14 : 8

Neurological manifestations associated with

HIV infection: Indian Perspective

Introduction
P Satishchandra,Thomas Mathew, Bangalore
Neurological manifestations are common in HIV infection.
(1) They occur in all stages of HIV infection, early or late; can
affect any parts of neuraxis. Neurological involvement causes is good, an acute aseptic meningitis mimicking any other viral
significant morbidity and mortality in HIV infected individuals. meningitis can occur (5).This resolves in 2-4 weeks by itself leaving
Next to sub-Saharan Africa, India has the second largest burden no sequelae.Acute encephalitis can also occur but is rare. Cranial
of HIV related pathology, predominantly caused by HIV-1 Clade nerves may also be affected especially VII and sometimes V and
C. (2). Opportunistic infections constitute almost 70-80% and the VIII nerves. CSF analysis usually reveals lymphocytic pleocytosis,
remaining 20-30% is due to direct HIV infection. HIV associated raised protein and normal glucose levels.
cognitive disturbances, myelopathy, CNS lymphoma and PML are Sub-acute and chronic meningitis results either from tuberculous
significantly less common compared to the west(2, 10). Which infection or from fungal infection mainly cryptococcal infection.
is probably due to clade difference, The type of neurological Other rare cause of meningitis is lymphomatous meningitis.
involvement depends on the stage of immune dysfunction. During Tuberculous meningitis is common in HIV infected individuals
early stages of immune dysfunction manifestations like Bell’s palsy especially in the developing world. Clinical manifestations
and Guillain-Barre syndrome are common while during late of tuberculous meningitis are same as that of non-infected
stages more severe disorders such as Neuro Infections such as individuals. Neuroimaging with MRI scan is more sensitive to
cryptococcal meningitis, T,B, Meningitis CMV encephalitis, PML, find the abnormalities and may show meningeal enhancement,
HIV Dementia and polyradiculopathy appears. Nervous system hydrocephalus, infarcts or granulomas. Incidence of focal brain
involvement can result from invasion by virus itself or by numerous lesions is four times higher in HIV infected patients with tuberculosis
opportunistic infections. (3) Virus damages the brain directly by when compared to non-HIV patients. (6,7) CSF analysis usually
invasion of CNS macrophages and glial cells or indirectly by reveals lymphocytic pleocytosis, with raised protein and reduced
release of neurotoxic cytokines such as IL-1b, TNF-a, IL-6, and glucose levels. Normal CSF proteins can be seen in 43% of HIV
TGF-b. Iatrogenic complications like drug induced neuropathies infected tuberculous meningitis patients while 14% may have
and myopathies secondary to the use of HAART do occur and add normal CSF glucose levels and 16% acellular CSF. Polymerase chain
further to the morbidity of the illness. With the advent of highly reaction (PCR) for detection of mycobacterium tuberculosis has
active antiretroviral therapy there is a decline in the incidence a sensitivity of 80%. (8) Anti tuberculous treatment is same as in
of primary HIV infection related disorders like HIV associated patients without HIV infection. Short-term corticosteroid therapy
dementia. An improvement in immune status with the initiation is probably beneficial as adjunctive treatment in complicated life
of highly active antiretroviral therapy (HAART) results in new threatening situations.
group of disorders called the immune reconstitution syndromes.
Cryptococcal meningitis has emerged as a leading cause of
(4) In this article we will approach neurological disorders as those
infectious morbidity and mortality in patients with AIDS.
affecting central nervous system and those affecting peripheral
Cryptococcal meningitis is the second most common cause of
nervous system.
opportunistic neuroinfection among HIV positive subjects and is
one of the AIDS-defining illnesses. (9) It occurs in patients with
Disorders affecting central nervous
advanced HIV infection when CD4 count is below 100 cells/
system (Meninges, Brain and Spinal cord) ml. Patients usually present with subacute to chronic, severe
Meningitis unbearable headaches with or without fever almost mimicking
subarachnoid hemorrhage (SAH) and in severe cases with
Meningitis is one of the commonest opportunistic neurological changes in the mental status. Neuroimaging is done to exclude
manifestations of HIV infection. Meningitis may be acute, sub-acute hydrocephalus and cryptococcomas but is usually normal or may
or chronic. In early stages of the illness when the immune function
 Neurological Manifestations Associated with Hiv Infection : Indian Perspective

show associated diffuse cerebral atrophy with ventriculomegaly various anticonvulsants sodium valproate appears to be more
(10) MRI brain may show punctuate non-enhancing foci of CSF appropriate for patients with HIV disease due to less chance of
density correlating with the presence of cryptococci in the drug interactions Other drugs such as enzyme inducers – such
Virchow-Robin spaces. CSF analysis shows mild to moderate as phenytoin should be avoided (3)
mononuclear pleocytosis, elevated protein, normal or decreased
Dementia
CSF sugar in 75% of cases. India ink for cryptococci is positive in
about 70% of cases, while CSF for cryptococcal antigen is almost HIV- associated neurocognitive impairment (HCNI) encompasses
always positive except in very early disease and in those with high a spectrum of disorders characterized by subsyndromic cognitive
titers (prozone effect). (11) CSF should be subjected to fungal deficits, mild cognitive impairment (MCI) to very severe cognitive
culture to determine the type of cryptococcal infection and to impairment. Latter is called HIV associated dementia (HAD) or
ascertain the drug sensitivity. Fungal cultures are positive in almost AIDS dementia complex or HIV encephalopathy. (12) HAD is a
90-95% of cases. Treatment of cryptococcal meningitis in HIV subcortical dementia and is usually seen in advanced stages of HIV
infected patients involves IV Amphotericin B at a dose of 0.75 mg/ infection when the immune dysfunction is moderate to severe.The
kg daily with total cumulative dose of not more than 1.5 / 2 grams, incidence HAD has been on the decline after the commencement
with flucytosine 25 mg/kg qid for 2 weeks or fluconazole, 400 mg/ of antiretroviral therapy. (3) The exact prevalence of HAD in
day for 10 weeks, and then fluconazole, 200 mg/day until the CD4 India is unknown but is found to be much less when compared
T cell count has increased to > 200 cells/ml for 6 months. Fungal to western population probably due to the strain difference(17).
meningitis can also result from rarely Coccidioides immitis and But in a small study from south India the prevalence of cognitive
Histoplasma capsulatum. Meningoencephalitis may also caused deficits in HIV-1 clade C infected drug-naïve patients were
by Acanthamoeba or Naegleria. (12,13) Syphilitic meningitis can reported similar to that of HIV-1 clade B infected patients from the
occur similar to non- HIV patients western world. (18) HIV-infected individuals with the E4 allele for
apo E are at increased risk for HAD and neuropathy. Patients often
Headaches
present with poor concentration, memory impairment, behavioral
Headaches are common in HIV infected patients. Patients with disturbances, personality changes, slow thought process and
early HIV disease (CD4 count above 500 cells/ml) usually have inability to perform complicated tasks. Other associated features
headaches of benign nature such as tension-type headaches or are clumsiness, bradykinesia, apathy, gait instability, tremor and
that due to underlying depression. In those with advanced HIV seizures suggestive of predominantly sub cortical dementia.They
(CD4 less than 200 cells/ml) the headaches are due to more may also have mood disorders like depression and hypomania.
ominous causes and detailed evaluation with neuroimaging and Detailed neuropsychological assessment will help to assess the
CSF analysis should be done to exclude opportunistic infections extent of cognitive impairment. All patients with a diagnosis
and lymphomas. Cryptococcal meninigitis patients can present of HIV infection should have their baseline Mini-Mental Status
with severe headaches mimicking subarachnoid hemorrhage.The Examination (MMSE) done for future reference and follow up. (12)
cause for this headache is not known but may be due to meningeal MR imaging of the brain should be done to rule out opportunistic
involvement, raised intracranial hypertension or sinovenous infections and progressive multifocal leukoencephalopathy (PML),
thrombosis. (10) These patients may require repeated therapeutic which may mimic or unmask dementia. (19) Cerebrospinal fluid
lumbar punctures to drain of CSF to reduce the raised intracranial (CSF) analysis should be obtained to exclude the possibility
tension. Drug induced headaches can occur from zidovudine and of a chronic meningitis. Serum and CSF VDRL also should be
stavudine. (14) performed to rule out neurosyphilis. (20) More than 50% of
patients of HAD improve with antiretroviral therapy hence it is
Seizure
important to recognize this entity early. Low dose dopaminergic
Seizure may be a presenting manifestation of HIV infection.Seizures drugs can be used for extrapyramidal symptoms while atypical
occur in patients with HIV due to retroviral infection per se or due antipsychotics with minimum extrapyramidal side effects may be
to various opportunistic infections or neoplasms. (15) In majority used for behavioral disturbances, as these sero-positive individuals
of patients (7-50%) it may be due to HIV itself or due to CNS are very sensitive to neuroleptics. (3)
toxoplasmosis (15-35%). 25 % of patients with seizure have HIV
Space occupying lesions
associated dementia.CNS tuberculomas,lymphomas,cryptococcal
meningitis and progressive multifocal leukoencephalopathy can Focal space occupying lesions in the brain can be due to toxoplasmosis,
also be associated with seizures. (16) Foscarnet or gancyclovir tuberculoma, progressive multifocal leukoencephalopathy (PML)
can result in hypocalcemia and hypomagnesemia, which in turn can and lymphomas. (21) Cryptococcomas usually occur in the
cause seizures. Seizures are usually focal or generalized and have context of cryptococcal meningitis.These space- occupying lesions
a high recurrence rate. Patients are usually evaluated with MRI of may manifest with seizures or focal deficits. Incidence of CNS
brain to exclude focal lesions. CSF analysis is done if MR imaging is toxoplasmosis is on the decline with the advent of antiretroviral
unremarkable to rule out cryptococcal and tuberculous meningitis. therapy. Toxoplasmosis usually occurs during the advanced stage
In view of high propensity for recurrence, anticonvulsant therapy of HIV infection when the CD4 count is usually less than 200
should be initiated even after a single episode of seizure. Of the cells/ml. Patients of CNS toxoplasmosis usually present with fever,

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Table 1: Differentiating features between toxoplasma granu- Stroke

loma and lymphoma
Transient ischemic attacks and strokes both ischemic and
Toxoplasma granuloma Lymphoma
hemorrhagic do occur in HIV infection. (25) In about 50% of
Usually multiple lesions One or two lesions
cases there is no cause apart from HIV infection itself and
Basal ganglia, thalamus, grey white Periventricular , corpus callosal
these events happen usually during the advanced stages of HIV
matter junction
infection when CD4 count is usually less than 200 cells/ ml. 50% of
Ring lesion/eccentric nodule Homogenous enhancement
patients will have associated HIV dementia and 25% will eventually
Not on PCP (pneumocystis Carinii) Patient on PCP prophylaxis
develop dementia. (3) The exact mechanism of thrombosis is not
prophylaxis
known but may be due to elevated anti cardiolipin antibodies,
Response to empirical antitoxo- No response
decreased protein S levels and HIV vasculopathy/vasculitis.
plasma treatment
(26) Secondary causes of stroke that should be excluded with
Thallium brain SPECT- 50% ­uptake 100% ­uptake
appropriate investigations include meningovascular syphilis,
Thallium brain SPECT – uptake ratio > 2.9
< 2.9
varicella vasculopathy, and tuberculous or cryptococcal meningitis
CSF PCR for Toxoplasma positive Negative
with arteritis. (12) Eighteen cases of cortical venous thrombosis
(60%) leading to haemorrhagic infarction secondary to HIV infection has
CSF PCR for Epstein-Barr virus Positive been reported recently by us (Satishchandra P et al 2009 under
negative publication) Various precipitating factors have been implicated.
These include chronic alcoholism which is very common co-
headache, focal neurological deficits and seizures. (12) Gadolinium morbidity with HIV, deficiency of substance P and elevated
enhanced MRI Brain scan will help to differentiate between anticardiolipin antibodies. However this has acute on chronic
various lesions. Tuberculomas are usually of mixed density, single course and relatively benign prognosis. Anti retroviral therapy
or multiple and will show a solid type or ring enhancement on along with low dose antiplatelet agents may be given to these
contrast administration.Patients with toxoplasmosis have multiple patients with ischemic strokes after excluding thrombocytopenia.
ring enhancing lesions with special predilection to basal ganglia or Anti-coagulants are required for the management of venous
posterior fossa with evidence of blooming on FLAIR. Lymphomas thrombosis along with antioedema measures
are usually solitary, periventricular and enhance uniformly on
Extrapyramidal Syndromes
contrast. (14) Differentiating features of toxoplasma granuloma
from lymphoma are shown in table 1.A stereotaxic biopsy may be Movement disorders like parkinsonism, choreoathetosis, dystonia
needed to confirm the diagnosis, if neuroimaging techniques and nad hemiballism can develop in patients with HIV infection. (27)
a therapeutic trial with antitoxoplasma drugs fail. (22) Standard They result from the affection of basal ganglia either by HIV itself
treatment for toxoplasma consists of sulfadiazine ( 3-4 gram/day) or due to opportunistic infections. (28) Of these opportunistic
and pyrimethamine (75mgs/day) with leucovorin for a minimum infection commonest is toxoplasma infection. Neuroimaging
of 4-6 weeks. The above drugs are given for maintenance usually with gadolinium enhanced MRI brain should be done to rule
half of their standard dose as long as their CD4 count is less than out toxoplasma infection in all immunocompromised patients
200 cells/ml. If CD4 count remains above 200cells/ml for 6 months presenting with movement disorders. In patients on antiretroviral
with effective antiretroviral treatment the maintenance therapy therapy a chronic low level immune activation can develop and may
for toxoplasmosis can be discontinued. (12) facilitate the development of neurodegeneration and accelerate
the appearance of diseases such as Parkinson disease (PD) by
Progressive multifocal leukoencephalopathy (PML) is a
mechanisms including inflammation, mitochondrial dysfunction,
demyelinating disorder occurring in HIV infection due to infection
and interference with the ubiquitin proteasome pathway (29).
by JC virus a human polyoma virus. It is a feared complication
Other than anti-retroviral therapy and treatment of opportunistic
of HIV disease and occurs even in patients on anti retroviral
infections, management of these movement disorders is similar
therapy. (23) Prevalence of PML is less in the Indian HIV infected
to those of its non-HIV counter parts but lower doses of drugs
population when compared to the western world. (24) Cerebral
may used in these patients.
and cerebellar white matter and brainstem can be affected.
Patients can present with ataxia, hemiparesis, visual field defects, Myelopathy
aphasia and seizures. (3) Headache and fever are characteristically
Spinal cord disease is seen in 20% of HIV infected individuals
absent. Lesions of PML are confined to white matter with the
and is often associated with HIV encephalopathy. Patients with
involvement of U fibers and does not enhance on contrast. They
myelopathy often present with weakness, spasticity or unsteady
are hypointense on T1-weighted images and hyperintense on
gait. Myelopathy as is the case with any level of neuraxis can be
T2-weighted images. Occipital and parietal lobes are commonly
due to HIV infection itself or due to opportunistic infections
affected. CSF PCR for JC virus DNA has a diagnostic sensitivity of
like tuberculosis, toxoplasmosis, herpes simplex, herpes zoster,
76% and specificity close to 100%. There is no specific treatment
cytomegalovirus and syphilitic infections. HTLV- I and II can also
for PML other than HAART. 50% of patients will show significant
cause myelopathy especially in endemic areas. HTLV I and II
neurological improvement with HAART. (3)

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 Neurological Manifestations Associated with Hiv Infection : Indian Perspective

Table 2: Causes of neuropathies according to the stage of im- above 500cells/ml, Bell’s palsy and Guillain-Barre syndrome (GB
mune dysfunction syndrome) can develop identical to its non-HIV counter parts.
Early HIV disease (CD4 count < 500 cells/ml, Seroconversion neuropa- Unlike GB syndrome in immunocompetent subjects lymphocytic
thies) pleocytosis are common in those with HIV infection. This is a
Mononeuropathies like Bell’s Palsy (VII,VIII, II and V nerves may be involved clue for clinician to rule out associated HIV infection. Similarly
Guillain-Barre syndrome in patients with more advanced HIV infection can have a chronic
Bilateral brachial neuritis inflammatory demyelinating polyradiculoneuropathy(CIDP).
Moderately advanced HIV disease (CD4 count - 200- 500 cells/ml) Treatment of these demyelinating neuropathies is similar to those
Chronic inflammatory demyelinating polyradiculoneuropathy without HIV infection (3). Mononeuritis multiplex can occur due
Mononeuritis multiplex to HIV vasculitis. In patients having electrophysiological evidence
Diffuse infiltrative lymphocytosis syndrome (DILS) of sural nerve involvement, a sural biopsy will help to confirm
Syphilitic polyradiculopathy diagnosis and will assist to exclude lymphomatous infiltration.
Advanced HIV disease (CD4 count < 200 cells/ml) (31) Serology for hepatitis B and C should be done in patients
Distal symmetric sensory neuropathy presenting with mononeuritis multiplex. Distal symmetric sensory
Autonomic neuropathy polyneuropathy (DSPN) occurs in patients with advanced HIV
HIV related lumbosacral polyradiculopathy infection. Patients have a length dependent neuropathy affecting
CMV related polyradiculopathy
the feet first resulting in painful burning sensations and loss of
CMV related mononeuritis multiplex
pain, touch and temperature in a stocking distribution.There can
myelopathy usually occurs during the early stages of HIV infection be mild weakness of intrinsic foot muscles and ankle reflexes are
unlike the myelopathy due to HIV per se which happens during the usually absent. (12) Treatment consists of antiretroviral therapy,
late stage of infection. HTLV I myelopathy in HIV infected patients correction of associated nutritional abnormalities and avoidance
can be treated with anti retroviral therapy and corticosteroids. (3) of neurotoxic antiretroviral drugs (‘d’ drugs) like stavudine (d4T),
There is no known therapy for HTLV II myelopathy. Myelopathy zalcitabine (ddC) and didanosine (ddI). Symptomatic treatment
due to HIV is mainly of following types – vacuolar myelopathy of paresthesias with gabapentin, carbamazepine or tricyclic
mimicking subacute combined degeneration of spinal cord, pure antidepressant is important. (3) Autonomic neuropathy may be
sensory ataxia secondary to dorsal column involvement or HIV associated with DSPN and can result in postural hypotension
myelitis. (12, 30) These are very less commonly reported from and gastroparesis. In advanced stages of HIV infection, CMV
India where HIV clade C is the predominant strain. MR imaging polyradiculopathy can occur. These patients present with sacral
of the spinal cord is done in all patients with myelopathy to rule and lower limb paresthesias, ascending sensory loss and difficulty
out opportunistic infections like tuberculosis and lymphoma. MRI in walking. The reflexes are usually absent. CSF analysis reveals
in patients with vacuolar myelopathy may show cord atrophy predominantly neurtrophilic pleocytosis, raised proteins and
or symmetric hyperintense signals on T2-weighted sequences. reduced glucose levels. CSF PCR for CMV DNA is positive in
Focal or serpiginous enhancing lesions may be seen in herpes majority of patients (90%) and confirms the diagnosis. Treatment
zoster myelitis. (14) Cytomegalovirus myelopathy usually occurs is initiated either with ganciclovir or foscarnet as early as
in association with polyradiculopathy. Serum vitamin B12 and possible to reduce neurological damage and hasten recovery.
folate levels should be estimated in patients suspected to (12) In patients previously treated for CMV disease combination
have vacuolar myelopathy. CSF analysis may show non-specific therapy with both drugs should be considered. The causes of
changes like lymphocytic pleocytosis, raised protein and normal peripheral neuropathy according to various stages of HIV disease
CSF glucose. CSF VDRL test should be carried out to exclude are summarized in table 2.
syphilitic myelopathy. Serum and CSF HTLV- I and II antibodies may
Myopathies
be done in endemic areas to diagnose HTLV I and II associated
myelopathy. CSF may be subjected to PCR for herpes simplex, Muscle can be involved in HIV disease resulting in HIV related
varicella zoster and cytomegalovirus as these organisms can rarely polymyositis which is similar in clinical manifestation to its non-
cause myelopathy. Primary HIV related spinal cord syndromes do HIV counter part (32). Patients often present with subacute
not respond well to antiretroviral therapy but it may help those onset progressive proximal limb and neck flexor weakness.
with HIV myelitis. (3) They also have fatigue, myalgia, cramps, dysphagia and wasting.
Dermatomyositis like picture can also occur in HIV infected
Disorders affecting peripheral nervous patients.Elevated creatine phosphokinase levels and muscle biopsy
system – Peripheral nerves and Muscles showing histopathological features of polymyositis will confirm
the diagnosis.Treatment is with low dose steroids with adequate
Neuropathies prophylaxis against opportunistic infections. HIV may also lead
All patterns of peripheral nerve involvement are seen in HIV to inclusion body myositis and a variety of other myopathies
infected individuals. Cranial nerves and peripheral nerves can like nemaline rod myopathy or mitochondrial myopathy. (3)
be affected. During the early stages when the CD4 count is Opportunistic pathogens like toxoplasma gondii, mycobacterium
avium-intracellulare and microsporidia may cause diffuse myositis

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usually in the context of systemic disease. Non-Hodgkin’s Conclusion

lymphoma and Kaposi’s sarcoma may occasionally infiltrate muscle
HIV infection can affect any level of neuraxis either directly or
resulting in a painful muscle mass. Long-term use of zidovudine
indirectly due to various opportunistic infections or neoplasms.
can result in myopathy. Patients with zidovudine myopathy have
More than 60% of HIV sero positive individuals develop
elevated creatine kinase levels and ragged red fibers on modified
neurological involvement at some time or the other during their
Gomori’s trichrome staining. An elevated plasma lactate may be
couse.Direct HIV related complications can either be inflammatory,
seen in some patients. (33)
demyelinating or degenerative in nature and can occur through
Immune Reconstitution Inflammatory Syndromes (IRIS) out the course of illness. Clinicians managing these patients should
be aware of these neurological manifestations as it can occur at
The use of highly active antiretroviral therapy (HAART) to treat
any stage of HIV infection. Use of HAART has resulted in decline
HIV infection, is associated with significant reductions in morbidity
of primary HIV related disorders like AIDS dementia complex
and mortality. However, in certain patients after the institution of
and distal symmetric sensory neuropathy but has not affected the
antiretroviral there occurs a paradoxical worsening of clinical status
incidence of certain diseases like PML. It also has resulted in a new
and /or appearance of new signs and symptoms, this worsening of
group of disorders called the immune reconstitution inflammatory
clinical status is known as Immune Reconstitution Inflammatory
syndromes(IRIS). Drug induced neurological disorders also can
Syndrome (IRIS). (34) Usually occurs within the first 4 to 8 weeks
develop during the course of treatment and clinician should be
after intiation of antiretroviral therapy.This is often noticed when
on watch out for these complications.
ART is instituted directly with very low CD 4 counts (often
below 50 cells/cm. IRIS is well described in the non-neurologic
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