Neurological complications are common in HIV disease. The ...
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
Venkat K. Rao, MD
Florian P. Thomas, MD, MA, PhD
WINTER 2005 BETA 37
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 (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)
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
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
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
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
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
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
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
(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-
often the diagnosis was not made cion is warranted. Early symptoms
and signs include headache, fever, Meningitis is an inflammation of
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
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
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
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)
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
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
primarily supportive. People with the hands typically become affected.
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
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
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
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
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,
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
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46 BETA WINTER 2005