Neurological complications are common in HIV disease. The ...


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Neurological complications are common in HIV disease. The ...

  1. 1. Neurological complications are common in HIV disease. The spec- trum of neurological disorders is broad and involves the central nervous system, or CNS (brain and spinal cord) and the peripheral nervous system, or PNS (nerves outside the brain and spinal cord, and related muscle). Neurological disorders related to HIV often result in reduced quality of life and shortened survival, especially in people with more advanced HIV disease. Nevertheless, some neuro- logical conditions are mild, readily treatable, or reversible. Several have become less common since the introduction of highly active anti- retroviral therapy (HAART). And, despite the fact that many anti-HIV drugs are unable to cross the blood- brain barrier and penetrate the brain, recent data published in the Journal of Acquired Immune Deficiency Syndromes support the claim that HAART can improve some neurocognitive functioning. Venkat K. Rao, MD Florian P. Thomas, MD, MA, PhD WINTER 2005 BETA 37
  2. 2. PATHOPHYSIOLOGY HIV-related neurological disorders may develop directly from infection with HIV, or indirectly as a result of neurological disorders and opportunistic illnesses (OIs) or treat- stages of HIV disease ment complications. For example, OIs such as toxoplasmosis often arise Early HIV disease from reactivation of previous infec- At the time of seroconversion and in the early stages of HIV disease tions when immune system defenses (CD4 cell levels above 500 cells/mm3) common neurological complica- break down. Viruses that cause tions may be undetectable or may include: progressive multifocal leukoencepha- • aseptic meningitis lopathy (PML) may be activated by • acute encephalopathy with seizures and confusion HIV itself. Toxic side effects of certain anti-HIV medications may affect • inflammatory demyelinating polyneuropathy (Guillain-Barré peripheral nerves and muscle. syndrome) Different neurological disorders • cranial nerve palsies (e.g., Bell’s palsy) are likely to be seen at different stages • herpes zoster (shingles) of HIV infection (see sidebar on this page). In a first evaluation, the clini- Moderate to severe immunodeficiency cian should determine whether clini- In moderate to severe immunodeficiency (200–500 CD4 cells/mm3), cal features suggest localized (limited the following are more likely to be seen: to a specific area) or global brain dys- • cognitive impairment function, meningitis (inflammation of • distal sensory polyneuropathy (may also appear in early HIV the membranes covering the brain disease) and spinal cord), spinal cord disease, • myelopathy neuropathy (nerve damage), or • myopathy myopathy (muscle disease). The likelihood of a given neuro- Late-stage HIV disease logical problem is partly related to the Illnesses in people with less than 200 CD4 cells/mm3 may include: stage of HIV disease as reflected by • HIV encephalopathy (dementia) immune response, viral load level, • CNS toxoplasmosis and CD4 cell count. Levels of cyto- • cytomegalovirus (CMV) infection kines (hormones that coordinate and regulate immune response) have also • primary CNS lymphoma been implicated. • progressive multifocal leukoencephalopathy (PML) GENERAL APPROACH People with HIV often have more than one medical or neurological physical therapists, and other reha- advanced HIV disease. Coinfected problem at the same time. A careful bilitation professionals, including individuals were also significantly history and exam may isolate the nutritionists. more likely to have HIV-associated diagnosis. Imaging and laboratory People with both HIV and hepati- cognitive impairment. studies may help document the diag- tis C virus (HCV) infection may war- nosis, and at times identify coexisting rant additional neurological observa- CONDITIONS illnesses. Neurological diseases are the tion. In a study published in the PREDOMINANTLY first manifestation of AIDS in 7–20% March 23, 2004 issue of Neurology, AFFECTING THE of people with HIV and may thus be Elizabeth Ryan, MD, and colleagues CENTRAL NERVOUS the AIDS-defining illness. reported that people with advanced Due to the complexity of HIV dis- HIV disease and HCV coinfection SYSTEM ease and its chronic course, a multi- tended to have worse neurocognitive Many conditions affecting the disciplinary approach is important. performance and greater impairment CNS are associated with HIV infec- This may involve general internists, of executive functioning (problem tion, and multiple illnesses may be infectious disease and other sub-spe- solving and other complex use of present simultaneously. CNS disorders cialists, neurologists, psychiatrists, information) than people with only affect the brain, the spinal cord (but 38 BETA WINTER 2005
  3. 3. not the nerves that branch off it, people with sulfa intolerance, clin- The most common clinical symp- which are part of the PNS), and the damycin is an alternative. Steroids toms of PCNSL are impaired cogni- membranes covering the brain and may be used to reduce associated tion, aphasia (loss of ability to use or spinal cord. Many of these conditions swelling in the brain. understand language), hemiparesis, may present either with or without Ninety-one percent of people and seizures. Onset is often more sub- symptoms. The descriptions of condi- treated improve by day 14 of therapy. tle, and progression slower, than with tions below include tests than can be After the initial regimen is completed, toxoplasmosis. used to make a differential diagnosis. oral maintenance treatment, usually CSF analysis is likely to show TMP/SMX (Bactrim, Septra), is con- pleocytosis (abnormally high number CNS Toxoplasmosis tinued indefinitely to suppress reacti- of cells), elevated protein, and malig- Toxoplasmosis, caused by the vation of the parasite. Prognosis is nant-appearing lymphocytes. The Toxoplasma gondii parasite, is the linked to parallel treatment with presence of EBV in the cerebrospinal most common CNS disease associated HAART to raise the CD4 cell count. fluid is a strong indicator of PCNSL in with AIDS. Usually it is due to reacti- People with HIV who by blood people with AIDS. vation of prior infections in the CNS tests appear not to have been exposed Brain CT or MRI may be useful in or elsewhere, but primary infections to T. gondii should avoid eating raw suggesting lymphoma by the location can also occur. The disease appears or undercooked meat, particularly and characteristics of tissue changes during advanced HIV infection pork, lamb, or venison. Fruits and or uptake of contrast material. when CD4 cell counts are below vegetables should be washed, as Multiple lesions can occur, although 200 cells/mm3. Clinical CNS toxoplas- should one’s hands after contact with less frequently than with toxoplasmo- mosis is seen in 3–10% of people raw meat, soil (as after gardening), or sis. MRI spectroscopy (measuring the with AIDS in the U.S. a cat’s litter box. Ideally, litter should chemical content of brain lesions) Onset is over days to weeks. be changed daily by an HIV negative, may be easily done during the initial People with CNS toxoplasmosis nonpregnant person. Household pet MRI brain scan, and, if certain typically develop headache and fever, feces should always be handled wear- chemicals are elevated, may suggest followed by impaired thinking and ing latex gloves. Keeping cats indoors lymphoma. vision, hemiparesis (weakness on and feeding them only commercial cat The prognosis for PCNS lym- one side of the body), and imbal- food, or well-cooked table food, may phoma is generally poor. Whole brain ance. Confusion, seizures, meningi- reduce their risk of becoming infected radiation therapy (radiotherapy) has tis, dementia (deterioration of men- with T. gondii. Stray cats should be been the mainstay of treatment; it tal function), and depression may avoided. provides for a median survival of 2–5 also occur. Primary Central Nervous months. Steroids are required for at A blood test for toxoplasmosis System Lymphoma least 48 hours before radiotherapy to antibodies should be done. A poly- Lymphoma refers to cancer of the minimize swelling; steroids should be merase chain reaction (PCR) assay of lymph system. It is characterized by continued throughout the course of the cerebrospinal fluid (CSF) may find the growth of abnormal lymphocytes, treatment. High-dose methotrexate T. gondii DNA. Magnetic resonance or white blood cells (B cells and T has been used with some success, imaging (MRI) is more sensitive than cells) that play a part in immune sys- given as frequently as every week for computed tomography (CT, CAT) scan tem defenses. HIV-associated primary five cycles. Combining methotrexate in detecting multiple brain abscesses. CNS lymphoma (PCNSL) occurs in and radiotherapy can achieve survival A single lesion (tissue abnormality) the brain, rarely in the spinal cord, of 1–2 years. Experimental chemother- might suggest a diagnosis of lym- and causes brain lesions and changes apy agents include thiotepa (Thioplex) phoma instead of toxoplasmosis (see in mental functioning. In almost all and procarbazine (Matulane). HAART “Primary CNS Lymphoma,” below). cases, Epstein-Barr virus (EBV) is should be continued. A brain biopsy is indicated if there is found in the lymphoma-related a single mass lesion and negative Progressive Multifocal lesions or the CSF. EBV’s effect on serological (blood testing) results, chronically activated lymphocytes is Leukoencephalopathy or if there is no response to 14 days the probable cause. Progressive multifocal leukoen- of therapy. PCNSL is associated with CD4 cephalopathy (PML) is characterized Toxoplasmosis is treatable. It is cell counts below 100 cells/mm3. by widespread demyelinating lesions generally responsive to intravenous With a prevalence of up to 5% among (loss of the insulating myelin sheath (IV) antibiotics, and response to ther- people with AIDS in the U.S., PCNSL around nerves in the brain and spinal apy is often rapid. Agents of choice is the second most common mass cord) and is caused by the JC papo- are sulfadiazine combined with lesion after toxoplasmosis. Rarely it is vavirus. Around 90% of the general pyrimethamine and folinic acid. For the presenting feature of AIDS. population have been exposed to this WINTER 2005 BETA 39
  4. 4. virus and have antibodies against it. brain. Causes of stroke and hemor- count, erythrocyte sedimentation rate The syndrome of PML occurs almost rhage in HIV positive people are (ESR), anticardiolipin antibody and exclusively in people whose immune numerous and variable. lupus anticoagulant, cryoglobulins, systems are suppressed due to HIV or Hypertension (high blood pres- serology for specific infections, organ transplantation. It is unclear sure), blood vessel abnormalities syphilis test, blood cultures, coagula- whether PML develops when JC virus (aneurysms, vein/artery malforma- tion studies including antithrombin in the brain is reactivated or when the tions), and cardiovascular disease III, and protein S and C levels. virus is reactivated elsewhere in the can lead to brain hemorrhage or Analysis of the cerebrospinal fluid body, such as the bone marrow, and stroke, just as in HIV negative people. may be indicated. migrates to the brain. HIV gene prod- Hypotension (low blood pressure) MRI is superior to CT, but both ucts such as the Tat protein may acti- can cause stroke in people who are are useful in identifying stroke and vate the JC virus directly. severely ill. Coagulopathies (defective hemorrhage. Magnetic resonance PML is usually seen when CD4 blood clotting) may occur in HIV angiography (MRA) is useful in cell counts fall below 200 cells/mm3, infection and can lead to stroke or detecting blood vessel narrowing. and it may be an AIDS-defining event. hemorrhage. Thrombotic thrombocy- Ultrasound of the carotid arteries The syndrome likely occurs in less topenic purpura (TTP; characterized (large vessels in the neck that supply than 4% of AIDS cases where HAART by low platelet counts and blood blood to the brain) is a less expensive is used. clots) may occur in early phases of alternative to MRA or CT angiography. Onset is usually over weeks to HIV disease and may also cause A test called transesophageal echocar- months. The clinical manifestations of stroke or hemorrhage. diography (TEE) may be needed to PML depend on the areas of the brain Specific forms of heart disease, evaluate the heart for stroke causes, affected. Weakness, chiefly hemipare- particularly accelerated “hardening” such as dilated cardiomyopathy (fail- sis, is most common. Other features of the coronary arteries due to ele- ing heart), open channels between the include behavioral and cognitive prob- vated lipids and heart inflammation cardiac chambers, or endocarditis lems, aphasia, ataxia (loss of ability to from various viral infections of the (inflammation of the heart valves coordinate muscle movement), and heart muscle, have been implicated in and lining). cortical blindness (loss of vision due HIV-associated cerebrovascular condi- In many cases, treatment parallels to a brain lesion). Headaches are tions. Herpes zoster (shingles) over that in the HIV negative population. If more rare. the forehead may cause underlying a stroke is diagnosed within three The cerebrospinal fluid is usually stroke weeks or months after appear- hours after onset, the person may be normal. The PCR assay is specific and ing, and must be considered even in a candidate for an infusion of TPA, an sensitive for the detection of JC virus the absence of a rash. Hepatitis C and agent that dissolves clots and opens and can possibly replace a brain other infections can also contribute to blood vessels. TPA is contraindicated biopsy. Both CT and MRI scans may cerebrovascular problems, such as by (not recommended) in cases of brain show distinctive tissue destruction impairing blood clotting or leading hemorrhage. Often lipid-lowering just below the cortex, the outer layer to abnormal levels of certain blood drugs (statins), blood thinners such as of the brain. proteins. warfarin (Coumadin), or antiplatelet PML typically progresses to Cocaine and heroin also can agents such as aspirin or clopidogrel severe dementia and death over cause cerebrovascular problems. (Plavix) are indicated. Specific causes several months. Whether HAART Cocaine use may lead to hypertension of stroke may require other forms of improves survival remains controver- with hemorrhage, or to blood vessel treatment. Brain hemorrhages occa- sial. Survival correlates with suppres- constriction and stroke caused by lack sionally may need to be treated with sion of plasma HIV viral load and of blood supply to the brain. Heroin surgery to remove the mass of blood. higher CD4 cell counts. Death may use can cause blood vessel inflamma- Prognosis after a stroke or brain result not from PML but from end- tion. Also, nonsoluble contaminants in hemorrhage depends on the size and stage immune deficiency. Some posi- illicit IV drugs can block blood vessels. location of the damage. After a stroke tive response has been reported with Stroke and hemorrhage are char- or hemorrhage, the person will recover use of cidofovir (Vistide). acterized by the abrupt onset of weak- the most during the initial few weeks, ness, language problems, or sensory but improvement often continues for Stroke and Hemorrhage loss. Symptoms often appear on only months. Inpatient and outpatient Stroke (“brain attack”) and hem- one side of the body. Imaging studies rehabilitation is often helpful. orrhage (spillage of blood from an help differentiate stroke, hemorrhage, Preventive treatment parallels artery into brain tissue) are major infection, and tumors. that in the HIV negative population. cerebrovascular events; cerebrovascu- Blood tests include complete Examples include antiplatelet agents lar refers to the blood vessels of the blood count (CBC) with platelet or blood thinning drugs. Removal of 40 BETA WINTER 2005
  5. 5. plaque from the walls of carotid Stage 0.5 (equivocal/subclinical): HAART. Imaging studies may reveal arteries and newer techniques of Symptoms may be absent, minimal, progressive brain atrophy (shrinkage) endovascular stenting (placing a tube or equivocal, with no impairment or characteristic white matter inside a blocked artery) may open of work or performance of activities changes. Electroencephalography and repair vessels. of daily living (ADL). Mild signs, (EEG; recording the electrical activity HIV Encephalopathy such as slowed eye or extremity of the brain) shows generalized movements, may be present. Gait slowing in the later stages of ADC. HIV encephalopathy, or AIDS (manner of walking) and strength Positron emission tomography (PET) dementia complex (ADC), is one of are normal. scanning is sensitive for dementia, but several neurological conditions that Stage 1 (mild): The person can not specific for HIV-related dementia. may be caused by HIV itself. Dementia perform all but the more demand- In general, depression and meta- refers to the deterioration of mental ing aspects of work or ADL but has bolic causes of cognitive decline, such function. ADC typically occurs as CD4 unequivocal evidence of functional, as other infections, vitamin deficien- cell counts fall below 200 cells/mm3, intellectual, or motor impairment. cies, thyroid dysfunction, and liver but mild-to-moderate abnormalities Signs or symptoms may include and renal dysfunction, should be may occur in earlier stages of HIV dis- diminished performance on memory aggressively corrected. Antiretroviral ease and are known as mild cognitive testing. The person can walk with- agents protect against ADC and can impairment (MCI). MCI is also associ- out assistance. induce remission, but when treatment ated with chronic hepatitis C and fails and viral load rebound occurs, insulin resistance, two conditions that Stage 2 (moderate): The person is cognitive function again deteriorates. are more common in HIV positive ambulatory and able to perform If ADC develops during treatment individuals. Fortunately, the frequency basic activities of self-care but can- with HAART, additional or alternative of HIV encephalopathy has declined not work or maintain the more agents should be tried. Neuroprotective with the use of HAART. demanding aspects of daily life. therapies or global memory enhancing HIV infection may cause ADC- Stage 3 (severe): The person has agents such as memantine (Namenda) related brain damage indirectly via the major intellectual incapacity (can- or donezepril (Aricept) may be useful production of chemokines, proinflam- not follow news or personal events, in some individuals. matory cytokines, nitric oxide, and cannot sustain complex conversa- Close follow-up is needed because other neurotoxic factors by both tion). Walking must be assisted the person’s cognitive impairment infected and uninfected activated (with a walker or personal sup- may progress to dementia, or the per- cells. Neurological damage may also port); walking is usually slowed son may develop seizures or psychosis occur through the actions of specific and accompanied by clumsiness (a severe mental disorder often char- HIV proteins, including gp120, gp41, of arms. acterized by delusions or hallucina- Tat, Nef, Vpr, and Rev, which can be tions). Also, people with ADC must Stage 4 (end stage): The person is toxic to nerve cells and their dendrites. often take multiple medications, many bedridden in a nearly vegetative People with ADC often present of which can affect thinking and state with urinary and fecal inconti- with diminished concentration and memory and thus make the symptoms nence. Intellectual and social com- memory. Apathy and withdrawal from of ADC worse. prehension and output are at a hobbies or social activities are com- rudimentary level. The person is Cytomegalovirus mon, but must be distinguished from nearly or absolutely mute. Encephalitis depression (see “Overcoming Depression,” BETA, Winter 2004). As is true for any dementing ill- Cytomegalovirus (CMV) is a Motor problems include imbalance, ness, other treatable causes should be herpesvirus that often infects healthy clumsiness, and weakness. Early signs sought and corrected if possible. people without causing symptoms. and symptoms are subtle and may be Vitamin B12 (cobalamin) levels should But in people with compromised overlooked. These symptoms may be determined; when B12 is border- immune systems, typically those with evolve into a severe, global dementia line, homocysteine and methylmalonic less than 50 cells/mm3, CMV may with memory loss and language acid levels are more sensitive. Thyroid cause serious disease. impairment. stimulating hormone (TSH) and CMV infection of the brain, spinal syphilis serology (RPR, VDRL, or cord, meninges, or nerve roots can Staging MHA-TP) should be checked. CSF lead to neurological problems such as The following clinical staging of analysis serves to exclude other encephalitis (inflammation of the ADC was proposed in 1988: causes of altered mental status. HIV brain), myelitis (inflammation of the Stage 0 (normal): Mental and in the CSF frequently is detected by spinal cord), retinitis (inflammation of motor functions are normal. PCR, and may suggest a need to alter the retina of the eye), polyradiculitis WINTER 2005 BETA 41
  6. 6. (inflammation of the spinal nerve people with AIDS. It develops when shunt (surgical drain of spinal fluid). roots), peripheral neuropathy, or CD4 cell counts fall below 100 Visual loss can be addressed by optic mononeuritis multiplex (see cells/mm3. Cryptococcosis presents as nerve surgery. “Mononeuritis Multiplex,” below). meningitis, a space-occupying lesion, Several studies report mortality Some 20% of people with CD4 cell or meningoencephalitis (inflammation rates of 17–20%, but with aggressive counts below 100 cells/mm3 harbor of the meninges and brain). It typi- therapy this may drop to 6%. A CMV in different organs and suffer cally reaches the CNS from the lungs. minority of people die within the first from colitis (inflammation of the large It can also affect skin, bone, and the six weeks after diagnosis despite treat- intestine), esophagitis (inflammation genitourinary tract. ment. Relapse rates without prophy- of the esophagus), or retinitis. Autopsy The nonspecific nature of early laxis range from 15% to 27%; this is studies reveal CMV in the CNS in features may lead to significant treat- reduced to 0–7% with prophylaxis. 5–40% of people with AIDS, and ment delay, so a high level of suspi- Meningitis often the diagnosis was not made cion is warranted. Early symptoms and signs include headache, fever, Meningitis is an inflammation of during life. malaise, nausea and vomiting, stiff the meninges, the membranes sur- People with HIV-associated CMV neck, double vision, altered mental rounding the brain and spinal cord. encephalitis may present with confu- status with drowsiness, and photo- HIV positive people are at higher risk sion and cognitive decline. The condi- phobia (abnormal sensitivity to light). than the general population of devel- tion can arise suddenly with rapid Hydrocephalus must be suspected oping bacterial or viral meningitis, progression of altered mental status with new-onset impaired conscious- which may be caused by HIV itself. and cognitive deterioration. Changes ness; motor signs such as a stiff, shuf- Cryptococcal meningitis, caused by might also develop more slowly and fling gait; nausea; vomiting; or visual the C. neoformans fungus, is also be indistinguishable from HIV impairment. Hydrocephalus is a common. More uncommon CNS encephalopathy. CMV encephalitis blockage of the normal flow of CSF infections are due to the Listeria may occur together with previously in and around the brain; it may occur monocytogenes bacterium, coccidio- known or newly diagnosed CMV- with cryptococcal meningitis and may mycosis (valley fever), histoplasmosis related inflammations or neuropathy. cause worsening headache and gait (caused by the Histoplasma capsulatum Typical CSF findings include low- imbalance. Occasionally, the spinal fungus), syphilis, and tuberculosis. to-normal glucose, normal-to-high cord may be involved, leading to Meningitis due to CMV or fungal protein, and increased numbers of radicular (nerve root) pain, stiffness infection occurs typically with very white blood cells. CMV can be or spasticity, limb weakness, and low CD4 cell counts. Rarely, lym- detected by PCR. A CT or MRI scan problems with bowel and bladder phoma can present as meningitis. may show nonspecific abnormalities, control. Allergic reactions are more common but a contrast enhanced MRI may CSF appearance on examination in people with HIV, and chemical strongly suggest the diagnosis. Mass may be clear or cloudy, and often meningitis associated with medica- lesions due to CMV are rare. shows mild abnormalities in cell tions such as pegylated interferon, Untreated CMV encephalitis is count or protein levels. C. neoformans and even ibuprofen, has been almost always fatal and causes death is found in nearly all CSF samples. described. in days to weeks. Anti-CMV drugs MRI is the preferred brain scan to Individuals with meningitis pres- must be started immediately, often reveal meningeal inflammation or ent with malaise (vague body discom- based on a suspected rather than cryptococcal abscesses. fort), fever, stiff neck, photophobia, proven diagnosis. Treatment relies on Untreated cryptococcal CNS infec- and headache. Less common are two drugs, ganciclovir (Cytovene) and tions are fatal. Treatment relies on cranial neuropathies (one-sided facial foscarnet (Foscavir), used alone or in amphotericin B (Fungizone), which weakness or double vision), confu- combination when monotherapy fails. may be combined with flucytosine sion, drowsiness, and personality Lifelong maintenance treatment is (Ancobon). An alternative for less changes. often necessary. More than 50% of severe cases is fluconazole (Diflucan), HIV invades the brain early and those who take anti-CMV agents stabi- which is also the drug of choice for may cause meningitis within days to lize or improve, but the overall prog- long-term prophylaxis (preventive weeks after HIV infection. Chronic nosis is determined by the stage of therapy). Amphotericin B is an alter- meningitis, or episodes of acute (rapid HIV disease. native maintenance therapy for people onset) meningitis for which no cause Cryptococcosis who relapse on fluconazole or do not is found, can occur anytime during Cryptococcosis, caused by the tolerate it. the course of HIV disease. These Cryptococcus neoformans fungus, is the Hydrocephalus can occur at times episodes may reflect HIV itself, or most common CNS fungal infection in and requires a ventriculoperitoneal may occur with outbreaks of herpes 42 BETA WINTER 2005
  7. 7. simplex type I (cold sores) or type II peripheral polyneuropathy, gait imbal- tuberculosis may lead to drowsiness (genital skin eruptions). ance, seizures, or stroke. or stupor and, later, coma. Spinal cord CT and MRI brain scans may The standard test for neuro- damage can occur if the vertebrae show inflammatory changes surround- syphilis is a VDRL (“syphilis”) test of (bones that encase the spinal cord) ing the brain. CSF analysis often gives the cerebrospinal fluid. A positive CSF are infiltrated by TB, also known as results that identify the type of menin- VDRL points to a neurosyphilis diag- Pott’s disease, or as a result of gitis and organism involved. nosis. However, a negative CSF VDRL abscesses inside or outside the Treatment and prognosis vary by cannot exclude neurosyphilis, and a spinal cord. the specific cause of meningitis, sever- high clinical suspicion of the condi- CSF studies are useful, especially ity at presentation, delay from symp- tion may be the ultimate test. A nega- DNA PCR probes for M. tuberculosis. tom onset to treatment, and status of tive syphilis antibody test of the CSF MRI brain scan may reveal thickening immunosuppression. For treatment of (for example, using the FTA-ABS of the coverings of the brain, abscesses, meningitis due to CMV or cryptococcal assay) excludes neurosyphilis. stroke, and enlarged ventricles (an infection, see the “Cytomegalovirus The VDRL or RPR test of the indication of hydrocephalus). Encephalitis” and “Cryptococcosis” blood may be negative in 25% of peo- Triple antibiotic therapy— sections, above. ple with neurosyphilis. Syphilis anti- isoniazid, rifampin (Rifadin), and body blood tests such as MHA-TP or pyrazinamide—for 12–24 months is Neurosyphilis FTA-ABS will remain positive with required. It is important that all doses Syphilis is a sexually transmitted neurosyphilis and should be added to be taken as directed. In cases of infection caused by the spiral-shaped the blood VDRL test. drug-resistant TB, a fourth drug Treponema pallidum bacterium. CSF cell count, glucose, and (ethionamide [Trecator]) should be T. pallidum gains access to the body protein levels may be normal in 30% added to the regimen above. HAART through tiny abrasions of the skin or of cases, and, again, clinical suspicion should be continued. Significant mucous membranes. This organism of syphilis may overrule negative or interactions can occur between may invade the CNS a few months normal tests. rifampin and protease inhibitors after initial infection. Some studies The choice of antibiotic depends (PIs), so an alternative anti-TB drug suggest that syphilis may follow a on the stage of syphilis and follows may be necessary. more aggressive course in people general guidelines. Most common are Tuberculomas (tumor-like masses) with HIV. different forms of penicillin. While can develop in people with HIV. Syphilis in people with HIV may people with HIV with neurosyphilis Combination medications are used ini- proceed more rapidly than usual respond to antibiotics, they are less tially, unless the tuberculoma is caus- from the primary stage (skin chan- likely to have serological improvement ing a critical brain swelling or spinal cres, or lesions, appearing about 21 than HIV negative individuals. HIV- cord paralysis. days after infection) to secondary associated neurosyphilis may be more (skin rash) and tertiary (infection of Myelopathy difficult to treat and more aggressive, different organs, including the brain) HIV-associated myelopathy likely due to impaired immune syphilis as early as two months after (spinal cord disease), or vacuolar responses to T. pallidum. exposure. myelopathy, is the most common A person with syphilis may not Tuberculosis Meningitis chronic spinal cord condition associ- recall the painless skin chancres and Tuberculosis (TB) is a bacterial ated with late-stage HIV disease, may present with secondary syphilis, disease caused by Mycobacterium when CD4 cell counts are very low. with a dusky red, roundish rash tuberculosis, which can be suspended Myelopathy often presents together (slightly raised with slightly peeling in tiny droplets in the air and trans- with ADC, peripheral neuropathies, overlying skin) on the palms of the mitted person to person by inhalation. and OIs or malignancies. The secre- hands. At this point, 24% of people Worldwide, TB is the most common tion of neurotoxic factors by HIV- will already have CSF abnormalities. OI associated with late-stage HIV dis- infected blood cells or the expression This early invasion of the brain, com- ease, when CD4 cell counts are very of HIV gene products in certain cells bined with a delayed or absent blood low. Neurological complications are of the nervous system may contribute test for syphilis, increases the risk of often present; tuberculosis meningitis to this condition. Impaired ability to delayed or missed syphilis diagnosis is the most common manifestation. use vitamin B12 for myelin mainte- and advancement to tertiary syphilis. Tuberculosis affecting the brain nance in the spinal cord may be a Tertiary syphilis may present as may cause persistent headache, fever, contributing factor. hearing loss, dizziness or vertigo, confusion, hemiparesis, seizures, People with HIV-associated headache, failing vision, cognitive stiff neck, double vision, or hearing myelopathy present with chronic pro- impairment, personality changes, loss. Hydrocephalus associated with gressive and painless leg weakness, WINTER 2005 BETA 43
  8. 8. stiffness, and imbalance. Sensory loss the extremities (feet and hands), is antiepileptic medications (gabapentin may be minor. Bowel and bladder the most common type of HIV- [Neurontin], lamotrigine [Lamictal], control are affected only if the legs are associated neuropathy. Nerves may be carbamazepine [Tegretol]). Duloxetine severely weak. injured directly by HIV or by HIV- (Cymbalta; an SSRI antidepressant) is CSF examination is usually nor- induced macrophages that secrete FDA approved for painful diabetic mal. CSF studies should include DNA neurotoxic substances. DSP may polyneuropathy, and is currently PCR tests for CMV and herpes zoster. also be caused by nutritional and vita- being used for HIV-associated painful CSF cytology (cell analysis) should be min imbalances or drug toxicity, espe- polyneuropathy. Pregabaline (Lyrica; done to exclude lymphoma. MRI cially use of d4T (stavudine, Zerit), an antiepileptic drug) is under FDA spine scan should be done to exclude ddI (didanosine, Videx), or ddC review. Drugs should be chosen that vertebral disc disease. It may also (zalcitabine, Hivid). are unlikely to interact with or influ- reveal changes specific to HIV myel- DSP may occur at any stage of ence the effectiveness of anti-HIV opathy. Vitamin B12 deficiency occurs HIV disease. People with DSP may drugs. Lidoderm patches may provide more frequently in people with HIV complain of tingling, burning, or partial pain relief without any sys- and may cause spinal cord and shooting pain on the soles of their temic side effects and can be com- peripheral nerve damage. feet. The pain slowly advances to the bined with oral drugs. For trials of Once treatable causes of myelopa- top of the foot and then may envelope therapies for neuropathy pain, see thy have been excluded, prognosis is the lower leg. As the DSP creeps up “Open Clinical Trials” on pages 51–52. poor, options are limited, and care is the leg to the knee, the fingertips and Inflammatory Demyelinating primarily supportive. People with the hands typically become affected. Polyneuropathy condition may improve after starting Bladder and bowel control may be HAART. To stabilize spinal cord dam- affected, as well as the ability to HIV infection is an important age, maximally potent HAART is achieve an erection in men. cause of inflammatory demyelinating required. L-methionine (also known Blood tests for diabetes mellitus, polyneuropathy (IDP), or inflamma- as SAMe, a common dietary supple- thyroid dysfunction, vitamin B12 level, tion of the myelin sheath that sur- ment) is an experimental treatment. syphilis, and many others should be rounds the spinal and peripheral done to exclude other treatable causes nerves. CONDITIONS of neuropathy. CSF studies are useful The acute form of IDP (AIDP), PREDOMINANTLY if CMV or syphilis is suspected. also known as Guillain-Barré syn- AFFECTING THE Electromyography and nerve con- drome (GBS), is characterized by PERIPHERAL NERVOUS duction studies may reveal damage to rapid onset and progression over SYSTEM axons (long nerve fibers that conduct hours to weeks. The chronic form impulses away from nerve cells) or to (CIDP) has slower onset and progres- A wide spectrum of PNS-related the insulating myelin sheath around sion over weeks to months, some- conditions is associated with HIV axons. Electromyography refers to times with a relapsing course. Both infection, and many people have more the insertion of small needles into forms are autoimmune conditions in than one specific diagnosis. PNS dis- affected muscles to monitor muscle which the immune system attacks orders affect the spinal nerve roots and nerve function; nerve conduction nerves. GBS can be triggered by infec- where the nerves exit the spinal cord, studies refer to the placing of elec- tions or immunizations, and is more and the route along the peripheral trodes on the skin over nerves and often seen at the time of HIV serocon- nerves down the arms and legs. HIV using small pulses of electrical current version, but can occur at any stage of also affects muscles. HIV-associated to monitor nerve response. HIV infection, as can the chronic form complications in the PNS and muscles It may be necessary for a person of IDP. are clinically apparent in over 30% of with DSP to stop taking d4T, ddI, or IDP causes varying degrees of people with HIV. Because they may be ddC. Vitamin B12 supplementation by weakness and sensory loss, which subclinical (without symptoms), neu- mouth is needed if there is a defi- can develop in the limbs. Nerves romuscular abnormalities are often ciency. Intake of vitamin B6 (pyridox- around the head may also be affected detected by electromyography and ine) should be reduced, if necessary, and cause symptoms such as facial nerve conduction studies or histologi- as more than 50 mg per day may weakness and double vision. Other cal studies, as described below. cause polyneuropathy. features may include pain and dimin- Distal Sensory Treatment of symptoms may ished reflex responses. Sometimes Polyneuropathy include local ointments (capsaicin, people with IDP have difficulty with Distal sensory polyneuropathy Aspercream), antidepressant medica- urination and bowel movements, and (DSP), or damage to sensory nerves in tions (amitriptyline [Elavil]), or occasionally respiratory paralysis, 44 BETA WINTER 2005
  9. 9. irregular heartbeat, and dangerously simplex I and II, and CMV may be may improve spontaneously without high or low blood pressure can ensue. useful. Nerve biopsy may also be use- treatment. CSF studies will show signifi- ful if a pathology lab familiar with the Myopathy cantly elevated protein during the first procedure is available. few days or weeks of the syndrome. Mononeuritis multiplex occurring Myopathy refers to many forms of Often the cell count is elevated as well early in HIV infection may resolve with muscle disease. HIV-associated in both acute and chronic IDP associ- HAART. IVIG or plasma exchange myopathies fall into several categories. ated with HIV infection, whereas GBS should be considered in early or late Some are caused by drug toxicity, for in people without HIV is characterized HIV stages. People with late-stage HIV instance, due to cholesterol lowering by normal cell counts. Repeated lum- disease may require anti-CMV medica- drugs (statins), ddI, or AZT (zidovu- bar punctures (spinal taps; inserting a tions (ganciclovir, foscarnet). dine, Retrovir). Others are caused by a needle into the spinal column to variety of bacterial, viral, and other Polyradiculopathy remove cerebrospinal fluid) may be infections. Still others, such as needed. Electromyography and nerve Polyradiculopathy is damage to polymyositis (inflammatory disease of conduction studies may be useful in the nerve roots where the nerves exit muscles), are due to an abnormal the spinal cord to form peripheral immune response. HIV wasting syn- diagnosing acute or chronic IDP. nerves. Polyradiculopathy may be drome may result from HIV infection Treatment and response rates are caused by CMV, or less likely by itself. similar to those seen in the HIV nega- lymphoma. It may also be idiopathic Progressive muscle weakness is tive population. Intravenous immuno- (of unknown origin). CMV poly- the typical presentation, with the globulin (IVIG), a highly concentrated radiculopathy occurs with very low speed of progression depending on antibody infusion from many pooled CD4 cell counts, and CMV may the cause. blood donations, is the mainstay of already be present at other sites, The serum creatine kinase (CK) therapy. Plasma exchange, or such as the retina. level is often increased but may be plasmapheresis, may be helpful; Rapidly progressive ascending normal. Electromyography, nerve con- in this procedure antibodies are numbness, pain, and weakness affect- duction studies, and muscle biopsy removed from the blood. Chronic ing the legs, and later occasionally are often indicated. Imaging studies IDP may also require corticosteroids also the arms, is characteristic of the such as prednisone. (CT, MRI, Gallium-67 scan, ultra- CMV form. Early bowel and bladder Mononeuritis Multiplex sound) are helpful when certain infec- control problems may suggest the syn- tions are suspected. Mononeuritis multiplex (MM) is a drome. A more benign, slower clinical When medications are the likely usually painful condition that involves progression characterizes the idio- cause, they may need to be stopped or isolated nerves over the arms, legs, or pathic form. replaced. Muscle infections are treated trunk. The nerves are affected asym- CSF analysis may show elevated with drugs specific to the responsible metrically. The involvement of more protein and white blood cells, and bacterium, virus, or other infectious than two nerves is generally seen in decreased glucose. A PCR test of the agent. When inflammation results people with advanced HIV, and may CSF is useful to identify or exclude from an overactive immune system, be caused by CMV. CMV. MRI of the spinal cord may be corticosteroids may be a treatment People with MM typically com- needed to exclude structural com- plain of burning or shooting pain option. pression of the spinal cord, such as down an arm, then, even as it is from a large disc herniation or tumor, CONCLUSION resolving, another burning pain will or spinal cord lesions due to lym- emerge over another nerve pathway phoma, syphilis, Kaposi’s sarcoma HIV is associated with a range of down a different arm or leg. Weakness (KS), or toxoplasmosis. Electro- neurological problems. Fortunately, in the distribution of specific nerves is myography and nerve conduction many of these conditions have common. Nerves can be affected in studies help differentiate polyradicu- become rarer with the use of HAART the head and the body. lopathy from other rapidly progres- and the subsequent improvements in Blood tests for diabetes mellitus sive neuropathies such as Guillain- health for many HIV positive people. and immune abnormalities should be Barré syndrome. Access to a clinician with experience done. Electromyography and nerve CMV polyradiculopathy is rapidly in neurological disorders specific to conduction studies may be useful in fatal without therapy. Treatment with HIV disease is essential for the pre- making the diagnosis. CSF studies foscarnet or ganciclovir may improve vention, early diagnosis, and treat- are usually nonspecific, but if done, or stabilize the condition. HAART also ment of neurological conditions in DNA PCR for herpes zoster, herpes may be useful. The idiopathic form this population. WINTER 2005 BETA 45
  10. 10. GLOSSARY PATHOPHYSIOLOGY: Chong, J. and others. MR findings in AIDS-associated myelopathy. American Journal of Neuroradiology 20: changes in function associated with disease. 1412–1416. 1999. BIOPSY: the removal of a small sample of cells or tissue for PLATELET: Cornblath, D.R. and others. Inflammatory demyelinating a type of blood cell that facilitates normal blood peripheral neuropathies associated with human T-cell microscopic examination and/or culture, typically lymphotropic virus type III infection. Annals of Neurology for diagnostic purposes. clotting. 21: 32–40. 1987. CEREBROSPINAL FLUID (CSF): POLYMERASE CHAIN REACTION (PCR) Cornblath, D.R. and McArthur, J.C. Predominantly sen- ASSAY: sory neuropathy in patients with AIDS and AIDS-related a clear fluid that circulates around and through the complex. Neurology 38: 794–796. 1988. brain and spinal cord. a highly sensitive test that can detect small amounts of genetic material in a blood or tissue sample. Clifford, D.B. and others. HAART improves prognosis in COMPUTED TOMOGRAPHY SCAN (CT SCAN, HIV-associated progressive multifocal leukoen- POSITRON EMISSION TOMOGRAPHY cephalopathy. Neurology 52: 623–625. 1999. CAT SCAN): a method of visualizing the bones and tissues of the (PET) SCAN: de Gans, J. and Portegies, P. Neurological complications body using x-rays. an imaging method in which a radioactive sub- of infection with human immunodeficiency virus type 1: a review of literature and 241 cases. Clinical Neurology stance is injected into the bloodstream and a scan- and Neurosurgery 91: 199–219. 1989. DEMENTIA: ner is used to measure cerebral blood flow in the deterioration of mental function. different parts of the brain. De Luca, A. and others. Response to cidofovir after fail- ure of antiretroviral therapy alone in AIDS associated DEMYELINATION: progressive multifocal leukoencephalopathy. Neurology PROGNOSIS: 52: 891–892. 1999. the loss of the lipid myelin sheath that surrounds a forecast of the probable course or outcome of a nerve cells and is necessary for proper transmission Di Rocco, A. and others. A pilot study of L-methionine disease. for the treatment of AIDS-associated myelopathy. of neural impulses. Neurology 51: 266–268. 1998. SEROCONVERSION: DIFFERENTIAL DIAGNOSIS: the change in a person’s blood antibody status from Dore, G.J. and others. Marked improvement in survival a method of diagnosis that involves determining following AIDS dementia complex in the era of highly negative to positive; development of antibodies active antiretroviral therapy. AIDS 17: 1539–1545. which of a variety of possible conditions is the prob- against a microorganism. 2003. able cause of an individual’s symptoms, often by a Ernst, T. and others. Abnormal brain activation on func- process of elimination. ULTRASOUND: tional MRI in cognitively asymptomatic HIV patients. an imaging technology using high-frequency sound Neurology 59: 1343–1349. 2002. HEMIPARESIS: waves. Forsyth, P.A. and DeAngelis, L.M. Biology and manage- weakness on one side of the body. ment of AIDS associated primary CNS Lymphomas. Hematology/Oncology Clin North America 10: HERPES ZOSTER (SHINGLES): 1125–1134. 1996. Venkat K. Rao, MD a condition characterized by painful blisters caused ( is a staff Freeman, R. and others. Autonomic function and human by reactivation of varicella-zoster virus (VZV). immunodeficiency virus infection. Neurology 40: physician in the Department of Blisters typically appear in a linear distribution on 575–580. 1990. Neurology at Saint Louis University the skin following nerve pathways; outbreaks occur Fung, H.B. and Kirschenbaum, H.L. Treatment regimens Health Sciences Center. more frequently and may be more severe in for patients with toxoplasmic encephalitis. Clinical Therapeutics 18: 1037–1056. 1996. immunocompromised individuals. Florian P. Thomas, MD, MA, PhD ( is an associate Gendelman, H.E. and others. The Neurology of AIDS. HYDROCEPHALUS: Chapman & Hall, New York. 1998. a blockage of the normal flow of cerebrospinal fluid professor in the Department of Neurology at Saint Louis University Gillams, A.R. and others. Cerebral infarction in patients in and around the brain. with AIDS. American Journal of Neuroradiology 18: Health Sciences Center. 1581–1585. 1997. LESION: any abnormal tissue change caused by disease or Gondim, F.A.A. and Thomas, F.P. On the relationship Selected Sources between intracranial venous sinus thrombosis and HIV- injury. (for a full listing of sources, please contact the associated nephropathy. AIDS Reader 13: 146–147. authors) 2003. MAGNETIC RESONANCE IMAGING (MRI): AAN Quality Standards Subcommittee. Evaluation and Huang, S.S. and others. Survival prolongation in HIV a sensitive, noninvasive method for viewing management of intracranial mass lesions in AIDS. associated progressive multifocal leukoencephalopathy organs and tissues of the body using a strong Neurology 50: 21–26. 1998. treated with alpha interferon. Journal of Neurovirology 4: magnetic field. 4324–4332. 1998. Antinori, A. and others. Role of brain biopsy in the man- agement of focal brain lesions in HIV-infected patients. Robertson, K.R. and others. Highly active antiretroviral MYELIN: Neurology 54: 993–997. 2000. therapy improves neurocognitive functioning. Journal of a white, fatty substance that forms a sheath around Acquired Immune Deficiency Syndromes 36(1): Childs, E.A. and others. Plasma viral load and CD4 lym- 562–566. April 15, 2004. nerve fibers and provides insulation necessary for phocytes predict HIV-associated dementia and sensory proper transmission of neural impulses. neuropathy. Neurology 52: 607–613. 1999. Ryan, E.L. and others. Neuropsychiatric impact of hepa- titis C on advanced HIV. Neurology 62(6): 957–962. PALSY: Chariot, P. and Gherardi, R. Myopathy and HIV infection. March 23, 2004. Current Opinion in Rheumatology 7: 497–502. 1995. muscle paralysis. 46 BETA WINTER 2005