from Neurogy clinics 2018

1. D R A M R U T A R A J A M A N Y A
D N B N E U R O L O G Y T R A I N E E
K M C M A N G A L O R E
An update on Multiple Sclerosis
- Neurologic Clinics

2. Multiple sclerosis
 Multiple sclerosis (MS) is a chronic autoimmune
disease of the central nervous system (CNS) in which
inflammation, demyelination, and axonal loss occurs
from very early stages of the disease.
 It mainly affects young people, between 20 and 40
years old, with a female predominance

4.  Multiple sclerosis (MS) is distinct among neurologic
diseases in that it is characterized by both acute
relapses and incremental progression of disability
 The topographical model of MS1 was proposed as a
clinical framework through which both archetypal
features of the clinical course of MS, as well as
essential factors driving interpersonal variability, can
be visualized.
 visually represents the dynamic nature of lesion patterns,
functional reserve, and transient fluctuations owing to
physiologic stressors, in the evolution of MS clinical course

6. Topographical model
 In the topographical model the central nervous system is
visualized as a pool with increasing levels of depth, with
the spinal cord and optic nerves at the shallow end, the
brainstem and cerebellum with intermediate depth, and
the cerebral hemispheres comprising the deep end.
 The depth of the water in this visual model corresponds
with the degree of functional reserve intrinsic to these
different regions of the central nervous system.
 Thus, the spinal cord and optic nerves—the simplest,
most linear structures commonly affected by MS—have
the least redundancy and capacity for organizational
plasticity and rewiring, whereas the cerebral
hemispheres possess the greatest such structural and
functional resilience.

7. DISEASE ACTIVITY IN THE TOPOGRAPHICAL
MODEL

10. USE OF THE TOPOGRAPHICAL MODEL IN
CLINICAL CARE AND EDUCATION
 The concept of reserve and the topographical model
of MS can facilitate communication about the clinical
course of MS with people with MS, particularly
around 3 key issues: understanding disease
phenotypes and the role of reserve, the importance of
asymptomatic lesions seen on MRI, and
distinguishing a true relapse from a
pseudoexacerbation.

11.  More recently, there has been an appropriate focus on
brain maintenance—the observation that brain-healthy
modifiable lifestyle factors (eg, diet, exercise) can help to
preserve remaining brain volume, which is a source of
reserve.
 In addition to protecting against disability, the goal of
“keeping the tank full” provides a psychologically healthy
agency for persons who may otherwise feel helpless in
the face of an unpredictable illness.
 The topographical model and the concept of reserve can
thus help clinicians to convey a more inclusive,
optimistic, and personalized description of MS disease
course to our patients.

13. THE ROLE OF MRI IN ESTABLISHING A
DIAGNOSIS OF MULTIPLE SCLEROSIS
 MRI plays a fundamentally important role in
establishing a diagnosis of MS
 MRI can support, or even replace, clinical criteria for
dissemination in space and time in patients with a
clinical presentation suggestive of a demyelinating
event.

14.  Dissemination in space can be demonstrated on MRI
by the presence of greater than or equal to 1 T2
lesion in greater than or equal to 2 of 4 areas
consistent with demyelination (periventricular,
juxtacortical, infratentorial, and spinal cord).
 Dissemination in time can be satisfied by the
simultaneous presence of asymptomatic gadolinium-
enhancing and nonenhancing lesions at any time, or
by a new T2 or gadolinium-enhancing lesion on any
follow-up MRI.

15.  Compared with earlier versions of the MRI criteria,
the current version is simplified because it
emphasizes lesion location rather than lesion counts,
making it easier to apply in practice, and because it
often allows a diagnosis of MS to be made with a
single MRI scan rather than requiring a follow-up
MRI after an arbitrary amount of time as in previous
versions.
 MRI criteria has been shown to have a sensitivity of
72% to 85% and a specificity of 67% to 92% to
diagnose MS

16.  Although MRI is highly sensitive to detect white
matter lesions caused by MS, it is not wholly specific
to MS; in other words, MRI is also highly sensitive to
detect white matter lesions from other etiologies (eg,
migraine or small vessel disease).

17.  Discriminating MS from other conditions is a
challenge that is routinely faced by clinicians and is
not addressed by current MRI criteria for MS.
 Moreover, once a diagnosis of MS has been
established, clinicians lack standardized,
quantitative methods to reliably measure changes in
the disease over time, which may help guide
treatment decisions.

18. Central Vein Imaging
 MS plaques tend to form around central blood
vessels (small veins or venules) is a pathologic
feature of the disease
 It is possible to observe central veins in MS lesions in
vivo using T2*-weighted MRI techniques.
 Deoxyhemoglobin disturbs the local magnetic field
and causes faster T2* relaxation, resulting in a
hypointense (dark) signal on T2*-weighted images

19.  7T is the most sensitive field strength to detect
central veins,20 detection rates of greater than 80%
 The 40% rule has been proposed based on data
suggesting that the presence of greater than 40%
perivenous lesions is highly predictive of
demyelinating disease, with 100% positive and
negative predictive value for a diagnosis of MS

21.  Simpler criteria -in which the 40% cutoff was originally
tested, the investigators showed that if only 10 lesions
per patient were sampled (in patients with 10 lesions),
MS could be accurately discriminated from non-MS In
90% of patients.
 More recent data suggest that if 6 or more perivenous
lesions are present or if fewer than 6 characteristic
lesions are present but characteristic lesions outnumber
nonperivenous lesions, the diagnosis is inflammatory
demyelination; otherwise, inflammatory demyelination
should not be diagnosed.
 This simple classification strategy was able to classify 20
MS/non-MS patients with 100% accuracy, in less than 2
minutes per case

22. Gray Matter (Cortical) Lesions
 Cortical lesions have been classified into 3 types:
 leukocortical, or type I, lesions(34%),
which a single lesion involves both the juxtacortical white
matter and cortex;
 intracortical, or type 2, lesions (16%),
which are entirely within the cortex and often contain a
central blood vessel (Fig. 2);
 subpial, or type 3, lesions (50%),
which extend from the pial surface into the cortex and
commonly span multiple gyri.

23.  double inversion recovery (DIR) and phase-sensitive
inversion recovery (PSIR)

24. Lesion Probability Mapping
 Lesion probability mapping is a postprocessing technique that
estimates the probability of a lesion occurring at each voxel in
the brain
 Requires
(1) segmenting white matter lesions and creating a binary lesion
mask, such that each voxel in the brain is labeled as lesional or
not;
(2) registering, or aligning, each subject’s MRI and lesion mask
to a standard template; and
(3) calculating the probability of a lesion being present at
each voxel.
 A generalized linear model can then be performed at each
voxel to measure the association between lesion probability
and the outcome of interest.

26. Automated Detection of New Lesions
 Intensity-based image subtraction is a promising
method to identify new, enlarging, shrinking, or
resolved white matter lesions.

27. Brain Volumetrics
 Brain volume measurements on MRI can offer an in
vivo measure of neurodegeneration and have been
studied extensively in MS.
 Thalamic atrophy seems clinically relevant and
sensitive to change over time throughout the disease
duration
 The brain parenchymal fraction (BPF), defined as
the ratio of brain parenchymal volume to the total
volume within the brain surface contour, is used to
measure whole brain atrophy

30. NEWLY RELEASED AND FORTHCOMING
DRUGS

31. Daclizumab
 humanized monoclonal antibody that binds to the a-chain of
the high-affinity interleukin (IL)-2 receptor blocking its
binding.
 endogenous increase of free available IL-2 that will bind to the
intermediate-affinity IL-2 receptor producing different
immunologic effects, such as expansion of the regulatory
CD56 natural killer cells, inhibition of T-cell activation, and a
reduction in lymphoid tissue inducer.
 Efficacy:
 54% and 45% reduction in the annualized relapse rate (ARR) compared
with placebo and to IM IFN-b treatment, respectively
 Safety:
 nonopportunistic infections, cutaneous events{2%}, and hepatic
disorders{16%}

32. Ocrelizumab
 Ocrelizumab is a humanized monoclonal antibody that selectively
binds to the B-cellsurface CD20 antigen.
 The adhesion of ocrelizumab to its target produces a selective
depletion of B cells presenting with the antigen: pre-B cells, mature
B cells, and memory B cells, but it will not affect lymphoid stem
cells and plasma cells
 Efficacy:
 The results of the 2 phase 3 clinical trials demonstrated that, compared with
subcutaneous IFN-b, ocrelizumab significantly reduced by 46% to 47% the ARR
after 2 years of treatment.
 reduced by 77% to 83% the mean number of new T2 lesions and by 94% to 95%
the mean number of Gd-enhancing lesions
 Safety:
 infusion-related reactions[35% to 40%.]
 nasopharyngitis, upper respiratory tract infection, and urinary tract
infections

33. Cladribine
 Cladribine is a synthetic purine analog that enters the cell via the
purine nucleoside transporters and is subsequently phosphorylated.
The accumulation of the active metabolite, 2-chlorodeoxyadenosine
triphosphate, disrupts cellular metabolism and damages DNA,
causing cell death. This process ultimately leads to lymphocyte
depletions and long-lasting lymphopenia
 Efficacy
 oral treatment with cladribine reduced in approximately 56% the ARR (57.6%
reduction for the 3.5-mg/kg dose, and 54.5% reduction for the 5.25-mg/kg dose)
and in approximately 32% the risk of presenting 3-month confirmed disability
progression
 reduced in approximately 75% the risk of presenting new T2 lesions
approximately 86% the risk of presenting Gd-enhancing lesions
 Safety
 Lymphocytopenia
 opportunistic infections

34. DRUGS UNDER DEVELOPMENT

35. Secukinumab
 Secukinumab is a fully human monoclonal antibody that
selectively binds to human IL-17A, a proinflammatory
cytokine involved in MS pathogenesis, neutralizing its
bioactivity
 Efficacy
 secukinumab reduced the mean cumulative CUAL by almost 50%
 reduced the mean cumulative number of new Gd-enhancing lesions
at each monthly visit starting at week 16. As for new or enlarging T2
lesions, secukinumab reduced the mean cumulative number at the
end of the study but not before
 Safety
 The overall incidence of adverse events was similar between both
treatment arms, although infections were more frequently reported
in patients receiving secukinumab

36. Sphingosine 1-Phosphate Receptor Modulators
 S1P1 receptor is mainly expressed in lymphocytes, neural cells,
endothelial cells, atrial myocytes, and smooth muscle cells;
 S1P2 receptor is expressed in the CNS, endothelial cells, and
smooth muscle cells; S1P3 receptor is expressed in neural cells,
endothelial cells, and smooth muscle cells;
 S1P4 receptor is expressed in lymphocytes; and
 S1P5 receptor is expressed in the CNS, oligodendrocytes, and
natural killer cells.
 Initial agonist actions between S1P with the S1P receptor in the
lymphocytes are followed by an internalization and degradation of
the receptor leading to a functional antagonism that will prevent
lymphocyte regression from the lymph nodes.

37. Ponesimod
 Ponesimod is a selective S1P1 receptor modulator.
 Efficacy
 double-blind, placebo- controlled, dose-finding phase 2b
study,all 3 doses of ponesimod significantly reduced the
cumulative number of new T1 Gd-enhancing lesions with a
greater reduction seen in the highest doses (43%, 83%, and
77% reduction for the 10-mg, 20-mg, and 40-mg doses,
respectively)
 Safety
 Bradycardia
 Lymphopenia and liver enzyme abnormalities

38. Ozanimod
 Ozanimod selectively modulates S1P1 and S1P5 recep
 Efficacy:
 A phase-2 double-blind, placebo-controlled clinical trial tested
the superiority of ozanimod as compared with placebo in
reducing radiological disease activity. In this study, both doses
of ozanimod significantly reduced the cumulative number of
Gd-enhancing lesions from week 12 to 24 (84% and 89%
reduction for the 0.5-mg and 1-mg dose, respectively
 Safety
 orthostatic hypotension

39. Amiselimod
 Amiselimod is another S1P receptor modulator with high
affinity for S1P1 receptor.
 Efficacy
 phase-2 placebo-controlled clinical trial, amiselimod proved to be
more effective than placebo in reducing radiological disease activity.
 Specifically, the number of Gd-enhancing lesions from week 8 to 24
was dose-dependently reduced by ozanimod treatment, with
significant reductions observed in the 0.2-mg and 0.4-mg treatment
arms (estimated incident rate ratio reduction of 61% and 77% for the
0.2 and 0.4 mg, respectively
 Safety
 headache, liver enzyme abnormalities, and lymphopenia

40. DRUGS UNDER DEVELOPMENT WITH
NEWER GOALS
 MD1003 or High-Dose Biotin
 Opicinumab
 GSK239512

41. MD1003 or High-Dose Biotin
 MD1003 is an oral formulation of high-dose biotin, an
oral ubiquitous vitamin also known as vitamin H>
 biotin may exert its effect by enhancing fatty acid
synthesis, through the activation of carboxylases, that
ultimately will support myelin repair
 Efficacy
 High-dose biotin has demonstrated to be able to reverse MS-related
disability21,22: almost 13% of the patients allocated to the biotin
treatment arm presented a disability improvement (measured either
with Expanded Disability Status Scale scale or timed 25-foot walk) at
month 9 that was confirmed at month 12
 Safety
 no special adverse events related to biotin intake

42. Opicinumab
 Leucine-rich repeat and immunoglobulinlike domain-containing neurite
outgrowth inhibitor receptor protein 1 (LINGO-1) is expressed exclusively
on oligodendrocytes and neurons of the CNS.
 LINGO-1 is a negative regulator of oligodendrocyte differentiation and
remyelination.
 LINGO-1 antagonism has proved to be beneficial to enhance remyelination
and axonal regeneration.
 Opicinumab is a human monoclonal antibody targeting LINGO-1 that has
been recently tested in patients with MS in 2 phase 2 clinical trials
 Efficacy
 Tested in acute optic neuritis
 the study failed to prove a linear dose response of opicinumab in improving disease
disability, as higher opicinumab doses were not associated with higher proportion of
patients presenting neurologic improvement
 Safety
 hypersensitivity reactions
 weight gain of more than 7%

43. GSK239512
 Histamine H3 receptors are expressed by neurons and
oligodendrocyte precursor cells (OPC) and have a role in
controlling OPC differentiation. GSK239512 is an oral
selective H3 receptor antagonist/inverse agonist drug that has
demonstrated to promote OPC differentiation in vitro and to
enhance remyelination in the cuprizone mouse model of
remyelination
 Efficacy:
 Compared with placebo, GSK239512 had a small positive effect (effect
size between 0.243 and 0.344) on lesion MTR, indicating a relative
increase in lesion remyelination
 Safety
 insomnia and
 sleep-related disorders

45. Fatigue
 30% to 80% of patients, and is a major symptom in
50% to 60%.

46. Depression
 lifetime prevalence of up to 50%.
 Medications
 high-dose vitamin A- 25,000 IU/d of retinyl palmitate (RP) for
6 months followed by 10,000 IU/d of RP for 6 months
 zinc sulfate (220 mg containing 50 mg of zinc element per day
 coenzyme Q10 at a dose of 500 mg/d
 omega-3 fatty acids (6 g/d)
 TCAs (desipramine, moclobemide)
 and SSRIs (sertraline, fluvoxamine)

47. Cognition
 40% to 65% of patients with MS
 Medications
 Memantine, a noncompetitive NMDA receptor antagonist
 lisdexamphetamine
 dimesylate,20amphetamine,41 and
 methylphenidate (Ritalin)

48. Bladder dysfunction
 50% to 90%
 Urgency, frequency, nocturnal frequency of urine, and/or
urge incontinence, detrusor-sphincter dyssynergia (DSD)
are common symptoms
 Medications
 solifenacin (VESIcare) and trospium (Sanctura)
 Mirabegron, a beta-adrenergic receptor agonist
 Intravesical botulinum A toxin
 Sacral neuromodulation(InterStim) is FDA approved for overactive
bladder
 Percutaneous tibial nerve stimulation

50. Bowel dysfunction
 50% of patients
 Chelated magnesium (250–500 mg) taken at
bedtime
 Osmotic laxatives or stimulant laxatives
 Prokinetic agents

51. Sexual dysfunction
 50% to 85%
 Sildenafil
 Flibanserin (Addyi) is a 5-hydroxytryptamine (5HT)
(1A) agonist/5HT (2A) antagonist

52. Spasticity
 Baclofen
 Tizanidine
 Cyclobenzaprine and carisoprodol
 Gabapentin dosed at 900 mg 3 times per day
 baclofen pump or from botulinum toxin A injections
 Marijuana
 cannabinoids include delta-9-tetrahydrocannabinol
(THC) and cannabidiol (CBD)
 Nabiximols (Sativex) is an oral mucosal spray that
contains delta-9-THC and CBD in a 1:1 ratio

53. A COMMENT ON AGENTS THAT MAY IMPROVE FUNCTION
GLOBALLY:
FAMPRIDINE, DALFAMPRIDINE, LOW-DOSE NALTREXONE, HIGH-
DOSE BIOTIN
 Dalfampridine and fampridine are both broad-
spectrum potassium channel blockers and improve
conduction along demyelinated pathways
 Dalfampridine is FDA approved to improve walking
in patients with MS - 10 mg twice per day
 LDN- greater than 50% reported an improvement in
fatigue as well as60%reporting stabilization or
improvement
 High-dose biotin (HDB)-89% of patients reported
stabilization/improvement after 3 to 8 months of
therapy