysregulated than the Th1 and Th2 pathways in untreated patients (Yamaguchi et al 2008). Interferon dysregulation is discussed with IFN-beta therapy in “Interferon immunology” in the Management section. Th17 cells are a subset of CD4 cells that amplify autoimmune CNS inflammation and may be important in multiple sclerosis. IL-6 plus transforming growth factor-beta generate IL-17- producing cells from naïve CD4 cells. IL-23 maintains this population and also induces IL-17 in memory CD4 cells. The inflamed blood-brain barrier and monocytes, which have transformed into dendritic cells, help polarize naïve T cells into Th17 cells (Ifergan et al 2008). IL-4, IL-27, IFN-gamma, and IFN-beta all inhibit IL-17 production. Th17 and regulatory T cells (Tregs) are induced by the aryl hydrocarbon receptor (AhR), which is bound by dioxin, breakdown products of aromatic amino acids (eg, tryptophan), and prostaglandins. Dioxin inhibits hematopoietic stem cell expansion. Effects on multiple immune cell populations and culture conditions could explain published differences in Th17 function. The commonly-used RPMI culture media has low levels of AhR ligands, but Iscoves media has high levels and is much more conducive to Th17 cell induction (Veldhoen et al 2009). IL-17-expressing cells increase during exacerbations and are higher in plaques and CSF than serum in multiple sclerosis (Matusevicius et al 1999; Durelli et al 2009), in optico- spinal multiple sclerosis (Ishizu et al 2005), and likely in some Devic variants of multiple sclerosis. IL-17 is produced by CD4 and CD8 cells and oligodendrocytes in perivascular areas of active lesions (Tzartos et al 2008). Cells simultaneously secreting IFN-gamma plus IL-17 are also increased in multiple sclerosis. CSF IL-17 and IL-8 levels correlate with the length of spinal cord lesions. CD2 is a costimulatory T cell molecule that binds CD58 (LFA-1). Although expression of the usually measured epitope of CD2 is normal on CD4 and CD8 cells, stimulation through CD2 is reduced in progressive multiple sclerosis. The conformation of CD2 is altered because there is a marked fall in avid rosette-forming cells (CD2 on T cells binds CD58 on RBC) and other antibodies do not bind normally (Reder et al 1991). An allele of CD58 that increases CD58 mRNA is protective against multiple sclerosis (odds ratio = 0.82), and CD58 mRNA is 1.2 times normal in exacerbations and 1.7 times normal in remissions (De Jager et al 2009). Activation through CD2 increases regulatory CD4 cells and CD4 suppressor function; effects on CD8 cells are unknown. Thus, there may be a reciprocal relation between multiple sclerosis state-specific low CD2 function and CD58 expression. Cytolytic CD8 cells and monocytes in plaques directly damage neurons and axons more than CD4 cells do. CD8 cells that produce Th1-like cytokines are elevated in optico-spinal multiple sclerosis (Ochi et al 2001). Expanded CD8, but not CD4, clones appear in blood, CSF, and multiple sclerosis plaques. Multiple sclerosis therapies tend not to target these cells. CD8+,CD28- suppressor cell function may be the most important form of immune suppression in multiple sclerosis. The antigen that induces these suppressor cells is unknown. When induced by concanavalin A, suppressor function drops during attacks of multiple sclerosis (Antel et al 1986; Karaszewski et al 1991; Correale and Villa 2008). In an extensive series of experiments, Antel and colleagues showed that the T cell population in PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 17 of 123 multiple sclerosis that suppresses immune reactions is predominantly CD8+CD28-, but is CD4-negative (Antel et al 1979; Crucian et al 1995). Thus, CD8 cells had much more potent suppressor effects than CD4 cells. CD8 suppressor cells form a 3-way bridge with monocytes and destroy HLA-E (mouse Qa-1)-expressing pathogenic CD4 cells (Tennakoon et al 2006; Correale and Villa 2008). CD8+,CD28-,FoxP3+ suppressor cells also induce tolerogenic ILT3 and ILT4 molecules on endothelial cells (Manavalan et al 2004) and on antigen-presenting cells. During exacerbations, high levels of IL-15 and likely IFN-gamma induce expression of the inhibitory NG2A protein on CD8 cells, and CD8 suppressor function falls (Correale and Villa 2008). In mice, similar CD8,CD122 regulatory cells produce IL-10 to inhibit proliferation and IFN-gamma production by CD8 cytotoxic cells. IL-10 also induces more of these suppressor cells, as does glatiramer therapy in humans. Transfer of neuroantigen-reactive CD8 cells inhibits experimental allergic encephalomyelitis (York et al 2010). In CD8 knockout mice, attacks resolve, but later relapses still occur. This would suggest that CD8 cells do not terminate the inflammation in mice but do prevent recurrent attacks. Generalizations across species are suspect, however. The major suppressor cell subpopulation in mice consists of CD4+CD25+ T regulatory cells, but in man and likely in multiple sclerosis, the more potent subset is CD8+CCD28-. The fall in mitogen-induced CD8 suppressor cell function is unexplained, but it correlates highly with clinical activity (r = 0.79) (Antel et al 1979), far better than MRI correlates with clinical disease (r = 0.25). MRI also correlates poorly with serum cytokine levels (Kraus et al 2002). This suppressor defect is corrected with IFN-beta, glatiramer acetate, beta2- adrenergic agonists, and Fc receptor ligands. Monitoring of CD8 expression, suppressor cell function, CD80 expression, or specific Th1, Th2, and Th17 markers could predict impending attacks of multiple sclerosis, could differentiate between multiple sclerosis attacks and transient worsening from fever, and reflect early therapeutic responses to drugs. Tr1 CD4 suppressor cells secrete 6 times less inhibitory IL-10 in multiple sclerosis; plus, target multiple sclerosis cells are resistant to IL-10 compared to normal controls (Martinez- Forero et al 2008). CD56bright NK suppressor cells (Takahashi et al 2004) and CD4+,CD25++,(CD39+),FoxP3+ T regulatory cells (Treg) may also be involved in immune regulation in multiple sclerosis, and the latter have reduced function in multiple sclerosis. Memory Tregs return to normal levels in progressive disease (Venken et al 2008). Treg development requires IL-2, IL7, vitamin A, TGF-beta, and indoleamine dioxygenase (induced by IFN-beta). The environment in the eye generates suppression; very small amounts of retinal antigens create CD4,CD25+ cells that inhibit immunity in mice. The CNS may behave similarly. Thymic export of new T cells is reduced in multiple sclerosis, so T cells have fewer T-cell receptor excision circles (Trec). Recent thymic emigrant cells, including Tregs, are reduced in relapsing-remitting multiple sclerosis (Haas et al 2007). The immune system in multiple sclerosis shows premature aging using this measure, and it is 30 years older than in healthy controls (Hug et al 2003). Trec numbers do not change with IFN-beta therapy. B cells reflect the abnormal T cell immunity. They also have direct effects on immune regulation and brain destruction (Meinl et al 2006). B cells secrete IL-6, IL-10, TNF-alpha, and chemokines. IL-6 can enhance generation of IL-17 T cells. Lipopolysaccharide-activated B cells produce nerve growth factor and brain-derived neurotrophic factor. Nerve growth factor is a survival factor for memory B cells. In multiple sclerosis, B cells secrete half as much inhibitory IL-10 after stimulation with anti-CD40 (a model of bystander T cell activation) and B cell receptor plus anti-CD40 (a model of B cell plus T cell activation) compared to healthy controls (Duddy et al 2007). B cells in multiple sclerosis blood express high levels of costimulatory molecules (CD80). As a result, they are potent antigen-presenting cells because they are exquisitely focused against specific antigens (Genc et al 1997b). B cells are activated by B-cell activating factor (BAFF), made by myeloid cells. CSF BAFF and the B-cell attracting chemokine, CXCL13, are increased during relapses and in secondary progressive multiple sclerosis (Ragheb et al 2011). CSF BAFF levels correlate with IL-6 and IL-10, suggesting that all of these factors amplify B cell function and CSF antibody production. PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 18 of 123 High CSF immunoglobulin synthesis and antibody titers to measles virus were reported in the 1950s. CSF IgG and oligoclonal bands are present in more than 95% of patients. High levels of IgG predict a worse prognosis and faster progression. In clinically isolated syndromes, clonal expansion is reflected by rearranged mRNA and certain heavy chains (VH4 or VH2) and is more likely to lead to multiple sclerosis, but these antibodies do not predominantly react against myelin (Bennett et al 2008). There are CSF and serum antibodies to unknown antigens, viruses, myelin proteins, axons (triose-phosphate isomerase), and DNA (ANA). Over 50% of brain plaques contain antibodies plus complement, although the antibodies and oligoclonal bands have not been shown to cause demyelination (Lucchinetti et al 1999). Some anti-brain antibodies can enhance remyelination in mice. In progressive multiple sclerosis, B cells have continued to clonally expand and are present in germinal center-like areas in the meninges. Chemokines attract immune cells. Monocytes secrete excessive CXCL8 (IL-8) in multiple sclerosis serum, and presumably CNS, to attract other monocytes and potentially polymorphonuclear neutrophils. However, polymorphonuclear neutrophils are not seen in multiple sclerosis CSF. In contrast, in Japanese optico-spinal multiple sclerosis, increased IL- 8 and IL-17 as well as both Th1 (IFN-gamma) and Th2 (IL-4 and IL-5) cytokines are seen. In a subset of patients with this Japanese Devic-like variant, IL-8 in CSF and neutrophils in lesions correlate with spinal cord lesion formation (Ishizu et al 2005). IFN-beta decreases IL- 8. Multiple sclerosis CSF and plaques contain CCR7+ dendritic cells; T cells express CCR7 only in the CSF. T cells in plaques have downregulated CCR7, a receptor needed for migration, and are then unable to leave the CNS (Kivisakk et al 2004). Monocytes and microglia present antigens and amplify immune responses. They communicate with cells hundreds of microns away through tunneling nanotubes that transmit calcium ions and antigens. They over-express receptors for immunoglobulins and are activated by low levels of serum receptor for advanced glycation end-products (RAGE). Inhibitory molecules expressed by monocytes (HLA-G, ILT3) are reduced in multiple sclerosis, but are upregulated by IFN-beta (Mitsdoerffer et al 2005; Jensen et al 2010). Peripheral monocytes produce excessive nitric oxide, which is neurotoxic and damages oligodendroglia but also destroys activated T cells. Microglia in the brain release nitric oxide, oxygen radicals, complement, protease, and cytokines. CSF nitric oxide metabolites correlate with gadolinium-enhanced MRI lesions, clinical activity, and progression of multiple sclerosis. Nitric oxide also modifies brain proteins to form nitrotyrosine. This creates neoantigens in the brain and generates antibodies to S-nitrosocysteine in the CNS (Boullerne et al 2002). Even though activated macrophages are generally toxic to CNS cells, they may have positive effects too. (See Recovery from relapses, below.) IFN-alpha-secreting plasmacytoid dendritic cells are more frequent in early multiple sclerosis in some studies. However, they produce less IFN-alpha and are defective as antigen-presenting cells (Stasiolek et al 2006). In contrast, myeloid dendritic cells in secondary progressive multiple sclerosis are activated and proinflammatory (Karni et al 2006). Trauma and stress have been implicated as causing multiple sclerosis or triggering exacerbations (McAlpine et al 1972; Poser 1986; Buljevac et al 2003; Li et al 2004). Stress and exacerbations are sometimes difficult to define, and studies conflict. Stress at home and physical abuse during childhood appear to prevent multiple sclerosis. Links of exacerbations to stress and trauma are nonexistent when stress, trauma, and concomitant clinical manifestations of multiple sclerosis are carefully analyzed (Sibley 1988; 1993; Siva et al 1993), even though there is a slight increase in new MRI lesions (Mohr et al 2000). Gunshot wounds and SCUD missile attacks actually seem to protect against exacerbations according to some reports (Sibley 1988; Nisipeanu and Korczyn 1993), but another war report suggests increased exacerbations (Golan et al 2008). Local irradiation of the brain can increase lesions of multiple sclerosis within the radiation field, possibly by disruption of the blood-brain barrier (Murphy et al 2003). The hypothalamus regulates autonomic functions, body temperature, sleep, and sexual PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 19 of 123 activity. It controls an endocrine cascade from corticotrophin releasing hormone (CRH), to adrenocorticotropic hormone, to cortisol. Serum cortisol and exogenous steroids turn down corticotrophin secretion. This endocrine activity has consequences for immune regulation. Hypothalamic plaques are common in multiple sclerosis and disrupt endocrine regulation (Huitinga et al 2004). Surviving myelin bundles are next to HLA class II positive microglia. Inflammation in the hypothalamus may explain the high number of corticotrophin and arginine-vasopressin double-positive neurons that are unique to multiple sclerosis, especially in disease of long duration. Arginine-vasopressin potentiates the action of corticotrophin on adrenocorticotropic hormone release. The resultant elevation in cortisol could be beneficial because high numbers of corticotrophin-releasing factor/arginine-vasopressin neurons correlate with low hypothalamic lesion load. Similarly, rats with high corticosterone are protected against experimental allergic encephalomyelitis. The hypothalamic-pituitary-adrenal (HPA) axis is hyper-responsive to corticotrophin- releasing hormone, especially in primary progressive multiple sclerosis (Then Bergh et al 1999). Chronic HPA axis overactivity may render cells insensitive to glucocorticoids and allow them to escape from immune restraint. Levels of cortisol, adrenocorticotropic hormone, dehydroepiandrosterone, and cells secreting corticotropin releasing hormone are increased most in progressive and active forms of multiple sclerosis (Ysrraelit et al 2008). Glucocorticoids plus antidepressants normalize the HPA axis in multiple sclerosis. Acute and chronic inflammation induces high serum cortisol levels that cause systemic and local steroid resistance. IL-1alpha, produced by activated macrophages, inhibits glucocorticoid receptor translocation to the cell nucleus (Pariante and Miller 2001). High levels of tumor necrosis factor and IL-1 and IL-6 correlate with hypothalamic-pituitary- adrenal axis (HPA) activation and with fatigue. In parallel, the hypothalamic-pituitary- adrenal axis is hyporesponsive to dexamethasone feedback during active multiple sclerosis, and so are immune cells ex vivo (Reder et al 1987). Conversely, cyclic adenosine monophosphate (cAMP) agonists (prostaglandins, beta-adrenergic agonists, and some antidepressants) enhance steroid receptor translocation and could potentiate glucocorticoids. The weak response to steroids correlates with high CSF white blood counts and enhancing lesions on MRI (Fassbender et al 1998). Mechanisms for this resistance include (1) downregulation from chronic high cortisol (mildly increased in multiple sclerosis), possibly from adrenocorticotropic hormone released by immune cells (Reder 1992; Reder et al 1994; Lyons and Blalock 1997); (2) a mutation in the steroid receptors; and (3) interaction with other signaling pathways. Recovery from relapses. Immune regulation causes the inflammation to wane. As clinical symptoms resolve, there is a rise in inhibitory Th2 cytokines, immunoglobulins, and glucocorticoids (Reder et al 1994a). There is suppression of inflammation, redistribution of axonal sodium channels in surviving axons, remyelination, and rewiring of the brain (compensatory adaptation or functional reorganization of neurons and synapses). Inflammation is turned off by apoptosis and suppression of activated immune cells. Apoptosis of Th1 cells is mediated by steroids (endogenous or therapeutic), IFN-gamma (Furlan et al 2001; Ahn et al 2004), tumor necrosis factor-alpha, and nitric oxide. IFN-beta causes apoptosis of Th17 cells, which express high levels of the type I interferon receptor (Durelli et al 2009). Toxic effects on neurons and oligodendroglia are caused by some of these same compounds: TNF-alpha, glutamate, nitric oxide, and other T-cell and monocyte products. Finally, as described above, subnormal suppressor T-cell function in clinically active multiple sclerosis may prolong inflammation. Macrophages secrete some compounds that are neuroprotective, suggesting there is a balance between destruction and repair during inflammation. Macrophages also produce trophic factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor beta (TGF-beta), insulin-like growth factor 1 (IGF-1), neural growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT3). BDNF is expressed in lesions by T cells, macrophages and microglia, and astrocytes. Immune cells secrete more BDNF during relapse, but levels fall with progression. After relapses, other neurotrophic factors rise, including glial cell-line derived neurotrophic factor PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 20 of 123 (GDNF), NT3, NT4, NGF, and possibly ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF). Foamy macrophages that have ingested myelin secrete anti- inflammatory IL-4, IL-10, and prostaglandin (PGE). These products, IL-4, IL-10, and granulocyte-macrophage colony-stimulating factor (GM-CSF), can, in turn, induce anti- inflammatory properties in microglia and monocytes. Staph A-activated monocytes produce 10 times more IL-10 (3000 pg/ml) than B plus T lymphocytes (Hamamcioglu and Reder 2007). IFN-gamma and IFN-beta cause macrophages to produce indoleamine 2,3 dioxygenase, an anti-inflammatory compound that helps induce regulatory T cells. Type II monocytes, which induce Th2 cells and regulatory CD4 T cells, inhibit experimental allergic encephalomyelitis and are induced by glatiramer acetate (Weber et al 2007a). The central nervous system is normally hostile to immune activation. The blood-brain barrier prevents access of white blood cells to the brain. Glia secrete transforming growth factor-beta, platelet-derived growth factor, and prostaglandin E that inhibit lymphocyte proliferation (Reder et al 1994b). As an example, brain tumors that produce inhibitory cytokines are more aggressive (Whelan et al 1989). Neurons secrete factors that prevent induction of apoptosis and a rise in cortisol. Astrocyte hypertrophy and gliosis follow the acute plaque. Brain antigens draining into the cervical lymphatics provoke strong antibody responses and Th2 immunity that can block Th1-mediated inflammation. The exacerbation rate falls during pregnancy (Birk et al 1990). Cytokines, interferons, and hormones such as estriol act together to frustrate Th1 responses and cause immunosuppression. A trial of estriol therapy in multiple sclerosis is ongoing. Remyelination occurs in most lesions (See Patterns I to IV and Pathology section, below). Remyelination may be the normal default response to the multiple sclerosis insult, reinforcing the utility of reducing inflammation with therapy. Remyelination is quite extensive in a subset of 20% of patients and in more than 40% of MRI lesions. It occurs in both relapsing-remitting and primary progressive disease and in both early and late multiple sclerosis (Patrikios et al 2006). Remyelination prevents axonal loss. It is more prominent in older patients, in disease of long duration, and in subcortical and deep white matter but not in periventricular plaques. Evolution of the progressive clinical course: multiple possible causes. Most patients change from repeated exacerbations and remissions to a progressive clinical course approximately 10 years after disease onset. In progressive multiple sclerosis, there is cumulative loss of oligodendroglia and neurons, with increasing demands on surviving, yet compromised, cells. Clinical remissions disappear, but constant low-grade immune activation continues or may change in character. There are 2 theories of the evolution from relapsing-remitting to progressive multiple sclerosis. Underlying subclinical neurodegeneration may be present early on and eventually becomes noticeable. Surprisingly, however, patients who continue to have frequent relapses after the first 2 years are less likely to become progressive (Scalfari et al 2010). This suggests that there is a distinctive transformation from relapsing-remitting to progressive multiple sclerosis. The mechanism for this gradual failure of immune regulation and CNS repair is unknown (Maimone and Reder 1991), but there are many changes that could provoke the transition from relapses to progression: (1) Spontaneous and activation-induced apoptosis are impaired in T cells during clinically active multiple sclerosis (Zipp et al 1999; Sharief 2000), so autoimmune cells may not be eliminated. (2) Interferon signaling becomes subnormal in mononuclear cells from patients with progressive multiple sclerosis--but not in relapsing-remitting disease (Feng et al 2002a). (3) A decline in suppressor T cell function, seen intermittently during exacerbations, becomes continuous with progression (Reder and Arnason 1985; Antel et al 1986). As a result, autoimmune T cells may accumulate over time, and there is loss of peripheral immune tolerance. (4) In relapsing-remitting and secondary progressive disease, there is low expression of adhesion molecules on lymphocytes and more shedding from the cell surface, leading to PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 21 of 123 high levels in serum. Levels are normal in primary progressive disease (Duran et al 1999). This suggests that T cell-endothelial cell adhesion is important in relapsing disease, but there is less endothelial activation in the primary progressive form. (5) T-cell clones from patients with progressive multiple sclerosis are insensitive to steroids. Steroids only weakly inhibit proliferation, and there is little apoptosis, ie, a “pre- leukemic state” (Correale et al 1996). (6) Gadolinium-enhancing MRI lesions decrease in frequency, possibly from a change in the makeup of inflammatory CNS cells or in endothelial cell activation. (7) Nonetheless, patients who have primary progressive multiple sclerosis and high MRI T2-weighted lesion volume have excessive IFN-gamma production and T-cell migration through endothelial cells (Prat et al 2000b). (8) Monocyte and microglial changes suggest an increase in innate immunity, with a proinflammatory profile. Monocytes produce 5- to 10-fold more IL-12 and IL-18, and more IL-23, in progressive multiple sclerosis (Balashov et al 1997). These interleukins induce IFN- gamma, along with a change in the character of dendritic cells (Karni et al 2006), to activate pro-inflammatory Th1 cells. In contrast, protective IL-10, PGE, and BDNF decrease. A fall in IL-10 is associated with more disability and more MRI lesions. In addition, immune cells in secondary progressive multiple sclerosis secrete high levels of kallikreins and destructive serine proteases; both are associated with more disability. (9) Plaques contain more monocytes and fewer T cells in chronic disease. Perhaps related to a shift to innate immunity, this form of multiple sclerosis does not respond clinically to potent anti-T cell therapy. (10) Germinal center-like areas appear in meninges. These sites of established chronic B- cell activation suggest there is a loss of immune control. (11) Neurotrophic function is lost as disability progresses, both in the central nervous system and in peripheral blood cells. Chronic defeat stress, and possibly the stress of brain inflammation, di-methylates the BDNF gene (a DNA-repressive modification, not demethylation) to reduce BDNF levels (Tsankova et al 2007). Nerve growth factor produced by endothelial cells drops with increasing disability (Biernacki et al 2005). (12) Cord atrophy is associated with neuronal loss in all forms of multiple sclerosis and correlates with disability and progression. (13) Regional brain atrophy is periventricular in relapsing multiple sclerosis, but atrophy is cortical in progressive multiple sclerosis (Pagani et al 2005), and the gray matter is more abnormal on MRI (Pulizzi et al 2007; Fisniku et al 2008). The rate of atrophy in gray matter accelerates at the transition to progressive multiple sclerosis, and gray matter loss is the main contributor to total brain atrophy (Fisher et al 2008). Deep cortical invaginations are most affected and abut the most germinal center-like inflammation (Lassmann 2008). (14) Destruction of oligodendrocytes continues at a faster pace in secondary progressive multiple sclerosis than in relapsing-remitting multiple sclerosis, and there is more myelin basic protein-like material in the urine. (15) Oligodendrocyte precursor cells (OPC) are lost with cumulative burden of plaques. OPC are not recruited to the lesion. Perhaps most importantly, OPC fail to differentiate, possibly from inhibitory factors in plaques such as hyaluronan, a glycosaminoglycan, or from inhibitory molecules on demyelinated axons such as poly-sialated neural cell adhesion molecule (PSA-NCAM) (Franklin and Ffrench-Constant 2008). (16) In chronic plaques, premyelinating progenitor oligodendrocytes often extend processes to axons but, importantly, do not wrap around them. The axons that spurn the oligo are not receptive. They remain dystrophic and swollen and become vulnerable to insults (Chang et al 2002). (17) Activated astrocytes also inhibit oligo process extension. Central nervous system astrocytes usually express beta2-adrenergic receptors, which reduce major histocompatibility complex class II and adhesion molecule expression, inhibit immune responses, and prompt secretion of trophic factors and lactate, an energy source for axons and oligodendrocytes. These adrenergic receptors are absent in multiple sclerosis and are also decreased in Alzheimer disease (De Keyser et al 1999). Loss of these receptors may PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 22 of 123 lead to overactive immune responses in the central nervous system. The CNS is ordinarily an immunosuppressive environment from high levels of TGF-beta and prostaglandins. The immunoregulatory status of the CNS is possibly altered in progressive multiple sclerosis. (18) A gradual increase in plaque burden may eliminate neural pathways that regulate immunity. Autonomic responses are frequently abnormal in progressive forms of multiple sclerosis. A "strategic hit" to central autonomic pathways may interfere with the immuno- inhibitory tone from spinal sympathetic fibers that innervate the spleen (Karaszewski et al 1990). A form of denervation supersensitivity appears in immune cells—beta2 adrenergic receptors are overexpressed on CD8 T cells in progressive multiple sclerosis. These cells have exaggerated cyclic AMP responses. This change may affect suppressor CD8 T cell function and possibly innate immunity. Terbutaline, a beta2-adrenergic agonist, does not enhance cytokine expression (IL-10 and IL-12) in whole blood cells activated with T-cell mitogens (Heesen et al 2002). Resistance to adrenergic agents is reversed with interferon therapy. (19) Cortisol levels rise, adrenals increase in size, and cortisol feedback inhibition of the hypothalamic-pituitary-adrenal axis is abnormal in progressive multiple sclerosis; this may be from excessive production of AVP/CRH in the plaque-filled hypothalamus. Glucocorticoid therapy no longer suppresses multiple sclerosis symptoms. High glucocorticoid levels, endogenous and therapeutic, are linked to hippocampal atrophy. Hypercortisolemia may be corrected with antidepressants. (20) Therapies, usually directed at T and B cells, which are effective in relapsing or transitional multiple sclerosis, do not work in progressive multiple sclerosis. These include alemtuzumab, glatiramer, IFN-beta, IVIG, mitoxantrone, and rituximab. Riluzole had MRI benefit in a small study; a large fingolimod trial is ongoing. Pathology of the lesions. Multiple sclerosis plaques are found in both gray and white matter throughout the brain and spinal cord. Lesions are random--but have predilection for some brain regions. Periventricular and periaqueductal sites are most likely to suffer, and optic nerves are almost always involved. Cord lesions are often subpial. “Normal-appearing white matter” is abnormal on histology and with magnetic resonance spectroscopy. A plaque is a well-demarcated area with myelin loss, inflammatory cells, gliosis, and relative but partial preservation of axons and neurons. Demyelination usually predominates, but in some cases axonal loss is severe (Trapp et al 1998). Swollen astrocytes at plaque edges contain dense core particles and sometimes endocytosed oligodendroglia. Astrocytes are initially hypertrophic or gemistocytic. Months to years later they become fibrillary and form fibrous scars (sclerosis). The preferential periventricular location of multiple sclerosis plaques has been explained by multiple theories: effects of CSF toxins or cytokines; regional variation in microglia or capillary pericytes; and slow blood flow in the post-capillary venules that facilitates T-cell adhesion. Local toxins are unlikely because abluminal molecules diffuse throughout the brain within 6 minutes, facilitated by arterial pulses (Rennels et al 1985). Rapidly diffusing cytokines should activate pericytes or endothelial cells throughout the central nervous system. MRI in multiple sclerosis suggests that a slow flow rate (less than 50% of normal) through periventricular veins allows immune cells time to attach to endothelium (Law et al 2004). All plaques are perivenular on MRI (Tan et al 2000), and areas with high vein density are most frequently affected. The blood-brain barrier consists of specialized endothelial cells connected by tight junctions. A few areas lack tight junctions but do not have increased plaque activity, suggesting there is active attraction of immune cells by activated endothelial cells in the post-capillary venules in the restricted areas. The endothelium is abnormal in multiple sclerosis. In 1872, Rindfleisch described abnormal blood vessels in all lesions (Kirk et al 2004; Ludwin 2006). This is also true in experimental allergic encephalomyelitis (Muller et al 2005). Active plaques appear on MRI because of Gd uptake by activated endothelial cells and/or leakage though the barrier. Lack of Gd+ lesions would suggest there is less breakdown of the blood-brain barrier in progressive multiple sclerosis, yet serum proteins extrude through the blood-brain barrier in progressive multiple PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 23 of 123 sclerosis more than in other forms (Leech et al 2007). Tight junctions may be compromised even with less apparent inflammation as fibrin is increased in the perivascular space, especially in chronic plaques (Kwon and Prineas 1994; Claudio et al 1995; Leech et al 2007). Many active demyelinating lesions are missed on MRI, suggesting a spectrum from profound inflammation in classical plaques, to moderate inflammation in slowly expanding plaques, to mild or no inflammation in inactive plaques (Lassmann 2008). Choroid plexus cells are activated in multiple sclerosis, with HLA-DR and VCAM-1 expression by macrophages, dendritic cells, and epiplexus cells (Vercellino et al 2008). It may be an important site for antigen presentation and for the earliest lymphocyte entry into the CNS. Adhesion molecules on endothelial cells are bound by T cell ligands. The T cells then penetrate directly through the endothelial cells (Astrom et al 1968), not necessarily through the tight junctions. The self-amplifying loop between activated endothelial cells and activated T cells can be blocked by natalizumab and interferon. After monocytes cross the blood-brain barrier, they pile up in the perivascular space. The basement membrane is breeched in a second step by matrix metalloproteases. Interferons decrease matrix metalloproteases, suggesting how the combination of natalizumab and IFN-beta could synergistically decrease leukocyte traffic into the CNS. The initial inflammatory lesion is a cuff of macrophages and CD4 T lymphocytes that surround vessels lined with endothelial cells that express major histocompatibility complex class II proteins (Traugott et al 1985; Raine 1991), similar to the lesions of experimental allergic encephalomyelitis. Very early, the margin may be indistinct (Raine 1991). Sensitive magnetization transfer ratio scans can detect abnormalities weeks prior to Gd+ enhancement. The cellular infiltration is minimal in some acute plaques, suggesting a direct insult to oligodendrocytes that is similar to the Lucchinetti type III lesions described below (Barnett and Prineas 2004). These authors argue that in some early cases, oligodendroglial damage precedes immune infiltration; then macrophages and then T cells arrive. This frequently debated proposition suggests multiple sclerosis is a primary degenerative disorder. In another series of very early plaques, there were clusters of activated microglia, a few CD8 > CD4 cells, activated complement but not on myelin, and mild to moderate demyelination, all near Virchow-Robin spaces filled with CD4 and B cells (Gay et al 1997). Acute plaques typically spread out from the post-capillary venules. Clonally expanded (“oligoclonal”) CD8 cells begin to outnumber CD4 cells at the plaque margins (Booss et al 1983; Babbe et al 2000). These margins are often abrupt and thin, suggesting a battle between the spread of inflammation and endogenous resistance to the intruders. “Immune privilege” in the brain, from many factors, contributes to the immune cloaking of brain cells. Neurons express immune inhibitory transforming growth factor-beta. Neuron-T cell contact converts encephalitogenic T cells to regulatory CD4 T cells that inhibit experimental allergic encephalomyelitis (Liu et al 2006). Nonetheless, CD8 cells can damage neurites, axons, and oligodendroglia. Mitochondrial number and protein expression are increased in axons and astrocytes of active and inactive lesions. Plaques are of various ages in multiple sclerosis, unlike the monophasic lesions of postinfectious and postvaccinal encephalomyelitis. Some old multiple sclerosis plaques show ongoing demyelination with infiltrating macrophages that phagocytose compact myelin. Gray matter is affected, as it does contain some myelinated fibers. There is neuronal and synaptic loss in the cerebral cortex, as well as death in up to 35% of thalamic neurons (Cifelli et al 2002). Cortical demyelination can be extensive, and atrophy correlates with fatigue, cognitive loss, and physical disability. Deep gray matter (thalamus, putamen, caudate) also atrophies and has reduced blood flow. Extensive neuronal loss in the hypothalamus is common (Huitinga et al 2004) and may explain circadian rhythm disruption and alterations in cortisol regulation, sexual function, depression, and even poor sleep (Javed and Reder 2006). Cortical lesions can be contiguous with expanding subcortical lesions (type 1), can be confined to small perivascular areas of the cortex (type 2), or can extend from pia to cortical layer 3 or 4, usually in progressive disease (type 3) (Peterson et al 2001). These multiple PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 24 of 123 sclerosis-specific, subpial lesions are mainly found in cerebellum, hippocampus, and deep invaginations—in the cortex of the insula, cingulate, and deep occiput and fronto-and temporal-basal areas (Lassmann 2008). Cortical plaques are easily missed on histopathology because a long Luxol Fast Blue destaining step is used to detect white matter demyelination. Cortical lesions themselves are less inflammatory than in white matter. There are 10 to 40 times fewer T cells and 6 times fewer macrophages and microglia, plus little edema. Nonetheless, activated microglia ensheath neurites, and apoptotic neurons appear. Lesions are associated with lymphoid germinal center-like B-cell inflammation. Type 1 cortical lesions have less GAP43 protein, suggesting that atrophic cortex has lost neurons (average 10% fewer) and glia (36%). (MRI appearance of plaques is discussed in MRI versus histopathological subtypes.) The oligodendrocyte is the major target. Each of these cells maintains myelin on up to 50 axons and has an extraordinary metabolic demand. They are easily damaged, yet contain plentiful protective mechanisms. Oligodendrocyte progenitor cells (OPC) are widely distributed and can remyelinate naked axons. Triggers for OPC differentiation include IL-11 (and survival) and chemokine CXCL2. Fibroblast growth factor enhances OPC recruitment but inhibits differentiation. Myelin basic protein inhibits OPC differentiation; IFN-gamma inhibits remyelination. (See Recovery from relapses, above.) Oligodendrocyte loss correlates with the number of macrophages but not with T cells or plasma cells in histological sections (Lucchinetti et al 1999). NK, gamma/delta T cells, and CD8 T cells are able to damage oligodendrocytes through the NKG2D protein and other targets. CD4 cells could secrete cytokines that activate CD8 cells and macrophages. Astrocytes secrete IL-15, which enhances function of CD8 cytolytic cells. Monocytes and microglia activate NOS and also cause lipid peroxidation, tyrosine nitrosylation, and DNA stand breaks (Zeis and Schaeren-Wiemers 2008). Within active lesions next to dystrophic axons, macrophages express high levels of glutaminase, involved in glutamate synthesis (Werner et al 2001). Glutamate is toxic to neurons and oligodendroglia. Monocytes and macrophages destroy neurons and oligodendroglia, and they may increase in later stages of multiple sclerosis. Inflammation increases p53 in oligos, increasing susceptibility to apoptosis. IFN-beta blocks secretion of anti-inflammatory, protective IL-10 in activated macrophages and possibly in microglia, contrary to its effect in the periphery where it increases T cell IL-10 (Feng et al 2002b). This suggests therapy should be tailored to the inflammatory makeup of the brain as the disease evolves. Partial remyelination takes place during recovery from relapse, especially in early multiple sclerosis, but also occurs in progressive multiple sclerosis (Patrikios et al 2006). Many fibers are thinly myelinated within acute plaques or at the edge of chronic plaques during and after active myelin breakdown. Remyelination is more extensive in the cortex than in the white matter (Albert et al 2007). Moderate remyelination by hyperplastic oligodendroglia sometimes gives the appearance of a "shadow plaque." There is severe demyelination in the center but thin myelin sheaths in the shadowy periphery of the plaque (Prineas et al 1993). Remyelination is enhanced by some cytokines and gliotrophic factors secreted by immune cells, including macrophages. Low levels of inflammatory cytokines may be able to trigger protective oligodendroglial genes such as HIF-1alpha and HSP70; oligos also can produce growth factors such as NGF, IGF-1, and TGF-beta (Zeis and Schaeren-Wiemers 2008). N-acetyl-aspartate (NAA), synthesized in the mitochondria of neurons, is reduced in lesions. As the brain recovers, NAA in plaques increases most in patients with better clinical outcome (Ciccarelli et al 2010). Oligodendroglia precursors, expressing the anti-apoptotic protein Bcl-2, arise in the plaque or may have migrated from out of the subventricular zone. In plaque subtypes I and II (Lucchinetti et al 2000), oligo precursors are preserved and can form remyelinating shadow plaques. There are premyelinating oligodendrocyte precursors in chronic plaques, yet few mature oligodendrocytes and surprisingly little remyelination of adjacent bare axons (Chang et al 2002). Multiple factors could be responsible for loss of axonal receptivity for remyelination and lack of remyelination: PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 25 of 123 • Persisting immune cells and inflammatory cytokines can interfere with neuronal function and cause demyelination. • Inflammation may have toxic effects on bare clusters of sodium channels at the axonal paranode and make the axon vulnerable to injury. • Demyelination also disrupts the complex architecture of this site, interfering with repair. • Insulin-like growth factor, but also its opponent insulin-like growth factor-binding protein, is increased on oligodendroglia in plaques. • Neuregulin decreases, interfering with remyelination. • With age, decreased histone deacetylase slows remyelination; their function in multiple sclerosis is unknown. In multiple sclerosis plaques lacking remyelination, activated astrocytes express Jagged1, a ligand for the Notch1 receptor on oligodendroglia (John et al 2002). Notch inhibits oligodendrocyte maturation and oligo process outgrowth, preventing remyelination (see CADASIL). • Other inhibitors of oligo differentiation and remyelination include myelin-associated glycoprotein (MAG), oligo-myelin glycoprotein (OMgp), Nogo, and Nogo receptor-interacting protein (LINGO-1). Soluble Nogo-A is elevated in relapsing and progressive multiple sclerosis serum and CSF (Jurewicz et al 2007). Nerve growth factor induces LINGO on oligos and axons. Therapy with anti-LINGO antibodies and siRNA promotes OPC differentiation and enhances remyelination, without affecting inflammation in experimental allergic encephalomyelitis (Mi et al 2007). With chronic multiple sclerosis and with each insult, more oligodendrocyte precursors and mature cells die, and the ability to remyelinate decreases. With chronic progressive disease, normal-appearing white matter shows diffuse reduction of myelin, infiltration of T cells, and microglial activation (Lassmann 2008). In addition, reactive oxygen species, glutamate, immune cell products (nitric oxide, IFN-gamma, and tumor necrosis factor alpha), proteases, and viruses also damage myelin. IFN-gamma protects mature oligos against oxidative stress, but damages immature oligos (Balabanov et al 2007). However, some patients exhibit remyelination that trumps the effect of age. Some shadow plaques show only small areas of remyelination at plaque margins, but others show extensive remyelination, including 2 elderly patients with longstanding disease (Patrikios et al 2006). Loss of trophic support from oligodendroglia, even in the absence of inflammation, also potentially damages axons. Axons are damaged in multiple sclerosis. During the earliest stages, there are abundant axonal “ovoids,” ends of transfected axons ballooning from ongoing retrograde transport (Charcot 1850;(Trapp et al 1998). There are 10,000 axonal spheroids/mm3 in multiple sclerosis plaques (indicating transection months or years earlier) but only 2/mm3 in controls (Trapp et al 1998). Early active lesions have 10% to 20% axonal loss. Even in normal- appearing multiple sclerosis white matter, axons are half as common as in control brains. In chronic progressive multiple sclerosis, two thirds of the axons are lost; in addition, one half of the axons in many long tracts and the corpus callosum disappear (Bjartmar and Trapp 2001). Unexpectedly, there is little correlation between plaque load and axonal loss, suggesting effects of different types of inflammation as well as an axonopathy. The atrophy rate on MRI in multiple sclerosis is approximately 1% per year; this rate is higher than in healthy controls (0.12%) but less than in Alzheimer disease (3%). Axonal damage predominates in selected pathways such as the optic nerve, corpus callosum, and spinal cord. In the cervical cord, up to 65% of the axons can be lost. In the corpus callosum, transcallosal bands from Wallerian degeneration predict poor prognosis. Axonal loss correlates with clinical disability and with central nervous system atrophy (Trapp et al 1998). The damage predominates in small-sized axons, in corticospinal axons at all levels, and in sensory axons largely in the cervical cord (DeLuca et al 2006). Axonal loss can be severe enough to cause elevation of neurofilament light protein in the CSF, Wallerian degeneration on MRI, low magnetization transfer ratio, and a contralateral decrease in N- acetyl aspartate (NAA) on MR spectroscopy (sometimes causing clinical diaschisis). Acute axonal damage is worst in the first year of disease activity. Damage correlates with the number of CD8 T cells, monocytes, and activated microglia in plaques (Kuhlmann et al PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 26 of 123 2002). Myelin-specific CD8 cells are more frequent in relapsing than in progressive multiple sclerosis. Antibodies generally bind to axons and not to myelin. Amyloid precursor protein reflects acute damage to neurons (days to weeks after the insult). It predominates in acute early multiple sclerosis but also in the active edges of chronic active plaques in secondary progressive multiple sclerosis (Bitsch et al 2000). Amyloid precursor protein levels correlate with the presence of monocytes and CD8 cells but not with CD4 cells or with TNF-alpha and iNOS levels. Cytotoxic CD8 cells attach to dendrites and axons and then transect them by releasing perforin. Monocytes release nitric oxide and glutamate--also toxic to neurons. Some CD8 cells secrete anti-inflammatory cytokines, but this type of CD8 cell is reduced in patients with high MRI T1 lesion load (Killestein et al 2003). Circulating anti-ganglioside antibodies in progressive multiple sclerosis reflect axonal damage. They present in 50% of primary or secondary progressive patients compared to only 3% of relapsing-remitting patients (Sadatipour et al 1998). T cells proliferate excessively to GM3 and GQ1b in primary progressive disease. Some antibodies are myelin- protective. As inflammation subsides, axonal sodium channels redistribute diffusely in demyelinated axons, away from the former nodes of Ranvier. More of these diffuse K+ and Na+ channels are activated per unit length of axon. This greater Na+ influx is accompanied by a greater Ca++ influx (one tenth of the Na+ flux), so these compromised axons must contend with sequestration of potentially toxic Ca++ (Rosenbluth et al 1999). Axonal mitochondria are dysfunctional, also leading to Ca++-mediated axonal degeneration. Altered channels affect function. Ten molecularly distinct subtypes of sodium channels control timing and duration of axon potentials. A transcriptional channelopathy can arise when new types of sodium channels appear at high density in demyelinated axons (Waxman 2002). There is also robust expression of sodium channels on activated microglia and monocytes. Blockade of Na channels with phenytoin decreases inflammation (Craner et al 2005), and phenytoin and flecainide inhibit experimental allergic encephalomyelitis. However, abrupt withdrawal of phenytoin or carbamazepine provokes exacerbation of experimental allergic encephalomyelitis, although this is not reported in multiple sclerosis. Lamotrigine, a Na channel blocker, slightly enhanced walking speed, but was linked to more brain atrophy (Kapoor et al 2010). Many mechanisms subvert immune privilege of the brain. CNS antigens drain through cervical lymphatics to secondary lymphoid organs where B cells are educated and produce antibodies. Myelin basic protein, tau, neurofilaments, and 14-3-3 proteins in CSF reflect neuronal and glial damage. Presumably sensing these brain antigens, deep cervical lymph nodes produce large amounts of antibodies and educated T cells that return to the CNS. The Virchow-Robin spaces in the brain contain extracellular matrix proteins, facilitating migration of MHC-expressing macrophages that are well-placed to interact with T and B cells plus activated B cells. In chronic plaques, astrocytes hypertrophy and express B7-1 and B7-2 costimulatory molecules, possibly allowing antigen presentation by astrocytes. B cells also act as antigen-presenting cells, co-stimulate T cells, and secrete cytokines (Cross et al 2001). Antibodies are produced within the CNS itself. B cells in the CNS undergo local clonal expansion, activation, “receptor editing,” and hypermutation and develop an activated memory cell phenotype (Monson et al 2004). Editing of surface immunoglobulin in response to antigens improves affinity but ordinarily reduces proclivity to autoimmune disease. These cells produce immunoglobulin in an oligoclonal band pattern. Lymph node medulla- and spleen germinal center-like areas appear in the perivascular spaces of some old multiple sclerosis plaques (Prineas 1979). Similar structures are seen in affected tissues in rheumatoid arthritis, Sjögren syndrome, Crohn disease, and Hashimoto thyroiditis. This organized inflammation appears in the meninges in 40% to 54% of autopsy cases. In the presence of TNF-alpha, B cells proliferate in the meninges and form germinal center-like areas. Lymphotoxin-alpha, essential in formation of tertiary lymphoid tissue, is elevated in multiple sclerosis CSF. Germinal center-like areas in the meninges contain follicular dendritic cells, proliferating B cells, and plasma cells (Serafini et al 2004). They PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 27 of 123 seem to be restricted to secondary progressive multiple sclerosis. The B-cell follicle-like areas are associated with subpial demyelination and cortical atrophy. These ectopic B cell follicles in some cases are major sites of Epstein-Barr virus persistence, possibly driving antibody production (Serafini et al 2007). T cells, which affect B-cell function, are present in the spinal meninges and activated microglia in the normal-appearing white matter of spinal cords. T cells correlate with 25% atrophy in multiple sclerosis spinal cords (Androdias et al 2010). These regions are potentially difficult to reach with multiple sclerosis therapies. An alternate explanation for these germinal center-like areas is that CNS injury itself triggers systemic autoimmunity and B-cell activation (Ankeny et al 2006). As the plaque ages, its inflammation and edema partially resolve. The relative number of B cells, CD8 cells, and monocytes increases, whereas CD4 cells decrease (Booss et al 1983; Lassmann et al 1994). In chronic inactive plaques, CD8 cells are 10 times more numerous than CD4 T cells. There is a distinct margin, with a residue of occasional inflammatory cells, myelin-laden macrophages, a glial scar, and damaged and demyelinated axons. In late chronic plaques, inflammation is minimal and comparable to other neurologic disease controls, macrophages predominate, and plasma cells and mast cells are present. Mast cells are typically missed by usual histological stains, but with specific stains they are seen in chronic active lesions (Ibrahim and Reder 1996). Mast cells may be a consequence of any kind of chronic inflammation and not specific to multiple sclerosis. Mast cells could enhance migration through the blood-brain barrier, activate Th1 cells, reduce Treg function with secreted histamine, and release destructive or neuroprotective molecules. On microarrays, there is high expression of mRNA for “allergic” molecules such as prostaglandin D synthase, histamine receptors, immunoglobulin Fc-epsilon receptor, tryptase, and chemokines (CCL5, stem cell factor) (Pedotti et al 2003; Couturier et al 2008). RNA profiling of plaques, usually post-mortem, shows differences from normal white matter. The signature is neuroprotection, anti-oxidative stress (inflammatory and anti- inflammatory), and mitochondrial de-activation, with nearby glial and astrocytic activation. Proteomic analysis shows activation of tissue factor and other coagulation molecules. Conclusions are difficult because of varying damage to a mix of cells and heterogeneity of lesion activity and age. Functional MRI shows activation of wide areas of primary cortex and supplementary motor cortex. This technique measures blood flow to areas of brain involved in various tasks. The enlarged cortical area on functional MRI is presumably less efficient because plaques have disrupted normal connections, forcing cortical reorganization or unmasking of less efficient latent pathways. Brain pathology in primary progressive multiple sclerosis differs from that in relapsing- remitting disease. Spinal cord lesions predominate over brain lesions and cause gradual paraparesis. Less inflammation is reflected by fewer Gd-enhancing lesions. However, myelin is pale (“dirty” MRI) in the “normal-appearing” white matter. There is also cortical atrophy and demyelinated plaques in deep gyri of the cerebral cortex, insula, cingulate, limbic circuit, and cerebellar cortex that is much more severe than in relapsing-remitting multiple sclerosis (Lassmann et al 2007). Extensive hippocampal demyelination in chronic multiple sclerosis is likely to interfere with cognition (Geurts et al 2007). Subpial germinal center-like areas may contribute to cortical damage. N-acetyl aspartame levels are low in the cortical gray (Sastre-Garriga et al 2005). Urine myelin basic protein-like material is lower than in secondary progressive multiple sclerosis, suggesting a slower rate of destruction in primary progression. The brain pathology in multiple sclerosis is not stereotypical. The MRI ranges from small lesions in the white matter to huge plaques that are sometimes mistaken for gliomas. Large solitary demyelinating lesions in the centrum semiovale are often biopsied. These large lesions, even if associated with multiple plaques, have surprisingly good prognosis (Kepes 1993). Distinct patterns in different brains, but similar within a given brain, appear in biopsies of large lesions and at autopsy (Lucchinetti et al 2000). Pathological subtypes depend on the degree of inflammation, myelin destruction, and oligodendroglial preservation. In each case, PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 28 of 123 the number of macrophages is 10-fold greater than T cells, that are themselves 10-fold more numerous than B cells. Four pathological subtypes are described in Table 1: I. T cell and macrophage-mediated demyelination (18% of 201 patients) II. T cell and macrophage, plus antibody-induced or complement-mediated demyelination (56%) III. Oligodendrocyte dystrophy and apoptosis with myelin protein dysregulation (24%) IV. Primary oligodendrocyte degeneration with features similar to viral, ischemic, or toxic oligodendrocyte damage (2%) Patterns I and II are seen in acute, early active multiple sclerosis. An intense perivenous immune reaction causes a sharply demarcated area of demyelination and destruction of oligodendroglia, astrocytes, and axons. There is preservation of oligodendrocytes and significant remyelination (shadow plaques) and less expression of multiple myelin proteins, without (pattern I) or with deposition of activated complement and IgG (pattern II). Many myelin proteins are decreased, but myelin-associated glycoprotein is not lost. Oligodendrocytes die at the plaque edge, but they reappear in the plaque center. Antibody and complement-facilitated pattern II is the most common. Most antibodies in multiple sclerosis plaques are “nonsense” antibodies to unknown determinants and their relevance is unknown. They usually do not react with myelin antigens. Some, especially IgM, may stimulate remyelination. Others are probably pathogenic, ie, antibodies to gangliosides (above) and IgM against S-nitrosocysteine (from nitric oxide reactants, some directed against myelin-associated glycoprotein on oligodendrocytes) (Boullerne et al 2002). Complement binding to antigens increases their immunogenicity. Nonetheless, myelin damage in pattern II appears to be macrophage-mediated. Plasma exchange appears to benefit pattern II, but not patterns I and III. Patterns I and II are similar to the lesions of experimental allergic encephalomyelitis in which there is an autoimmune attack against myelin. Pattern I resembles destruction of myelin by macrophage products (tumor necrosis factor-alpha and reactive oxygen species). Pattern II is similar to experimental allergic encephalitis induced by myelin oligoglycoprotein, mediated by T cells interacting with anti-myelin oligodendrocyte glycoprotein antibodies. Patterns III and IV exhibit primary oligodendroglial dysfunction with subsequent demyelination. Pattern III consists of an inflammatory infiltrate of macrophages, microglia, and T cells, but no immunoglobulin. Ill-defined, non-perivenous areas of demyelination (preservation of oligodendroglia near venules) and limited remyelination are seen, sometimes with concentric rings of demyelination reminiscent of Balo concentric sclerosis, “dying back” destruction and apoptosis of oligodendrocytes, and a marked fall in myelin- associated glycoprotein compared to other myelin proteins. Myelin-associated glycoprotein is needed for myelin attachment to axons, and possibly in remyelination, and is located in distal periaxonal oligodendrocyte processes (Chang et al 2002). This pattern of demyelination resembles acute white matter hypoxia and suggests a virus or toxin such as nitric oxide that could interfere with mitochondrial energy production. Pattern IV consists of an inflammatory perivenous plaque with a sharp border of destruction and apoptotic loss of oligodendroglia with little remyelination. This rare pattern is seen only in some patients with primary progressive multiple sclerosis. It may reflect an underlying dysfunction in oligodendroglia (oligo-opathy) (Gulcher et al 1994). Patterns I, II, and III are seen in acute, relapsing-remitting, and secondary progressive multiple sclerosis. Patterns I, II, and IV are seen in progressive multiple sclerosis. All active plaques throughout a given brain have a similar histopathological subtype, suggesting a consistent style of immune and brain response at the time of autopsy or biopsy. The pattern of MRI lesions is also similar in a given brain (Lucchinetti et al 2000). In late “established” multiple sclerosis, all lesions show complement and antibodies associated with macrophages in areas of active demyelination, suggesting that heterogeneity disappears over time (Breij et al 2008). Differences in pathology between patients suggest there is heterogeneity in the pathogenesis of the disease, a fundamental difference in the mechanism and targets of demyelination, and probably in therapeutic responses. For PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 29 of 123 instance, agents that modify cellular immunity (eg, interferons) are theoretically best for subtype I. Plasmapheresis or intravenous immunoglobulin might be of benefit in antibody- mediated subgroup II. Growth factors for oligodendroglial progenitors or actual transplants are potential therapies for types III and IV. Note that, in a smaller series there were combinations of different categories in the same brain, with pattern IV plus other plaques with remyelination (ie, patterns I or II) (Barnett and Prineas 2004). They also suggest in some cases oligodendroglial apoptosis may precede inflammation. MRI versus histopathological subtypes, clinical symptoms, and behavior in trials. MRI is important in determining extent of brain and cord lesions, presence of new lesions, atrophy, and possibly responses to therapy (Lassmann 2008). Perivascular inflammation is associated with gadolinium-enhancing lesions on MRI. Ring- enhancing lesions on MRI are areas of new inflammation, consisting largely of a sharp border of macrophages that secrete TNF-alpha, some T cells, oligodendroglia with DNA fragmentation, and axonal loss. This ring surrounds older lesions, and is characterized by protein leakage (blood-brain barrier breakdown), MRI T1 isointensity, and T2 hyperintensity (Bruck et al 1997). T2 activity persists for 10 weeks after contrast enhancement, suggesting it measures degeneration and repair. Smaller T2 lesions are disproportionately more damaging than larger ones (Meier et al 2007). Ring-enhancing lesions correspond to pattern I and II lesions described above. Demyelinated or remyelinating lesions have less inflammation, significant axonal loss, and modest blood-brain barrier breakdown. They are hypointense on T1 (less so with remyelination) and hyperintense on T2, and are variably enhancing (Bruck et al 1997). T2 signal is from edema; T1 hypointensity is from axonal loss, myelin loss, edema, and widening of the extracellular space. Although MRI films are a dramatic way to show CNS lesions to patients, there are caveats for using MRI as a biological marker for multiple sclerosis. The T2 edema signal alone cant differentiate between demyelinated and partially myelinated lesions. Two of nine T2 MRI lesions show no demyelination on postmortem analysis (Barkhof et al 2003). Lesions in many parts of the brain are clinically silent. Correlation between T2 lesions and clinical symptoms is poor (r = 0.2 to 0.3; less than 6% of the variance) (“clinico-tomographic dissociation”). In 1354 placebo-treated relapsing-remitting patients from 45 clinical trials and natural history databases, T2 total lesion load did not predict change in disability from baseline to trials end (Daumer et al 2009). There was a small predictive effect of total lesion load on disability in secondary progressive multiple sclerosis (r = 0.21). Gd+ lesions did not predict relapses. T1 black holes, a measure of lost axons, correlate well with spinal cord atrophy and also with clinical deterioration in secondary progressive multiple sclerosis (r = 0.8) (Barkhof 1999), but not in relapsing-remitting multiple sclerosis (r = 0.3) (Simon et al 2000). Glatiramer acetate and IFN-beta reduce the chance that black holes will become permanent (Filippi et al 2001; 2011), and IFN-beta prevents them ab initio. Gd+ lesions are more common early in the course of multiple sclerosis, and they are more common in relapsing forms of multiple sclerosis compared to primary progressive disease. Multiple new and reactivated old Gd+ lesions appear in concert during disease activity. Occasional new T2 lesions may arise without enhancement, especially in periventricular areas (Lee et al 1999). Two or more Gd+ lesions strongly predict the development of multiple sclerosis (96%) after an isolated clinical attack (Group CHAMPS 2002). Long- duration Gd+ lesions are most likely to evolve into a hypointense T1 MRI lesion. However, Gd-enhancing lesions are only modest predictors of a worse clinical course. Changes in therapy must be made in the context of clinical patterns and not simply based on Gd+ lesions. After Gd-positive scans in untreated patients, the number of contrast-enhancing lesions falls at 3 months by 4%, at 6 months by 29%, and at 9 months by 48% (Zhao et al 2008). Brain regions differ in Gd enhancement. Cortical gray matter lesions are difficult to see on T2-weighted MRI, likely because immune responses and edema are influenced by less myelin, little water, and 10 times fewer inflammatory cells than in white matter lesions (Peterson et al 2001). This may explain why plaques enhance in subcortical U fibers but do not extend into the gray matter on T1 MRI. A single plaque often enhances in the white PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 30 of 123 mater portion but not in the gray matter, forming an “open ring”—highly specific for a demyelinating lesion. Cortical lesions are rare on T2 MRI but are often seen with FLAIR (fluid-attenuated inversion recovery) (Bakshi et al 2001). Double inversion recovery MRI is more sensitive for detecting cortical lesions. It detects cortical lesions in over 80% of primary progressive multiple sclerosis brains (Calabrese et al 2009). MRI with 8 Tesla magnets easily demonstrates gray matter plaques (Bakshi et al 2005). Even with minimal inflammation, cortical neurons are injured, contributing to motor, sensory, and cognitive losses and possibly fatigue. Lesion location sometimes determines clinical symptoms. Patients with “benign multiple sclerosis” and those with severe disability can have similar brain atrophy and N-acetyl aspartate content. The disabled group often has significant atrophy at the second cervical cord level (Brass et al 2004). Some patients with primary progressive multiple sclerosis have only diffuse MRI abnormalities in brain and cord (“dirty white matter”) (Zwemmer et al 2008). This represents ongoing inflammation and significant axonal pathology. The rate of brain atrophy is increased up to 10-fold in multiple sclerosis. Atrophy is caused by loss of neurons and axons, with some contribution from damage to oligodendroglia and myelin. Dehydration can confound measurement of atrophy; dehydration for 16 hours reduces brain volume by 0.55%. Studies do not account for possible diuretic effects of interferons. Gd+ lesions often do not predict brain atrophy (Saindane et al 2000), but are more predictive of future atrophy when they are ring-enhancing with central contrast pallor (Leist 2001) and when they are present at onset of multiple sclerosis (Simon et al 2000). T2 lesions do not predict cord atrophy (Bergers et al 2002). Newer MRI measures, such as the inter-caudate nucleus ratio, correlate better with loss of clinical function (brain atrophy versus disability, r = 0.67; versus cognitive function, r = -0.42). Cord atrophy may correlate best with clinical disability and poor walking; deep gray atrophy correlates with slowed cognition. In early relapsing-remitting multiple sclerosis, gray matter atrophy on MRI is seen at twice the normal rate (Tiberio et al 2005). Gray matter atrophy includes cortex (especially in deep sulci), thalamus, and hippocampus (CA1 and subiculum). Hippocampal volume loss is associated with high cortisol and depression in multiple sclerosis. Cigarette smoking correlates with lower brain volume and trends with faster progression (Durfee et al 2008). Atrophy is potently slowed by IFN-beta, glatiramer, and natalizumab therapy. Magnetic resonance spectroscopy detects constituents of neurons and glial cells. The corpus callosum and normal appearing white matter are sensitive sites for this analysis. N- acetyl-aspartate is part of an osmoregulatory molecular water pump, synthesized by neurons (Baslow 2002). It is a marker of neuronal and axonal function but not necessarily of neuronal loss. N-acetyl aspartate concentrations are high in mast cells and present in oligodendroglia; this could confuse magnetic resonance spectroscopy readings of presumed neuron and axon integrity. Early in multiple sclerosis, “normal-appearing white matter” as well as thalamic and cortical gray matter have decreased N-acetylaspartate (Chard et al 2002; Filippi et al 2003). The N-acetylaspartate decrease correlates with the number of clinical relapses over the preceding 2 years (Parry et al 2003), suggesting that N- acetylaspartate forecasts prognosis even before T2 lesions are visible, and before detectable inflammation. Loss of N-acetyl aspartate precedes atrophy and strongly correlates with disability (Bjartmar and Trapp 2001), fatigue, lateralized cognitive dysfunction, and abnormal visual evoked potentials. A fall in cortical N-acetyl aspartate correlates with disability in primary progressive multiple sclerosis (Sastre-Garriga et al 2005). Periventricular N-acetylaspartate falls with progression and is lowest in secondary progressive multiple sclerosis (Matthews et al 1996), more than in primary progressive disease. Levels continue to fall in untreated patients, but rise back toward normal in affected areas after 6 months of IFN-beta therapy (Narayanan et al 2001). Thus, metabolic disturbances and axonal shrinkage may be reversible. MRI using ultra-small particles of iron oxide (USPIO) can trace macrophage activity. Oligodendrocyte progenitor and hematopoietic stem cells can be labeled and traced with these nanoparticles. This complements Gd imaging of blood-brain barrier function. Cholesterol increases by 4.4% for each gadolinium-enhancing MRI lesion (Pantano et al PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 31 of 123 2001). Cytokines, chemokines, autoantibodies, and Th1/Th2/monocyte ratios vary between patients and over time, possibly explaining some of the differences in course, pathology, or MRI (Hickey 1999). Correlation of data on immune function, urine myelin basic protein (Whitaker et al 1995), and MRI subtypes versus clinical responses in drug trials is essential to define whether these subtypes can be used to determine prognosis or the best drug therapy. Other new techniques, such as ultra-small-particle iron oxide uptake by macrophages on MRI and benzodiazepine receptor-labeled microglia on PET scans (with PK1195) (Banati et al 2000), show lesions not detectable on regular MRI. Epidemiology The prevalence of multiple sclerosis in the United States is 250,000 to 350,000 (Anderson et al 1992), revised to 400,000 by the U.S. National Multiple Sclerosis Society in 2007 to account for population growth. World prevalence is estimated at 1.25 million (Dean 1994). The incidence was 3.2 per 100,000 cases a year in the United States in the 1990s (Jacobson et al 1997), 4.2 in the U.S. in 2007, and 7.5 in Olmsted County, Minnesota, the home of the Mayo Clinic (Mayr et al 2003). Although some studies show a stable incidence of multiple sclerosis, the number of cases in other locales is increasing. In Olmsted County, the prevalence quintupled and the incidence quadrupled in the past 70 years (Wynn et al 1989), although it appears to have stabilized in high prevalence areas (Mayr et al 2003). In Canada, the increase is largely in females (Orton et al 2006). The prevalence of multiple sclerosis has increased in regions of Scotland, Finland, Norway, Lower Saxony, Sardinia, Italy, Sicily, and the French West Indies (Kurtzke 1991). Allergy, Crohn disease, and type I diabetes show similar geographical distribution and increasing incidence. The increase has been attributed to altered immune regulation as exposure to infectious diseases has diminished (Bach 2002). Geographical variation in the prevalence of multiple sclerosis is striking. Multiple sclerosis is rare in equatorial countries. The disease becomes more common with distance from the equator in either hemisphere. This variation is partially due to Northern European, especially Scandinavian, ancestry in affected populations, but there is also an environmental influence (Page et al 1993). In the United States, early studies showed that northern areas had a prevalence of over 100 per 100,000, whereas it was only 20 per 100,000 in southern states. This gradient has attenuated over time. Incidence is high (greater than 30 in 100,000) in northern Europe from Iceland to Russia, and in Canada, New Zealand, and southern Australia. Incidence is moderate (5 to 29 in 100,000) in the Mediterranean basin, the southern United States, and southern South America. Incidence is low (less than 5 in 100,000) in East Asia, India, Africa, the Caribbean, Central America, Mexico (especially in Indians and mestizos), and northern South America (Kurtzke 1975; 1993; Pugliatti et al 2002). Is the cause of multiple sclerosis genetic or environmental? Migration, ethnic, and twin studies suggest that genes and environment both influence the development of multiple sclerosis. Northern European ancestry is a major risk factor for development of multiple sclerosis. Scandinavian ancestry is strongly correlated with multiple sclerosis risk (Pearson product moment correlation = 0.5). English ancestry is negatively correlated in the United States (-0.5) (Page et al 1993). The rate in England is 42 to 80 per 100,000 (Kurtzke 1975). Israeli Jews have a prevalence of up to 62 per 100,000, but Christians (35 per 100,000), Moslem Arabs (15), Druze (11), and Bedouins (17) have lower rates (Alter et al 2006). Genetically similar immigrants have half the rate of native-born Jews, suggesting an environmental factor. Other groups also have a low incidence of multiple sclerosis (Gypsies, Asians, and native black Africans). Five percent of multiple sclerosis patients in the United States are black. Black Americans of African ancestry (often racially mixed) born anywhere in the United States have a relatively high risk compared to native Africans, but half the rate of Caucasians in the United States (Kurtzke et al 1979). They are more likely to have optico- spinal symptoms, larger MRI lesion volumes, and faster disease progression than whites. In PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 32 of 123 contrast, people of Japanese ancestry in the United States have low rates of multiple sclerosis (Detels et al 1977), but much or all of the association disappears when covariates such as socioeconomic status are excluded (Marrie et al 2006). Genetic influences. There are many genetic influences on the development of multiple sclerosis. In studies of twins, the monozygotic concordance rate is 31% (200 times background), the dizygotic rate is 5% after 7.5 years of observation (Sadovnick et al 1993), and the sibling risk is 3.5%, indicating a genetic component to multiple sclerosis. First- degree relatives have a 25-fold increased risk of developing multiple sclerosis compared to the general population (Hogancamp et al 1997), and there may be a greater maternal influence. When both parents are affected, 9% of the children develop multiple sclerosis. In theory, the highest risk monozygotic twin has an affected parent and a twin sister with onset before 21 years of age. Mothers and fathers are equally likely to transmit the disease, with no evidence of a Carter effect-- where the parent who is less likely to be affected is more likely to transmit the disease (Herrera et al 2007). Gender, age at onset, disease course, and severity are more similar than expected among affected patients in a family (Kantarci et al 2002). There are reports of a familial predisposition for a similar course of multiple sclerosis (Hensiek et al 2007), but others believe phenotypes are not concordant (Ebers et al 2000). Children of multiple sclerosis patients (Fulton et al 1999), 10% of first degree relatives, and unaffected twins often have abnormal MRIs (Mumford et al 1994), but their T cell responses to myelin basic protein are normal (Martin et al 1993; Ragheb 1993). The large number of unaffected monozygotic twins (70%) is a strong argument for a significant environmental contribution. No single Mendelian locus causes multiple sclerosis. However, a limited number of interacting genes might affect susceptibility (Sadovnick 1993). Linkage to DR2 (HLA- DRB1*1501, possibly with DQB1*0602) is strongest in Northern Europeans, but other HLA- DR subtypes are seen in multiple sclerosis patients in the Middle East, Turkey, Sardinia, and Japan. Western forms of multiple sclerosis are linked to DR2 in Japan (Kira et al 1996). In black Americans, African HLA ancestry correlates with disability; DRB1*15 is less likely to be associated with neuromyelitis optica than with typical Western multiple sclerosis. In non- DR2 Japanese patients, multiple sclerosis often resembles Devic disease (eye and spinal cord involvement, seldom with CSF oligoclonal bands). DR4 is linked to a primary progressive course (Kantarci et al 2002). DR2 correlates with the presence of oligoclonal bands in the CSF but not with MRI lesions (Soderstrom et al 1998). This suggests 2 different HLA-linked mechanisms in central nervous system lesions. HLA-Bw4, DRB5 (less progression and severity), DRB1*01, CDR1*14, B*4402, and HLA-C*05 may be resistance factors. HLA- B12 has been linked to multiple sclerosis, and as fate would have it, to vitamin B12 deficiency and myelopathy. Non-HLA genes that have weak links to multiple sclerosis or to its course include T cell receptors, immunoglobulin allotypes, POU2AF1 (transcriptional coactivator that regulates immunoglobulin expression), complement factors (C6, C7, properdin), the IL-2 receptor beta chain, IL-7 receptor alpha chain, intercellular adhesion molecule-1 (K469E), tumor necrosis factor alleles, the CD45 tyrosine phosphatase, CD24 (a heat stable antigen that may enhance T cell persistence in the brain), synapsin III, Tyk2 in the interferon response pathway, and possibly mitochondrial DNA. Other candidate genes code for myelin basic protein, transketolase, IL-10, chemokines, p53, estrogen and vitamin A receptors, Jagged1 (oligodendrocyte differentiation), and proteolytic enzymes such as calpain. With many of these correlations, a genetic link is possible, but likelihood of a type I error is strong. Single nucleotide polymorphisms (SNPs) linked to multiple sclerosis appear in the IL-1, IL- 2 receptor, IL-7 receptor alpha chain, T cell receptor-related SH2D2A, CD24 costimulatory and antigen presentation molecule, CD58 adhesion molecule, IFN-gamma, IFN-gamma receptor (debated), interferon regulatory factor-5 (IRF-5), MxA, brain-derived neurotrophic factor (BDNF), RAGE, chemokines (CCL3, CCL15, and others), tissue plasminogen activator, GPC5 and KIF1B (axonal transport of mitochondria and synaptic vesicles), mitochondrial complex I, free radical scavengers (paraoxonase I), and anti-glycation (glyoxalase I). SNP links are absent for interferon regulatory factor 1, bax, bcl-2, bcl-x, and p53. The IL-7 PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 33 of 123 receptor alpha link is weak, but altered functions could be important in a subset of patients, as IL-7 enhances immunity and the receptor chain is upregulated by steroids, tumor necrosis factor, and type I interferons. Some genes modify the course of multiple sclerosis (This does not equate to linkage with the presence of the disease, or susceptibility). These genes affect immune regulation and glial or neuronal vulnerability. Three percent of Europeans have a homozygous deletion of ciliary neurotrophic factor (CNTF), a growth factor for neurons (Linker et al 2001). In this group, the disease is more severe and onset is earlier (Giess et al 2002). Mice lacking ciliary neurotrophic factor or leukemia inhibitory factor (LIF) have worse experimental allergic encephalomyelitis. ApoE4 may be more common in progressive forms of multiple sclerosis and auger cognitive impairment, a faster rate of disability progression, and more MRI destruction, although some studies and a large meta-analysis find no link. Monocytes expressing the chemokine receptor, CCR5, accumulate in multiple sclerosis lesions, and CCR5+ T cells correlate with MRI lesions. A mutation of the receptor, CCR5-delta 32, (homozygous in 1% and heterozygous in 13% of Caucasians) protects against HIV infection as well as severe rheumatoid arthritis (Marmor et al 2001). This mutation is associated with multiple sclerosis (Favorova et al 2002) and slows progression (Kantor et al 2003). Other putative or unconfirmed genetic links to the course of multiple sclerosis include the IL-1beta receptor and IL-1 receptor antagonist, transforming growth factor-beta, immunoglobulin Fc receptors, CD24, CTLA-4, alpha B-crystallin (linked to progression), and phenylethanolamine N-methyl transferase (converts norepinephrine to epinephrine). Genetic or environmental control of response to target antigens. Antibody response to certain viruses, particularly measles, is increased. Antiviral responses are probably not specific for a single inciting agent, as they vary among plaques and among patients (Mattson et al 1980). Excessive antibody responses may be part of the immune dysregulation that characterizes multiple sclerosis. Nonspecific activation of B cells and exposure to CNS antigens are potential driving factors. The apparent increase in anti-virus antibody responses could simply be due to a nonspecific rise in all titers, making it easier to detect the antibodies. There is a significant increase of autoantibodies to 2,3 cyclic nucleotide 3 phosphodiesterase (IgM), alpha B- and alpha A-crystallin (anti-inflammatory), aquaporin-4 (Devic variant), cardiolipin, contactin-2/TAG-1 or contactin/TIP30 of the juxtaparanodal domain (rats), DNA, galactocerebroside, gangliosides, glial fibrillary acidic protein (GFAP; in secondary progressive multiple sclerosis, strong correlation with clinical deficits), glyceraldehyde-3-phosphate dehydrogenase (GAPDH, linked to fatigue), glycopeptides, heat shock proteins (60 and 90), myelin proteins (MAG, MBP, MOG, OSP, phosphatidylcholine, and PLP), neurofilament light chains (axons), neutrophil cytoplasmic antigen, NG-2 (AN-2), Nogo (debated), nuclear antigens, proteasomes, transaldolase, thyroid microsomal antigens, smooth muscle, and thyroglobulin (Reindl et al 2006). Elevations are most common in progressive forms of multiple sclerosis (Spadaro et al 1999). There are reports of excessive responses to chlamydia. IFN-beta does not induce autoantibodies, but interferon therapy on a background of autoantibodies is more likely to lead to neutralizing antibodies to interferon. Excessive T-cell reactions to a variety of brain antigens approach the threshold of statistical significance. This might be expected in a chronic inflammatory disease of the central nervous system and does not prove causation. Myelin basic protein-reactive T cells are more common than in controls, especially when high avidity cells are detected with low, physiologically relevant levels of myelin basic protein (Bielekova et al 2004). However, myelin basic protein-reactive cells are equivalent between patients and their normal family members (Fredrikson et al 1994), maybe reflecting familial HLA-regulated responses to antigens. Cytokine production in both innate and adaptive immunity is hereditary and predicts the type of multiple sclerosis. Th1 responses are strongly linked in families, with 0.8 to 0.9 hereditability. In healthy family members of patients, lipopolysaccharide-stimulated IL-10 is reduced by 12%, and tumor necrosis factor-alpha is increased by 10% compared to multiple sclerosis-free families. Low IL-10 plus high tumor necrosis factor-alpha in a family predicts a PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 34 of 123 4-fold increased risk of developing relapsing or remitting multiple sclerosis, and an 8-fold increase of relapsing-remitting over primary progressive multiple sclerosis (de Jong et al 2000). Environmental influences. Migration studies show that environment determines some of the risk for multiple sclerosis (Hogancamp et al 1997). Migrants to a low incidence area have a smaller risk of developing multiple sclerosis than if they had remained in situ (Ebers and Sadovnick 1993). Asians and Latinos maintain their low risk after migration (Detels et al 1977; Ebers and Sadovnick 1993). People who migrate from a low incidence area to a high incidence area before the age of 15 years have a high risk of developing multiple sclerosis. After the age of 15, migration does not affect the risk of developing multiple sclerosis, although not all studies agree. The ratio of “Asian” (prominent optic nerve and spinal cord demyelination) to “Western” clinical phenotypes has changed in Japan from 2:1 in patients who were born in the 1920s to 1:4 in patients born in the 1970s. This suggests environmental alterations have modified the form of multiple sclerosis (Kira et al 1999). Canine distemper virus, related to measles, or other viruses carried by small house pets were once implicated, but the association was a result of recall bias. In the Faroe Islands, 4 epidemics of multiple sclerosis appeared after British troops occupied the islands in 1940 through 1944. Multiple sclerosis onset was attributed to a virus carried by the British. The virus required prolonged exposure (2 years) in people 11 to 45 years old, and the agent is theorized to cause multiple sclerosis 5 to 8 years after exposure (Kurtzke et al 1993). It is also possible that contact with the multiple sclerosis agent at an early age (0 to 3 years old) is protective; Faroese born between 1941 and 1945 do not have multiple sclerosis (Cooke 1990). Virus infections sometimes trigger exacerbations of multiple sclerosis. One third of patients with upper respiratory infections will have an exacerbation (Sibley et al 1985; Panitch et al 1991; Correale et al 2006) and one third develops new MRI lesions during the “at risk” period, especially in early multiple sclerosis (Sibley 2001). Picornaviruses and perhaps all rhinoviruses may be the most potent triggers. Nonetheless, virus infections decrease by 20% to 50% in multiple sclerosis (Sibley et al 1985), especially when the disease becomes progressive. Faster progression correlates with fewer virus infections (Sibley 2001). Dysregulated interferon responses are suspect (Feng et al 2002a). High antibody titers to canine distemper virus correlate with a 5-fold increased risk of multiple sclerosis, but many patients have not been exposed. Epstein-Barr virus titers are also elevated, but Epstein-Barr virus in brain lesions has not been confirmed. Bacterial infections increase exacerbations by 3-fold (Rapp et al 1995; Correale et al 2006) although some believe virus infections are more likely to trigger true exacerbations. Smokers may induce multiple sclerosis in themselves and their children. Smokers have a 60% increase in exacerbations, possibly from chronic bronchitis and immune activation, but there is no increase in progression. Interferon therapy does not reduce virus infection rates, but it prevents virus infections from triggering exacerbations (Panitch 1994). There seems to be no effect of interferon-neutralizing antibodies on infections. Multiple sclerosis is not transmitted vertically (breast milk), through transfusions, or conjugally. Doctors, nurses, and spouses of patients do not have an increased incidence of multiple sclerosis. This lack of transmission argues against known viral or retroviral infections. Environmental antigens and age shape immune responses. A dirty environment (ie, viral and bacterial exposure) allows transgenic mice (with V-beta-8.2, V-alpha-2.3, myelin basic protein-specific T cell antigen receptor genes) to develop experimental allergic encephalomyelitis. However, no lesions develop in transgenic mice raised in a clean, specific pathogen-free facility (Goverman et al 1993). Moreover, it is very difficult to induce experimental allergic encephalomyelitis in wild mice from a non-laboratory environment. In humans, all environments contain pathogens, but the type and timing of exposure could affect immunity as well as tolerance. Parasites and microbiome richness are associated with balanced selection of interleukin polymorphisms that are effective against viruses and bacteria. Exposure to infant siblings during the first 6 years of life decreases the incidence of PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 35 of 123 multiple sclerosis by up to 8-fold (Ponsonby et al 2005). Multiple sclerosis patients generally have more education and higher socioeconomic status than average. As a corollary, sanitation may be better, and childhood infections occur later in patients than in the general population (Alter et al 1986; Delasnerie-Laupretre and Alperovitch 1990). Regions with a high incidence of multiple sclerosis have a low incidence of hepatitis B and schistosomes. This suggests that a strong immune response to less-frequent viruses triggers an autoimmune or bystander reaction in multiple sclerosis. "Clean" environments (in man this may mean exposure to pathogens late in childhood) seem to predispose one to multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease—the “hygiene hypothesis.” Antibiotics can have a prolonged effect on some taxa of gut microbiota. They reduce complexity of the microbiome in mice and shift immunity from a mix of Th17 and T- regulatory cells to one of Th17 predominance. The intestinal microflora is a diverse ecosystem, and most of its bacterial RNA sequences are from novel uncultivated microorganisms. Toll-like receptors on immune cells in the gut are activated by intestinal microbes, leading to tolerance of food antigens, less inflammatory bowel disease, and possibly to altered immune responses in multiple sclerosis. Some microbiota induce IL-10-secreting regulatory T cells, others induce Th17 or Th1 proinflammatory cells (Ivanov et al 2008). Stress, antibiotics, opiates, and ischemia all increase virulence of gut flora (Alverdy et al 2005) and induce IL-17 and tumor necrosis factor. Dental caries correlate with higher incidence of multiple sclerosis. Periodontal disease bacteria increase the severity of experimental allergic encephalomyelitis. Some bacteria, “probiotics,” as well as parasitic infestation with helminths induce Th2 responses and reduce the severity of experimental colitis as well as human ulcerative colitis and Crohn disease. Infestation with the parasites may prevent multiple sclerosis from developing (Fleming and Cook 2006). A trial is in progress using ova from Trichuris trichiuria, the pork whipworm. Parasites induce eosinophilia, but also regulatory T and B cells and regulatory macrophages, plus secretion of IL-4 and IL-10 and transforming growth factor-beta. Parasites also reduce secretion of IFN-gamma and IL-12 and reduce new MRI lesions, clinical progression, and attack frequency 20-fold (Correale and Farez 2007). Oral tolerance with myelin basic protein antigens does not affect the course of multiple sclerosis, but the richer antigenic repertoire of parasites and probiotics could have benefit. Seasonal variation in activity of multiple sclerosis differs in various locales (Goodkin and Hertsgaard 1989), perhaps related to vitamin D levels or virus exposure. In autumn and winter, IFN-gamma production by activated mononuclear cells is increased in multiple sclerosis patients compared to controls (Balashov et al 1998), but this does not correlate with MRI lesions (Killestein et al 2002b). MRI activity peaks in late springtime (Auer et al 2000). Vitamin D affects the onset and the course of multiple sclerosis. The provitamin 7- dehydrocholesterol is synthesized in the skin. Ultraviolet sunlight converts it to vitamin D3 (cholecalciferol). This compound leaves the skin to be further activated in liver and then in renal mitochondria to calcitriol (1,25(OH)2; cholecalciferol; vitamin D2). Foods that contain vitamin D are fatty seafood, egg yolks, and chanterelle mushrooms. Serum vitamin D levels fluctuate with the seasons, possibly linked to the May/November birth-month ratio of 1.43 for development of multiple sclerosis (Sadovnick et al 2007). More people with multiple sclerosis are born in the springtime than in the fall, suggesting a vitamin D effect on the fetus. Vitamin D activates cAMP, which inhibits inflammation. It also induces regulatory T cells (Ghoreishi et al 2009); regulatory T cells migrate from the mother into fetal lymph nodes (Mold et al 2008), so an effect of sunlight during pregnancy is possible. Tasmanian children exposed to large amounts of sunlight, especially in winter, as well as white United States soldiers are one third as likely to develop multiple sclerosis later in life (van der Mei 2003). Subjects with darker buttock skin (presumably not exposed to sunlight, thus, a measure of genetic background) were less likely to develop multiple sclerosis. Whites have higher vitamin D levels than blacks, and levels in whites correlate with resistance to development of multiple sclerosis. Fish consumption, outdoor work, and rural life lowers PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 36 of 123 multiple sclerosis mortality. Nurses taking vitamin D supplements (greater than or equal to 400 IU daily) are 40% less likely to develop multiple sclerosis (Munger et al 2004; Ponsonby et al 2005), though their lifestyle could differ from those without vitamin D supplements. Similar correlations are seen in Norway (Kampman and Steffensen 2010). Women shrouded for religious reasons develop osteoporosis, especially in Northern European countries. Lack of sunlight could increase the incidence of multiple sclerosis in these women. Multiple sclerosis patients have low vitamin D levels and demineralized bone due to a combination of fear of the suns heat, treatment with antiepileptics for pain, immobility, and possibly alterations in interferon responses and sympathetic innervation of bone (interferon therapy enhances bone formation; depression and sympathetic hyperactivity is linked to osteoporosis). Vitamin D metabolic pathways genes do not correlate with multiple sclerosis risk. Vitamin D increases intestinal calcium uptake and promotes bone mineralization. Receptors for vitamin D, vitamin A, thyroid hormone, numerous “orphan receptors,” and the peroxisome proliferator-activated receptor are similar. Vitamin D receptors increase on T cells that are activated with mitogens plus vitamin D3. Vitamin D inhibits CD4 T cell proliferation. CD8 cells express 2- to 3-fold more receptors than CD4 cells, but effects of vitamin D on CD8 cells are unknown. Vitamin D is immunosuppressive. It induces IL-4, transforming growth factor-beta, and regulatory CD4 T cells, and it inhibits production of IL-2, IL-12, IFN-gamma, TNF-alpha, and function of Th1 and type I dendritic cells. It inhibits onset (more in females) and relapses of experimental allergic encephalomyelitis via an IL-10 pathway. Ultraviolet radiation and sunburn are strong inducers of IL-10 and Th2 responses, and sunburn can block immune responses to vaccination and various antigens. It is unknown whether rapid fluctuations in IL-10 affect the course of multiple sclerosis. In contrast, melatonin induces IL-12 and IL-18, leading to Th1 responses and worsening experimental allergic encephalomyelitis. Other putative environmental factors that modify multiple sclerosis activity include in vitro fertilization (LHRH agonists), exposure to wool or sheep, and consumption of smoked sausage or fresh cow milk (the milk protein, butyrophilin, shares antigens with myelin oligodendrocyte glycoprotein). A high socioeconomic status confounds some of these factors (Ben-Shlomo 1992). Regular smoking doubles the risk of having multiple sclerosis; men are more susceptible than women, and adolescence may be a critical period of susceptibility to smoking effects on multiple sclerosis. A diet low in saturated fats (the Swank diet), or treatment with evening primrose oil (rich in linoleic and gamma-linolenic acids) may modestly lower the rate of exacerbations (Dworkin et al 1984). It appears to add to the benefit of interferon and glatiramer therapy. Leptin, made by adipocytes, is proinflammatory and is increased in multiple sclerosis (Matarese et al 2010). Association with autoimmune diseases. Most autoimmune diseases are not associated with multiple sclerosis (Reder and Arnason 1985; Wynn et al 1989). There are scattered reports of multiple sclerosis coexisting with Crohn disease or ulcerative colitis and possibly with myasthenia gravis, type I diabetes, narcolepsy (also HLA-DR2-linked), and thyroid disease, but other associations are lacking. This suggests that the etiology of multiple sclerosis differs from most autoimmune diseases. Therapy with alemtuzumab (anti-CD52, Campath-1H) induces antithyroid antibodies, presumably by altering immune regulation. Importantly, the demyelinating variant of multiple sclerosis, Devic disease/neuromyelitis optica, is highly associated with autoimmune diseases (10-fold increase). Epidemiological mixing of multiple sclerosis with this variant leads to spurious associations with other autoimmune diseases. Some diseases are infrequent in multiple sclerosis. Asthma and allergies are half as common as in the general population. Cancer is reduced to two thirds or three fourths in multiple sclerosis compared to controls (Sadovnick et al 1992; Koch-Henriksen et al 1998; Bahmanyar et al 2009). During trials of subcutaneous IFN-beta-1a, the reported to expected ratio of cancer was 1:11, with 50% more cases in the placebo groups than in the interferon groups (Sandberg-Wollheim et al 2011). Multiple sclerosis patients have low uric acid levels and rarely develop gout. Uric acid ameliorates experimental allergic encephalomyelitis. Therapeutic attempts to raise uric acid in multiple sclerosis are underway. There is a strong PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 37 of 123 negative association with Down syndrome, possibly because chromosome 21 codes for type I interferon receptors and S100b (Weilbach and Toyka 2002). Lupus is rare in multiple sclerosis. Lupus has excessive interferon production and responses to interferon compared to low serum levels and interferon resistance in multiple sclerosis (Feng et al 2009b; Javed and Reder 2006). Prevention There is no known cause for multiple sclerosis. Viruses are often implicated as the primary cause, but in no case has this been substantiated. There is no apparent risk of transmitting multiple sclerosis to spouses or medical personnel. Symptoms and exacerbations frequently follow virus infections (Sibley et al 1985; Panitch et al 1991; Edwards et al 1998), bacterial and bladder infections (Rapp et al 1995), prostatitis, and decayed or missing teeth (Craelius 1978). Exacerbations during systemic infections are twice as likely to lead to a sustained clinical deficit, though there is no difference on MRI (Buljevac et al 2002). It is wise to prevent immune activation with good bladder and dental hygiene and by minimizing exposure to people with upper respiratory infections. There is a 1.6 relative risk of multiple sclerosis in smokers (Hernan et al 2001). Smokers are more likely to develop a progressive course (Durfee et al 2008), possibly from an effect on the blood-brain barrier or an influence of chronic bronchitis. Vaccinations and immunizations usually do not cause exacerbations of multiple sclerosis (Sibley et al 1985; Ascherio et al 2001). Measles, mumps, rubella, and human papilloma virus vaccines are considered safe. Tetanus vaccination is associated with a reduced chance of developing multiple sclerosis (0.67) (Hernan et al 2006). Influenza vaccination should be encouraged in order to obviate the risk of exacerbation following virus infections. There is debate about exacerbations from recombinant hepatitis B vaccine (Hernan et al 2004). Live virus vaccines, however, are likely to induce a cytokine storm and should be administered with caution. Yellow fever vaccinations, for instance, increase the risk of exacerbations 9- fold in relapsing-remitting multiple sclerosis. Diet and environment appear to affect the development and course of multiple sclerosis. In Norway, cod liver oil and fish intake (omega-3 fatty acids) reduce risk of developing multiple sclerosis (Kampman and Steffensen 2010). High risk groups such as unaffected relatives of multiple sclerosis patients could benefit from a dirty environment, a diet rich in polyunsaturated fats (evening primrose and flaxseed oil), sunlight, and vitamin D (Bielby personal communication 2005;(Ponsonby et al 2005). Theoretical reasons exist to avoid several drugs, but therapeutic need may outweigh theory. Cimetidine, a histamine H2 blocker (Anlar 1993), and melatonin (Constantinescu 1995) enhance immune function, which could be detrimental in multiple sclerosis. Beta- adrenergic blockers inhibit suppressor cell function (Karaszewski et al 1991). Occasional patients worsen with fluoroquinolone antibiotics (eg, ciprofloxacin), which induce inflammatory cytokines in addition to their antibacterial effects (Riesbeck 2002). Some patients are extremely sensitive to low doses of carbamazepine. Weakness is probably caused by blockade of Na+ channels in demyelinated axons. Stress does not provoke attacks of multiple sclerosis in controlled trials. However, there are widespread anecdotes of stress worsening multiple sclerosis. Exercise, physical therapy, social contacts, better diet, and drug treatment of symptoms can improve quality of life. All of these interventions allow patients to realize that they can control some of the symptoms of multiple sclerosis. Differential diagnosis Monosymptomatic illnesses from focal or multifocal insults can mimic the first attack of multiple sclerosis and cover a wide spectrum of neurologic diseases. Postinfectious and postvaccinal encephalomyelitis follow inflammation-induced sensitization PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 38 of 123 to myelin antigens. Postvaccinal or postinfectious reactions cause inflammatory demyelination that is localized (eg, transverse myelitis, optic neuritis) or diffuse (eg, encephalomyelitis). The symptoms often develop after upper respiratory tract infections (usually viral or mycoplasma) or vaccinations, leading to acute disseminated encephalomyelitis. Oligoclonal bands in CSF are less common than in multiple sclerosis and, if present, often disappear. MRI lesions should all be of the same age, but several weeks after onset, partially-resolved lesions can appear to be different ages. The perivascular inflammation and demyelination is similar to the pathology of multiple sclerosis, but these fever-associated disorders are monophasic (Tselis and Lisak 1995). Experimental allergic encephalomyelitis is the animal model. If multiple sclerosis patients are vaccinated with porcine myelin basic protein, they can develop postinfectious encephalomyelitis. Nonrecurring demyelinating disease suggests (1) a primary response to the antigen and (2) that myelin basic protein does not trigger multiple sclerosis. Recurrent symptoms that mimic relapsing-remitting multiple sclerosis may be caused by focal repetitive insults such as transient ischemic attacks or exacerbations of connective tissue disease. Vascular insults usually have a rapid onset (Hamamcioglu and Reder 2005). periventricular sites, are not in cerebellar outflow pathways, and do not spare subcortical U fibers. Some authors have implicated anticardiolipin antibodies and granulomatous angiitis in multiple sclerosis-like syndromes. CADASIL, Binswanger disease, hemiplegic migraine, Sjögren syndrome, and Behçet disease can cause episodic, multifocal central nervous system lesions that can be confused with multiple sclerosis clinically and on MRI. Progressive cord symptoms can be caused by subacute combined degeneration, adrenoleukodystrophy, chronic fatigue syndrome, and tropical spastic paraparesis from human T cell lymphotropic virus infection. Damage from a spinal dural arteriovenous fistula, cavernous hemangioma, or tumor can cause indolent cord symptoms. Progressive symptoms also suggest metabolic problems (copper, vitamin B12, vitamin E, or folate deficiency—often from complications of gastric bypass surgery), genetic disorders (adrenoleukodystrophy, sometimes with a late inflammatory phase; hereditary spastic paraplegia; Wilson disease), and mitochondrial disorders (Natowicz and Bejjani 1994). Magnetic resonance spectroscopy can help differentiate plaques from central nervous system tumors. “Phenocopies” of multiple sclerosis appear on MRI scans. CADASIL, hypertensive vascular disease, Susac syndrome, leukodystrophies, vanishing white matter disease, Alexander disease, sarcoid, and migraine all cause MRI changes that overlap with the appearance of multiple sclerosis. Transverse myelitis can be an isolated event or the first sign of multiple sclerosis or neuromyelitis optica. The cord lesion in multiple sclerosis is more often partial, patchy, and asymmetric, and not symmetrical and bilateral as in idiopathic transverse myelitis. MRI abnormalities and local demyelination may be extensive in transverse myelitis, but CSF abnormalities are less common than in multiple sclerosis. Optic neuritis is often the first sign of multiple sclerosis. Isolated optic neuritis involves only the optic nerves, without dissemination of other lesions in time and space. CSF oligoclonal bands are less common than in multiple sclerosis. However, one third of patients with optic neuritis will eventually develop multiple sclerosis. Demyelination of the optic nerve is often pronounced in isolated optic neuritis. Optic neuritis must be differentiated from ischemic optic neuropathy, increased intracranial pressure causing papilledema, vitamin B12 deficiency, vasculitis (temporal arteritis), viral infections, and Devic disease. Conditions that can be confused with multiple sclerosis: • Acoustic neuroma. Nerves VIII, V, and VII are compressed by slowly expanding neuroma or meningioma. • Acute disseminated encephalomyelitis (ADEM) often follows an infection or vaccination (postinfectious or postvaccinal encephalomyelitis). ADEM is more likely to occur in children and to have a polysymptomatic or multifocal presentation, with systemic symptoms that are uncommon in multiple sclerosis. Patients develop sudden pyramidal symptoms, bilateral optic neuritis (unilateral optic neuritis is seldom or never seen and suggests multiple PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 39 of 123 sclerosis). Importantly, there is also fever, headache, vomiting, shooting pains, meningismus, encephalopathy, altered consciousness, EEG changes, and blood and CSF pleocytosis. Oligoclonal bands in CSF are uncommon (0% to 30%), but protein is often greater than 100 mg/dl. MRI lesions are large, “fluffy,” enhancing, often in ring patterns, often in a diffuse bilateral pattern, often in the corpus callosum and thalamus (thalamic T2 lesions are rare in multiple sclerosis), seldom in a Dawson finger shape, and less often periventricular and seldom cause T1 black holes (Dale et al 2000). Macrophages and sleeves of (later) demyelination surround venules in many small and large inflammatory lesions. Axons are relatively preserved. Myelin loss is more pronounced in multiple sclerosis than in acute disseminated encephalomyelitis and experimental allergic encephalomyelitis. All lesions are approximately the same age in the initial attack. A storm of many cytokines appears, with high granulocyte colony stimulating factor but no IL-17. ADEM is usually monophasic, and MRI lesions are of similar age. This basic form lasts up to 3 months. Symptoms can fluctuate, and MRI may transiently show Gd-enhancing and nonenhancing lesions as ADEM evolves. If similar lesions reappear 3 months later, it is termed “recurrent ADEM.” In “multiphasic ADEM,” new brain areas are involved during a second episode. It is possible that abrupt discontinuation of steroid therapy allows recrudescent lesions. Therapy with high-dose glucocorticoids and then a prolonged taper is advised in ADEM. There is more genetic linkage in multiple sclerosis. Multiple sclerosis eventually develops in 20% to 33% of ADEM patients. Thus, most patients with ADEM (66% to 80%) do not develop multiple sclerosis and should not be treated for multiple sclerosis when oligoclonal bands are negative. • Acute hemorrhagic leukoencephalitis appears to be a more severe form of ADEM but may have a distinct etiology. • Acute ischemic optic neuropathy has a sudden onset, may progress over several days with an unremitting course, and is typically seen in patients 60 to 100 years old. Pain is uncommon. Visual loss involves the central fixation area but is altitudinal, with sharp borders. Ischemic optic neuropathy is likely to cause disc swelling, pallor, arterial attenuation, hemorrhage, and permanent loss of vision. • Acute necrotizing encephalopathy of childhood, seen in Asian countries, follows several days of fever with a respiratory or gastrointestinal virus infection. Lesions are hypointense on T1 and hyperintense on T2 MRI in the bilateral thalami (classic for this condition) but are not present in the basal ganglia and cerebral cortex. • Aminoaciduria: 3-methylglutaconic aciduria type I causes adult onset leukoencephalopathy. • Amyloid angiopathy causes cerebral microhemorrhages but also a leukoencephalopathy that involves the U-fibers. Iron in lesions can be seen on T2-weighted MRI. • Aneurysm of intracranial blood vessels. • Atopic myelitis, idiopathic eosinophilic myelitis, hyperIgEaemic myelitis. • Autoimmune thyroid disease--often familial, causes tremor, seizures, and predominant cord involvement. • Balo concentric sclerosis has large concentric lesions with centrifugal waves of demyelination and remyelination. There is loss of myelin-associated glycoprotein and oligodendrocyte apoptosis. Demyelinated areas are high in nitric oxide synthetase (iNOS). Hypoxic conditioning may explain the rings, where sublethal hypoxia provides resistance to later injury. In the outer edge of preserved tissue, hypoxia-inducible factor1alpha (HIF) is increased (Stadelmann et al 2005), as it is in normal-appearing white matter in multiple sclerosis. • Behçet disease – CSF pleocytosis, large MRI lesions in upper brainstem and basal ganglia, occasional punctuate parenchymal enhancement. Behçet disease causes intermittent cranial nerve deficits, but it is associated with genital and oral ulcers, uveitis, and meningoencephalitis. Biopsies show polymorphonuclear cells and eosinophils surrounding arterioles. Optic neuropathy is relatively rare in Behçet disease. PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 40 of 123 • CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), caused by a mutation of the Notch gene. Notch affects oligodendrocyte maturation and lymphocyte development. The intermittent strokes in midlife on a background of patchy MRI T1 holes plus diffuse increased white matter T2 signal can be confused with multiple sclerosis. T2 lesions are large and confluent and often significantly involve the anterior temporal lobes. It is diagnosed with skin biopsy (forearm) for granular osmiophilic material in arterioles, or with DNA analysis for the Notch mutation. • Cancer--primary and secondary brain tumors. Hemophagocytic lymphohistiocytosis, Langerhans cell histiocytosis, and neoplastic angioendotheliosis can be confused with multiple sclerosis. • Carcinomatous polyradiculopathy (typically with adenocarcinoma of breast and lung, lymphoma, or melanoma). • Cavernous sinus thrombosis affects cranial nerves III, IV, V, and VI. • Celiac antibodies are not increased in multiple sclerosis, but celiac disease can cause myelopathy and encephalopathy. • Cerebellar degeneration and Friedreich ataxia can mimic progressive cord symptoms. • Cerebrotendinous xanthomatosis (progressive myelopathy in a young patient, but with cataracts, diarrhea, ankle tendon xanthomas, and cerebellar dentate lesions on MRI). • Cervical compression (disc, spondylosis, or tumor) can cause a progressive paraparesis, gait disorder, and bladder dysfunction. • Charcot-Marie-Tooth disease (brain MRI lesions and progressive course). • Chemotherapy can cause a leukoencephalopathy (Ara-C, cisplatin, 5-fluorouracil, 5- florauracil+levamisol); neurotoxicity is worse with radiotherapy and progresses over time. • Chronic inflammatory demyelinating polyradiculoneuropathy with optic neuritis. • Cogan syndrome (vestibulo-auditory problems). • Congenital adrenal hyperplasia (diffuse brain white matter and corpus callosum abnormalities). • Connective tissue diseases can mimic multiple sclerosis. These diseases can cause vasculitis with neuropathy, cranial nerve damage, and CNS destruction. Systemic lupus erythematosus causes a severe, progressive thoracic myelopathy also called “lupoid sclerosis” or “acute lupus myelopathy.” It is acute or subacute with scattered white matter lesions in the cortical/subcortical junction but can affect gray and white matter. Twenty percent of patients have optic neuropathy in one or both eyes. When the cord is involved, the damage extends over many segments or the entire cord. Most patients with systemic lupus erythematosus, however, have no cord lesions. Treatment of connective tissue disorders diametrically differs from multiple sclerosis therapy, as interferons could cause worsening. (Sjögren syndrome is described below.) Craniofacial scleroderma is associated with bilateral-enhancing MRI lesions and oligoclonal bands. • Copper deficiency causes a progressive myelopathy and neuropathy, often related to gastrointestinal disorders, post-gastric bypass, and zinc excess (similar to the cuprizone model in rodents). • Cortical blindness must be discriminated from optic neuritis. • Cranial arteritis can affect the posterior optic nerve, without papilledema, in 70- to 80- year-old patients. It is associated with devastating visual loss; temporal pain, fever, weight loss, headache, fever, elevated sedimentation rate, and polymyalgia rheumatica. • Devic disease, or neuromyelitis optica, is a demyelinating, sometimes necrotic, inflammatory disease of the spinal cord and the optic nerves. Attacks are more severe and more frequent than in multiple sclerosis. In Asia and South America and in Native American Indians, Devic disease is more common than multiple sclerosis, and IL-17 may play a role in pathology (Ishizu et al 2005). In Europe and the United States, multiple sclerosis is far more common. Devic disease traditionally accounted for less than 1% of Occidental demyelinating disease, but a test (NMO-IgG) suggests that approximately 5% of “multiple sclerosis” cases with optic neuritis and longitudinal cord lesions are the Devic variant. This IgG1 neuromyelitis optica antibody recognizes aquaporin-4, a water transport channel that is localized in astrocyte foot processes over paranodal axons and near blood vessels. PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 41 of 123 Aquaporin-4 is present in high levels in renal tubules, possibly explaining the low glomerular filtration rate in progressive multiple sclerosis (Calabresi et al 2002). Antibodies to aquaporin predict development of Devic disease and a more severe course. Devic disease is associated with connective tissue disease, rheumatoid arthritis, pernicious anemia, hypothyroidism and antibodies to thyroid antigen, and myasthenia gravis. The odds ratio of having another autoimmune disease is 10. Linkage of multiple sclerosis to these autoimmune disorders becomes unlikely when the Devic disease cases are eliminated from the “multiple sclerosis” pool. CNS Sjögren disease is similar to Devic disease (detailed below). Only 40% of CNS Sjögren patients are NMO-IgG positive, although 85% have positive minor salivary gland biopsies. Devic disease is monophasic in one third of patients and relapsing in two thirds (Wingerchuk et al 1999). Devic disease has severe and frequent relapses and does not become progressive. The damage in the optic nerves and cord is diffuse, often total, and includes significant axonal loss. Lesions are sometimes cavitary and necrotic and are often hypointense on T1-weighted MRI scans. The spinal lesions extend over more than 2 vertebral segments and are usually cervical. Cervical MRI images in Devic disease are similar to CNS Sjögren disease. In the strict definition, MRI scans of the brain are normal; there is no demyelination in the brain, brainstem, or cerebellum (Mandler et al 1993). However, 20% later evince large brainstem and hypothalamic lesions, sometimes enhancing. CSF protein and neurofilament heavy chain levels are elevated. Seventy-five percent of patients have CSF pleocytosis, and 35% have greater than 50 cells/mm3; polymorphonuclear cells are often present. CSF IgG synthesis is usually normal, and CSF IgG1 is not elevated (it is elevated in multiple sclerosis). Oligoclonal bands are less common (40% or less) than in multiple sclerosis (97%) and can disappear over time. Lesions in parenchyma and meninges have more IgM than IgG. There are few T cells but prominent eosinophils and granulocytes, likely related to excess IL-17. Aquaporin-4 is modulated off the astrocyte foot processes in Devic disease but not in multiple sclerosis. Although this antibody is present at all times, the attacks are intermittent. Rituximab was therapeutic in a series of 8 patients (Cree et al 2005). Plasmapheresis may also reduce symptoms. Interferon therapy may cause worsening (Javed and Reder 2006; Wang et al 2006; Warabi et al 2007). • Eales disease, a syndrome of retinal perivasculitis and recurrent intraocular hemorrhages, is infrequently associated with neurologic abnormalities (7 of 17 patients). • Folate deficiency can cause encephalopathy and spastic paraparesis. • Gadolinium encephalopathy (MRI lesions). • Genetic—see storage disease. • Guillain-Barré Syndrome, Fisher variant, affects cranial nerves and eye movements. There are rare cases of this disorder and chronic inflammatory demyelinating polyneuropathy along with multiple sclerosis. • Hemophagocytic lymphohistiocytosis (associated with Epstein-Barr virus or a perforin mutation) loss of function prevents termination of immune response and inflammation of brain and peripheral nerves. • Hepatic encephalopathy, with symmetric high MRI T1 signal in the globi pallidi, likely from manganese deposition. • Hereditary spastic paraplegia (vs primary progressive multiple sclerosis). • Hypothyroidism--can cause constipation and fatigue even though the motivation to act remains. In multiple sclerosis, abulia is sometimes associated with fatigue. • Increased intracranial pressure and normal pressure hydrocephalus can cause visual and long tract findings. • Infection. Tuberculosis, tuberculomas, sarcoidosis, fungus such as Cryptococcus, syphilis, Lyme disease (Borrelia burgdorferi), chlamydia, mycoplasma, toxoplasmosis, brucellosis (abscesses, occasionally intramedullary, can involve spinal cord), familial Mediterranean fever, Listeria monocytogenes (cervical cord lesions), CNS Whipple disease, toxocariasis, purulent leptomeningitis, or intraocular inflammation. Inflammation of the paranasal sinuses seldom causes optic nerve inflammation. PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 42 of 123 • Inflammatory bowel disease with brain lesions. • Leber hereditary optic neuropathy is a hereditary, maternally transmitted mitochondrial disease (base pair 11778 of mitochondrial DNA, causing loss of function of the reduced form of nicotinamide adenine dinucleotide dehydrogenase 4). It causes bilateral, often sequential, visual loss. In females, but not in males, it is sometimes indistinguishable from multiple sclerosis because of associated multiple sclerosis-like symptoms, destructive white mater lesions containing macrophages and CD8 T cells, widespread and periventricular white matter lesions on MRI, abnormal evoked potentials, and sometimes abnormal CSF (Harding et al 1992; Kovacs et al 2005). In men, diffuse white matter lesions are not present, but affected optic nerves show abnormalities on short-term inversion recovery MRI. The symptoms are often unilateral but eventually are bilateral. Visual loss is permanent and untreatable. Although neurons (third order retinal neurons) are the main targets in Leber disease, a parallel mitochondrial defect could theoretically also make oligodendroglia more susceptible to damage in multiple sclerosis. Other ocular disorders include Eales disease and retrobulbar vasculopathy of Susac (Weinshenker and Lucchinetti 1998; Susac et al 2003). • Leukoencephalopathy with vanishing white matter in adults causes slow neurologic deterioration and white matter lesions. Autosomal recessive mutation in eukaryotic initiation factor 2B (eIF2b) increases unfolded proteins. • Lyme disease is occasionally associated with unilateral or bilateral optic neuritis or ischemic optic neuropathy (in addition to retinal vasculitis), internuclear ophthalmoplegia, deafness, and multiple other neurologic signs. • Lymphoma can form white matter MRI lesions. • Maculopathy or macular degeneration. • The Marburg variant of multiple sclerosis has axonal loss and severe widespread diffuse or multifocal demyelination. Lesions can be of different ages and contain massive macrophage and CD8 cell infiltrates; in one case, inflammation preceded the demyelination. Death is within a year. Death in 1 month is frequent, often from brainstem or upper cord lesions. Steroids and chemotherapy prolong life to 3 months; plasmapheresis may be helpful. • Marchiafava-Bignami disease causes demyelination of the corpus callosum; lesions usually involve the medial corpus callosum, and there is clinical hemispheric disconnection. • Metastasis from cancer. • Metronidazole causes transient cerebellar dentate lesions. • Migraine can cause visual disturbances, vertebrobasilar symptoms, and disseminated T2 lesions on MRI. In women, when migraines are frequent and associated with aura, MRIs show small cerebellar infarcts—the location is more lateral than the cerebellar peduncle lesions of multiple sclerosis. Occasionally deep white matter lesions are seen in the centrum semiovale, likely from associated hypertensive disease (Kruit et al 2004). • Miller-Fisher syndrome (subacute ataxia and ophthalmoplegia from Guillain-Barré syndrome). • Mitochondrial disorders. Genetic mitochondrial syndromes can cause strokes, diffuse periventricular T1 holes and T2 white matter lesions, including the spinal cord. Non- syndromic mitochondrial disorders can cause scattered white matter lesions on FLAIR MRI. • Myasthenia gravis can cause diplopia and muscle weakness. • Myotonic dystrophy types 1 and 2 (brain white matter lesions on MRI). • Neoplastic (lymphoma, intravascular lymphoma, primary or metastatic central nervous system tumor; can involve eyes also). • Neuroretinitis. This is a form of papillitis with associated deposits of lipids and protein. These deposits radiate from the macula and form a stellate pattern at the macula or a half star between the macula and the disc. The "macular star" is formed as fluid from leaking disc capillaries accumulates within Henle layer around the fovea. The macular star may take up to 2 weeks to form after the onset of papillitis. The symptoms are similar to those in typical optic neuritis, but neuroretinitis seldom progresses to multiple sclerosis, suggesting that another etiology has been confused with multiple sclerosis. • Nutritional neuropathy includes Jamaican neuropathy and Cuban epidemic neuropathy. • Optic nerve glioma ("benign" glioma of childhood–a pilocytic astrocytoma; malignant PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 43 of 123 glioblastoma is more common in adults). • Orbital pseudotumor with proptosis, pain, and ophthalmoplegia, but infrequent visual loss. • Paraneoplastic (anti-CV2 antibodies for optic neuritis. Also possible are limbic encephalitis, brainstem encephalitis, cerebellar degeneration, and lobar encephalopathy with large MRI lesions). • Parasites can migrate into the CNS and cause focal symptoms and must be excluded in patients from endemic areas, eg, cysticercosis. • Pelizaeus-Mertbacher disease (brain MRI lesions and progressive course), including proteolipid protein-1 mutation. • POLG-1 mutations (mitochondrial DNA polymerase gamma) can cause progressive CNS signs in childhood or late teens. • Porphyria. Hereditary coproporphyria can cause progressive CNS and PNS symptoms. • Posterior reversible leukoencephalopathy (PRES). There is increased T2 MRI signal in white > gray matter. Triggers include eclampsia, acute renal failure, hypertensive encephalopathy, and immunosuppressive drugs such as cyclosporin (high dose) and methotrexate. • Progressive multifocal leukoencephalopathy (PML). There are progressive symptoms such as cognitive loss, occipital visual loss, and hemiparesis. MRI lesions are usually large and rarely enhance. Optic neuritis or cord lesions are very likely. • Progressive necrotizing myelopathy provoked by mycoplasma pneumoniae, m Tb. In rats with experimental allergic encephalomyelitis, it is provoked by tilorone, an IFN-alpha/beta inducer. • Pseudotumor cerebri (visual loss). • Pseudoxanthoma elasticum (brain MRI lesions and vascular disease). • Radiation necrosis. Possibly treated with corticosteroids and hyperbaric oxygen. • Raeder paratrigeminal syndrome is unilateral facial pain in the V1 and V2 branches of the trigeminal nerve; it is associated with ptosis and miosis from a parasellar mass and must be differentiated from trigeminal neuralgia due to multiple sclerosis. • Sarcoidosis can involve single or multiple cranial and peripheral nerves, the brainstem, hypothalamus, and meninges. • Schilder disease (diffuse sclerosis) causes large hemispheral demyelinating lesions. • Sjögren syndrome. When associated with central and peripheral nervous system lesions, classic symptoms (sicca and rheumatic) are less common than in primary Sjögren disease. Serum antibodies to Sjögren syndrome A and B proteins (SSA and SSB) are positive in only one third of patients and are more often negative than in Sjögren disease without neurologic symptoms. A lip or parotid biopsy is needed to clinch the diagnosis (Alexander et al 1986; Sandberg-Wollheim et al 1992; Javed and Reder 2006). In CNS Sjögren syndrome, one third have MRI, CSF, or evoked potential evidence of cerebral abnormalities; one third have longitudinal spinal cord lesions; the rest have optic neuritis and diffuse symptoms such as seizures, cognitive loss, and encephalopathy (Delalande et al 2003). In patients with CNS Sjögren lesions, there are small white matter MRI lesions in two thirds (occasionally in basal ganglia, infrequently in corpus callosum), oligoclonal bands in one third, and abnormal visual evoked potentials in about two thirds (de Seze et al 2003). PNS Sjögren disease can cause sensory ganglionitis, painful sensory neuropathy, and distal sensory-motor axonopathy. Adil Javed has described a new Sjögren-related entity, seen predominantly in young black women. Patients with severe destruction from optic neuritis and longitudinal cervical cord lesions resemble patients with Devic disease, but NMO-IgG levels are negative in 60%. However, minor salivary gland biopsy is positive for Sjögren disease (inflammation grade 4+/4) in 85%, often when SSA and SSB serology is negative (Javed et al 2008). Other autoimmune diseases (myasthenia gravis, primary biliary cirrhosis) are often present. Treatment differs from multiple sclerosis therapy, as interferons may cause worsening. Mycophenolate mofetil provides some benefit, but the best responses are with rituximab (Javed personal communication 2007). • Storage disorders and genetic diseases versus childhood multiple sclerosis. Leukodystrophies are usually confluent and bilateral on MRI. Juvenile metachromatic PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 44 of 123 leukodystrophy and late onset Tay Sachs disease have MRI signatures that could be confused with multiple sclerosis. Also to be considered are adult polyglucosan body disease (glycogen-branching enzyme mutation causes accumulation of polyglucosan bodies throughout the nervous system and cerebral myelin loss), Alexander disease (frontal, cerebellar, brainstem, and spinal cord T2 MRI lesions), childhood ataxia with cerebral hypomyelination (eIF2b mutation), late onset Canavan disease (mutations of aspartoacylase gene, restricted to oligodendrocytes, with accumulation of the substrate molecule N-acetyl- aspartate, NAA), Fabry disease (periventricular lesions, but non-multiple sclerosis clinical symptoms), Pelizaeus-Merzbacher disease (PLP mutation and dysmyelination; “jimpy” mouse is model), Refsum disease (ataxia and MRI lesions), and Wilson disease. • Subacute myelo-optic neuropathy (SMON) from halogenated hydroxyquinolines, including Entero-Vioform, diodoquin, and clioquinol. • Subacute sclerosing panencephalitis (SSPE)--T2 MRI lesions in periventricular and subcortical white matter, but this progressive disorder follows measles infection, with high titers of anti-measles antibodies. • Susac syndrome. Retrobulbar vasculopathy of Susac causes encephalopathy, branch (distal) retinal artery occlusions, and hearing loss (Weinshenker and Lucchinetti 1998). It affects 20- to 40-year-old women and is associated with headaches, hearing loss, tinnitus, pseudobulbar speech, and encephalopathy. There are microangiopathic infarcts in gray and white matter, and bilateral branch artery occlusions in the retina. MRI shows many multifocal white matter lesions of the central corpus callosum, plus lesions in deep gray, posterior fossa, brain parenchyma, and occasionally the leptomeninges. Acute large “snowballs” and multiple older small “punched-out” areas riddle the central corpus callosum (Susac et al 2003). Intravenous immunoglobulin and corticosteroids improve hearing and MRI. • Syphilis also has huge variety in its presentation. • Thyroid ophthalmopathy can cause diplopia. • Tobacco-alcohol amblyopia. • Tolosa-Hunt syndrome. Painful ophthalmoplegia with subacute boring eye pain, palsy of extraocular muscles, V1 sensory loss, sympathetic denervation of pupils, and rapid responses to 100 mg prednisone. • Trauma; direct or after anterofrontal deceleration. • Tuberculomas in the brain parenchyma. • Tuberous sclerosis can cause subcortical tubers that appear in white matter on MRI. • Tumor necrosis factor receptor-1-associated periodic syndrome (TRAPS; familial Hibernian fever) from a mutation in the p55 receptor for TNF occasionally has onset and MRI features of multiple sclerosis (Kumpfel et al 2008). It does not respond or have side effect with multiple sclerosis therapies, but improves with anti-TNF therapy. • Vaccination (polio and possibly influenza). Associations reported in a few papers are likely spurious, as the vast majority of studies find no link. Some find a 3-fold increase in the incidence of multiple sclerosis after vaccination with recombinant hepatitis B vaccine, but not with vaccines against other viruses (Hernan et al 2004), yet others report no increase. Confusion clouds this issue from statistical and reporting problems--combining data on recombinant and nonrecombinant vaccines, written versus computer records, and date of onset versus date of diagnosis. Most experts urge caution with live virus vaccines (measles, mumps, rubella, varicella/zoster, and yellow fever). • Vanishing white matter disease, from a defect in eukaryotic translation factor eIF2B, occurs rarely in adults, with progressive symptoms and white matter lesions on FLAIR MRI. • Vascular disease lesions are usually spherical and tend to be located in the centrum semiovale instead of “fingers” radiating outward from the corpus callosum. Some lesions in hypertensive elderly patients, however, are periventricular and are quite similar to multiple sclerosis lesions. Lacunes are common in the basal ganglia, but not in the corpus callosum. Vascular lesions with aging tend to be smaller and random but sometimes symmetrically involve the periventricular white matter in confluent posterior ischemic damage (Arnold and Matthews 2002). Vascular malformations and cavernous hemangiomas show persistent Gd PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 45 of 123 enhancement. • Vasculitis (temporal arteritis, angiitis, cranial arteritis, Churg-Strauss syndrome). • Viruses or viral encephalitis (measles, mumps, rubella, chickenpox, cytomegalovirus, hepatitis A and B, herpes zoster vasculopathy, HHV-6 encephalomyelitis, acute HIV infection, HTLV-I (also associated with Sjögren syndrome), infectious mononucleosis, Japanese encephalitis (a flavivirus with bilateral thalamic lesions and polio-like flaccid paralysis), post-measles autoimmunity and subacute sclerosing panencephalitis, poliomyelitis (central cord lesions on MRI), West Nile virus (flavivirus) with a polio-like presentation. • Vitamin B12 deficiency causes subacute combined degeneration with centrocecal scotomata, optic atrophy, MRI lesions around the corpus callosum (not Dawson fingers), partially reversible leukoencephalopathy, and long tract signs from cord degeneration. • Vitamin E deficiency causes ataxia, myelopathy, and neuropathy. Diagnostic workup Multiple sclerosis is traditionally described as 2 central nervous system lesions separated in time and space and not caused by other central nervous system disease. These lesions can be detected with a history and neurologic exam--the sine qua non of a diagnosis of multiple sclerosis. MRI and CSF analysis help to confirm the diagnosis (Poser et al 1983; McDonald et al 2001). Each of these are abnormal in more than 95% of definite multiple sclerosis cases. MRI has become essential to rule out conditions that could mimic multiple sclerosis. A standardized brain and cord imaging and reporting protocol from the (Consortium of Multiple Sclerosis Centers) (CSMC) enhances diagnosis, clinical trial assessment, and monitoring of disease activity and damage (Simon et al 2006). Criteria that define “MS” have been revised several times: 2001, 2005, and 2010 (Polman et al 2011). Additional diagnostic criteria now allow diagnosis of multiple sclerosis when new MRI lesions define separation in time and space—ie, a new T2 MRI lesion more than 30 days or enhancement more than 3 months after the initial event (McDonald et al 2001). These criteria are helpful in diagnosing multiple sclerosis in patients after a clinically isolated demyelinating syndrome. However, the broader inclusion criteria for a diagnosis can lead to spurious improvements in prognosis, the “Will Rogers phenomenon” (Sormani et al 2008). This also allows patients with milder disease into recent studies, necessitating larger patient cohorts to see a drug effect. MRI in diagnosis. Early active MRI lesions are typically hyperintense on T2 with a hypointense ring, possibly containing activated macrophages. Some acute plaques enhance with gadolinium, but early on, they can be almost isointense on T2 MRI (Bruck et al 1997). Late active lesions are hyperintense on T2 but are hypointense on T1-weighted images (“black holes”), indicating axonal loss and demyelination. Over 90% of patients with primary progressive disease have brain lesions. T1 MRI and magnetization transfer ratio often show lesions of the corpus callosum and periventricular white matter. Large, fluffy T2 lesions often have preserved axons and repletion of oligodendroglia. Inactive lesions (demyelinated or myelinating) are hypointense on T2 scans and normal or hypointense on T1 scans. There is temporal variation in the duration of enhancement, plus some regional differences interfere with comparison of Gd+ and Gd- lesions. For instance, Gd+ MRI lesions in white matter are easier to see than lesions in the cortical gray matter. This means that 1 Gd+ and 1 Gd- lesion on a single scan cannot be used to pronounce “separation in time” in the diagnosis of multiple sclerosis. However, new criteria at time of first attack allow that Gd- and Gd+ lesions on different scans are strongly suggestive of multiple sclerosis. Certain MRI features are typical of multiple sclerosis, such as multiple ovoid-shaped bright lesions on T2-weighted MRI, abrupt loss of T2 signal at the gray matter (“open ring”), and periventricular lesions, often radiating up from the corpus callosum or out from the ventricle (called “Dawson fingers”), especially near the body and posterior horn of the lateral ventricle; a lesion greater than 5 mm; lesions in the corpus callosum, brainstem, or cortical gray matter; and lesions below the tentorium, especially in the cerebellar peduncle (Offenbacher et al 1993). Perivenular spaces, which do not contain CSF, are also prominent PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 46 of 123 from inflammation (lymphocyte cuffing) (Ge et al 2005). Corpus callosum lesions can also be caused by vascular disease, tumor, CADASIL, Marchiafava-Bignami disease, echovirus 9, and adrenoleukodystrophy. Callosal atrophy is a poor prognostic sign. Ring-enhancing lesions with central pallor may correlate with disease severity and are larger and last longer than homogenously enhancing lesions. Arcuate U fibers below gyri may be bright on T2. These arcs may form an “open ring” and are a strong indicator of demyelinating disease. A “sand-like appearance” of the high convexity white matter is from dilated Virchow-Robin spaces (Achiron and Faibel 2002). These dilated spaces correlate with Gd+ lesions (Wuerfel et al 2008), suggesting there is diffuse activation of multiple areas of the brain when there are Gd+ lesions. T2 lesion volume has a weak correlation with disability (r = 0.2 to 0.3). T1 holes correlate more strongly, especially in secondary progressive multiple sclerosis. Early active MRI lesions are typically hyperintense on T2 with a hypointense ring, possibly containing activated macrophages. Some acute plaques enhance with gadolinium, but early on they can be almost isointense on T2 MRI (Bruck et al 1997). Plaque pathology with antibody and complement (Lucchinetti Type II) causes a T1-enhancing ring and hypointense T2 ring (Konig et al 2008). Late active lesions are less hyperintense on T2 and can become hypointense on T1-weighted images (“black holes”), indicating axonal loss and demyelination. Without treatment, 56% of acute black holes will remain as permanent black holes. T1 MRI and magnetization transfer ratio scans often show lesions in the corpus callosum and periventricular white matter. Large, fluffy T2 lesions often have preserved axons and repletion of oligodendroglia. Inactive lesions (demyelinated or myelinating) are hypointense on T2 scans and normal or hypointense on T1 scans. Spinal cord lesions are usually only 1 to 2 segments long, diffuse in only 13%, often multiple, and predominantly cervical (66%) (Bot et al 2004). In recently diagnosed multiple sclerosis, cord lesions help define dissemination in space (85% are brain plus cord MRI positive versus 66% using brain MRI alone). Gd enhancement lasts 2 weeks (median) to 3 weeks (mean) (Cotton et al 2003). There is temporal variation in the duration of enhancement. This suggests that there could be a tail of enhancing lesions several weeks after a clinically isolated syndrome, so “old” and “new” lesions could still be from the initial insult. Regional differences also interfere with comparison of Gd+ and Gd- lesions. For instance, Gd+ MRI lesions in white matter are easier to see than lesions in the cortical gray matter. A leak through the tight junctions of the blood-brain barrier is usually invoked as the cause of Gd enhancement. It is also likely that T cells are constantly activating endothelial cells, and the immune feedback maintains the enhancement. Activated, enlarged endothelial cells pinocytose gadolinium, essentially causing a capillary blush on MRI (Brown 1978; McDonald and Barnes 1989; Claudio et al 1995). Treatment with glucocorticoids blocks MRI enhancement, probably through a direct effect on endothelial cells. IFN-beta and antibodies to VLA-4 also block gadolinium enhancement, interrupting T cell-endothelial interaction. Several months before overt MRI lesions appear, normal-appearing white matter evinces slight MRI and MR spectroscopy abnormalities and also more cerebral perfusion (Goodkin et al 1998; Filippi et al 1999; Wuerfel et al 2004). MR spectroscopy shows biochemically abnormal lipid peaks in gray matter. Scans with 8 Tesla magnets reveal multiple lesions in gray matter and many in subpial and perivenous locations (Rammohan 2003). PET scans show decreased cerebral glucose utilization in frontal and parietal cortex. Magnetization transfer values in normal-appearing white matter are lowest in chronic progressive multiple sclerosis. They are also slightly low in benign multiple sclerosis, but here values do not decrease over time (Filippi et al 1999). Gray matter MTR loss correlates with progression on the EDSS and long-term disability. Of patients with clinically or lab- supported multiple sclerosis, 1.5% have negative conventional MRI scans yet low magnetization transfer values in pons, cerebellum, and periventricular areas (Filippi et al 1999). The mechanism in MTR may involve different immune or neurotrophic responses than in MRI-positive multiple sclerosis. T2+ plus T1+ MTR lesions have more demyelination and more axonal swelling and are often chronic inactive compared to T2+ only lesions (Fisher et al 2007). Gd+ lesions show some recovery in MTR. PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 47 of 123 Brain atrophy is present in early multiple sclerosis and averages 0.9% per year. It evolves 5 times more rapidly than in normal brains, and up to 14 times faster during active secondary progressive multiple sclerosis. Atrophy is largely from axonal loss but also from demyelination and contraction of the neuropil. Axonal loss and T2 lesion volume are only partially correlated. Gray matter volume loss appears at first presentation in the thalamus and putamen, caudate, cerebellum, and cortex. Volume decline is most pronounced in progressive multiple sclerosis. Cerebellar gray atrophy correlates with loss of locomotion. White and gray matter atrophy correlate with cognitive decline and can be measured with third ventricular volume, a reflection of thalamic loss. Brain atrophy correlates better with changes in disability than T2 MRI lesions do, and is especially important in the cervical cord (Zivadinov and Bakshi 2004). Atrophy is predicted by the presence of early T2 hypointensity and T1 Gd+ lesions (Simon et al 2000), T1 “black holes,” and low brain volume in some studies. T2 hypointensity is likely from iron deposition (perhaps neurotoxic) and correlates with later brain atrophy. CNS atrophy can also be measured with transcranial sonography of the third ventricle (width vs. disability is inversely correlated at, r = -0.6). IFN-beta and glatiramer therapy slow atrophy. Atrophy is slower with weekly IFN-beta than with high- dose, high-frequency interferon, possibly because the latter reduces inflammation or because there are differences in neurotrophin induction. Rare patients can develop nephrogenic systemic fibrosis (NSF) from gadolinium. NSF is more likely with low glomerular filtration rate and diabetes, and it can be diagnosed with a skin biopsy. CSF diagnosis. The CSF is the best non-MRI marker of multiple sclerosis. There is CNS inflammation in the absence of a blood-brain barrier leak (Freedman et al 2005). The CSF, in order of increasing frequency and importance for a diagnosis of multiple sclerosis, shows elevated protein, a moderate increase in white blood cells, increased IgG, IgG/albumin index, IgG synthesis rate (Tourtellotte or Link formulas), and oligoclonal bands. The index, synthesis rate, and oligoclonal bands are increased in black compared to white patients by 30% to 40%, suggesting more active inflammation (Rinker et al 2007). When suspected cases of multiple sclerosis have no bands in CSF, a repeat CSF study shows bands in half of them (Thompson and Freedman 2006). Inflammatory conditions such as SSPE, lues, Lyme disease, lupus, Behçet disease, and adrenoleukodystrophy often have unique CSF bands. Serum bands are increased in 44% of multiple sclerosis patients and are 10 times more common in women than in men (Thompson and Freedman 2006). Intrathecal synthesis of antibodies to measles was described in 1962, and many other viruses such as HHV-6 are targets of a polyspecific B-cell response. An index of CSF antibodies to measles, rubella, and herpes zoster (the MRZ reaction) improves sensitivity (Felgenhauer 1992) and may be low in neuromyelitis optica. The IgG indices correlate with CSF IL-10 levels. Antibodies to galactocerebroside, triose-phosphate isomerase, and glyceraldehyde-3-phosphate are elevated. Reports of CSF antibodies to MOG and MBP have not been replicated but are under intense study; conformational changes in the assays may be important. CSF white blood cells are 90% CD3+ T cells (70% CD4, 20% CD8), 3% natural killer, 4% macrophages, 5% B cells (Cepok et al 2001). During active disease, these T and B lymphocytes are often activated blasts. The CSF cell count is often slightly elevated at 5 to 10 per um. T cells are 80% of the count in stable multiple sclerosis and in healthy controls; T cells rise to 90% in active multiple sclerosis (Reder and Arnason 1985). The CD4/CD8 ratio reflects the blood (2/1) in relapsing- remitting multiple sclerosis, but CSF CD8 cells fall in progressive disease. Many CSF lymphocytes are activated (Noronha et al 1980). B cells are at lower levels than in blood and are often blasts. A high CSF B cell to monocyte ratio in CSF correlates with IgG levels and with rapid disease progression in relapsing and progressive multiple sclerosis (Cepok et al 2001). CSF reflects damage to brain cells. S-100b protein in CSF increases during flares. Elevated proteins include axon cytoskeleton markers (neurofilament light chains, present in first multiple sclerosis attacks; neurofilament heavy chains, highest in secondary progressive multiple sclerosis, but present even in clinically isolated syndromes; actin; NAA; tau; and PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 48 of 123 tubulin), membrane markers (24S-hydroycholesterol, apoE4), glial markers (GFAP), and amyloid precursor protein (Teunissen et al 2009) and the endothelial marker, endothelin. N- acetyl aspartate (NAA), abundant enough (10 mM) in neurons to be detectable with magnetic resonance spectroscopy, decreases in CSF during secondary progressive multiple sclerosis. Tau protein, a marker of axonal damage, increases 2-fold. Tau levels increase in progressive multiple sclerosis, but also in other inflammatory diseases, and levels correlate with the IgG index. 14-3-3, a neuronal, axonal, and glial protein, is present in 10% of patients with transverse myelitis and multiple sclerosis (de Seze et al 2002). In clinically isolated syndromes, 14-3-3 predicts an earlier conversion to multiple sclerosis. It is elevated in various dementias after extensive damage of the brain, especially in Creutzfeldt-Jacob disease where levels are high. DJ-1 (PARK7) is elevated 6-fold in relapsing/remitting Japanese multiple sclerosis CSF vs. non-inflammatory disease) and correlates well with the multiple sclerosis severity scale (MSSS; r = 0.509) (Hirotani et al 2008). Cystatin C may be uniquely cleaved by endogenous CSF proteases. Urinary myelin basic protein-like material (not MBP) also increases in progressive multiple sclerosis and correlates with the number of MRI T1 black holes. A high level of myelin basic protein (MBP) in CSF and MBP-like material in the urine reflects damage to myelin and oligodendroglia in progressive multiple sclerosis (Whitaker et al 1995). None of these is diagnostic in itself, but multiplex analysis coupled with reliable assays may be used in the future. CSF neurotrophic factors also rise at some times. During recovery, neural cell adhesion molecule (N-CAM) and ciliary neurotrophic factor (CNTF) increase. During exacerbations, nerve growth factor sometimes increases, although it falls as the disease becomes advanced. However, there are low levels of CSF growth hormone, which is neuroprotective and induces insulin-like growth factor-1 and remyelination. Evoked potentials in diagnosis. Evoked potentials are occasionally helpful for confirming multiple sclerosis (eg, when MRI and CSF are normal), but they should not be used for the routine diagnosis of multiple sclerosis. The frequency of abnormal evoked potentials in definite multiple sclerosis is visual=90%, auditory=80%, and somatosensory=70%. Auditory-evoked potentials are seldom helpful in making the diagnosis. Neurophysiological studies such as vestibular evoked myogenic potentials, multifocal visual evoked potentials, motor (magnetic) evoked potentials, and the P300 event-related potential also could provide information about central nervous system function and prognosis (Leocani and Comi 2000). Serum tests in diagnosis. Sedimentation rate or C-reactive protein, antinuclear and anticardiolipin antibodies (Cuadrado et al 2000), Sjögren syndrome A and B antibodies, angiotensin converting enzyme, vitamin B12, and possibly vitamin D levels should be ordered when appropriate. C-reactive protein, a marker for inflammation from many etiologies, has a modest correlation with relapses, progression, and MRI activity. DNA transcription from many genes is controlled by methylation. Circulating methylated DNA profiles are highly abnormal in multiple sclerosis plasma. Ophthalmologic diagnosis. The optic neuritis basic workup is funduscopy, visual acuity, perhaps optical coherence tomography (below), a neurologic exam, MRI, and possibly lumbar puncture. Perimetry shows a scotoma that is typically central or diffuse but sometimes is peripheral. Low-contrast Sloan letter charts are more sensitive than the standard Snellen measure of visual acuity. A loss of one line of low-contrast acuity correlates with a 3 mm2 increase in MRI T2 lesion volume; one line of high-contrast loss correlates with a 6 mm2 increase in MRI T2 lesions (Wu et al 2007). Loss of acuity also detects post- geniculate white matter damage. Visual evoked potentials are often abnormal in the affected eye but return to normal within 2 years in one third of eyes. Low contrast stimuli and multifocal visual evoked potentials are more sensitive than conventional potentials. In patients with multiple sclerosis and normal visual acuity but no history of optic neuritis, subclinical optic tract lesions are detected with tests of visual evoked potentials (82%), contrast sensitivity (73%), optical coherence tomography (OCT) (60%), pupillary light reflex (52%), flight of colors (36%), and color vision (Ishihara plates) (32%) (van Diemen et al 1992; Naismith et al 2009). Note that visual evoked potentials are more sensitive than OCT (Naismith et al 2009). PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 49 of 123 Retinal tomographs (optical coherence tomography, OCT) reproducibly measure retinal nerve fiber layer thickness (RNFL), retinal ganglion cells, and macular volume. OCT usually shows RNFL thinning 3 to 6 months after optic neuritis. OCT is abnormal in half of the “normal” fellow eyes in multiple sclerosis patients after an episode of optic neuritis. Thinning of RNFL is faster in optic neuritis eye (69 um) than in “normal fellow” eye (partially affected, at 95 um) and healthy control eyes (103 um) (Trip et al 2006). RNFL loss occurs over time in some patients, even without symptoms of optic neuritis. Optic nerve cross-sectional area on MRI correlates with RNFL thickness (r = 0.66). OCT measures correlate with visual evoked potential amplitude but not latency. Atrophy is associated with motor disability (r=0.2-0.4) and cognitive problems (r=0.5) (Toledo et al 2008). RNFL loss in progressive multiple sclerosis is greater than in relapsing-remitting multiple sclerosis; loss is even worse in neuromyelitis optica, especially in the superior and inferior quadrants. OCT can define acute optic neuritis, demonstrate a second lesion in clinically isolated syndromes, and monitor atrophy and progression as a surrogate marker to complement the neurologic exam. It is not a replacement for evoked potential and MRI, especially in clinically isolated syndromes, because with current technology it is less sensitive. One third of macular volume is from neurons, and macular edema correlates with visual function. MRI studies show multiple cerebral white matter lesions in one fourth to three fourths of optic neuritis patients, depending on the series; most of the MRI lesions involve the visual radiations. The spinal fluid in optic neuritis contains elevated protein, mild lymphocytosis, elevated IgG index, and oligoclonal bands (50% to 70% vs. 95% in multiple sclerosis). Quality of life scales in diagnosis. Quality of life scales are inexpensive, simple to administer, and measure a wide range of the problems seen in multiple sclerosis (Cella et al 1996). They predict changes in disability and are objective measures of therapeutic outcomes. However, present scales are insensitive and have not contributed to trial monitoring. Confusion in diagnosis. In some patients with clinically definite multiple sclerosis but negative MRI, other techniques such as evoked potentials or magnetic transfer imaging will show damage. When no oligoclonal bands are seen in the CSF, as in approximately 3% of patients, prognosis is better and brain MRI lesions are fewer. Four years after a diagnosis of multiple sclerosis, only half of these oligoclonal band-negative patients become positive (Zeman et al 1996). Similarly, one third of patients with 1 oligoclonal band who develop multiple bands on follow-up will develop multiple sclerosis (Davies et al 2003). Incidental, unexpected multiple sclerosis-like lesions on an MRI scan, without symptoms or signs of multiple sclerosis, are often referred to neurologists (“radiologically isolated syndrome”). The autopsy studies mentioned above show a significant reservoir of undetected multiple sclerosis. However, multiple sclerosis-like MRI lesions could be from vascular disease, tumor, and possibly migraine headache. Yet, in 30 patients with incidental MRI lesions, 23 (77%) developed new MRI lesions by 6 months, and 11 (37%) had clinical conversion to multiple sclerosis (Lebrun et al 2008). In 41 patients (7 treated) followed for 2.7 years, 59% had new MRI lesions; 30% had clinical attacks at a median time of 5.4 years (Okuda et al 2009). These papers suggest early treatment is reasonable for some cases with MRI lesions only. A diagnosis of multiple sclerosis should be questioned, judiciously, when there are “red flags” such as: • no eye findings (optic nerve or motility) or prominent uveitis • no remissions • localized disease • atypical clinical features: aphasia, altered consciousness, extrapyramidal symptoms, homonymous visual field defects, no long tract findings, no fatigue or heat sensitivity, no sensory or bladder symptoms, no constipation, progressive myelopathy without bladder involvement, peripheral neuropathy, or late or early age of onset • repeated episodes in the same part of the CNS • normal CSF and no oligoclonal bands (Rudick et al 1986); high white count > 50/ul or PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 50 of 123 protein > 100 mg/dl • normal MRI, or atypical MRI with small lesions (<3 mm), basal ganglia or internal capsule involvement, diffuse confluent white mater lesions, or longitudinal cord lesions spanning more than 2 vertebral segments. In the absence of objective evidence for multiple sclerosis or other disease, follow-up investigations should be kept to a minimum. Prognosis and complications The overall life expectancy for multiple sclerosis patients is 7 years less than normal, or 75% to 85% of expected survival (Weinshenker and Ebers 1987; Sadovnick et al 1992). Mortality increases with disability. Case fatality ratios are 1:5 for patients with Kurtzke disability scores of less than or equal to 7, but 4:4 for those with scores greater than 7 (Sadovnick et al 1992). The suicide rate is increased 7.5-fold (Sadovnick et al 1991). The lifetime risk of suicide is 2%. Less-disabled young patients within 5 years of diagnosis are the most likely actors (Sadovnick et al 1992; Stenager et al 1992). The cause of death in 50% of a clinic population and in approximately 75% of all multiple sclerosis patients is from complications of multiple sclerosis, usually pneumonia (Sadovnick et al 1991). Patients most commonly die when disability scores approach 8.0. Brainstem lesions occasionally cause loss of inspiratory drive, causing the patient to stop breathing; this is most common at night. Deaths from malignancy are less common than in age- matched controls (Sadovnick et al 1991). Multiple sclerosis reduces quality of life throughout its course. Some predictions of the future course of multiple sclerosis can be made. Poor prognostic predictors are cerebellar or pyramidal symptoms, slow timed walk test at baseline, early sphincter symptoms, multi-site onset, frequent early attacks, development of progression or a primary progressive course, and age over 40 years at onset. Good prognostic signs include optic neuritis, sensory symptoms, or an exacerbating-remitting course (Weinshenker and Ebers 1987; Phadke 1990). The course is a more important predictor than age of onset. Development of a progressive course is the strongest predictor of poor outcome. The second strongest predictor is the number of relapses in the first 2 years. After a first attack, a second is more likely to follow in younger patients with abnormal CSF, more than 8 T2 MRI lesions (dissemination) or 1 Gd enhancing lesion (activity). Long-duration, low-disability multiple sclerosis is likely to remain stable. Complete recovery is more likely with mild severity and mono-lesional exacerbations. Clinic-based cohorts have more severe multiple sclerosis than population-based groups, where many patients remain stable or progress minimally over 10 years (Pittock et al 2004). The cumulative lifetime dose of disease- modifying therapy improves prognosis. Children with isolated symptoms at onset, multiple MRI lesions, elevated IgG index, and oligoclonal bands in CSF are more likely to develop multiple sclerosis than those with polyclonal onset and negative CSF tests. Patients with relapsing-remitting multiple sclerosis take 15 years from onset to reach an Expanded Disability Status Scale of 6.0 (using a cane to walk 100 meters), based on longitudinal studies in Ontario, Canada (Ebers 2000). Those with primary progressive multiple sclerosis take 8 years, and early progression and multi-system symptoms hasten the rate of progression. Later onset multiple sclerosis is more common in men and is often primary progressive. Even when beginning as relapsing-remitting disease, the transition to primary progressive multiple sclerosis is earlier in men than in women. Patients with 1 attack in the first 2 years do not need a cane for 20 years; those with 5 or more attacks need a cane within 7 years. Once a patient becomes unable to walk 500 m (EDSS =4; typically after 11 years), progression is no longer affected by relapses. The rate of decline is similar in all groups once multiple sclerosis becomes progressive (including primary progressive at onset, “bout onset progression,” or at the transition from relapsing-remitting to secondary progression) (Rice 1997; Ebers 2000; Kremenchutzky et al 2006). This happens on average at the age of 40, preferentially targets the corticospinal tract, and is not PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 51 of 123 obviously influenced by prior relapses. Within the progressive group, however, rates vary (“sooner to cane, sooner to wheelchair”). On MRI, bad prognostic signs include a large number of T2 lesions, many enhancing lesions, and lesions in certain sites (juxtacortical, infratentorial, and periventricular), low magnetization transfer, and brain atrophy, especially early atrophy. Good signs are little tissue damage and sparing of important regions. An MRI with a few large lesions gives a better prognosis than one with the same volume of many, smaller lesions (Kepes 1993; Zivadinov personal communication 2005). In a 20-year follow up of 107 relapse-onset patients, lesion growth was 0.80 cc/year in those who were relapsing-remitting but was 2.89 cc/year in secondary progression (Fisniku et al 2008). In clinically isolated syndromes (CIS, optic nerve, brainstem, or spinal cord), total T2 lesion volume on MRI at onset correlates with disability at 10 years (r = 0.45), and all patients with a total lesion volume greater than 3cc progress to definite multiple sclerosis by 4 years (Sailer et al 1999). Ventricular enlargement or new T2 MRI lesions 3 months after the first symptoms strongly predict clinically definite multiple sclerosis – 88% after a positive MRI versus 19% after a negative MRI (Brex et al 2002). In 532 patients with clinically isolated syndromes followed for up to 9 years, definite multiple sclerosis developed in only 35% of those with no asymptomatic baseline lesions but in 74% of those with 3 of 4 of the following lesions: a) 1 enhancing or 9 T2, b) 3 periventricular, c) 1 juxtacortical, or d) 1 infratentorial (revised McDonald criteria) (Korteweg et al 2006). In the BENEFIT CIS study, 9 baseline T2 lesions (hazard ratio = 1.6) or 3 periventricular lesions (hazard ratio = 1.7), or when one lesion changed to more than one, predicted conversion to multiple sclerosis. Corpus callosum lesions are also predictive (hazard ratio = 2.7). Brain atrophy is often present in mild-to-moderate multiple sclerosis. Atrophy is most likely to progress when there are Gd-enhancing lesions at baseline (Simon et al 2000). Ventricles in relapsing-remitting multiple sclerosis increase in size by 5% per year, compared to 1% to 2% in normal controls. In most cases of multiple sclerosis that come to medical attention, disease activity never sleeps and atrophy progresses relentlessly in all multiple sclerosis subtypes. However, there are a large number of subclinical cases with benign courses and presumably much milder inflammation. Magnetic (motor) and electric evoked potentials do not correlate with disability at first presentation. However, abnormal evoked potentials do predict disability at 2 years (r = 0.6 with motor and visual potentials) (Fuhr et al 2001) and at 5 years (r = 0.5 with motor and sensory) (Kallmann et al 2006). CSF with a high white cell count predicts Gd+ MRI lesions (Rudick et al 1999). CSF with high numbers of natural killer cells and monocytes augurs slower progression (Cepok et al 2001), although subsets of both of these cell types can damage oligodendroglia. B cells and plasma cells in CSF predict faster progression, as do increased myelin basic protein and increased IgM. Antibodies to myelin basic protein in clinically isolated syndromes were highly predictive for development of multiple sclerosis in 1 study, but other labs have not been able to replicate these findings. Patients who progress quickly typically have high B cell to monocyte ratio in CSF, high peripheral Th1 cytokines, dysregulated proteins (Imitola et al 2006), and genetic influences such as homozygous HLA-DRB1*1501 and polymorphisms in multiple genes (Frohman et al 2005). A study of rituximab (anti-B-cell antibody) in primary progressive multiple sclerosis is underway. Other markers may be helpful in the future. Some of these include monitoring B7 costimulatory molecules (CD8, CD86, PD-1, PD-L1) and adhesion molecule expression on mononuclear cells, serum cytokines or cytokine receptors, kallikrein proteases and matrix metalloproteases, newer MRI techniques, antibodies to myelin-oligodendrocyte glycoprotein and galactocerebroside, 14-3-3 protein in CSF (neuronal loss), increased CSF myelin basic protein (oligodendrocyte damage), CSF or serum soluble intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM) (correlate with MRI activity), and molecular indicators of interferon efficacy. The lifetime cost of multiple sclerosis in the United States is high compared to other PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 52 of 123 neurologic diseases. Multiple sclerosis, with a total lifetime cost of $2,200,000 and an annual cost of $34,000 is more expensive than ischemic stroke ($100,000 lifetime) and Alzheimer disease ($49,000 to $490,000 lifetime) (Whetten-Goldstein et al 1998). In a disease of long duration, the expense accrues from earnings lost, rehabilitation, drug therapy, medical equipment, and formal and informal care. The cost of multiple sclerosis in the United States is estimated at $47,000 per year by another analysis. Fifty-three percent is direct (40% drugs, 3% inpatient hospital care), 10% is informal care, and 37% is productivity loss (reduced work time and retirement) (Kobelt et al 2006). A British analysis of the cost- effectiveness of therapy suggests that each relapse avoided during interferon therapy costs 28,700 British pounds (Parkin et al 2000). Note that relapses are easy to count but have weak correlation with progression--a better indicator of disability. Management TREATMENT OF SYMPTOMS. Many symptoms of multiple sclerosis can be treated (Schapiro 2003). Education of patients about the consequences of demyelination is an important first step. The second intervention should be to avoid drugs that cause fatigue, weakness, or confusion, or lifestyles that increase disease activity (eg, smoking). Multiple dietary supplements are used by 50% of multiple sclerosis patients (Bowling and Stewart 2004) and should be evaluated along with prescription therapy. Some symptoms are primary, such as CNS inflammation and damage; others are secondary, like social disruption, muscle deconditioning, and drug side effects. Fatigue. The most common complaint in multiple sclerosis is fatigue. Primary multiple sclerosis-induced fatigue is discussed above. Causes of “secondary fatigue” include sleep problems, temperature dysregulation, limitation of mobility and spasticity, itching, anxiety, pain, deconditioning, depression, infections, drugs, and other medical disorders (anemia, hypothyroidism) (Krupp and Christodoulou 2001). Initial therapy should be directed at removing these precipitants. In heat-sensitive patients, morning exercise in cool morning air, precooling before workouts, cooling vests, a glass of ice water, swimming in cool water, or wearing a hat while in sunlight can bring about astonishing improvements in fatigue and weakness, especially during the afternoons circadian rise in body temperature. Aspirin, which lowers temperature, can reduce heat-induced fatigue even if the patient is afebrile. Yoga and individual or group exercises improve fatigue caused by deconditioning, as do education in relaxation and energy conservation. Proper sleep hygiene, more sleep, and sometimes long-term use of sleep-inducing drugs are needed for this chronic problem. Lassitude and overwhelming tiredness caused by multiple sclerosis is often reduced with modafinil (100 to 200 mg in the morning), which activates histaminergic and certain noradrenergic nuclei. Amantadine (100 mg morning and noon) is effective in one half of patients. Some patients improve with methylphenidate (5 to 10 mg, 2 or 3 times a day) or the extended release form (20 mg per day), or with amphetamine, atomoxetine, and terbutaline (1.25 to 2.5 mg twice a day). L-carnitine one gram twice a day may restore muscle energy metabolism (Smith and Darlington 1999) and is more effective than amantadine. Pemoline (37.5 mg, 1 to 4 times a day) was withdrawn by the United States Food and Drug Administration in 2005 because of liver toxicity. Fatigue in some patients improves, in descending order, with natalizumab, glatiramer acetate, and IFN-beta. Antidepressants such as venlafaxine, bupropion, sertraline, and fluoxetine sometimes reduce fatigue. Oral dehydroepiandrosterone (or 10% cream) and 4- aminopyridine reduce subjective fatigue. Two aspirin twice a day may reduce fatigue and prevent symptoms of premenstrual pseudo-exacerbations, likely by reducing temperature or inflammation. A dermal absorption patch containing caffeine and histamine had a modest effect on fatigue in a small trial (but no effect on the course of multiple sclerosis) (Gillson et al 2002). Serum caffeine levels did not predict changes in fatigue. The histamine could affect wake- inducing neuronal pathways. There is potential immune benefit—histamine induces Th2 cells and inhibits experimental allergic encephalomyelitis; caffeine enhances adenosine signaling, PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 53 of 123 and adenosine A2A receptors decrease Th1 cell function. However, histamine patches should be used with caution as histamine suppresses IFN-alpha production and has complex effects on IFN-gamma and on the Th1/Th2 ratio. Potentially related, modafinil activates the tuberomammillary nucleus, the sole source of histamine in the brain. Vitamin B12 plus lofepramine (a norepinephrine uptake-inhibiting antidepressant) and L- phenylalanine (norepinephrine precursor) (the “Cari Loder regimen”) has nonsignificant trends for symptom improvement. Some report more or less fatigue with IFN-beta therapy, but fatigue does not improve with therapy on average. Cognition. Slowed cognition is temporarily ameliorated with glucocorticoid or adrenocorticotropic hormone treatment. However, long-term steroid exposure can damage hippocampal neurons. IFN-beta-1b improved visual memory between years 2 and 4 of therapy on 2 of 4 neuropsychiatric measures that correlated with MRI changes (Pliskin et al 1997). It possibly enhanced verbal memory in a retrospective study of treated versus untreated subjects (Selby et al 1998). IFN-beta-1a in earlier, milder disease improved information processing and memory and showed trends for better visual-spatial and verbal abilities (Fischer et al 2000; Cohen et al 2002). IFN-alpha has dose-dependent benefit on cognition in relapsing- remitting multiple sclerosis (Cabrera-Gomez et al 2003). Analysis of long-term (16-year) effects of IFN-beta-1b and comparisons to the original Pliskin study are underway. In a 2-year study, glatiramer had no effect on cognition (Weinstein et al 1999). Differences in clinical severity between studies did not explain the lack of effect (Kurtzke scores were 3.0 to 4.9 for IFN-beta-1b, 2.3 for IFN-beta-1a, and 2.4 to 2.8 for glatiramer acetate). Natalizumab improves cognition. Fingolimod does as well, based on unpublished comments. In mice, both of these agents interfere with short- and long-term learning because they block IL-4 production by meningeal cells, which, in turn, induces BDNF (Derecki et al 2010); however, the therapeutic benefit in multiple sclerosis outweighs this concern. Donepezil had cognitive benefit in initial studies, but the same investigators later found no effect (Krupp et al 2011). In other studies, cognition improved in multiple sclerosis with cholinesterase inhibitors, from a baseline of 50 on a 100-point scale up to 70 (Reder unpublished), which also improved airplane pilots retention of complex skills in flight simulators. Memantine has significant benefit in multiple sclerosis (Reder unpublished) and in healthy controls, and it is potentially neuroprotective. A study that titrated the dose up to 30 mg/day was terminated because of side effects (the recommended dose is 20 mg per day). Combination of memantine with amantadine, a related compound, can induce out-of- the-body, psychedelic reactions. Rapid dose escalation also increases side effects. There are trends for amantadine > 4-amino-pyridine > modafinil and pemoline = 0 to improve cognition, and for amantadine to speed up evoked potentials and reaction times. Abstracts report improved cognition or no effect from ginkgo biloba. There is a marked cognitive increase with l-amphetamine, 30 mg/day, in memory-impaired multiple sclerosis patients (Sumowski et al 2011). Auditory/verbal memory improved in 49% of those treated, compared to 7% of placebos, and visual/spatial memory improved in 48% versus 0% of placebos. Affective disorders. Antidepressants treat depression in multiple sclerosis, but may be even more effective for mood swings and pseudobulbar affect. For depressed patients with fatigue, a low dose of selective serotonin reuptake inhibitors can treat both problems (sertraline 50 mg every morning; paroxetine 10 to 20 mg; citalopram 20 mg; or fluoxetine 20 mg). In combination with nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors increase the risk of gastrointestinal bleeding 6-fold. For patients with insomnia and spastic bladder, amitriptyline (25 mg at bedtime) is helpful but potentially interferes with cognition because of its anticholinergic activity. Correction of depression correlates with a fall in IFN-gamma production (ie, it may have immune benefit) (Mohr et al 2001). Another potential benefit of antidepressants is induction of brain-derived neurotrophic factor (BDNF) (Arnason 2005). Imipramine acetylates and methylates the BDNF gene, leading to increased BDNF levels (Tsankova et al 2007). Fluoxetine induces PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 54 of 123 BDNF and restores plasticity in the visual cortex. It also reduced Gd+ MRI lesions 3-fold in a 40-person study (Mostert et al 2008). Abulia, sometimes responsible for physical inactivity and social withdrawal, may be countered with dopamine agonists such as amantadine or bromocriptine. Pramipexole and ropinirole may be more effective for abulia, in this authors opinion. Pseudobulbar affect and lability is reduced with an oral combination of dextromethorphan and quinidine (AVP-923, formerly Neurodex, now Nuedexta), which is now approved by the United States Food and Drug Administration. At 12 weeks, a mix of 40% multiple sclerosis and 60% amyotrophic lateral sclerosis patients on placebos had improvement of 3.0 fewer daily pseudobulbar episodes, whereas the approved dose had 4.1 fewer episodes (p=0.005) (Pioro et al 2010). Antidepressants, which also reduce episodes, were not compared to this drug. Anorexia can be countered with nutritional supplements, and possibly some antidepressants and dronabinol. Visual loss. Improve lighting at home and work, use glow-in-the-dark tape, adjust computer brightness, and increase size of print in reading material. Vertigo. Vertigo is sometimes severe and prolonged. It responds to vestibular suppressants (meclizine12.5 to 25 mg several times per day), memantine, or glucocorticoids. Benign paroxysmal vertigo symptoms can overlap and can be treated with particle repositioning maneuvers. This vertigo is associated with torsional-upbeat nystagmus of short duration during the Hallpike maneuver (Frohman et al 2000). Brainstem auditory evoked potentials could help discriminate central from peripheral lesions. Severe nystagmus and oscillopsia sometimes respond to dronabinol, memantine, and gabapentin, possibly because of specific receptors in cerebellar and extraocular pathways. The response to smoked marijuana is more rapid (2 to 3 minutes) than with oral dronabinol. Other potential therapies include gabapentin, baclofen, clonazepam, trimethobenzamide, and anticholinergics. Lack of coordination. Cerebellar intention tremor and severe lack of coordination from multiple sclerosis are difficult to treat. Arm weights, braces, and friction devices reduce the amplitude of the movements. Clonazepam (a GABA-A blocker), baclofen (a GABA-B blocker), primidone, and dronabinol are occasionally helpful. Anecdotal reports suggest benefit from topiramate, memantine (30 to 40 mg per day) (Javed 2008), buspirone, gabapentin, levetiracetam, glutethimide, isoniazid, and odansetron. Essential tremor could amplify the multiple sclerosis tremor and is suppressed with ethanol and GABA-ergic drugs. Beta- adrenergic blockers (propranolol) are occasionally helpful but should be used with caution because of immune hyperreactivity to adrenergic drugs in multiple sclerosis (Karaszewski 1991). Piracetam and valproate reduce myoclonus but have not been tested in multiple sclerosis. Thalamic stimulation or stereotaxic radiosurgery sometimes reduce tremor. These are less effective than in Parkinson disease because multiple sclerosis plaques are diffusely distributed. Cooling the affected arm may reduce feedback from spindle afferents (Leocani and Comi 2000). Balance can improve with a balance master machine, standing “wobble boards” or Wii balance board, and exercises, including physical therapy, yoga, and tai chi. Weakness. fMRI shows diffuse cortical activation. This indicates that for a given action, the energy expenditure in the multiple sclerosis brain is much greater than normal. Patients with fatigue also have reduced maximal voluntary force, possibly from conversion to fatigable, deconditioned muscle fibers. Weakness improves by cooling with ice packs, swimming, or environmental adjustment in heat-sensitive patients. Pre-cooling before therapy improves performance and reduces the transient deficits from a rise in core temperature. Inpatient or outpatient rehabilitation, locomotor training, and exercise on land or in water reduce disability and improve quality of life in multiple sclerosis. Exercise can benefit general health, social function, mood, anxiety, depression, strength, and fatigue. Exercise programs can reverse deconditioning and muscle weakness that patients incorrectly perceive as multiple sclerosis progression (Schapiro 2003). Exercise, stretching, and strengthening PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 55 of 123 should not be pushed to the point of severe fatigue because the fatigue will often persist, sometimes for days. Weight loss is an obvious intervention in corpulent patients. This will improve balance, lessen fatigue from moving heavy limbs, and allow better cooling on hot days. Crutches, braces, and bandage ankle supports can also improve function. Bone mineral density is low in multiple sclerosis, a consequence of less activity, use of steroids and antidepressants, and possibly abnormal vitamin D metabolism, low sun exposure, and elevated osteopontin levels. Weight-bearing exercise can prevent osteoporosis. Some patients report increased leg strength from IFN-beta, possibly because it increases tone. 4-aminopyridine enhances strength, cognition, sensation, sexual and bladder function, and vision in some patients. However, generalized seizures occur with high doses. The United States Food and Drug Administration has approved a slow-release form (3,4- diaminopyridine; Fampridine-SR) that improves walking speed. This author provides an initial 2-week test dose because of its high cost. Spasticity. Spasticity can be relieved by stretching the affected muscles and by reducing pain and stress. Physical therapy, energy conservation, yoga, and tai chi improve both spasticity and fatigue. Drug therapy includes baclofen (5 to 80 mg per day); lethargy and weakness are side effects at higher doses. Tizanidine (2 to 36 mg per day) causes less weakness than baclofen and may also reduce pain; clonidine has similar but modest effects. Side effects are dry mouth and sedation, especially if it is taken with meals. Second choices are diazepam (5 to 15 mg per day) and dantrolene (25 mg per day to start, with gradual increases and careful monitoring of liver function; seldom used). Some patients report benefit from clonazepam (0.5 to 3 mg per day), gabapentin (100 to 2400 mg per day) or dronabinol (5 to 15 mg per day; Marinol). A large study with cannabis and tetrahydrocannabinol in the United Kingdom showed subjective improvement in spasticity, pain, sleep, cachexia, and mood, as did a combination of delta9-tetrahyocannabinol (27 mg/ml; Marinol) and cannabidiol (25 mg/ml; Sativex). Nabilone (Cesamet, 1 mg) reduces nausea and vomiting associated with chemotherapy and should benefit multiple sclerosis. The endocannabinoid system is highly activated in multiple sclerosis plaques (Eljaschewitsch et al 2006). Cannabinoids reduce the Th1/Th2 cell ratio and have theoretical benefit on immunity. They suppress glutamate- induced excitotoxicity of neurons by inducing a protective phosphatase in microglial cells. Pain anywhere in the body often amplifies spasticity. Non-steroidals and cyclooxygenase II inhibitors can reduce spasticity and severe spasms associated with pain. Abstracts suggest improvement with cyproheptadine (4 to 12 mg per day) and threonine. Local spasticity can be reduced with injection of botulinum toxin. In large muscles, botulinum toxin is expensive and reduces strength. Intrathecal baclofen pumps are beneficial in intractable cases. This pump improves function in the affected arm after strokes and could reduce spasticity from asymmetric multiple sclerosis symptoms. It improves quality of life in multiple sclerosis. Tonic spasms. Tonic spasms are reduced with antispasticity agents (baclofen, tizanidine, benzodiazepines), antiepileptics (carbamazepine, phenytoin, valproate, gabapentin), and carbonic anhydrase inhibitors (acetazolamide, possibly topiramate). Episodic visual problems may also respond to these drugs. Myoclonus and restless legs. Myoclonus is inhibited by clonazepam or primidone. Cramps can be ameliorated with anti-spasticity drugs and with magnesium oxide (400 mg twice a day). Many other paroxysmal symptoms respond well to carbamazepine, oxcarbazepine, phenytoin, gabapentin (up to 2000 mg per day), and acetazolamide (250 mg, twice a day). Some respond to cannabinoids, L-dopa, bromocriptine, and quinine. Restless legs improve with dopamine agonists, benzodiazepines, and narcotics. Serum calcium and magnesium should be checked. Spastic bladder. The bladder is usually small and spastic in multiple sclerosis. Anticholinergics such as tolterodine (1 to 2 mg twice a day or 4 mg extended release; night administration may be best), oxybutynin (5 mg 2 or 3 times a day or 10 to 20 mg extended release per day, also transdermal), hyoscyamine, flavoxate, solifenacin (M3 blocker), PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 56 of 123 darifenacin (M3 blocker, at 7.5 to 15 mg per day), troposium, amitriptyline (25 mg at bedtime), and botulinum toxin injections relieve urinary frequency. They can cause bladder distention and urinary retention at excessive doses. A trial with botulinum toxin A is in progress (DIGNITY). Desmopressin (DDAVP), an antidiuretic hormone analogue, decreases nighttime micturition (Andrews and Husmann 1997). Cannabinoids attenuate urgency and nocturia. Urinary retention, with a post-void residual of greater than 100 mL, should be evaluated with a cystometrogram. Retention and hesitancy from a tight external sphincter is occasionally reduced with baclofen (10 to 20 mg), terazosin (1 to 10 mg per day; also doxazosin, tamsulosin, and alfuzosin), clonidine, phenoxybenzamine, or cannabinoids. Applying a vibrator over the bladder or mowing the lawn can stimulate contraction. Clean intermittent self-catheterization is important if urinary retention occurs, and it helps prevent infections that typically amplify bladder spasticity. Urine should be acidified (cranberry or blueberry juice, can be sugar-free; vitamin C). Sexual function. Sexual function improves with physical exercise, a romantic environment, lubricants (Astroglide, K-Y jelly), vacuum tumescence (men), the Eros device (women), alternative forms of stimulation (oral sex, vibrator), pelvic floor (Kegel) exercises, and emptying the bladder before sex. Discontinuing drugs that interfere with sexual function such as antidepressants, antihypertensives, and smoking is helpful. Phosphodiesterase-5 inhibitor therapy is effective in men and occasionally in women (sildenafil 50 to 100 mg; tadalafil 10 mg; vardenafil 10 mg). These drugs cause vasodilation in the presence of high levels of nitric oxide. Potentially important, nitric oxide is elevated in multiple sclerosis plaques, and sildenafil promotes remyelination and prevents axonal loss in experimental allergic encephalomyelitis. In men, intracorporeal injections of alprostadil (PGE1) or intraurethral pellets of prostaglandin sometimes help. Testosterone, 1% gel, 50 mg, applied to the skin (with monitoring of prostate and prostate-specific antigen) has been used in men with low libido. Testosterone levels are lower in women with clinically active multiple sclerosis, so testosterone supplementation (testosterone patch, 300 ug/day) may increase interest in sex and orgasms (Davis et al 2008). Slight hair growth and possible breast cancer are side effects. Alprostadil cream, a vasodilator applied to female genitalia showed benefit in a 2005 abstract (www.medscape.com/viewarticle/515150, but no paper has been published. Constipation. Constipation is sometimes relieved with bowel training (diary, external sphincter, and puborectalis strengthening) and “scheduling”; more or less bulk in the food; more fluids; stool softeners, or enemas and laxatives (lactulose 10 mL per day); and polyethylene glycol (macrogol, Miralax, and others). Coffee, exercise, large intestine self- massage, electrical stimulation, and an external vibrator to stimulate the colon are also helpful. Methylnaltrexone, an opiate antagonist, is potentially effective. Sensory loss. Sensory loss is sometimes reversible with cooling or 4-aminopyridine. Vitamin B12 levels are low in some patients with multiple sclerosis (Reynolds 1992). Estimates may have been high because of referral bias in this study, but B12 deficiency is easily treated. Some patients report increased energy and improvement in proprioceptive sensation after receiving monthly B12 injections; however, the effect has not been studied in a controlled trial (see synergy with interferon, below). Knee or ankle wraps add proprioceptive input (orthotic feedback) and can improve balance. Gabapentin, carbamazepine, acetazolamide, or bromocriptine may prevent paresthesias. Pain. Pain is a problem in two thirds of patients at some time. Neurogenic pain responds to gabapentin (100 to 2400 mg per day), oxcarbazepine (75 to 600 mg), carbamazepine (25 to 400 mg, some multiple sclerosis patients are very sensitive to this drug), phenytoin (50 to 300 mg), topiramate (15 to 200 mg), lamotrigine (25 to 200 mg), levetiracetam (125 to 1500 mg), tiagabine (2 to 12 mg), and duloxetine (20 to 60 mg). Modest additional benefit is seen from tizanidine, baclofen plus amitriptyline, lidocaine/mexiletine, nonsteroidal anti- inflammatory drugs, cannabinoids, and glucocorticoids. Long-term treatment with opioids is sometimes effective but often leads to tolerance and drug-seeking. Intrathecal opiates and triamcinolone alleviate pain. PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 57 of 123 Reduction of skeletal muscle and bladder spasticity, constipation, malpositioning, and pressure sores is essential. High-dose vitamin D (2000-3000 U/day) is described as effective in the pain literature. Hypercalcemia is a contraindication. Trigeminal neuralgia (tic douloureux) shows dramatic improvement with misoprostol (200 µg 4 times a day), even in cases refractory to other drugs such as carbamazepine and phenytoin (Reder and Arnason 1995). This prostaglandin analogue elevates cAMP, and may deactivate the pain-facilitating microglia by interfering with inflammatory TLR4 signaling and by inducing anti-inflammatory Th2 cells and IL-4 and IL-10. cAMP induction has important anti-inflammatory effects in monocytes (Feng et al 2002b) and neuroprotective effects after facial nerve damage (Wainwright et al 2008). Case reports also suggest benefit from botulinum toxin injected into muscles near the site of pain. Gamma knife radiosurgery had apparent benefit in an uncontrolled study. Vascular surgery is less effective in multiple sclerosis (plaques in central V nerve pathways) than in older hypertensive patients with tortuous blood vessels (compressing peripheral V nerve). TREATMENT OF THE UNDERLYING DISEASE. The course of multiple sclerosis can be modified. However, there is no cure, and no treatment completely halts the disease. Smoking cessation should prevent some exacerbations. Generalized immunosuppression. Chemotherapy is sometimes beneficial in multiple sclerosis. It is most efficacious in early inflammatory multiple sclerosis. Long-term benefits are unclear. These agents increase the risk of progressive multifocal leukoencephalopathy (PML) in patients who are later started on natalizumab. Brain atrophy and deleterious effects on cells that secrete neurotrophins are possible. Azathioprine only modestly reduces progression in relapsing-progressive multiple sclerosis, although it reduces enhancing MRI lesions by 64% (uncontrolled study). Cladribine (Mylinax, 2-chloro-2-deoxyadenosine) binds to DNA in lymphocytes but largely spares other hematopoietic cells. CD4 and CD8 cells are depleted by 80% after therapy. Twenty-five percent to 30% crosses the blood-brain barrier. The drug is well-tolerated, and the injectable form reversed progression in 2 of 3 studies. In the third study, MRI improved but clinical scores did not. In a fourth study, brain volume continued to diminish during therapy. Side effects included injection site reactions, upper respiratory infections, and herpes zoster. Oral cladribine, in a phase III trial showed reduction in Gd+ MRI (86% to 88%), relapse rate (55% to 58%), and progression (31% to 33%). There were minimal side effects, with only suggestions of an increase in cancer and herpes zoster skin lesions; long-term follow- up will tell the risk of these potential long-term complications. Vaccinations may be needed before therapy. Unknown risks of cladribine led to denial by the United States Food and Drug Administration and to abrupt removal of this agent from the international market, despite earlier approval in several countries. Cyclophosphamides benefit is hotly debated. It may be most effective in relapsing multiple sclerosis (Weiner and Cohen 2002) and severe refractory disease. After intense immunosuppression, cells recover at different rates, starting with red cells and platelets (3 weeks) and then lymphocytes (3 months). CD4 cells and CD8+CD28- suppressor cell number can take a year to recover. Methotrexate caused slight improvement on a composite score of neurologic function. Mitoxantrone (12 mg/m 2 every 3 months) significantly reduced relapses, progression, and MRI lesions in multiple studies. This anthracenedione inhibits proliferation of T and B cells and macrophages, kills antigen-presenting cells, and inhibits migration of monocytes and to some extent T and B cells. It has 3 major side effects: (1) a fall in the white blood cell count, (2) acute myelogenous leukemia (approaching 1 in 125 treated, with 30% dying), and (3) cardiotoxicity with cumulative doses greater than 140 mg (approximately 2.5 years of therapy) and sometimes earlier. There is a 12% risk of impaired left ventricular ejection and a 0.4% risk of congestive heart failure. Measurement of left ventricular ejection fraction with cardiac echo or multiple gated radionucleotide angiography (MUGA) is now recommended before each dose. Iron chelation with dexrazoxane has suppressed cardiotoxicity. Reversal of the low leukocyte count with granulocyte colony stimulating factor PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 58 of 123 (G-CSF) is unnecessary and can cause exacerbations. A 3-month induction with this drug before starting glatiramer and IFN-beta is more effective than either of the other agents alone. (See Combinations, below.) Paclitaxel and teriflunomide (below) are under study. Glucocorticoids and adrenocorticotropic hormone (ACTH) reduce edema, inflammation, and oligoclonal bands and temporarily ameliorate symptoms and MRI signs of multiple sclerosis. They shorten the duration of exacerbations but do not alter the course of multiple sclerosis and should not be used for mild symptoms. Therapy should be started soon after the onset of the attack because this coincides with immune activation. High-dose intravenous methylprednisolone (1 g per day for 3 days) lessens recurrences of optic neuritis and delays the development of multiple sclerosis (Beck et al 1993). With long-term follow-up, however, the groups do not differ. An alternative to intravenous glucocorticoids is oral dexamethasone (96 mg twice a day for 3 days) or 1 g of methylprednisolone powder from a vial sprinkled into an iced fruit drink (approximately 4 oz) or chocolate pudding to mask bitterness. Oral and intravenous absorption are equivalent. Concomitant aspirin and nonsteroidal anti-inflammatory drugs should be completely avoided to prevent gastrointestinal bleeding. Experience with lupus, possibly with acute disseminated encephalomyelitis, and with experimental allergic encephalomyelitis suggests that a prolonged prednisone taper is prudent after high-dose steroid therapy (Reder et al 1994a). In experimental optic neuritis, dexamethasone, given before and early after onset of inflammation, prevents retinal ganglion cell loss (Dutt et al 2010). Late administration, however, causes apoptosis of the ganglion cells. In multiple sclerosis, however, positive or even negative effects of a taper are unknown. Beneficial effects of steroids on MRI last longer when patients are taking interferons, but intermittent high-dose steroid pulses added to interferon have no clinical benefit (Cohen et al 2009). Glucocorticoids and interferons both trigger apoptosis of activated T cells. However, some steroid-resistant inflammatory CD4+,CD25intermediate cells can survive repeated courses of steroids. High-dose glucocorticoids cause apoptosis of neurons and neural precursor cells in the hippocampus (Sapolsky 1999) and retina (Diem et al 2003), delay remyelination after ethidium bromide toxicity in rodents (Chari et al 2006), possibly cause brain atrophy, and can enhance production of proinflammatory cytokines (MacPherson et al 2005). Five days of therapy leads to declarative memory loss at day 6; it is reversible by day 60 (Uttner et al 2005). Muscle loss (possibly worse with dexamethasone than methylprednisolone), hyperglycemia, weight gain, aseptic necrosis of bone, and a plethora of other side effects must be considered in light of mere short-term clinical benefit. Adrenocorticotropic hormone is now seldom used because of its mineralocorticoid side effects, but the hormone occasionally benefits patients who are resistant to glucocorticoids. It induces cortisol and additionally induces cAMP to inhibit lymphocytes (eg, less IFN-gamma production), facilitates sodium channel redistribution in demyelinated axons, and is a neuroprotectant. Cyclosporin A had a modest benefit in relapsing-remitting multiple sclerosis and trends in early progressive multiple sclerosis, but renal side effects are significant. Many agents have failed in therapeutic trials. Abatacept (Ig fused to CTLA-4, binds to B-7/CD80, CD86; Orencia) had no effect on multiple sclerosis or its immune abnormalities. Anti-CD154 (CD40 ligand) caused thromboemboli. Anti-CCR2 failed. Anti-chlamydial drugs have not had dramatic benefit. Cladribine was withdrawn, although trials showed efficacy. (Discussed above.) CTLA-4Ig and antibodies to LFA-1 (to all isoforms of CD11/CD18) had no clinical or immunological benefit. Anti-viral drugs have not had dramatic benefit. Hyperbaric oxygen and total lymphoid irradiation are no longer used because of side effects PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 59 of 123 and lack of efficacy. Oral interferon, oral myelin, and oral glatiramer acetate had no side effects but no benefit either. Inhaled interferon may have caused pulmonary fibrosis. Linomide/roquinimex induces tumor necrosis factor, but it reduces clinical and MRI activity. However, it caused heart attacks—a local inflammatory reaction in serous membranes, possibly idiosyncratic to multiple sclerosis. Laquinimod, a related compound with less toxicity, reduces Gd+ MRI lesions by 44% in 24 weeks and is under study. MBP analogues and altered peptide ligands that bind the T-cell receptor have failed (Jones et al 2004). The Tovaxin vaccine against myelin antigens was remarkably unimpressive (Lublin personal communication 2008). Vaccination with plasmid DNA that encodes full-length human myelin basic protein (BHT- 3009) could induce tolerance to brain antigens. Preliminary data show that low doses reduce MRI lesions, but higher doses increase lesions in some patients, possibly because the vector contains immunostimulatory DNA (Garren et al 2008). Myelin peptides and altered peptide ligands, however, have caused exacerbations. This suggests that specific anti-CNS responses are responsible for some multiple sclerosis exacerbations. Despite the theory, a tolerization trial of intravenous myelin basic protein for progressive multiple sclerosis failed in a phase III trial. MBP82-98 was given intravenously, a potent route for generating tolerance (Gaur et al 1992). In phase II studies of HLA-DR2- and DR4- positive multiple sclerosis patients (62% of all patients), the peptide suppressed autoantibodies against myelin basic protein, caused a shift to Th2 cells, and slowed progression. Intermittent high-dose steroid pulses or methotrexate added to interferon had no additional clinical benefit in a well-designed trial (Cohen et al 2009). Sulfasalazine, used to treat Crohn disease, caused early improvement at 1 year but showed no benefit at 2 years. This argues against short trials in multiple sclerosis. Soluble tumor necrosis factor receptor-immunoglobulin fusion protein (a TNF blocker) precipitated clinical disease (even though MRIs improved). Peripheral immune activation, loss of normal apoptosis by feral T cells, blockade of tumor necrosis factor-induced remyelination, and lack of penetration into the brain by these agents are potential problems. Related drugs include etanercept, infliximab, and adalimumab. Anti-TNF antibodies and blockers make multiple sclerosis worse and occasionally induce demyelinating diseases when they are used to treat connective tissue disease. Tumor necrosis factor inhibits formation of interferon-producing plasmacytoid dendritic cells and reduces IFN-alpha levels (Palucka et al 2005), perhaps amplifying a preexisting defect in multiple sclerosis (Feng et al 2002). Ustekinumab (anti IL-12/23 p40) had no effect on multiple sclerosis MRI lesions, although it was beneficial in experimental allergic encephalomyelitis. VLA-4 inhibitor CDP323 is an oral agent with a natalizumab-like mechanism of action that was effective in experimental allergic encephalomyelitis and safe in humans, but failed in phase II multiple sclerosis trials. Somewhat-specific immunosuppression or other alteration of immunity. Within the past 18 years, 7 therapies have altered the course of multiple sclerosis: IFN-beta-1a intramuscular and subcutaneous, IFN-beta-1b, glatiramer acetate, mitoxantrone, natalizumab, and fingolimod (Goodin et al 2001). These therapies are important advances for patients and for understanding the cause of multiple sclerosis, but they are expensive and only partially effective on average. Many of these agents function differently in animal models and have unexpected mechanisms of action in multiple sclerosis. Interferon. Interferon-beta (IFN-beta-1a; IFN-beta-1b) and probably IFN-alpha and IFN- tau alter the course of relapsing-remitting multiple sclerosis. Benefits last for at least 5 years on study (Reder 1997), and recent data show clinical benefit over 21 years of therapy. IFN- beta reduces Gd+ MRI lesions by 85%, prevents severe relapses by up to 50%, and slows progression. Interferons also improve quality of life and cognition (Pliskin et al 1997), sometimes dramatically (“I read the first book of my life;” “I could finish my PhD thesis”). Clinically, IFN-beta is most effective in relapsing-remitting forms of multiple sclerosis, PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 60 of 123 especially in early disease. In clinically isolated demyelinating syndromes, there is a 50% lower chance of developing clinically definite multiple sclerosis with IFN-beta-1b treatment (BENEFIT trial) (Kappos et al 2007), 40% less progression, and 50% to 60% fewer new MRI lesions. IFN-beta slows progression by 27% in relapsing-progressive multiple sclerosis (Kappos et al 2001), but not in patients with later, progressive forms of multiple sclerosis or in primary progressive disease (Goodkin 2000; Javed and Reder 2006). Brain atrophy slowed in the subgroup of patients who completed 2 years of IFN-beta-1a therapy. It may slow development of T1 holes compared to placebo in progressive multiple sclerosis (Barkhof et al 2001). However, others find no effect on T1 MRI in secondary progressive multiple sclerosis (Brex et al 2001) and relapsing-remitting multiple sclerosis (Simon et al 2000). Increasing the interferon dose beyond current levels (6 to 12 million units of IFN-beta-1a weekly or 8 to 16 MU of IFN-beta-1b every other day) does not significantly improve outcomes in stable relapsing-remitting multiple sclerosis. There are suggestions, however, that higher doses of subcutaneous IFN-beta-1a reduce relapses, slow progression, and also improve cognition (Ebers and PRISMS Study Group 1998). Effects are more pronounced in patients with Kurtzke scores of greater than 3.5. High-dose IFN-beta benefits cognition. The odds ratio of cognitive decline over 3 years is 0.51 for 44 ug versus 22 ug of IFN-beta-1a (Patti et al 2010). Arguments for early treatment are as follows: • Axonal destruction starts early, with the first exacerbations, and cannot be reversed. • Clinically isolated first symptoms, with concomitant evidence of multiple old and new MRI lesions, are less likely to progress to multiple sclerosis if therapy is begun early (Coyle and Hartung 2002). • Children treated with IFN-beta have few side effects and a good prognosis (Banwell et al 2006). • Interferons reduce the chance that MRI T1 black holes will develop, ab initio. • Immune activity becomes more difficult to control with time. The early inflammatory character is most responsive to interferon, glatiramer acetate, and chemotherapy. • With a 2-year delay before starting IFN-beta-1a, lost function is not regained. • IFN-beta has little benefit in secondary progressive multiple sclerosis (Panitch et al 2004). • IFN-beta-1b prevents death (see below). Caveats to early treatment include: • The diagnosis should be definite before therapy is begun. • Justification for instituting expensive therapy with a partially effective agent is difficult, although the alternative is worsening of multiple sclerosis. Starting therapy is less important when multiple sclerosis has been stable, clinically and on MRI, for years. Long-term treatment is beneficial: • With each exacerbation, there is a 40% chance of persistent neurologic deficit (Lublin et al 2003). • In the 16- and 21-year long-term follow-up IFN-beta-1b studies, interferon use during the original 5-year study led many years later to no significant adverse events, frequent loss of neutralizing antibodies, fewer relapses, 50% less conversion to secondary progressive multiple sclerosis, and an unexplained 47% reduction in mortality (Reder 2010; Reder et al 2010). Sixteen years after the start of the 5-year pivotal trial, 88% of 375 relapsing-remitting patients who had begun to receive IFN-beta-1b approximately 5 years after the onset of disease were evaluated. Annualized relapse rate for those remaining on interferon versus those on therapy for less than 10% of the time was 36% lower at 5 years, 35% lower at 10 years, and 40% lower at 16 years. Patients with the longest time on IFN-beta had less progression and 50% less transition to a progressive course, compared to those on minimal IFN-beta (Ebers et al 2010), which also perhaps partly explains the effect on survival. Note that “responders” would tend to remain on interferon, leading to more apparent benefit. However, deaths were not included in the progression data and would strongly bias data in the other direction. PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 61 of 123 The 5-year period of treatment with IFN-beta reduced mortality 16 years later. There were 20 deceased in the placebo-treated group, 9 in the 1.6-million unit group, and only 6 in the IFN-beta-1b 8-million unit group. This pronounced effect on survival persisted at 21 years, with a 47% reduction in mortality seen in the greater than 98% identified original patients (p < 0.017) (Goodin et al 2011). The 5-year randomization and nearly 100% ascertainment, the equivalent use of multiple sclerosis therapies in all groups after study end, plus the implicit definition of death as a serious adverse event in all trials makes this a powerful prospective study showing that IFN-beta-1b prevents death. The mechanism is unexplained. Interferon immunology. IFN-beta was initially anticipated to kill the “multiple sclerosis virus.” Current thinking is that interferon modifies immunity in multiple ways to ameliorate multiple sclerosis. It reduces adenovirus infections and decreases relapses during periods of severe air pollution (Oikonen and Eralinna 2008) (see aryl hydrocarbon receptor, above), and treatment does reduce the chance that a virus infection will lead to an exacerbation (Panitch 1994). IFN-beta has pleiotropic effects on immunity. Interferon generates some (-) proinflammatory products as well as (+) immunoinhibitory and (+) neurotrophic products. Potential proinflammatory (-) and neurotoxic (-) effects of IFN-beta are part of its antiviral and anticancer properties, and include: • Transient induction of IFN-gamma, TNF-alpha, nitric oxide; reduction of TGF-beta. • Reduced production of IL-10 by activated monocytes. • Some reports contest the putative reduction of Th1 inflammatory cytokines. IFN-beta induces both anti- and pro-inflammatory cytokines, especially with the initial injections (Byskosh and Reder 1996; Duddy et al 1999; Feng 2001). Type I interferons increase long- lived central memory Th1 and CD8 cells, but decrease Th2 cell differentiation. • Induces immature dendritic cells to become immunostimulatory DC1. • Enhances expression of CD14, CD80, and CD86 on monocytes. • Type I interferons plus antigen stimulate IFN-gamma and antibody production in rodents (IgM, IgG1, 2a, 2b, 3, and 4). Interferon exposure prior to antigen inhibits antibody production, but interferon exposure before or with antigen enhances antibody production (Le Bon et al 2001). This may affect antibody responses to newly released brain antigens during CNS destruction. IgG3 levels are not induced in patients by IFN-beta-1a. • Enhanced macrophage, cytolytic T-cell, and natural killer cell function. Potential anti-inflammatory (+) effects of IFN-beta that are potentially of benefit in multiple sclerosis include: • Lymphopenia (especially of natural killer cells). Some of the lymphopenia is from sequestration of lymphocytes in lymph nodes, akin to the effect of fingolimod. • Increase in a suppressor subpopulation of natural killer cells that may be low in untreated multiple sclerosis. • Reversal of the CD8 suppressor T-cell (Noronha et al 1990) and CD4 regulatory T-cell (Venken et al 2008) defects in multiple sclerosis. • A shift from Th1 to Th2 cells in Japanese patients, but not in Caucasians (Ochi et al 2004). • Reduction of inflammatory Th17 cells (Durelli et al 2009) by induction of IL-27. • Increase in IFN-gamma receptors on lymphocytes, possibly allowing activated T cells to die through IFN-gamma-mediated apoptosis (Ahn et al 2004). • Increase in the subnormal expression of the inhibitory immunoglobulin-like transcript-3 (ILT3) on dendritic cells and monocytes (Jensen et al 2010). • Induction of survival of dendritic cells, increasing production of type I interferons. This may reverse the defective plasmacytoid dendritic cell dysfunction in multiple sclerosis. • Induction of mature dendritic cells to inhibit Th1 cells. • Induction of myeloid dendritic cells (mDC) to produce IL-6 and IL-10 (reversing the low level of production in multiple sclerosis). • Increase in dendritic cell expression of PD-L1, an inhibitor of T-cell activation; decrease in their expression of costimulatory proteins. Causes apoptosis in mature mDC and decreases their number. • Induction of plasmacytoid dendritic cells to produce more IFN-beta and less IFN-alpha. PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 62 of 123 • Reduction of IL-23 production. • Reduction of B7-1 (CD80) costimulatory molecules on B cells (Genc et al 1997) and also reduction of CD40, which is needed for B-cell differentiation. • Decrease in production of most chemokines, including CXCL8/IL-8. • Increase in RGS-1, a G-protein coupled receptor that inhibits chemokines and migration. • Decrease in IL-2, IL-17, osteopontin, tumor necrosis factor-alpha, and IFN-gamma levels, as well as IFN-gamma- and IL-4-secreting cells with prolonged therapy. • Increase in activated T-cell production of anti-inflammatory IL-10 in serum and CSF. • Elevation of serum soluble vascular cell adhesion molecules (potentially blocking T cell- endothelial cell adhesion, although serum levels may be too low). • Serum from IFN-beta-treated patients reduces permeability of the blood-brain barrier in a model system. • (+/-) Increase in CD73 on endothelial cells to increase immunoinhibitory adenosine and cAMP levels--but CD73 may increase passage of cells through the choroid plexus into the brain. • Blocks matrix metalloprotease secretion (MMP-9) and enhances tissue inhibitor of metalloprotease secretion (TIMP). • Inhibition of T-cell migration through the blood-brain barrier, preferentially blocking Th1 cell migration more than Th2 cell migration in a model system (Prat et al 2005). • Blocks neutrophil infiltration into the CNS (in rats). • Reduction of the toxic effects of H2O2 and TNF-alpha on brain endothelial tight junctions (Javed and Reder 2006). • Suppression of production of glutamate and superoxide by activated microglia. IFN-beta therapy increases IL-10 in the CSF (Rudick et al 1998); samples may have contained lysed CSF T cells. This IL-10 is likely produced by T cells, and possibly by astrocytes (Hulshof et al 2002), because IFN-beta reduces IL-10 production by activated monocytes yet elevates production by activated T cells (Feng et al 2002b; Hamamcioglu and Reder 2007). Within plaques with a typical 20:1 monocyte:T cell ratio, however, IFN-beta may have immunostimulatory effects because it reduces IL-10 in activated monocytes-- which produce 10-fold more IL-10 than T and B cells (Feng et al 2002b). Potential neurotrophic effects of IFN-beta are: • Induction of neurotrophic and gliotrophic factors such as enkephalins and beta-endorphin in MNC immune cells during active multiple sclerosis (Gironi et al 2000), adrenocorticotropin (ACTH) in immune cells (Reder 1992). • Leukemia inhibitory factor (LIF) in mononuclear cells (also involved in stem cell growth) (Byskosh and Reder 1996). • Nerve growth factor (NGF) by astrocytes (Boutros et al 1997) and endothelial cells (Biernacki et al 2005). • Insulin-like growth factor-1 (IGF-1, along with IGF-binding proteins that block its effect) in relapsing-remitting, but not in secondary progressive multiple sclerosis (Hosback et al 2007). • BDNF by T cells (Hamamcioglu and Reder 2007). • Four to eight hours after the first intramuscular injection, there is a rise in serum ACTH, cortisol, prolactin, and growth hormone and a 1.5 degree C rise in temperature (Then Bergh et al 2007). After 3 months, these hormones do not increase, body temperature rises by 0.6 degrees, and there is a trend for increased serum testosterone. • Alternate transcription of genes, converting an estrogen receptor-binding protein to a neurotrophic factor during IFN-beta therapy (Croze et al 2009). Exon shuffling may be important in neurotrophic genes, which often have complex regulation. • Induction of a large number of genes involved in cytoprotection and energy metabolism after years of therapy, but not after acute administration (Croze et al 2010). • BDNF increases in clinical responders to IFN-beta therapy. • Dose-dependent induction of Schwann cell myelination. • (+/-) Diminished neurite outgrowth and maturation of neural precursor cells, but only at very high doses (100 to1000 units/ml) that are presumably not reached during multiple PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 63 of 123 sclerosis therapy (Wellen et al 2009). • Less astrocyte gliosis and scarring. • IFN-beta, but not IFN-alpha, prevents demyelination in the Theiler virus mouse model. • Indirect neuroprotection by reducing inflammation, conferring 22% survival in retinal ganglion cells during optic neuritis, compared to the 50% survival imparted directly by erythropoietin or CNTF (Sattler et al 2006). • Improved axonal integrity and NAA increases on MRI spectroscopy (Narayanan et al 2001). Interferon dysregulation in multiple sclerosis. Endogenous IFN-alpha/beta production and responses to type I interferon in multiple sclerosis are subnormal (Feng et al 2002a; Billiau et al 2004; Stasiolek et al 2006). Microarrays show the IFN-alpha/beta pathway is surprisingly more dysregulated than the Th1 and Th2 pathways in untreated patients (Yamaguchi et al 2008). Plasmacytoid dendritic cells (pDC) produce less IFN-alpha (Stasiolek et al 2006), and toll-like receptor agonists (TLR7 and TLR9) induce less IFN-alpha than in controls. Low endogenous type I interferon in multiple sclerosis may lead to a propensity to generate more IL-17 and less IL-10. Interferon therapy could compensate for the defect. The interferon signaling pathway differs between mice and men. Interferon responses in the animal model of multiple sclerosis, experimental allergic encephalomyelitis (EAE), differ from multiple sclerosis. IFN-gamma is protective in EAE, yet multiple sclerosis is worsened. IFN-beta, however, ameliorates or worsens EAE in a large number of conflicting studies. Interferon posology. With the same total interferon dose in a week, daily low doses are more effective than a weekly high dose at inhibiting tumor growth (Slaton et al 1999), virus infections, and cytokine production (Rothuizen et al 1999). This high-dose and frequency effect is also true with early inhibition of MRI Gd enhancement and relapses and is suggested, but not proven, for effects on progression of multiple sclerosis. Lower doses of interferon have diminishing clinical efficacy, ie, with IFN-beta-1a, 22 µg < 44 µg subcutaneous weekly, and with IFN-beta-1b, 1.6 < 8 million units subcutaneously every other day. Reduction of dose and frequency provokes attacks. Importantly, however, there was significant benefit of weekly IFN-beta-1a on progression in its pivotal trial. There is a maximum “ceiling” effect of weekly IFN-beta-1a injections in reducing relapses; 60 µg is no better than 30 µg. Doubling every-other-day high dose IFN-beta-1b treatments also had little or no additional benefit on stable multiple sclerosis. Interferon pharmacodynamics. Interferon injections initiate multiple phenomena: • Serum IFN-beta levels peak at less than 1 hour, followed by a second burst of interferons alpha and beta several hours later (Khan and Dhib-Jalbut 1998; van Boxel-Dezaire et al 2006). • Biological response markers are induced for several days (MxA, 2,5-oligoadenylate synthetase, neopterin, and beta-2 microglobulin). Levels fall slightly after a year of therapy (Byskosh and Reder 1996). Intramuscular IFN-beta induces neopterin and beta2- microglobulin with a peak at 24 to 48 hours and a return to baseline by 6 days. Subcutaneous and intramuscular interferon effects are similar. Elevated TRAIL (tumor necrosis factor-related apoptosis inducing ligand) is associated with good clinical response. • Alterations in cytokines, chemokines, and immune cell function. • Cortisol is not induced; however, IFN-alpha does activate cortisol production. • There is more bone growth and osteoclasts dont proliferate—thus, less osteoporosis. • A local depot effect causes red skin and vasodilatation for weeks, suggesting immune cells are also stimulated for a prolonged time. • Gradual shifts occur in immune cell subset survival and distribution over months, especially in immune-suppressive NK cells (Perini et al 2000). Importantly, temporal differences are seen in therapeutic responses to IFN-beta in MRI enhancement (one week), relapses (3 to 6 months), progression (more than 1 year), and possibly neuroprotection. Clinical activity correlates better with immune markers (r = 0.5 to 0.79 in multiple immune assays) than with MRI T2 lesions (r = 0.25) (Feng et al 2002a). Markers of biological responses to IFN-beta. Clinical disease progression and relapses are PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 64 of 123 currently the best markers of therapeutic efficacy, but a biological marker that predicts efficacy would aid in therapy. Before therapy, patients with high T cell proliferation to mitogen (PHA) or anti-CD2/CD28 are more likely to be clinical responders to interferon (88% vs. 16% in this dichotomy) (Killestein et al 2002a) (see CD58, above). High pre- therapy serum IL-17F and IFN-beta (Axtell et al 2010) and MxA mRNA (Reder 2010; van der Voort et al 2010), low IL-10 RNA, and more old and active MRI lesions (Hesse et al 2010) also predict later poor response. Low baseline levels of IL-12 mRNA predict good response to IFN-beta (van Boxel-Dezaire et al 2000), as does low baseline IL-10. During therapy, patients are more likely to relapse when they have high mitogen-induced lymphocyte proliferation, high IFN-gamma plus low IL-10 production, and no decline in serum immunoglobulin. Relapses also occur when ongoing injections do not induce MxA protein (Kracke et al 2000; Feng et al in press). On MRI, interferons rapidly reduce the number of enhancing lesions. IFN-beta reduced new and enlarging T2 lesions by a median of 71% versus placebo (Sormani et al 2005); however, 7% were “non-responders.” The heterogeneity of responses to interferon in this study suggested that MRI is a poor predictor of future treatment failure. In serial studies, 50% are early MRI non-responders, but some of them later become MRI responders (Chiu et al 2009). Prevention of contrast-enhancing MRI lesions after 1 year of therapy generally prevents new lesions from becoming “black holes” in the first place and predicts lower T1 black hole volume in the next 2 years of therapy, as well as less brain atrophy. Continuing atrophy during therapy predicts worse clinical outcome, as does clinical progression on therapy. Suppression of new white matter lesions in later, progressive multiple sclerosis does not slow brain atrophy or disability. Changes in MRI and relapses alone (compared to MRI-, relapse-, and progression- negative) did not predict response to IFN-beta therapy over months 12 to 36. However, a combination of relapses and MRI worsening had an odds ratio of 8.3 for new relapses and 4.4 for progression. With relapse, MRI, plus progression, the odds ratios were 9.8 for predicting new relapses and 6.5 for progression (Río et al 2009). Interferon therapy induces MxA protein in lymphocytes; IFN-beta-1b is the most potent in this regard. This suggests pharmacokinetics differ between IFN-beta-1a and beta-1b, or that there is an ongoing conformational change from inactive to active molecules in the high protein load of IFN-beta-1b. Black patients, compared to whites, are less likely to respond to IFN-alpha therapy for hepatitis C (Kimball et al 2001), and allelic variations in several genes control interferon responses. In the EVIDENCE trial, black patients had poorer response to IFN-beta-1a than white patients (Cree et al 2006). High levels of MxA in white blood cells after starting interferon therapy correlate with fewer relapses (Kracke et al 2000). Approximately 10% of patients have poor MxA induction, regardless of neutralizing antibody status. Interferon inhibitory activity from soluble interferon receptors, virus-induced proteins, drugs such as statins, or intrinsic resistance to interferon signaling are possible causes. It is unclear if there are truly separate groups of responders and non-responders the entire treated population responds. It is unknown if nonresponsive patients would be even worse without treatment. Accurate measurement of activity before therapy versus activity after randomized therapy would separate these 2 models. Before interferon therapy, high serum IL-17F and IFN-beta levels predicted poor response to IFN-beta therapy in approximately 20% of patients (Axtell et al 2010). So did high levels of baseline interferon-stimulated genes (Comabella et al 2009) and MxA (Reder 2010; van der Voort et al 2010). High on therapy responses to IFN-beta are also associated with poor clinical response (Rudick et al 2011). Importantly, however, the majority of multiple sclerosis patients have low serum interferon levels before therapy (Feng et al 2009b) and low responses to IFN-beta therapy (Feng et al 2002). This majority may respond to interferon therapy. Neutralizing antibodies. All interferons induce neutralizing antibodies. Neutralizing antibodies cross-react with all forms of recombinant IFN-beta, but not with IFN-alpha. The PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 65 of 123 incidence of neutralizing antibodies is highest with frequent (every other day) and subcutaneous IFN-beta-1b (30%), lower with subcutaneous IFN-beta-1a (15%), and lowest with weekly intramuscular IFN-beta-1a (2%) (Ross et al 2000; Bertolotto et al 2002). Assays differ: a titer of 1:400 with IFN-beta-1b is comparable to a titer of 1:100 with IFN- beta-1a, so IFN-beta blocking ability at a given titer will also differ. Low doses of IFN-beta-1b and IFN-beta-1a are stronger inducers of neutralizing antibodies than high doses of the same interferon. Concomitant glucocorticoid therapy reduces formation of neutralizing antibodies. Antibodies usually appear within 1 to 2 years of IFN- beta-1b treatment, but they eventually disappear (Rice 1997). Neutralizing antibodies tend to persist during IFN-beta-1a therapy. With high-titer neutralizing antibodies, interferon-induced biological response markers fall, and so do side effects. The blocking effect is most visible with low doses of IFN-beta and with high titers of neutralizing antibodies. A double dose of IFN-beta doubles MxA protein in patients who have neutralizing antibodies. During the neutralizing antibody-positive period, some MRI enhancement reappears, and biological markers such as serum beta2- microglobulin, MxA, neopterin, viperin, IFIT-1, and 2,5-OAS fall. However, other markers such as IL-10 secretion are not affected. The differential gene responsiveness to neutralizing antibodies is partially explained by the huge variability in interferon response between patients (Reder et al 2008). Treatment effects are restored after patients revert back to antibody-negative. Neutralizing antibodies correlate with reduced efficacy of interferon therapy (Sorensen et al 2003; 2005; 2006; Francis et al 2005) and partial loss of benefit on MRI (Pachner et al 2009). This (logical) relationship has not been clinically proven. With IFN-beta-1b, antibody- positive patients do at least as well as antibody-negative patients (Goodin et al 2007a; 2007b). Rate of progression tends to improve in neutralizing antibody-positive patients. Improvement in the presence of NAb is unexplained, but there are a number of disquieting facts that suggest that antibodies to interferons have complex effects, some of which could enhance interferon signaling (Reder 2007; Moll et al 2008). In the first year of therapy, patients destined to become neutralizing antibody positive (but not yet positive), have a better clinical response to interferon therapy in all published trials. It is possible that binding antibodies, induced early, enhance interferon signaling or prolong its half life. Neutralizing antibodies could also have a non-specific effect on Fc receptors, paralleling the inhibition induced by intravenous immunoglobulin therapy. With longer therapy, 43% of the patients in the pivotal IFN-beta-1b trial were antibody positive, and therefore, one would expect even higher frequencies in any population with clinical worsening. However, only 12% of patients with worsening multiple sclerosis have high titers of neutralizing antibodies (greater than 1:100 dilution), and only 21% have detectable antibodies (1:20) (Goodin et al 2007a; 2007b). Certain patients are predisposed to the development of neutralizing antibodies (NAb) (Reder 2007). Before starting interferon, this subgroup of patients tends to have higher pokeweed mitogen-induced immunoglobulin secretion (Oger et al 1997), high serum ApoE (immunosuppressive), more exacerbations (Petkau et al 2004), and possibly more enhancing lesions on MRI (Calabresi et al 1997). Patients with these active responses are predestined to have a worse course of multiple sclerosis. Table 2 compares the putative effect of neutralizing antibodies on interferon efficacy. This is a hypothetical comparison of different populations (varied placebo and treated groups), drug doses, and trial designs. It could be argued that with these large populations, drug and antibody effects on relapsing-remitting multiple sclerosis are more important than minor differences in study populations and trial design. Table 2. A Therapeutic Calculus of Multiple Sclerosis Treatments: Effect of NAb Titer vs. NAb Duration Pivotal Relapses: Progression: Progression: T2 Gd+ PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 66 of 123 trial % fewer % less vs. % less vs. MRI: MRI: data vs. PL PL° PL°° % % benefit benefit vs PL vs PL Avonex 32 21 61*** 52*** 6 MU per wk (a) Avonex 18 37 xxxxx xxxxx ITT Betaseron 16 0 75 1.6 MU every other day Betaseron 34 29 31 75 8 MU @ 2y Rebif 27 22 67 22 mcg 3 times a week Rebif 33 30 78 84 44 mcg 3 times a week (b) Copaxone 29 12 30**** 29 20 mg per day Tysabri 68 42 83 92 300 mg each month ° Confirmed (Data from pivotal trials) °° Unconfirmed; significant in both Betaseron & Copaxone; not used below for putative effect of NAb (Data from pivotal trials) *** 61 and 52 are subsets of the total study population **** 30 = percentage of new lesions vs placebo (PL) @ 9 months Relapses: NAb effect x frequency of NAb [Pivotal relapse rate-{pivotal relapse rate x % blocking x % NAb positive} ] 100% block 50% block 33% block (change in (change in (change in RRate) RRate) RRate) Avonex 1 x 0.05 (d) 0.5 x 0.05 0.33 x 0.05 6 MU each week (30.4) (31.2) (31.5) PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 67 of 123 (a) Avonex ITT 1 x 0.05 0.5 x 0.05 0.33 x 0.05 (17.1) (17.6) (17.7) Betaseron 1 x 0.385 0.5 x 0.385 0.33 x 0.385 1.6 MU @ 2y (9.84) (12.9) (14.0) Betaseron 1 x 0.365 0.5 x 0.365 0.33 x 0.365 8 MU @ 2y (21.6) (27.8) (29.9) (NAb peak) Betaseron 1 x 0.10 0.5 x 0.10 0.33 x 0.10 8 MU @ 4y (c) (30.6) (32.3) (32.9) (NAb falling) Rebif 1 x 0.238 0.5 x 0.119 0.33 x 0.22238 22 mcg 3 times a (20.6) (22.5) (24.9) week Rebif 1 x 0.125 0.5 x 0.125 0.33 x 0.125 44 mcg 3 times a (28.9) (30.9) (31.6) week (b) Copaxone No effect 20 mg each day (benefit?) (X) (X) Tysabri/Antegren 1 x 0.06 300 mg each (63.9) (X) (X) month Progression: NAb effect x frequency of NAb (e) 100% block 50% block 33% block (change in (change in (change in progression) progression) progression) Avonex 1 x 0.05 (d) 0.5 x 0.05 0.33 x 0.05 6 MU each week (20.0) (20.5) (20.7) (a) Avonex ITT 1 x 0.05 0.5 x 0.05 0.33 x 0.05 (35.2) (36.1) (36.4) Betaseron 1 x 0.385 0.5 x 0.385 0.33 x 0.385 1.6 MU @ 2y (0) (0) (0) Betaseron 1 x 0.365 0.5 x 0.365 0.33 x 0.365 8.0 MU @ 2y (NAb (18.4) (23.7) (25.5) peak) Betaseron 1 x 0.10 0.5 x 0.10 0.33 x 0.10 8.0 @ 4y (c) (26.1) (27.6) (28.0) (NAb falling) Rebif 1 x 0.238 0.5 x 0.119 0.33 x 0.22238 PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 68 of 123 22 mcg 3 times a (16.8) (18.3) (20.3) week Rebif 1 x 0.125 0.5 x 0.125 0.33 x 0.125 44 µg 3 times a (26.3) (28.1) (28.8) week (b) Copaxone NA 20 mg each day (benefit?) (X) (X) Tysabri/Antegren 1 x 0.06 300 mg each (39.5) (X) (X) month Adversities: Relative importance (f) Flu-like LFT/WBC IPIR Skin Sx Avonex + (early) + 0 Redness: 0 6 MU each week (a) Lumps: 0 Necrosis: 0 Betaseron + +/- 0 1.6 MU @ 2y Betaseron ++ + 0 Redness: ++ 8.0 MU @ 2y (early) (most) Lumps: + (in 5%) Necrosis: +++ (in 2%) Rebif 22 mcg 3 times a week Rebif ++ + 0 Redness: ++ 44 µg 3 times a (early) (most) week (b) Lumps: 0 Necrosis: +++ (rare) Copaxone 0 0 ++ Redness: + 20 mg each day (1/1000) (most) Lumps: 0 Necrosis: 0 Tysabri/Antegren 0 0 + 300 mg each month (a) Based on subset of 2-year completers (164/272); instead of all subjects entered (272) and comparisons with intent-to-treat analysis (ITT). (b) Faster therapeutic onset with high dose interferons may be important in very active multiple sclerosis. (c) Effect at 2 years (at peak NAb positivity) and at then 4 years (when most on IFN-beta-1b return to NAb-negative status). Two-year values are used for putative 4-year calculations. PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 69 of 123 IFN-beta-1a induces higher and more persistent titers than IFN-beta-1b. Measured titers can be off by 3-fold, depending on the subtype of interferon used to spike the assay (Files et al 2007). (d) NAb % age (5%=0.005) is not from pivotal trial (22%); but from experience with later Avonex product. Danish data show 20% NAb development in relapsing-remitting multiple sclerosis with 2 attacks/2y. (e) Effects on progression are unclear; several studies suggest NAbs have a beneficial effect on progression. NAb could affect innate immunity or the NAb+ subgroup may be immunologically unique--and predestined to behave differently, regardless of NAb status. (f) Convenience is important to some. An international airline stewardess may not want frequently-dosed, refrigerated drugs. Ataxic patients may require the easiest injections. Compliance increases with tolerability and convenience. CBC = complete blood count, IPIR = immediate post-injection reaction, LFT = liver function tests, Nab = neutralizing antibody, PL = placebo. Note: Cross-study comparisons are not valid. Nonetheless, these large studies provide well- controlled large-population data. NAb data from more recent interferon studies are pending. Neutralizing antibody to interferons could also predict development of autoantibodies to other antigens. There are reports of autoimmune thyroiditis, systemic lupus erythematosus, and rheumatoid symptoms with IFN-alpha therapy, usually in subjects with pre-existing autoantibodies. However, there is little or no increase over background incidence of autoantibodies with IFN-beta therapy. Correlation of autoantibodies before and after interferon therapy and links to neutralizing antibodies is under study. Withdrawal of interferons leaves a window of safety from multiple sclerosis activity that lasts weeks to months. A small series shows no MRI lesions for 6 to 10 months after discontinuation. Occasionally, however, patients who were deemed “interferon failures” have exacerbations or rapid progression several weeks after discontinuation of interferon. This indicates that therapy had been partially effective, even in patients with some clinical symptoms during treatment. Side effects with IFN-beta are relatively rare and are largely from induced cytokines. Acute toxicities include transient influenza-like symptoms, headache, increased temperature (sometimes prolonged) and heart rate, fatigue, maculopapular rash (rare), and sometimes spasticity, especially with preexisting cord lesions. At 24 hours blood lymphocytes diminish, but monocytes rise. Flu-like symptoms correlate with induced levels of prostaglandins and IL-6. IL-6 levels and temperature rise more with evening than with morning injections. Side effects are comparable in children, although those younger than 10 years old are more likely to develop elevated liver function tests. Flu-like side effects improve with time and with acetaminophen, aspirin, hydration, and other interventions (Walther and Hohlfeld 1999). A personalized nursing program increases adherence to therapy. Chronic toxicities appear in a small percentage of patients and include weight loss (approximately 2 kg), a mild fall in white blood cell count and neutrophils that usually disappears by 4 months, increased liver function tests especially at 1 to 2 months after start of high-dose therapy, and an increase in triglycerides yet a decrease in cholesterol (Byskosh and Reder 1996; Tremlett and Oger 2004). There have been several cases of serious liver injury, autoimmune hepatitis, and pancreatitis with IFN-beta-1a, often on a background of associated autoimmune markers. De novo thyroid dysfunction and autoantibodies are not a problem with IFN-beta (Reder et al 2010). Patients on IFN-alpha and, occasionally, IFN-beta therapy for hepatitis C develop cotton-wool spots (from retinal hypoperfusion) and retinal hemorrhage. One quarter treated with IFN-alpha (for hepatitis B) have slowed visual evoked potentials. However, visual evoked potentials actually improved with IFN-beta-1b in a small study (Pliskin et al 1997). Some women, often with a prior history, develop menstrual disorders with weekly IFN-beta-1a, but IFN-beta-1b seems to reduce complaints on average. Rare patients, often with a history of depression, complain of worsening depression. In large PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 70 of 123 controlled studies, however, depression was not induced. Selective serotonin reuptake inhibitor antidepressants or a switch to glatiramer are the drugs of choice. A 2 cm warm red macule often appears at the injection site. The pain from subcutaneous IFN-beta-1a injections can be ameliorated by injecting room-temperature interferon solution, possibly pre-cooling the skin with ice, allowing an air bubble to enter as the last part of the injection, and possibly by rubbing the site after injections. Skin necrosis and panniculitis occasionally develop with subcutaneous IFN-beta-1b. The rate has decreased with better patient education, vertical as opposed to oblique injections, interferon-free needle techniques, and an auto-injector apparatus. The skin necrosis rate over 2 years was 1% in 3 of 292 patients (Kappos et al 2007). Necrosis is less common with subcutaneous IFN-beta-1a and glatiramer acetate, and is not seen with intramuscular interferon injections. Japanese patients, who are 15 kg lighter and who have different diets than American patients, had 14% necrosis rates over 2 years with IFN-beta-1b. Skin Langerhans cells could be activated by interferon aggregates. Interferon may prevent angiogenesis and wound healing by decreasing IL-8. (IFN-beta induces IP-10/CXCL10, which downregulates IL-8 and also induces migration of T cells into the lesion; interferon-induced MCP-1/CCL2 promotes macrophage migration.) There is strong synergy between interferon and lipopolysaccharide to induce tristetraprolin, a protein that shortens the half-life of many cytokines (Sauer et al 2006). It is likely that any systemic infection (dental procedures, periodontal disease, surgery, cystitis, and smoking with bronchitis) could potentiate a localized interferon bolus. Following dental procedures, a short course of antibiotics before the next interferon injection may be advisable (Arnason personal communication 2006). Primary Sjögren syndrome, lupus manifestations, and dermatomyositis have appeared after IFN-beta therapy. Lupus erythematosus and Sjögren syndrome have a marked “interferon signature” unlike the hypo-response to interferon that characterizes multiple sclerosis (Javed and Reder 2006), and it is possible that a rise in interferon levels provokes these diseases that are rarely associated with multiple sclerosis. There are suggestions that there is less cancer in patients treated with intramuscular IFN- beta-1a. Interferons enhance fertility, perhaps by enhancing implantation. Type I IFN-tau in ungulates enhances implantation, similar to human chorionic gonadotrophin. IFN-beta is a category C drug and not advised during pregnancy. Women who remained on IFN-beta for an average of 5 weeks while pregnant had smaller babies (114 g and 1.2 cm less), but no excess of spontaneous abortions or developmental abnormalities (Amato et al 2010). Interferon therapy during breastfeeding is not recommended. However, a huge dose, 30 million units, of intravenous interferion-alpha-2b only slightly elevates milk inteferon levels (from 1249 to 1551 IU/ml) (Kumar et al 2000), and most of this should be eliminated in the babys gastrointestinal system. Pumping and disposing of the milk for 5 hours after the injection is another option, as most interferon should be cleared, but this would be “off- label” use. Delaying interferon therapy for the first few days after delivery allows the baby to ingest colostrum. Glatiramer acetate. Glatiramer acetate, 20 mg subcutaneously daily, reduces exacerbations by one third. Glatiramer reduces the chance of developing clinically definite multiple sclerosis after a first attack by 45% compared to placebo (PreCISe study). In a well- designed study, cognition was not affected, but the placebo group did not decline over time. Doubling the daily dose has no additional benefit in stable relapsing-remitting patients. Anecdotal reports claim benefit in childhood onset multiple sclerosis. Every-other-day drug was equivalent to every day dosing in 30 patients (Khan personal communication 2008). Long-term follow-up of the original trial showed low relapse rates and low rates of progression. However, only 43% of the patients were identified, so the majority may or may not have stopped therapy because of worsening. Mechanism of action of glatiramer. Glatiramer suppresses immune responses to brain antigens. It binds with high affinity to some major histocompatibility proteins on antigen- presenting cells, possibly acting as an altered peptide ligand or a competitor to pathogenic antigens. HLA-DR2 patients may respond best to glatiramer. Glatiramer inhibits expression PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 71 of 123 of activation molecules on monocytes and also transforms them to type II monocytes. These cells release fewer inflammatory monokines, but more IL-10, and induce deviation to Th2 cells (Weber et al 2007b). Glatiramer acetate induces a Th2-biased response in 30% to 50% of patients; these cells penetrate the blood-brain barrier more easily than Th1 cells and are present in CSF 12 months after therapy is begun. Glatiramer polarizes T cells to Th2 cells that in turn induce immunosuppressive type 2 monocytes and microglia (and B cells), which further amplify the Th2 deviation (Kim et al 2004). Therapy reduces elevated IL-12, but not IL-10, in mononuclear cells. Effects on IL-17 are unknown. Glatiramer increases numbers of regulatory CD4 T cells in relapsing-remitting multiple sclerosis (Venken et al 2008). Glatiramer acetate and cross-stimulating myelin antigens (Stapulionis et al 2008) induce secretion of Th2 cytokines (including neuroprotective BDNF) and in turn induce elevated titers of IgG4 and of IgG1, greater than IgG2 (no IgM or IgE). Antibodies to glatiramer are mostly IgG1 (a Th2-induced subtype). They do not block function and actually appear to enhance efficacy. Clinical effects of glatiramer in mice are rapid and dramatic; in man they appear at 3 months. This suggests that the mechanism of action differs between mice and men. Before treatment, CD8 cells proliferate poorly to glatiramer acetate; this normalizes after 1 year of therapy (Karandikar et al 2002). These CD8 cells secrete IFN-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta. Glatiramer induces oligoclonal proliferation of CD8 T cells (Karandikar et al 2002). CD8+high,CD28-,CD57+ suppressor cells kill pathogenic activated Th1 CD4 cells linked with monocytes in a CD8/CD4/APC interaction (Tennakoon et al 2006) and are an important therapeutic target. Glatiramer reduces the excessive levels of the activating zeta chain of the T cell receptor on CD4 cells and increases levels on CD8 cells (Khatibi and Reder 2008). It also reverses a defect in the small human population of CD4+,CD25+ regulatory/suppressor T cells. Glatiramer acetate reduces new and enlarging MRI lesions. These effects were weaker and delayed compared to interferon therapy in the pivotal trials, but were equivalent in large face-to-face studies. Gd+ lesions do not discriminate between clinical responders and non- responders to glatiramer. However, glatiramer may facilitate repair of T1 black holes from acute lesions on MRI (Filippi et al 2001). Brain atrophy slows over 18 months of glatiramer therapy. On MR spectroscopy, the N-acetyl aspartate/creatinine ratio increases after 1 year of therapy, possibly from a neuroprotective effect. Although brain inflammation is not desirable, activated T cells can produce neurotrophic factors. Activation of T cells, B cells, and monocytes with myelin or glatiramer acetate will induce brain-derived neurotrophic factor, insulin-like growth factor, platelet-derived growth factor, and other neurotrophic factors (Hohlfeld et al 2000). Glatiramer enhances Th2, but not Th1, cell migration across human brain microvascular endothelium in vitro (Prat et al 2005). Glatiramer acetate, injected in complete Freund adjuvant, induces murine T cells that protect against neuronal damage from multiple causes (Schori et al 2001). It is hoped that glatiramer induces neurotrophic factors in multiple sclerosis plaques. Glatiramer also directly interacts with neurons and prevents stress-induced death. Additionally, it prevents prion infection of cells (Cashman personal communication 2000). Side effects of glatiramer include injection site erythema (reduced by 5 minutes of skin pre-warming), skin pigmentation, and rare lymphadenopathy. Atrophy of subcutaneous fat occurs in nearly half of patients. Lipoatrophy is most common in thin, red-headed women (Edgar et al 2004). The panniculitis includes infiltrating polymorphonuclear neutrophils, eosinophils, CD8 cells, B cells, and formation of germinal centers. Suggestions to prevent injection site reactions include warm compresses, and suggestions to prevent atrophy include never injecting cold solution and rotating sites. The package insert cautions against rubbing the injection site, but there is no rationale given for this; rubbing reduces skin reactions to IFN-beta. There is an “immediate post-injection reaction” (IPIR) in 1/1000 to 1/3000 injections. This reaction consists of chest tightness and shortness of breath, palpitations, dizziness, flushing, and anxiety. It may be from abrupt pulmonary passage of a bolus of intravenous glatiramer. PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 72 of 123 Glatiramer versus interferon, glatiramer plus interferon, and comparison with natalizumab. Patients who have disease activity despite IFN-beta treatment have a reduced relapse rate after switching to glatiramer (Wolinsky 2004), but a non-switch control group was not studied. In another study of 101 patients with some disease activity, switches, and likely regression to the mean, reduce disease activity over 4 years as follows: IFN-beta at a baseline of 42% relapse-free becomes 53% relapse-free after a switch to glatiramer; glatiramer to interferon, 12% becomes 87% relapse-free; and intramuscular IFN-beta-1a to subcutaneous IFN-beta, 41% becomes 67% relapse-free (Gajofatto et al 2009). Changing again was even more effective. Two large trials in patients with stable relapsing-remitting multiple sclerosis showed that high-dose, high-frequency IFN-beta and glatiramer had very similar effects on relapse rates and T2 MRI lesions. Glatiramer reduced the relapse rate as well as IFN-beta-1b, 250 or 500 ug every other day (BEYOND trial), and as well as subcutaneous IFN-beta-1a, 44 ug thrice weekly (REGARD trial). There were also no MRI differences between glatiramer and IFN-beta when using triple-dose gadolinium in a 3T magnet, a technique perhaps so sensitive that unquenched low-level MRI activity was detected with both drugs. Glatiramer had more troublesome skin reactions, but no flu-like symptoms. IFN-beta-1b had less black hole evolution on trial than glatiramer. A study of glatiramer versus weekly intramuscular IFN- beta-1a versus the combination is in progress. The combination of glatiramer and natalizumab in 55 patients over 20 weeks was safe. It reduced new T2- and Gd-enhancing MRI lesions by 3-fold compared to glatiramer alone in the GLANCE study. Natalizumab. Natalizumab is an antibody to a late activation antigen (VLA-4) expressed on activated T cells and monocytes. The antibody prevents adhesion of activated T cells to endothelial cells. Six monthly intravenous infusions caused a 10-fold drop in Gd+ MRI lesions and a 50% decline in relapses compared to placebo (Miller et al 2003). There was also benefit in the one third of patients with progressive disease. A large phase III trial showed 83% and 92% fewer new and enhancing MRI lesions, 42% less conversion of MRI T2 lesions to T1 holes, 66% reduction in relapse rate, 43% slowing in progression, less visual loss, improvement in quality of life, and less fatigue. This drug prevents axonal damage, measured by normalization of neurofilament light chain levels in the CSF (Gunnarsson et al 2011), and improves visual and sensory evoked potential function. After stopping therapy, there was no clinical rebound in the controlled trials, and suggestions of long-term benefit remained (OConnor et al 2011). Several small series later found many new MRI lesions or more clinical activity after stopping therapy in several patients. Because many of the patients on therapy had highly active multiple sclerosis before treatment, it was not clear if this was a true rebound or simply a return to baseline high activity. Many patents switching to this therapy have somewhat active multiple sclerosis despite other treatments. However, discontinuation of the other agents is often followed by abrupt worsening. This author recommends no more than a 1-week gap between discontinuation of interferon or glatiramer and start of anti-VLA-4 therapy. Six percent of patients develop persistent neutralizing antibodies that block efficacy. If these neutralizing antibodies persist, the therapy should be stopped. Progressive multifocal leukoencephalopathy (PML) was seen in 2 patients on the interferon and natalizumab combination in the pivotal trials, but this was not statistically different from the 0 patients in the natalizumab only group. To prevent PML, however, natalizumab monotherapy is required. As of June 30, 2011, 145 cases of PML have occurred, in approximately 83,000 patients, many on more than 2 years of therapy; 143 patients were on natalizumab monotherapy. The overall risk of PML during natalizumab therapy is generally assumed to be approximately 1/1000. The risk is actually 1/415 after the first year of therapy, and other factors change the risk. The incidence of PML is 4-fold higher with prior chemotherapy. Because approximately 50% of the population is John Cunningham virus (JCV) positive, the risk for PML doubles in JCV-positive patients. If JCV-negative, the risk of PML is low-- PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 73 of 123 approximately 1/30,000 per year assuming 1% conversion to JCV-positive per year and 2% false negative on the JCV titer test. Assume the overall risk is 1/1000. After 11 years of therapy, the risk is 1/100. If JCV-positive, the risk of PML rises from 1/1000 to 1/360. If JCV-positive with prior chemotherapy, the risk increases to 1/125 per year. Importantly, these are the risks for each year, so after a total of 11 years on therapy, the risks are approximately 1/100 for all patients, 1/36 (3%) for JCV-positive patients, and 1/12.5 (8%) for JCV-positive patients with prior chemotherapy. Occasional cases of CNS lymphoma and toxoplasmosis may be related to drug use. Fingolimod. Fingolimod, FTY720, is a sphingosine 1-phosphate receptor agonist that is derived from the ascomycete metabolite ISP-1 (myriocin). It interferes with S1P receptor function and prevents egress of lymphocytes from lymphoid organs. The quarantined cells become tolerized or suppressed, possibly by lymph node stromal cells. Cells affected are T >B, CD4>CD8, and T-helper>T-regulatory. S1P receptors are upregulated in Sjögren syndrome, suggesting that doses may need to be modified in the face of some concurrent diseases. Oral FTY720 compared to placebo reduced relapses (54%), slowed progression (17.7% vs. 24.1% in placebo), and reduced MRI lesions (0.2/scan vs. 1.1/scan in placebos) [phase III FREEDOMS trial, nearly 1300 patients (Kappos et al 2010)]. There was slower atrophy on MRI. Oral FTY versus intramuscular IFN-beta-1a had similar benefit on relapses, some reduction in MRI lesions, and no difference in progression (Cohen et al 2010). The 0.5 mg dose was approved by the United States Food and Drug Administration in 2010 as first-line therapy for relapsing forms of multiple sclerosis. Side effects include slowing of heart rate only at the first dose, elevated liver enzymes, a possible increase in DNA virus infections, and macular edema. Diabetes, smoking, and past uveitis increase the risk of macular edema. It is prohibited during pregnancy. There was no increase in cancer in treated patients in the short term of the study. Of note, the mandated chest CT scans that were part of this study have an expected risk of 1:2000 cases of cancer in the younger multiple sclerosis patients. FTY720 readily crosses the blood-brain barrier. FTY720 dose- and time-dependently stimulates neuronal and oligodendroglial growth, and enhances astrocyte support of neurons. In oligos, lower doses facilitate growth and survival; higher doses are toxic, and S1P5 and S1P1 receptors are involved (Eskan et al 2008; Miron et al 2008). Experimental allergic encephalomyelitis studies suggest that the FTY benefit is more from effects on astrocytes than on T cells. It also induces IFN-beta secretion (Eskan et al 2008). Interferons may synergize with FTY in preventing egress by increasing CD69--linked to the sphingosine 1-phosphate receptor. Plasmapheresis and plasma exchange. Plasmapheresis had no effect in a series of studies in the 1980s, although in a study of 200 chronic progressive multiple sclerosis patients, many of the 139 patients followed for 3 years improved (Khatri et al 1991). The number of dropouts precludes firm conclusions, and a later Canadian study found no benefit. There was some benefit in a mixed population of demyelinating diseases in patients who have fulminant severe motor deficits and have not recovered with steroid therapy (Weinshenker and Lucchinetti 1998; Keegan et al 2002). Similar responders to plasma exchange typically show Lucchinetti pathological pattern II, but not patterns I and III, in brain-lesion biopsies (Keegan et al 2005). Intravenous immunoglobulin. Intravenous immunoglobulin (IVIG) had unimpressive effects in most North American and Danish studies. A large randomized trial in Austria showed benefit on relapse rate that was comparable to interferons and glatiramer acetate (Fazekas et al 1997), but a follow-up study was negative (Fazekas et al 2008). Intravenous immunoglobulin may reduce the probability of developing definite multiple sclerosis after the first attack (Achiron et al 2004). The number of enhancing MRI lesions is the same, but their volume is reduced, suggesting a suppressive effect at the margin of the lesions. IVIG may prevent CNS atrophy. In interferon- or glatiramer-treated patients (45% black, 55% white) with optic neuritis who had failed glucocorticoids (13% improved), IVIG led to improvement in 78% (Tselis et al 2008). Differences between intravenous immunoglobulin studies may lie PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 74 of 123 in plasma donor populations from different centers, in formation of aggregates in the commercial intravenous immunoglobulin preparations, or in Fc receptor polymorphisms in the patients. IVIG has many effects on immunity relevant to multiple sclerosis. Aggregated immunoglobulin induces suppressor T cells or prostaglandin-secreting monocytes. IVIG may also block endogenous cytokines or transport bound cytokines into the recipient. Intravenous immunoglobulin binds to Fc receptors. Fc receptor allotypes are correlated with disease course in multiple sclerosis (Vedeler et al 2001). Novel Fc-based ligands that block the excitatory Fc receptor potently prevent T cell and macrophage activation before the cells enter the brain (White et al 2001). There may be synergy between intravenous immunoglobulin and IFN-beta. The immunostimulatory high-affinity Fc gamma receptor I is downregulated by IFN-beta, especially in multiple sclerosis (Van Weyenbergh et al 1998). Whether to treat. Expert clinicians debate about when to treat. Multiple sclerosis has a variable course, some forms of multiple sclerosis are less responsive to therapy than others, and treatments are not perfect. Some argue for caution because 17% of cases are benign at 10 years, 40% are progressive and not as responsive to therapy, reduction of brain atrophy is not dramatic, and neutralizing antibodies could appear. Treatment is avoided in those with low disability at 5 years, little MRI activity, progressive disease and inactive MRI, and clinically mild disease (Pittock et al 2006). In the pro-treatment camp, it is argued that most axonal damage occurs in the first year, most patients will (unpredictably) develop significant disability, the drugs have benefit, and any delay in therapy causes more MRI and clinical disability. These authors suggest the earliest reasonable treatment (Frohman et al 2006). Once treatment is started, discontinuation is highest in patients who have more disability, those who feel the drug is not efficacious, and those who have side effects. Appropriate patient expectations, plus dose escalation, smaller needles, access to medical personnel in clinic or through a drug hotline, clean needle injections, and analgesics such as acetaminophen and long-acting naproxen can enhance drug compliance (Frohman et al 2002). Experimental therapies. Therapies that are experimental or undergoing testing in patients include antibodies and small proteins that destroy T cells (anti-CD52) and B cells (anti-CD20), or that block T cell receptors, block inflammatory cytokines (anti-IL-1, anti-IL- 12, anti-IFN-gamma), chemokines, costimulatory proteins (anti-CD80/CD86, B7-1/B7-2), or adhesion molecules (anti-LFA-1/anti-CD18 and anti-VLA-4 oral small molecules or intravenous antibodies). • Antibodies: - Alefacept (anti-CD2) reduces psoriasis in 50% of patients, but non-responders had increased expression of immune activation molecules. This mixed agonist/antagonist reduces effector memory T cells but may also decrease regulatory T cells. In multiple sclerosis, CD2 binding is abnormal (Reder et al 1991); trials should be performed with caution. - Alemtuzumab (CAMPATH) is a monoclonal antibody against CD52. It depletes mature T cells for years, although hematopoietic stem cells are said not to express CD52. During delayed immune reconstitution, after therapy, first B cells, then Treg and Th2 cells increase sequentially. Alemtuzumab therapy reduces MRI lesions and relapse rate for 18 months, but many patients continued to progress in early studies. Compared to a thrice-weekly IFN- beta-1a competitor, alemtuzumab reduced MRI lesion burden, and attack rate by 74%, progression by 71% and was effective at extremes of all subgroups (CAMMS223 Trial Investigators et al 2008). In the 2-year, phase III CARE-MS trial, relapses were 55% less than with IFN-beta-1a, but there was no significant effect on progression (8% vs. 11 on interferon worsened). It is not effective in progressive multiple sclerosis. There was a 33% incidence of (treatable) hypothyroidism in the initial study; the mechanism is unexplained. Viral infections, idiopathic (immune) thrombocytopenic purpura and glomerular basement membrane disease occurred in several patients in the second trial. PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 75 of 123 - Atacicept blocks B-cell activation by BLyS and APRIL. This study was stopped. - Belimumab blocks BLyS (BAFF), a B-cell activation factor. - Daclizumab binds to IL-2-receptor-alpha on T cells and expands CD56bright suppressor NK cells and Treg cells. Daclizumab decreases relapses by 33% (or trends to do so) and MRI activity by 50% over 1 to 2 years; it decreases relapses by 78% from the prior rate in patients who failed interferon therapy. CD4 and CD8 cells decline; NK cells are elevated and may kill activated T cells. Another phase IIb study is in progress. - DC2219 targets CD22 and CD19 on B cells and kills them. - Epratuzumab (anti-CD22) targets an adhesion molecule that upregulates B-cell receptors. It depletes 40 % of B cells, but does not change antibody levels. - Recombinant human IgM may engender remyelination. - Rituximab, an antibody against CD20 memory B cells, reduced relapses by 50% in relapsing-remitting disease (Hauser et al 2008). It completely depletes B cells from the cerebral perivascular spaces, suggesting it would benefit progressive multiple sclerosis. A trial in progressive multiple sclerosis did not slow progression by 50% in the entire group, but there was benefit in younger patients who had a stronger inflammatory signature. Fc receptor polymorphisms affect drug responses. CSF B-cell counts decrease by one half in 55% of patients. Ocrelizumab, a humanized form of rituximab, has similar effects in early studies. - A modified anti-CD3 antibody can induce tolerance and expand CD8 regulatory T cells. - Antibodies to LINGO may stop inhibition of remyelination. • Adenosine 2A receptor agonists (ATL313) inhibit neuropathic pain. • Chemokine receptor blockade. • Chemotherapy. Antimetabolites (inhibitors of pyrimidine biosynthesis [FK778, gemcitabine, leflunomide, teriflunomide], inhibitor of inosine monophosphate dehydrogenase [VX-97]). Early studies show a 60% reduction in MRI total lesion volume and 30% slower disability progression. There is an additive effect with IFN-beta-1b. • Anti-inflammatory cytokines (IL-4, IL-10, IFN-tau, alpha-melanocyte stimulating hormone) (Skurkovich et al 2001). • Estriol, the hormone that increases during the low-attack, later trimesters of pregnancy, has some benefit in early relapsing multiple sclerosis and reduces expression of costimulatory molecules. A combination study with glatiramer is in progress. High estradiol levels in men correlate weakly with clinical disability and more tissue damage on MRI (Tomassini et al 2005). Estriol inhibits experimental allergic encephalomyelitis in male and female mice. • Firategrast (oral anit-VLA-4) reduced new MRI lesions by 50% at 6 months. • Fish oil (cod liver oil), omega-3 fatty acids, and long-chain fatty acids (evening primrose oil, flaxseed oil) are anti-inflammatory. They have a modest but debatable benefit on relapses. • Fumarate (BG00012; BG12) is an oral agent used for psoriasis. It causes a Th1 to Th2 shift, reduction of new enhancing MRI lesions by 69%, a 32% nonsignificant fall in relapses in a small study, and possible neuroprotection with fewer new T1 MRI lesions. Gastrointestinal side effects occur. • Glatiramer double-dose is being tested. • Granulocyte-colony stimulating factor (G-CSF) reduces Th1 cytokines, increases regulatory CD4 T cell and dendritic cell production of IL-10, TGF-beta, and IFN-alpha (Rutella et al 2005). IL-10 and IFN-alpha induce Treg cells in mice. However, there are reports of exacerbations after G-CSF in multiple sclerosis. • Helminth ova (pork whipworm) to shift gut and then peripheral immunity from Th1 to Th2 is in a safety trial (J Fleming, U Wisconsin, personal communication). • Immune cell inhibitors. Blocking protein kinase cascades (Janus kinase [JAK], lymphocyte- specific cytoplasmic protein kinase [p56 Lck], mitogen-activated protein kinase [MAPK], protein kinase C [PKCtheta], TCR zeta chain associated protein [ZAP-70]) or nuclear factor of activated T cells [NFAT]). • Interferon conjugated to polyethylene glycol (PEG)-interferon, IFN-tau, and high-dose IFN- PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 76 of 123 beta in progressive multiple sclerosis. • IL-10 (through anti-inflammatory effects--but only in certain concentrations). • IL-12 blockade. Trials are on hold. • Laquinimod (related to roquinimex/Linomide) inhibits migration of CD4 T cells and macrophages into the spinal cord and causes a Th2 shift and reduces Th17 cells. It reduces active MRI lesions by 40% to 52%. The main side effect is elevation of liver enzymes. Phase III trials are in progress. Note, roquinimex (Linomide, a related compound) benefitted multiple sclerosis, but enhanced NK cell function and caused serositis and myocardial infarctions. • Leukocytapheresis removes activated T cells instead of antibodies. It is potentially effective in Devic disease (Nozaki et al 2006) as well as multiple sclerosis (Bloom and Reder 2006). • Matrix metalloproteinase inhibitors including minocycline. • Methionine-enkephalin, intrathecal. • Minocycline deactivates microglia and possibly dendritic cells, monocytes, and T cells; may reduce antigen presentation and induce tolerance; and decreases inducible NO synthase, matrix metalloproteases, cyclooxygenases, and p38 mitogen-activated protein kinase (MAPK). In a small study, it dramatically reduced relapse frequency, and it may be additive with glatiramer acetate. However, it increases the rate of decline in amyotrophic lateral sclerosis, indicating it should not be used in multiple sclerosis until controlled trials are completed. Evaluation of doxycycline is in progress. • Transdermally applied myelin peptides are under study. (See failed MBP, above.) • Low-dose naltrexone, at 3 to 4.5 mg per day, improved several quality-of-life measures in controlled trials. • Opioid growth factor (Met5-enkephalin) inhibits experimental allergic encephalomyelitis. • Oxidized phospholipids (lecinoxoids, VB-201) are anti-inflammatory and inhibit experimental allergic encephalomyelitis. • Peroxisomal proliferator-activated receptor-gamma agonists (PPAR-gamma; oral agents for treating diabetes; also PPAR-alpha agonists, used for lowering cholesterol). Pioglitazone added to IFN-beta-1a had no clinical benefit, but reduced gray matter atrophy. Benefits and cautions should be evaluated in light of the interferon/statin interactions (below). • Statins are oral agents used to lower cholesterol, but they also reduce inflammation in atherosclerotic plaques and possibly in multiple sclerosis (Neuhaus et al 2002). Statins inhibit experimental allergic encephalomyelitis, cause a Th1 to Th2 shift, reduce Th17 cells, may slow brain atrophy, and strengthen the blood-brain barrier. Synergy with natalizumab in this regard is unknown. Conversely, statins also increase matrix metalloprotease activity (Kieseier et al 2004), decrease coenzyme Q10 levels (possibly responsible for statin toxicity), and inhibit interferon signaling (Zamvil personal communication;(Reder 2007). The SIMBICOMBIN statin versus placebo trial suggested there was modest benefit on MRI of statins alone. Others state they do not affect clinical or molecular responses to intramuscular IFN-beta-1a (Rudick et al 2009). However, there are red flags: statins block interferon signaling in vitro (Dhawan et al 2007) and in vivo (Feng et al 2009a), and combination with interferon therapy increases exacerbations (Birnbaum et al 2008; Sorensen et al 2011). Other trials are in progress. • Teriflunomide is an immunosuppressant that inhibits pyrimidine synthesis, mitochondrial dihydroorotate dehydrogenase, and calcium mobilization. It causes a Th2 shift. In relapsing multiple sclerosis versus placebo, it reduces MRI lesions and reduces relapses by 30% and progression by 30%. It is additive with IFN-beta therapy. Trials in clinically isolated syndromes and other forms of multiple sclerosis are in progress. • Testosterone is potentially neuroprotective in men. It induces BDNF and reduces delayed- type hypersensitivity immune responses. However, low serum levels correlate with more Gd+ MRI lesions in women (Tomassini et al 2005). • Vitamin A enhances regulatory T cell differentiation and potentiates IFN-beta signaling. • Vitamin D is possibly anti-inflammatory and inhibits experimental allergic encephalomyelitis; high levels correlate with lower incidence of multiple sclerosis. PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 77 of 123 • Vitamin B12 (below, in combinations). Other therapies and neurotrophic factors under study in multiple sclerosis. Neuroprotective and axonal-protective agents are the Holy Grail for many neurodegenerative diseases and would complement anti-inflammatory drugs in multiple sclerosis therapy. For instance, sodium- and calcium-channel blockers protect axons from cytokine-mediated degeneration (Kapoor et al 2003). Neurotrophic factors are produced by macrophages and T cells. They include brain-derived neurotrophic factor, ciliary neurotrophic factor, neurotrophin-3, nerve growth factor, and leukemia inhibitory factor. IFN-beta induces nerve growth factor secretion in astrocytes and (acting through T cells) on endothelial cells. It stimulates growth of neurons but may interfere with myelination in some CNS neurons. BDNF in T cells is increased in multiple sclerosis relapses, by glatiramer therapy, by IFN-beta (in non-depressed patients) (Hamamcioglu and Reder 2007), by antidepressants (in depressed patients), and in mice who exercise--where it increases hippocampal cell proliferation and learning. Leukemia inhibitory factor, a member of the IL-6 superfamily, enhances oligodendrocyte survival and is induced by IFN-beta (Byskosh and Reder 1996). Some monoclonal IgM antibodies bind oligodendroglia and increase remyelination, glial-derived growth factor, and leukemia inhibitory factor. Erythropoietin is neurotrophic (below). • ACE inhibitors. • Adrenocorticotropic hormone and analogues. This cAMP inducer facilitates a Th1 to Th2 shift, increases glucocorticoid receptor function, increases uptake of toxic glutamate by astrocytes, and is neurotrophic. • AMPA receptor antagonists can be neuroprotective. • Angiotensin-converting enzyme (ACE) inhibitors could inhibit autoimmunity by reducing Th1 and Th17 function and increasing Treg function. • Anticholinergic agents (promote neurogenesis) inhibit Th1, Th17, and leukocyte migration and increase Th2. • Antidepressants such as fluoxetine induce BDNF and restore visual plasticity. • Antioxidants (vitamins E and C). • Aspirin inhibits innate immune responses, potentially important in progressive multiple sclerosis. • Ca++ channel blockers. N-type voltage-dependent calcium channels allow pathological influx of Ca++ and are increased on demyelinated axons and activated microglia. Blockade of these channels in rat models is protective. • Caffeine, through CD73, activates adenosine receptors and inhibits experimental allergic encephalomyelitis, possibly by increasing adenosine, cAMP, type I interferons, and IL-10. • Cannabinoids are anti-inflammatory and possibly neuroprotective (delta9-tetracannabinol [Marinol]; Sativex). CB1 receptor activation reduces release of inflammatory cytokines, has psychotropic effects, reduces norepinephrine release from sympathetic nerves, and may thereby increase bone density. CB2 receptors increase progenitor and mature oligodendrocyte survival, and also neural stem cell survival, and are anti-inflammatory. Dexanabinol (a tetrahydrocannabinol derivative) may reduce excitotoxicity. • Circumin at high doses inhibits inflammation and, at low doses, promotes neural stem cell growth. • Chondroitin sulphate (CS) binds to trophic factors. Also, CS proteoglycans inhibit differentiation of oligo progenitor cells in culture. • Coenzyme Q10 enhances mitochondrial function (serum levels are reduced by statins). • Cranial nerve noninvasive neuromodulation (CN-NINM), electrotactile stimulation, stimulates the tongue during other exercises. Mechanisms are theorized to be related to deep brain and vagus nerve stimulation as in other neurologic diseases (U Wisconsin). • Cyclic adenosine monophosphate (cAMP) agonists (beta2-adrenergic agonists; prostaglandins and analogues such as misoprostol) and phosphodiesterase IV inhibitors (mesopram) are strongly anti-inflammatory. They aid regeneration of spinal axons (blocked by myelin associated glycoprotein, MAG) (Qiu et al 2002) and may be neuroprotective (PGE2). Rolipram inhibits Th1/ Th17 cell responses, but increases contrast-enhancing MRI PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 78 of 123 lesions in multiple sclerosis. Ibudilast, a phosphodiesterase inhibitor, had no effect on inflammation, but reduced brain atrophy and conversion from Gd-enhancing lesions to MRI T1 holes (Barkhof et al 2010). This may be from a direct inhibition of microglia. Prostaglandin E, a cAMP agonist, induces IL-10 in monocytes (Feng et al 2002). • Desferrioxamine. Iron chelation may reduce toxicity of oxygen radicals to myelin. • Dimethylfumarate (BG12) reduces proinflammatory cytokines and induces Nrf2, a potential neuroprotectant. In early trials, it reduced progression and multiple sclerosis relapses. • Eliprodil, a sigma opioid receptor ligand, promotes myelination in neuronal-oligodendrocyte cultures. • Erythropoietin is a neurotrophic factor that has had substantial benefit in experimental allergic encephalomyelitis (Genc et al 2004), prevents axonal degeneration, and can synergize with glucocorticoids (Diem et al 2004) and insulin-like growth factor-1 to prevent neuronal damage. • Flavonoids (luteolin, quercetin) are antioxidants found in green tea that suppress experimental allergic encephalomyelitis. • Food additives are under study, including green tea (epigallocatechin-3-gallate), cumin, and vitamins B3 and D. • Fumarate is used treat psoriasis. An analogue is dimethylfumarate (see above). • Glutamate antagonists (Riluzole). • Immunoglobulins sometimes enhance oligodendrocyte repair (M Rodriquez). • Inosine raises uric acid, a peroxynitrite scavenger; urate is low in multiple sclerosis. • Intrathecal glucocorticoids (triamcinolone acetonide). • Lactam antibiotics increase glutamate transporter expression. • Neuroprotective effects of interferons and glatiramer are discussed above. • Insulin-like growth factor-1 (IGF-1) is required for the survival of oligodendrocytes and is increased in serum by IFN-beta therapy. • IL-6-agonists. IL-6-positive cells in multiple sclerosis lesions correlate with oligodendroglial preservation (Schonrock et al 2000). IFN-beta directly induces IL-6 in astrocytes. However, IL-17 induction by TGF-beta plus IL-6 is a potential danger. • Memantine, an uncompetitive N-methyl-d-aspartate receptor antagonist, blocks excitotoxic high concentrations of glutamate and increases BDNF in the limbic cortex. • Mesenchymal stem cells (see stem cells). • Metformin, an anti-diabetic drug that activates AMP-activating protein kinase, is anti- inflammatory and inhibits experimental allergic encephalomyelitis. • Modafinil is neuroprotective in Parkinson models. • Myelin-associated glycoprotein, MAG, oligo-myelin glycoprotein, Nogo, LINGO, and jagged/Notch inhibit axonal growth and are present in gliotic plaques. Interference with these proteins is a possible treatment for neurodegeneration. • Na+ channel blockers. Flecainide protects axons from nitric oxide and electrical activity. Microglia and macrophages express excessive numbers of Na-v1.6 channels in multiple sclerosis and experimental allergic encephalomyelitis. Phenytoin ameliorates inflammation in experimental allergic encephalomyelitis by 75% (Craner et al 2005); sudden withdrawal provokes attacks. Lamotrigine reduced deterioration in the 25-foot walk, but decreased gait and balance and caused cerebral atrophy. • Neural precursor cells (Neurospheres). • Neuregulin-1 determines whether axons are ensheathed by Schwann cells. • Phenytoin may act as a neuroprotectant but could have toxic effects if suddenly withdrawn. • Phosphodiesterase (see cyclic AMP). • Potassium K+ channel blockers. K2P5.1 channels are overexpressed in multiple sclerosis and in activated CD4 and CD8 cells. • Prostaglandins (PGE2) are cAMP agonists that inhibit experimental allergic encephalomyelitis and stop pain from trigeminal neuralgia in multiple sclerosis (Reder and Arnason 1995). • Remyelination induction: insulin-like growth factor, nerve growth factor, transforming PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 79 of 123 growth factor-beta. • Resveratrol, from red wine, ameliorates experimental allergic encephalomyelitis through activation of the aryl hydrocarbon and estrogen receptors. • Riluzole, a glutamate blocker, is neuroprotective. It slowed cervical atrophy and T1 degeneration on MRI but had no clinical effect in primary progressive multiple sclerosis in a small study (Kalkers et al 2002). • Sirolimus (rapamycin; immune suppression) and CCI-779, an ester of Sirolimus, blocks T cell proliferation. However, K-506/tacrolimus (which inhibits calcium-dependent T cell activation) and mycophenolate mofetil (a purine synthesis inhibitor) are potentially dangerous as they inhibit regeneration of pancreatic beta cells after a toxic insult (Nir et al 2007), and their safety on oligodendrocyte precursors must be studied. • Stem cells (Payne et al 2008). Bone marrow transplantation with hematopoietic stem cells is a multi-step process. Mobilization with cyclophosphamide and G-CSF preconditioning releases large numbers of CD34+ hematopoietic stem cells from bone marrow into the peripheral blood. This also causes a Th2 shift and fewer Th17 cells, and these cells secrete neurotrophic factors. Ablative chemotherapy before stem cell transplantation then destroys the remaining peripheral immune cells. Chemotherapy at this stage causes significant brain atrophy. Some protocols deplete T cells with anti-thymocyte globulin or alemtuzumab. Importantly, alemtuzumab is effective on its own and could be responsible for some or all of the reported benefit. Reinfused stem cells allow the thymus to generate a new T cell repertoire. Recipients of allogeneic stem cell transplants still have ongoing intrathecal lymphocyte activation, demyelination, and neurodegeneration, even though inflammation is suppressed. Some feel this is a reasonable therapy for aggressive multiple sclerosis. Autoimmune disorders occasionally follow stem cell transplants. After bone marrow transplants, 0.1% of the 15 million Purkinje neurons in the brain are from donor stem cells, possibly from fusion with brain cells. The brain of rats injected with 6-hydroxydopamine to destroy the substantia nigra becomes neurotrophic for tyrosine hydroxylase-positive neural stem cells (Nishino et al 1990). It is possible that neural and oligodendroglial stem cells would also be attracted to multiple sclerosis plaques. These cells can also be engineered to deliver neurotrophic factors such as BDNF. Mesenchymal stem cells (non-hematopoietic) and olfactory ensheathing cell transplants may be able to replace neurons and oligodendroglia, and home to areas of brain inflammation. They reside in the perivascular zone as pericytes. They secrete an altered form of chemokine CCL2, thus inhibiting migration of cells into inflammation. They have complicated effects in immune regulation, with less Th1 but more Th17 response, and less IL-10 secretion. Administration is relatively safe and may suppress clinical disease. A large study is ongoing. • Transplantation of autologous peripheral nerve Schwann cells and olfactory bulb ensheathing cells as well as hematopoietic stem cells (see above). • Xaliproden, an agonist of 5-HT1A receptors and multiple kinases, is neuroprotective and ameliorates experimental allergic encephalomyelitis. • Zonisamide, which is used in epilepsy, induces glutathione in astroglia, potentially protecting against oxidative stress. Less traditional treatments are under evaluation, eg, magnets and bee stings. The mechanism in bee stings is proposed to be from modification of immunity or through an excitatory neurotoxin. Surprisingly few multiple sclerosis patients have had anaphylactic reactions to bee stings, perhaps because of a Th1 immune bias in multiple sclerosis. However, no evidence of clinical benefit exists. Potentially dangerous drugs include any that amplify inflammation and are described at the end of the Prevention section of this clinical summary. Combinations. Many small studies have described the safety of drug combinations. Unfortunately, few were designed to show efficacy. Combinations directed against the early inflammatory phase of multiple sclerosis are under study or being contemplated. IFN-beta is being tested in combination with cAMP agonists, glatiramer (CombiRx, enrollment complete in 2010), lamotrigine, matrix metalloprotease inhibitors, minocycline, statins, and vitamins PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 80 of 123 B12 and D. In progressive disease, reducing chronic macrophage-mediated inflammation may require drugs such as cAMP agonists, like prostaglandins, beta-adrenergics, or phosphodiesterase inhibitors (Feng et al 2002b), or thalidomide and minocycline. Combinations with interferon include the following: • In a group of 10 IFN-beta failures, combination with cyclophosphamide reduced relapses, progression, and MRI activity (Patti et al 2004). • Relapsing patients with disease activity despite intramuscular IFN-beta-1a were treated with oral placebo, methotrexate, intravenous methylprednisolone, or both for one year in the ACT trial (Cohen et al 2009). Although the steroids reduced neutralizing antibody titers to interferon, there were no clinical differences between groups. • Minocycline plus IFN-beta inhibits murine experimental allergic encephalomyelitis and attenuates neuronal death. • Mitoxantrone induction for 6 months followed by IFN-beta had better clinical outcome than IFN-beta alone. • Natalizumab plus intramuscular IFN-beta-1a was more effective than interferon alone, with 52% reduction in relapses and 24% less progression. • Phosphodiesterase inhibitors and interferon synergize in blocking the production of inflammatory cytokines. • Rituximab, added to ongoing therapy in patients who had some activity on interferon or glatiramer (numbers not clear), reduced Gd-enhancing lesions by 88%. • Statins appeared to reduce MRI lesions in several uncontrolled trials. However, after Gd- positive scans in untreated patients, the number of contrast-enhancing lesions fell by 29% at 6 months (Zhao et al 2008). Caution is needed when combining statins with interferons. In a randomized, double-blind study, there was an excess of clinical or MRI worsening (1/10 on interferon alone vs. 10/15 on the combination) when patients who had been stable on thrice-weekly IFN-beta-1a were placed on high-dose atorvastatin (Birnbaum et al 2008); similar trends were found in another study (Sorensen et al 2011). Statins repress interferon signaling in vitro and in vivo (Feng et al 2008). • Vitamin B12 methylates arginine on the STAT1 transcription factor and enhances IFN-beta signaling, and the two synergistically reduce inflammation and increase oligodendroglia maturation in mice (Mastronardi et al 2004). The human equivalent dose is 15 million units of interferon and 1 million micrograms vitamin B12. Nitrosocobalmin, which releases nitric oxide, synergizes 200-fold with IFN-beta in cancer therapy. Combinations with glatiramer include the following: • When compared to glatiramer alone, albuterol, a beta2-adrenergic agonist, plus glatiramer increased neurologic function and time to next exacerbation and reduced secretion of IFN- gamma (Khoury et al 2010). However, 40% of the patients did not complete the study and IL-13, a Th2 cytokine, was also decreased. • Mitoxantrone induction followed by glatiramer had better MRI outcome than glatiramer alone. • Alemtuzumab is a potential induction therapy. Critical issues in multiple sclerosis therapy: • Treatments that are more than 33% effective are being developed. Early treatment with current approved drugs elevates the response to 50% or 60%. But this is still a “plateau” and suggests a second agent may be needed, perhaps one not directed against T cells. • Treating acute inflammation (relapses) versus chronic neurodegeneration (progression). There are no effective treatments for progressive forms at this time. • Differentiating between subtypes of multiple sclerosis. • Switching therapy. Trials without a “remain-on-drug” control group cant be evaluated because attack frequency tends to regress to the mean. Secondly, because multiple sclerosis is highly variable, a drug could reduce exacerbations in all multiple sclerosis patients, but some “partial responders” would still appear to be non-responders. It is also possible that some patients are true “non-responders,” and biomarkers are essential for better treatment. (See figures “Response to Therapy A” and “Response to Therapy B” in Interferon immunology, above.) PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 81 of 123 • Biomarkers. MRI (Gd+, T2, and T1 lesions, and newer techniques), CSF immunoglobulins, antigens, and glial and neuronal products, and biological markers in the blood. Pregnancy Pregnancy is as potent as any available therapy for multiple sclerosis. The exacerbation rate declines during pregnancy (0.14 per year) compared to baseline (0.36 per year). The severity and rate of attacks increase during the 3 to 6 months postpartum (1.00 attack per year) (Roullet et al 1993; Damek and Shuster 1997). The average exacerbation rate during the entire year (pregnancy and postpartum period) is equivalent to the baseline rate. Multiple sclerosis is less likely to appear de novo during pregnancy. Pregnancy decreases the later risk of a progressive course (Runmarker and Andersen 1995). The decline in exacerbations during pregnancy is presumably due to a shift from Th1 to Th2 type immunity and from immunosuppressive factors that prevent rejection of the placenta and fetus. Estriol progressively increases during pregnancy. The progesterone/17- beta-estradiol ratio falls during the third trimester of pregnancy, when clinical activity is low. A rebound in immune function after delivery may exacerbate disease activity. Female hormones affect disease activity; 82% of women report worse symptoms before menses (Smith and Studd 1992). The progesterone/17-beta-estradiol ratio increases during the luteal phase of the menstrual cycle, and this corresponds to higher MRI activity (Pozzilli et al 1999). MRI activity increases during ovulation when estradiol is high and progesterone is low (Bansil et al 1999). Symptoms improve with aspirin, without affecting body temperature. Fifty-four percent of women have worse symptoms during menopause, and 75% feel symptoms improve with hormone replacement therapy. Menopause and removal of ovaries cause low-grade systemic inflammation, which can be prevented with low-dose estrogen replacement (Abu-Taha et al 2009). A small clinical trial suggests estriol decreases relapses and MRI lesions. Fertility drugs, follicle-stimulating hormone, and gonadotrophin-releasing hormone increase proinflammatory cytokines. They increase the relapse rate 15-fold. Interferons enhance fertility, perhaps by enhancing implantation, and in contrast, they prevent multiple sclerosis exacerbations. Breastfeeding, which elevates prolactin, has no effect on the exacerbation rate in most studies (Nelson et al 1988), but this is under active investigation. Some patients breastfeed for several days after delivery and then stop in order to begin an immunomodulatory drug. (Breast-pumping for 5 hours after injections to clear interferon from milk is described at the end of the interferon section.) Mothers with multiple sclerosis in Norway had babies with slightly lower birth weights (Dahl et al 2005). They also needed more frequent induction and interventions during delivery, but had no increase in birth defects or mortality. These mothers were 2 years older than the control group. Other studies show similar data (Franklin and Tremlett 2009). Studies of interferons and glatiramer have shown no greater risk of pregnancy loss. However, multiple sclerosis therapies are classified as pregnancy category B (glatiramer), C (interferons, natalizumab), and D (mitoxantrone). Anesthesia General anesthesia has no effect on multiple sclerosis (Bamford et al 1978). Direct trauma to the spinal cord or brain, barbotage, or intracerebral electrodes may predispose to lesions (Poser 1986), but there are also reports of multiple sclerosis patients with direct brain trauma and surgery that did not cause any plaque formation (Riechert et al 1975). Recent experience suggests that brain biopsy and thalamic stimulation do not induce plaques. PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 82 of 123 ICD codes ICD-9: Multiple sclerosis: 340 ICD-10: Multiple sclerosis: G35 OMIM Multiple sclerosis: #126200 Associated disorders Optic neuritis Pars planitis (peripheral uveitis) Seizure disorder Transverse myelitis Trigeminal neuralgia Uveitis Related summaries Affective disorders in neurologic disease Baclofen Clinical trials in neurology Fatigue in multiple sclerosis Glatiramer acetate Hiccups Interferon beta 1a Interferon beta 1b Intravenous immune globulin Mitoxantrone Multiple sclerosis: neurobehavioral aspects Natalizumab Sleep disorders associated with multiple sclerosis Spasticity Vaccines for neurologic disorders Differential diagnosis 3-Methylglutaconic aciduria type I Acute disseminated encephalomyelitis Acute necrotizing hemorrhagic leukoencephalitis Adrenoleukodystrophy Adrenomyeloneuropathy Alexander disease Antiphospholipid antibody syndrome Atopic myelitis, Idiopathic eosinophilic myelitis, HyperIgEaemic myelitis Autoimmune thyroid encephalopathy Balo concentric sclerosis Behcet disease Brainstem encephalitis PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 83 of 123 CADASIL Canavan disease Carbon monoxide poisoning Carotid transient ischemic attacks Cavernous malformations of the brainstem Celiac disease (gluten ataxia) Cerebral infarction (multiple) Cerebrotendinous xanthomatosis Cervical spondylotic myelopathy Charcot-Marie-Tooth disease Chiari malformation Chlamydia Chronic fatigue syndrome Chronic inflammatory demyelinating polyradiculoneuropathy with optic neuritis Cogan syndrome Congenital adrenal hyperplasia Conversion disorder Copper deficiency myelopathy (human swayback) Creutzfeldt-Jacob disease Cysticercosis Devic disease Eales disease Episodic ataxia/Familial paroxysmal ataxia Erdheim-Chester histiocytosis Folate deficiency Friedreich ataxia Gliomatosis cerebri Granulomatous angiitis Guillain-Barré Syndrome, Fisher variant Hashimoto encephalopathy Hemophagocytic lymphohistiocytosis HIV encephalopathy HTLV-1 associated myelopathy Ischemic optic neuropathy Leber hereditary optic neuropathy Lyme disease Mad cow disease (variant spongiform encephalopathy) Marburg variant of multiple sclerosis Metachromatic leukodystrophy Migraine (with multiple infarcts or MRI lesions) Mitochondrial disorders Myasthenia gravis Myelinoclastic diffuse sclerosis Myotonic dystrophy types 1 and 2 Neurofibroma Neurologic disorders related to chemical and biological warfare agents Neuromyelitis optica Neurosarcoidosis Neurosyphilis Paraneoplastic limbic encephalitis, cerebellar degeneration, polymyoclonus/opsoclonus Peroxisomal disorders Post-chemotherapy leukoencephalopathy (see Neurologic complications of chemotherapy) Postinfectious encephalomyelitis (see Acute disseminated encephalomyelitis) Postpartum reversible posterior leukoencephalopathy (see Central neurologic complications of pregnancy) PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
    • Multiple sclerosis Page 84 of 123 Postvaccinal encephalomyelitis (see Acute disseminated encephalomyelitis) Primary central nervous system lymphoma Progressive multifocal leukoencephalopathy Progressive necrotizing myelopathy (see Transverse myelitis) Pseudoxanthoma elasticum Schilder disease Sjögren syndrome, including CNS Sjögren disease Sjögren-Larsson syndrome Spinal infarction (see Vascular disorders of the spinal cord) Spinal meningioma Subacute combined degeneration (see Vitamin B12 deficiency) Subacute sclerosing panencephalitis Susac syndrome Syringomyelia or syringobulbia Systemic lupus erythematosus Transverse myelitis Tropical spastic paraparesis Tuberculosis of the central nervous system Vasculitis (see Vasculitides presenting with dementia, Drug-induced cerebrovascular disease, Wegener granulomatosis, Cogan syndrome, Churg-Strauss syndrome) Venous sinus thrombosis (see Cerebral venous thrombosis) Vertebrobasilar transient ischemic attacks Viral encephalitis Vitamin B12 deficiency Vitamin E deficiency (see Vitamin E in neurologic disorders) Whipple disease Wilson disease (cerebellar and brainstem) Demographics For more specific demographic information, see the Epidemiology, Etiology, and Pathogenesis and pathophysiology sections of this clinical summary. Age 06-12 years 13-18 years 19-44 years 45-64 years Population Caucasians Northern Europeans Occupation None selectively affected. Sex female>male, >2:1 and ratio is increasing for the past 50 years, now up to 3.2:1 in Canada (Orton et al 2006) Family history family history may be obtained Heredity heredity may be a factor PDF Created with deskPDF PDF Writer - Trial :: http://www.docudesk.comhttp://www.medlink.com/cip.asp?UID=mlt000a3&src=Search&ref=33900608 5/4/2012
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