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Neurological Complications of HIV/AIDS

Winter 2004/2005

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!


Neurological Complications of HIV/AIDS
Neurological complications are common in HIV disease. The spectrum 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 neurological conditions are mild, readily treatable, or reversible. Several have become less common since the introduction of highly active antiretroviral 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.


Pathophysiology

HIV-related neurological disorders may develop directly from infection with HIV, or indirectly as a result of opportunistic illnesses (OIs) or treatment complications. For example, OIs such as toxoplasmosis often arise from reactivation of previous infections when immune system defenses break down. Viruses that cause progressive multifocal leukoencephalopathy (PML) may be activated by HIV itself. Toxic side effects of certain anti-HIV medications may affect peripheral nerves and muscle.

Different neurological disorders are likely to be seen at different stages of HIV infection (see table below). In a first evaluation, the clinician should determine whether clinical features suggest localized (limited to a specific area) or global brain dysfunction, meningitis (inflammation of the membranes covering the brain and spinal cord), spinal cord disease, neuropathy (nerve damage), or myopathy (muscle disease).

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The likelihood of a given neurological problem is partly related to the stage of HIV disease as reflected by immune response, viral load level, and CD4 cell count. Levels of cytokines (hormones that coordinate and regulate immune response) have also been implicated.


Neurological Disorders and Stages of HIV Disease

Early HIV Disease

At the time of seroconversion and in the early stages of HIV disease (CD4 cell levels above 500 cells/mm3) common neurological complications may be undetectable or may include:

  • aseptic meningitis

  • acute encephalopathy with seizures and confusion

  • inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome)

  • cranial nerve palsies (e.g., Bell's palsy)

  • herpes zoster (shingles)

Moderate to Severe Immunodeficiency

In moderate to severe immunodeficiency (200-500 CD4 cells/mm3), the following are more likely to be seen:

  • cognitive impairment

  • distal sensory polyneuropathy (may also appear in early HIV disease)

  • myelopathy

  • myopathy

Late-Stage HIV Disease

Illnesses in people with less than 200 CD4 cells/mm3 may include:

  • HIV encephalopathy (dementia)

  • CNS toxoplasmosis

  • cytomegalovirus (CMV) infection

  • primary CNS lymphoma

  • progressive multifocal leukoencephalopathy (PML)


General Approach

People with HIV often have more than one medical or neurological problem at the same time. A careful history and exam may isolate the diagnosis. Imaging and laboratory studies may help document the diagnosis, and at times identify coexisting illnesses. Neurological diseases are the first manifestation of AIDS in 7-20% of people with HIV and may thus be the AIDS-defining illness.

Due to the complexity of HIV disease and its chronic course, a multidisciplinary approach is important. This may involve general internists, infectious disease and other sub-specialists, neurologists, psychiatrists, physical therapists, and other rehabilitation professionals, including nutritionists.

People with both HIV and hepatitis C virus (HCV) infection may warrant additional neurological observation. In a study published in the March 23, 2004 issue of Neurology, Elizabeth Ryan, MD, and colleagues reported that people with advanced HIV disease and HCV coinfection tended to have worse neurocognitive performance and greater impairment of executive functioning (problem solving and other complex use of information) than people with only advanced HIV disease. Coinfected individuals were also significantly more likely to have HIV-associated cognitive impairment.


Conditions Predominantly Affecting the Central Nervous System

Many conditions affecting the CNS are associated with HIV infection, and multiple illnesses may be present simultaneously. CNS disorders affect the brain, the spinal cord (but not the nerves that branch off it, which are part of the PNS), and the membranes covering the brain and spinal cord. Many of these conditions may present either with or without symptoms. The descriptions of conditions below include tests than can be used to make a differential diagnosis.


CNS Toxoplasmosis

Toxoplasmosis, caused by the Toxoplasma gondii parasite, is the most common CNS disease associated with AIDS. Usually it is due to reactivation of prior infections in the CNS or elsewhere, but primary infections can also occur. The disease appears during advanced HIV infection when CD4 cell counts are below 200 cells/mm3. Clinical CNS toxoplasmosis is seen in 3-10% of people with AIDS in the U.S.

Onset is over days to weeks. People with CNS toxoplasmosis typically develop headache and fever, followed by impaired thinking and vision, hemiparesis (weakness on one side of the body), and imbalance. Confusion, seizures, meningitis, dementia (deterioration of mental function), and depression may also occur.

A blood test for toxoplasmosis antibodies should be done. A polymerase chain reaction (PCR) assay of the cerebrospinal fluid (CSF) may find T. gondii DNA. Magnetic resonance imaging (MRI) is more sensitive than computed tomography (CT, CAT) scan in detecting multiple brain abscesses. A single lesion (tissue abnormality) might suggest a diagnosis of lymphoma instead of toxoplasmosis (see "Primary CNS Lymphoma," below). A brain biopsy is indicated if there is a single mass lesion and negative serological (blood testing) results, or if there is no response to 14 days of therapy.

Toxoplasmosis is treatable. It is generally responsive to intravenous (IV) antibiotics, and response to therapy is often rapid. Agents of choice are sulfadiazine combined with pyrimethamine and folinic acid. For people with sulfa intolerance, clindamycin is an alternative. Steroids may be used to reduce associated swelling in the brain.

Ninety-one percent of people treated improve by day 14 of therapy. After the initial regimen is completed, oral maintenance treatment, usually TMP/SMX (Bactrim, Septra), is continued indefinitely to suppress reactivation of the parasite. Prognosis is linked to parallel treatment with HAART to raise the CD4 cell count.

People with HIV who by blood tests appear not to have been exposed to T. gondii should avoid eating raw or undercooked meat, particularly pork, lamb, or venison. Fruits and vegetables should be washed, as should one's hands after contact with raw meat, soil (as after gardening), or a cat's litter box. Ideally, litter should be changed daily by an HIV negative, nonpregnant person. Household pet feces should always be handled wearing latex gloves. Keeping cats indoors and feeding them only commercial cat food, or well-cooked table food, may reduce their risk of becoming infected with T. gondii. Stray cats should be avoided.


Primary Central Nervous System Lymphoma

Lymphoma refers to cancer of the lymph system. It is characterized by the growth of abnormal lymphocytes, or white blood cells (B cells and T cells) that play a part in immune system defenses. HIV-associated primary CNS lymphoma (PCNSL) occurs in the brain, rarely in the spinal cord, and causes brain lesions and changes in mental functioning. In almost all cases, Epstein-Barr virus (EBV) is found in the lymphoma-related lesions or the CSF. EBV's effect on chronically activated lymphocytes is the probable cause.

PCNSL is associated with CD4 cell counts below 100 cells/mm3. With a prevalence of up to 5% among people with AIDS in the U.S., PCNSL is the second most common mass lesion after toxoplasmosis. Rarely it is the presenting feature of AIDS.

The most common clinical symptoms of PCNSL are impaired cognition, aphasia (loss of ability to use or understand language), hemiparesis, and seizures. Onset is often more subtle, and progression slower, than with toxoplasmosis.

CSF analysis is likely to show pleocytosis (abnormally high number of cells), elevated protein, and malignant-appearing lymphocytes. The presence of EBV in the cerebrospinal fluid is a strong indicator of PCNSL in people with AIDS.

Brain CT or MRI may be useful in suggesting lymphoma by the location and characteristics of tissue changes or uptake of contrast material. Multiple lesions can occur, although less frequently than with toxoplasmosis. MRI spectroscopy (measuring the chemical content of brain lesions) may be easily done during the initial MRI brain scan, and, if certain chemicals are elevated, may suggest lymphoma.

The prognosis for PCNS lymphoma is generally poor. Whole brain radiation therapy (radiotherapy) has been the mainstay of treatment; it provides for a median survival of 2-5 months. Steroids are required for at least 48 hours before radiotherapy to minimize swelling; steroids should be continued throughout the course of treatment. High-dose methotrexate has been used with some success, given as frequently as every week for five cycles. Combining methotrexate and radiotherapy can achieve survival of 1-2 years. Experimental chemotherapy agents include thiotepa (Thioplex) and procarbazine (Matulane). HAART should be continued.


Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is characterized by widespread demyelinating lesions (loss of the insulating myelin sheath around nerves in the brain and spinal cord) and is caused by the JC papovavirus. Around 90% of the general population have been exposed to this virus and have antibodies against it. The syndrome of PML occurs almost exclusively in people whose immune systems are suppressed due to HIV or organ transplantation. It is unclear whether PML develops when JC virus in the brain is reactivated or when the virus is reactivated elsewhere in the body, such as the bone marrow, and migrates to the brain. HIV gene products such as the Tat protein may activate the JC virus directly.

PML is usually seen when CD4 cell counts fall below 200 cells/mm3, and it may be an AIDS-defining event. The syndrome likely occurs in less than 4% of AIDS cases where HAART is used.

Onset is usually over weeks to months. The clinical manifestations of PML depend on the areas of the brain affected. Weakness, chiefly hemiparesis, is most common. Other features include behavioral and cognitive problems, aphasia, ataxia (loss of ability to coordinate muscle movement), and cortical blindness (loss of vision due to a brain lesion). Headaches are more rare.

The cerebrospinal fluid is usually normal. The PCR assay is specific and sensitive for the detection of JC virus and can possibly replace a brain biopsy. Both CT and MRI scans may show distinctive tissue destruction just below the cortex, the outer layer of the brain.

PML typically progresses to severe dementia and death over several months. Whether HAART improves survival remains controversial. Survival correlates with suppression of plasma HIV viral load and higher CD4 cell counts. Death may result not from PML but from end-stage immune deficiency. Some positive response has been reported with use of cidofovir (Vistide).


Stroke and Hemorrhage

Stroke ("brain attack") and hemorrhage (spillage of blood from an artery into brain tissue) are major cerebrovascular events; cerebrovascular refers to the blood vessels of the brain. Causes of stroke and hemorrhage in HIV positive people are numerous and variable.

Hypertension (high blood pressure), blood vessel abnormalities (aneurysms, vein/artery malformations), and cardiovascular disease can lead to brain hemorrhage or stroke, just as in HIV negative people. Hypotension (low blood pressure) can cause stroke in people who are severely ill. Coagulopathies (defective blood clotting) may occur in HIV infection and can lead to stroke or hemorrhage. Thrombotic thrombocytopenic purpura (TTP; characterized by low platelet counts and blood clots) may occur in early phases of HIV disease and may also cause stroke or hemorrhage.

Specific forms of heart disease, particularly accelerated "hardening" of the coronary arteries due to elevated lipids and heart inflammation from various viral infections of the heart muscle, have been implicated in HIV-associated cerebrovascular conditions. Herpes zoster (shingles) over the forehead may cause underlying stroke weeks or months after appearing, and must be considered even in the absence of a rash. Hepatitis C and other infections can also contribute to cerebrovascular problems, such as by impairing blood clotting or leading to abnormal levels of certain blood proteins.

Cocaine and heroin also can cause cerebrovascular problems. Cocaine use may lead to hypertension with hemorrhage, or to blood vessel constriction and stroke caused by lack of blood supply to the brain. Heroin use can cause blood vessel inflammation. Also, nonsoluble contaminants in illicit IV drugs can block blood vessels.

Stroke and hemorrhage are characterized by the abrupt onset of weakness, language problems, or sensory loss. Symptoms often appear on only one side of the body. Imaging studies help differentiate stroke, hemorrhage, infection, and tumors.

Blood tests include complete blood count (CBC) with platelet count, erythrocyte sedimentation rate (ESR), anticardiolipin antibody and lupus anticoagulant, cryoglobulins, serology for specific infections, syphilis test, blood cultures, coagulation studies including antithrombin III, and protein S and C levels. Analysis of the cerebrospinal fluid may be indicated.

MRI is superior to CT, but both are useful in identifying stroke and hemorrhage. Magnetic resonance angiography (MRA) is useful in detecting blood vessel narrowing. Ultrasound of the carotid arteries (large vessels in the neck that supply blood to the brain) is a less expensive alternative to MRA or CT angiography. A test called transesophageal echocardiography (TEE) may be needed to evaluate the heart for stroke causes, such as dilated cardiomyopathy (failing heart), open channels between the cardiac chambers, or endocarditis (inflammation of the heart valves and lining).

In many cases, treatment parallels that in the HIV negative population. If a stroke is diagnosed within three hours after onset, the person may be a candidate for an infusion of TPA, an agent that dissolves clots and opens blood vessels. TPA is contraindicated (not recommended) in cases of brain hemorrhage. Often lipid-lowering drugs (statins), blood thinners such as warfarin (Coumadin), or antiplatelet agents such as aspirin or clopidogrel (Plavix) are indicated. Specific causes of stroke may require other forms of treatment. Brain hemorrhages occasionally may need to be treated with surgery to remove the mass of blood.

Prognosis after a stroke or brain hemorrhage depends on the size and location of the damage. After a stroke or hemorrhage, the person will recover the most during the initial few weeks, but improvement often continues for months. Inpatient and outpatient rehabilitation is often helpful.

Preventive treatment parallels that in the HIV negative population. Examples include antiplatelet agents or blood thinning drugs. Removal of plaque from the walls of carotid arteries and newer techniques of endovascular stenting (placing a tube inside a blocked artery) may open and repair vessels.


HIV Encephalopathy

HIV encephalopathy, or AIDS dementia complex (ADC), is one of several neurological conditions that may be caused by HIV itself. Dementia refers to the deterioration of mental function. ADC typically occurs as CD4 cell counts fall below 200 cells/mm3, but mild-to-moderate abnormalities may occur in earlier stages of HIV disease and are known as mild cognitive impairment (MCI). MCI is also associated with chronic hepatitis C and insulin resistance, two conditions that are more common in HIV positive individuals. Fortunately, the frequency of HIV encephalopathy has declined with the use of HAART.

HIV infection may cause ADC-related brain damage indirectly via the production of chemokines, proinflammatory cytokines, nitric oxide, and other neurotoxic factors by both infected and uninfected activated cells. Neurological damage may also occur through the actions of specific HIV proteins, including gp120, gp41, Tat, Nef, Vpr, and Rev, which can be toxic to nerve cells and their dendrites.

People with ADC often present with diminished concentration and memory. Apathy and withdrawal from hobbies or social activities are common, but must be distinguished from depression (see "Overcoming Depression," BETA, Winter 2004). Motor problems include imbalance, clumsiness, and weakness. Early signs and symptoms are subtle and may be overlooked. These symptoms may evolve into a severe, global dementia with memory loss and language impairment.

Staging

The following clinical staging of ADC was proposed in 1988:

Stage 0 (normal): Mental and motor functions are normal.

Stage 0.5 (equivocal/subclinical): Symptoms may be absent, minimal, or equivocal, with no impairment of work or performance of activities of daily living (ADL). Mild signs, such as slowed eye or extremity movements, may be present. Gait (manner of walking) and strength are normal.

Stage 1 (mild): The person can perform all but the more demanding aspects of work or ADL but has unequivocal evidence of functional, intellectual, or motor impairment. Signs or symptoms may include diminished performance on memory testing. The person can walk without assistance.

Stage 2 (moderate): The person is ambulatory and able to perform basic activities of self-care but cannot work or maintain the more demanding aspects of daily life.

Stage 3 (severe): The person has major intellectual incapacity (cannot follow news or personal events, cannot sustain complex conversation). Walking must be assisted (with a walker or personal support); walking is usually slowed and accompanied by clumsiness of arms.

Stage 4 (end stage): The person is bedridden in a nearly vegetative state with urinary and fecal incontinence. Intellectual and social comprehension and output are at a rudimentary level. The person is nearly or absolutely mute.

As is true for any dementing illness, other treatable causes should be sought and corrected if possible. Vitamin B12 (cobalamin) levels should be determined; when B12 is borderline, homocysteine and methylmalonic acid levels are more sensitive. Thyroid stimulating hormone (TSH) and syphilis serology (RPR, VDRL, or MHA-TP) should be checked. CSF analysis serves to exclude other causes of altered mental status. HIV in the CSF frequently is detected by PCR, and may suggest a need to alter HAART. Imaging studies may reveal progressive brain atrophy (shrinkage) or characteristic white matter changes. Electroencephalography (EEG; recording the electrical activity of the brain) shows generalized slowing in the later stages of ADC. Positron emission tomography (PET) scanning is sensitive for dementia, but not specific for HIV-related dementia.

In general, depression and metabolic causes of cognitive decline, such as other infections, vitamin deficiencies, thyroid dysfunction, and liver and renal dysfunction, should be aggressively corrected. Antiretroviral agents protect against ADC and can induce remission, but when treatment fails and viral load rebound occurs, cognitive function again deteriorates. If ADC develops during treatment with HAART, additional or alternative agents should be tried. Neuroprotective therapies or global memory enhancing agents such as memantine (Namenda) or donezepril (Aricept) may be useful in some individuals.

Close follow-up is needed because the person's cognitive impairment may progress to dementia, or the person may develop seizures or psychosis (a severe mental disorder often characterized by delusions or hallucinations). Also, people with ADC must often take multiple medications, many of which can affect thinking and memory and thus make the symptoms of ADC worse.


Cytomegalovirus Encephalitis

Cytomegalovirus (CMV) is a herpesvirus that often infects healthy people without causing symptoms. But in people with compromised immune systems, typically those with less than 50 cells/mm3, CMV may cause serious disease.

CMV infection of the brain, spinal cord, meninges, or nerve roots can lead to neurological problems such as encephalitis (inflammation of the brain), myelitis (inflammation of the spinal cord), retinitis (inflammation of the retina of the eye), polyradiculitis (inflammation of the spinal nerve roots), peripheral neuropathy, or mononeuritis multiplex (see "Mononeuritis Multiplex," below). Some 20% of people with CD4 cell counts below 100 cells/mm3 harbor CMV in different organs and suffer from colitis (inflammation of the large intestine), esophagitis (inflammation of the esophagus), or retinitis. Autopsy studies reveal CMV in the CNS in 5-40% of people with AIDS, and often the diagnosis was not made during life.

People with HIV-associated CMV encephalitis may present with confusion and cognitive decline. The condition can arise suddenly with rapid progression of altered mental status and cognitive deterioration. Changes might also develop more slowly and be indistinguishable from HIV encephalopathy. CMV encephalitis may occur together with previously known or newly diagnosed CMV-related inflammations or neuropathy.

Typical CSF findings include low-to-normal glucose, normal-to-high protein, and increased numbers of white blood cells. CMV can be detected by PCR. A CT or MRI scan may show nonspecific abnormalities, but a contrast enhanced MRI may strongly suggest the diagnosis. Mass lesions due to CMV are rare.

Untreated CMV encephalitis is almost always fatal and causes death in days to weeks. Anti-CMV drugs must be started immediately, often based on a suspected rather than proven diagnosis. Treatment relies on two drugs, ganciclovir (Cytovene) and foscarnet (Foscavir), used alone or in combination when monotherapy fails. Lifelong maintenance treatment is often necessary. More than 50% of those who take anti-CMV agents stabilize or improve, but the overall prognosis is determined by the stage of HIV disease.


Cryptococcosis

Cryptococcosis, caused by the Cryptococcus neoformans fungus, is the most common CNS fungal infection in people with AIDS. It develops when CD4 cell counts fall below 100 cells/mm3. Cryptococcosis presents as meningitis, a space-occupying lesion, or meningoencephalitis (inflammation of the meninges and brain). It typically reaches the CNS from the lungs. It can also affect skin, bone, and the genitourinary tract.

The nonspecific nature of early features may lead to significant treatment delay, so a high level of suspicion is warranted. Early symptoms and signs include headache, fever, malaise, nausea and vomiting, stiff neck, double vision, altered mental status with drowsiness, and photophobia (abnormal sensitivity to light). Hydrocephalus must be suspected with new-onset impaired consciousness; motor signs such as a stiff, shuffling gait; nausea; vomiting; or visual impairment. Hydrocephalus is a blockage of the normal flow of CSF in and around the brain; it may occur with cryptococcal meningitis and may cause worsening headache and gait imbalance. Occasionally, the spinal cord may be involved, leading to radicular (nerve root) pain, stiffness or spasticity, limb weakness, and problems with bowel and bladder control.

CSF appearance on examination may be clear or cloudy, and often shows mild abnormalities in cell count or protein levels. C. neoformans is found in nearly all CSF samples. MRI is the preferred brain scan to reveal meningeal inflammation or cryptococcal abscesses.

Untreated cryptococcal CNS infections are fatal. Treatment relies on amphotericin B (Fungizone), which may be combined with flucytosine (Ancobon). An alternative for less severe cases is fluconazole (Diflucan), which is also the drug of choice for long-term prophylaxis (preventive therapy). Amphotericin B is an alternative maintenance therapy for people who relapse on fluconazole or do not tolerate it.

Hydrocephalus can occur at times and requires a ventriculoperitoneal shunt (surgical drain of spinal fluid). Visual loss can be addressed by optic nerve surgery.

Several studies report mortality rates of 17-20%, but with aggressive therapy this may drop to 6%. A minority of people die within the first six weeks after diagnosis despite treatment. Relapse rates without prophylaxis range from 15% to 27%; this is reduced to 0-7% with prophylaxis.


Meningitis

Meningitis is an inflammation of the meninges, the membranes surrounding the brain and spinal cord. HIV positive people are at higher risk than the general population of developing bacterial or viral meningitis, which may be caused by HIV itself. Cryptococcal meningitis, caused by the C. neoformans fungus, is also common. More uncommon CNS infections are due to the Listeria monocytogenes bacterium, coccidiomycosis (valley fever), histoplasmosis (caused by the Histoplasma capsulatum fungus), syphilis, and tuberculosis. Meningitis due to CMV or fungal infection occurs typically with very low CD4 cell counts. Rarely, lymphoma can present as meningitis. Allergic reactions are more common in people with HIV, and chemical meningitis associated with medications such as pegylated interferon, and even ibuprofen, has been described.

Individuals with meningitis present with malaise (vague body discomfort), fever, stiff neck, photophobia, and headache. Less common are cranial neuropathies (one-sided facial weakness or double vision), confusion, drowsiness, and personality changes.

HIV invades the brain early and may cause meningitis within days to weeks after HIV infection. Chronic meningitis, or episodes of acute (rapid onset) meningitis for which no cause is found, can occur anytime during the course of HIV disease. These episodes may reflect HIV itself, or may occur with outbreaks of herpes simplex type I (cold sores) or type II (genital skin eruptions).

CT and MRI brain scans may show inflammatory changes surrounding the brain. CSF analysis often gives results that identify the type of meningitis and organism involved.

Treatment and prognosis vary by the specific cause of meningitis, severity at presentation, delay from symptom onset to treatment, and status of immunosuppression. For treatment of meningitis due to CMV or cryptococcal infection, see the "Cytomegalovirus Encephalitis" and "Cryptococcosis" sections, above.


Neurosyphilis

Syphilis is a sexually transmitted infection caused by the spiral-shaped Treponema pallidum bacterium. T. pallidum gains access to the body through tiny abrasions of the skin or mucous membranes. This organism may invade the CNS a few months after initial infection. Some studies suggest that syphilis may follow a more aggressive course in people with HIV.

Syphilis in people with HIV may proceed more rapidly than usual from the primary stage (skin chancres, or lesions, appearing about 21 days after infection) to secondary (skin rash) and tertiary (infection of different organs, including the brain) syphilis as early as two months after exposure.

A person with syphilis may not recall the painless skin chancres and may present with secondary syphilis, with a dusky red, roundish rash (slightly raised with slightly peeling overlying skin) on the palms of the hands. At this point, 24% of people will already have CSF abnormalities. This early invasion of the brain, combined with a delayed or absent blood test for syphilis, increases the risk of delayed or missed syphilis diagnosis and advancement to tertiary syphilis.

Tertiary syphilis may present as hearing loss, dizziness or vertigo, headache, failing vision, cognitive impairment, personality changes, peripheral polyneuropathy, gait imbalance, seizures, or stroke.

The standard test for neurosyphilis is a VDRL ("syphilis") test of the cerebrospinal fluid. A positive CSF VDRL points to a neurosyphilis diagnosis. However, a negative CSF VDRL cannot exclude neurosyphilis, and a high clinical suspicion of the condition may be the ultimate test. A negative syphilis antibody test of the CSF (for example, using the FTA-ABS assay) excludes neurosyphilis.

The VDRL or RPR test of the blood may be negative in 25% of people with neurosyphilis. Syphilis antibody blood tests such as MHA-TP or FTA-ABS will remain positive with neurosyphilis and should be added to the blood VDRL test.

CSF cell count, glucose, and protein levels may be normal in 30% of cases, and, again, clinical suspicion of syphilis may overrule negative or normal tests.

The choice of antibiotic depends on the stage of syphilis and follows general guidelines. Most common are different forms of penicillin. While people with HIV with neurosyphilis respond to antibiotics, they are less likely to have serological improvement than HIV negative individuals. HIV-associated neurosyphilis may be more difficult to treat and more aggressive, likely due to impaired immune responses to T. pallidum.


Tuberculosis Meningitis

Tuberculosis (TB) is a bacterial disease caused by Mycobacterium tuberculosis, which can be suspended in tiny droplets in the air and transmitted person to person by inhalation. Worldwide, TB is the most common OI associated with late-stage HIV disease, when CD4 cell counts are very low. Neurological complications are often present; tuberculosis meningitis is the most common manifestation.

Tuberculosis affecting the brain may cause persistent headache, fever, confusion, hemiparesis, seizures, stiff neck, double vision, or hearing loss. Hydrocephalus associated with tuberculosis may lead to drowsiness or stupor and, later, coma. Spinal cord damage can occur if the vertebrae (bones that encase the spinal cord) are infiltrated by TB, also known as Pott's disease, or as a result of abscesses inside or outside the spinal cord.

CSF studies are useful, especially DNA PCR probes for M. tuberculosis. MRI brain scan may reveal thickening of the coverings of the brain, abscesses, stroke, and enlarged ventricles (an indication of hydrocephalus).

Triple antibiotic therapy -- isoniazid, rifampin (Rifadin), and pyrazinamide -- for 12-24 months is required. It is important that all doses be taken as directed. In cases of drug-resistant TB, a fourth drug (ethionamide [Trecator]) should be added to the regimen above. HAART should be continued. Significant interactions can occur between rifampin and protease inhibitors (PIs), so an alternative anti-TB drug may be necessary.

Tuberculomas (tumor-like masses) can develop in people with HIV. Combination medications are used initially, unless the tuberculoma is causing a critical brain swelling or spinal cord paralysis.


Myelopathy

HIV-associated myelopathy (spinal cord disease), or vacuolar myelopathy, is the most common chronic spinal cord condition associated with late-stage HIV disease, when CD4 cell counts are very low. Myelopathy often presents together with ADC, peripheral neuropathies, and OIs or malignancies. The secretion of neurotoxic factors by HIV-infected blood cells or the expression of HIV gene products in certain cells of the nervous system may contribute to this condition. Impaired ability to use vitamin B12 for myelin maintenance in the spinal cord may be a contributing factor.

People with HIV-associated myelopathy present with chronic progressive and painless leg weakness, stiffness, and imbalance. Sensory loss may be minor. Bowel and bladder control are affected only if the legs are severely weak.

CSF examination is usually normal. CSF studies should include DNA PCR tests for CMV and herpes zoster. CSF cytology (cell analysis) should be done to exclude lymphoma. MRI spine scan should be done to exclude vertebral disc disease. It may also reveal changes specific to HIV myelopathy. Vitamin B12 deficiency occurs more frequently in people with HIV and may cause spinal cord and peripheral nerve damage.

Once treatable causes of myelopathy have been excluded, prognosis is poor, options are limited, and care is primarily supportive. People with the condition may improve after starting HAART. To stabilize spinal cord damage, maximally potent HAART is required. L-methionine (also known as SAMe, a common dietary supplement) is an experimental treatment.


Conditions Predominantly Affecting the Peripheral Nervous System

A wide spectrum of PNS-related conditions is associated with HIV infection, and many people have more than one specific diagnosis. PNS disorders affect the spinal nerve roots where the nerves exit the spinal cord, and the route along the peripheral nerves down the arms and legs. HIV also affects muscles. HIV-associated complications in the PNS and muscles are clinically apparent in over 30% of people with HIV. Because they may be subclinical (without symptoms), neuromuscular abnormalities are often detected by electromyography and nerve conduction studies or histological studies, as described below.


Distal Sensory Polyneuropathy

Distal sensory polyneuropathy (DSP), or damage to sensory nerves in the extremities (feet and hands), is the most common type of HIV-associated neuropathy. Nerves may be injured directly by HIV or by HIV-induced macrophages that secrete neurotoxic substances. DSP may also be caused by nutritional and vitamin imbalances or drug toxicity, especially use of d4T (stavudine, Zerit), ddI (didanosine, Videx), or ddC (zalcitabine, Hivid).

DSP may occur at any stage of HIV disease. People with DSP may complain of tingling, burning, or shooting pain on the soles of their feet. The pain slowly advances to the top of the foot and then may envelope the lower leg. As the DSP creeps up the leg to the knee, the fingertips and hands typically become affected. Bladder and bowel control may be affected, as well as the ability to achieve an erection in men.

Blood tests for diabetes mellitus, thyroid dysfunction, vitamin B12 level, syphilis, and many others should be done to exclude other treatable causes of neuropathy. CSF studies are useful if CMV or syphilis is suspected.

Electromyography and nerve conduction studies may reveal damage to axons (long nerve fibers that conduct impulses away from nerve cells) or to the insulating myelin sheath around axons. Electromyography refers to the insertion of small needles into affected muscles to monitor muscle and nerve function; nerve conduction studies refer to the placing of electrodes on the skin over nerves and using small pulses of electrical current to monitor nerve response.

It may be necessary for a person with DSP to stop taking d4T, ddI, or ddC. Vitamin B12 supplementation by mouth is needed if there is a deficiency. Intake of vitamin B6 (pyridoxine) should be reduced, if necessary, as more than 50 mg per day may cause polyneuropathy.

Treatment of symptoms may include local ointments (capsaicin, Aspercream), antidepressant medications (amitriptyline [Elavil]), or antiepileptic medications (gabapentin [Neurontin], lamotrigine [Lamictal], carbamazepine [Tegretol]). Duloxetine (Cymbalta; an SSRI antidepressant) is FDA approved for painful diabetic polyneuropathy, and is currently being used for HIV-associated painful polyneuropathy. Pregabaline (Lyrica; an antiepileptic drug) is under FDA review. Drugs should be chosen that are unlikely to interact with or influence the effectiveness of anti-HIV drugs. Lidoderm patches may provide partial pain relief without any systemic side effects and can be combined with oral drugs. For trials of therapies for neuropathy pain, see "Open Clinical Trials" in this issue.


Inflammatory Demyelinating Polyneuropathy

HIV infection is an important cause of inflammatory demyelinating polyneuropathy (IDP), or inflammation of the myelin sheath that surrounds the spinal and peripheral nerves.

The acute form of IDP (AIDP), also known as Guillain-Barré syndrome (GBS), is characterized by rapid onset and progression over hours to weeks. The chronic form (CIDP) has slower onset and progression over weeks to months, sometimes with a relapsing course. Both forms are autoimmune conditions in which the immune system attacks nerves. GBS can be triggered by infections or immunizations, and is more often seen at the time of HIV seroconversion, but can occur at any stage of HIV infection, as can the chronic form of IDP.

IDP causes varying degrees of weakness and sensory loss, which can develop in the limbs. Nerves around the head may also be affected and cause symptoms such as facial weakness and double vision. Other features may include pain and diminished reflex responses. Sometimes people with IDP have difficulty with urination and bowel movements, and occasionally respiratory paralysis, irregular heartbeat, and dangerously high or low blood pressure can ensue.

CSF studies will show significantly elevated protein during the first few days or weeks of the syndrome. Often the cell count is elevated as well in both acute and chronic IDP associated with HIV infection, whereas GBS in people without HIV is characterized by normal cell counts. Repeated lumbar punctures (spinal taps; inserting a needle into the spinal column to remove cerebrospinal fluid) may be needed. Electromyography and nerve conduction studies may be useful in diagnosing acute or chronic IDP.

Treatment and response rates are similar to those seen in the HIV negative population. Intravenous immunoglobulin (IVIG), a highly concentrated antibody infusion from many pooled blood donations, is the mainstay of therapy. Plasma exchange, or plasmapheresis, may be helpful; in this procedure antibodies are removed from the blood. Chronic IDP may also require corticosteroids such as prednisone.


Mononeuritis Multiplex

Mononeuritis multiplex (MM) is a usually painful condition that involves isolated nerves over the arms, legs, or trunk. The nerves are affected asymmetrically. The involvement of more than two nerves is generally seen in people with advanced HIV, and may be caused by CMV.

People with MM typically complain of burning or shooting pain down an arm, then, even as it is resolving, another burning pain will emerge over another nerve pathway down a different arm or leg. Weakness in the distribution of specific nerves is common. Nerves can be affected in the head and the body.

Blood tests for diabetes mellitus and immune abnormalities should be done. Electromyography and nerve conduction studies may be useful in making the diagnosis. CSF studies are usually nonspecific, but if done, DNA PCR for herpes zoster, herpes simplex I and II, and CMV may be useful. Nerve biopsy may also be useful if a pathology lab familiar with the procedure is available.

Mononeuritis multiplex occurring early in HIV infection may resolve with HAART. IVIG or plasma exchange should be considered in early or late HIV stages. People with late-stage HIV disease may require anti-CMV medications (ganciclovir, foscarnet).


Polyradiculopathy

Polyradiculopathy is damage to the nerve roots where the nerves exit the spinal cord to form peripheral nerves. Polyradiculopathy may be caused by CMV, or less likely by lymphoma. It may also be idiopathic (of unknown origin). CMV polyradiculopathy occurs with very low CD4 cell counts, and CMV may already be present at other sites, such as the retina.

Rapidly progressive ascending numbness, pain, and weakness affecting the legs, and later occasionally also the arms, is characteristic of the CMV form. Early bowel and bladder control problems may suggest the syndrome. A more benign, slower clinical progression characterizes the idiopathic form.

CSF analysis may show elevated protein and white blood cells, and decreased glucose. A PCR test of the CSF is useful to identify or exclude CMV. MRI of the spinal cord may be needed to exclude structural compression of the spinal cord, such as from a large disc herniation or tumor, or spinal cord lesions due to lymphoma, syphilis, Kaposi's sarcoma (KS), or toxoplasmosis. Electromyography and nerve conduction studies help differentiate polyradiculopathy from other rapidly progressive neuropathies such as Guillain-Barré syndrome.

CMV polyradiculopathy is rapidly fatal without therapy. Treatment with foscarnet or ganciclovir may improve or stabilize the condition. HAART also may be useful. The idiopathic form may improve spontaneously without treatment.


Myopathy

Myopathy refers to many forms of muscle disease. HIV-associated myopathies fall into several categories. Some are caused by drug toxicity, for instance, due to cholesterol lowering drugs (statins), ddI, or AZT (zidovudine, Retrovir). Others are caused by a variety of bacterial, viral, and other infections. Still others, such as polymyositis (inflammatory disease of muscles), are due to an abnormal immune response. HIV wasting syndrome may result from HIV infection itself.

Progressive muscle weakness is the typical presentation, with the speed of progression depending on the cause.

The serum creatine kinase (CK) level is often increased but may be normal. Electromyography, nerve conduction studies, and muscle biopsy are often indicated. Imaging studies (CT, MRI, Gallium-67 scan, ultrasound) are helpful when certain infections are suspected.

When medications are the likely cause, they may need to be stopped or replaced. Muscle infections are treated with drugs specific to the responsible bacterium, virus, or other infectious agent. When inflammation results from an overactive immune system, corticosteroids may be a treatment option.


Conclusion

HIV is associated with a range of neurological problems. Fortunately, many of these conditions have become rarer with the use of HAART and the subsequent improvements in health for many HIV positive people. Access to a clinician with experience in neurological disorders specific to HIV disease is essential for the prevention, early diagnosis, and treatment of neurological conditions in this population.

Glossary
BIOPSY: the removal of a small sample of cells or tissue for microscopic examination and/or culture, typically for diagnostic purposes.

CEREBROSPINAL FLUID (CSF): a clear fluid that circulates around and through the brain and spinal cord.

COMPUTED TOMOGRAPHY SCAN (CT SCAN, CAT SCAN): a method of visualizing the bones and tissues of the body using x-rays.

DEMENTIA: the deterioration of mental function.

DEMYELINATION: the loss of the lipid myelin sheath that surrounds nerve cells and is necessary for proper transmission of neural impulses.

DIFFERENTIAL DIAGNOSIS: a method of diagnosis that involves determining which of a variety of possible conditions is the probable cause of an individual's symptoms, often by a process of elimination.

HEMIPARESIS: weakness on one side of the body.

HERPES ZOSTER (SHINGLES): a condition characterized by painful blisters caused by reactivation of varicella-zoster virus (VZV). Blisters typically appear in a linear distribution on the skin following nerve pathways; outbreaks occur more frequently and may be more severe in immunocompromised individuals.

HYDROCEPHALUS: a blockage of the normal flow of cerebrospinal fluid in and around the brain.

LESION: any abnormal tissue change caused by disease or injury.

MAGNETIC RESONANCE IMAGING (MRI): a sensitive, noninvasive method for viewing organs and tissues of the body using a strong magnetic field.

MYELIN: a white, fatty substance that forms a sheath around nerve fibers and provides insulation necessary for proper transmission of neural impulses.

PALSY: muscle paralysis.

PATHOPHYSIOLOGY: changes in function associated with disease.

PLATELET: a type of blood cell that facilitates normal blood clotting.

POLYMERASE CHAIN REACTION (PCR) ASSAY: a highly sensitive test that can detect small amounts of genetic material in a blood or tissue sample.

POSITRON EMISSION TOMOGRAPHY (PET) SCAN: an imaging method in which a radioactive substance is injected into the bloodstream and a scanner is used to measure cerebral blood flow in different parts of the brain.

PROGNOSIS: a forecast of the probable course or outcome of a disease.

SEROCONVERSION: the change in a person's blood antibody status from negative to positive; development of antibodies against a microorganism.

ULTRASOUND: an imaging technology using high-frequency sound waves.

Venkat K. Rao, MD (kit2savi@yahoo.com) is a staff physician in the Department of Neurology at Saint Louis University Health Sciences Center.

Florian P. Thomas, MD, MA, PhD (thomasfp@slu.edu) is an associate professor in the Department of Neurology at Saint Louis University Health Sciences Center.


Selected Sources

(for a full listing of sources, please contact the authors)

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This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.
 
See Also
Neurological Complications of AIDS Fact Sheet
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