STS-2010

CO-REALTION OF CSF AND NEUROLOGICAL FINDINGS IN HIV POSITIVE PATIENTS

Student Ref. ID - 2010-01973

INTRODUCTION

HIV (Human Immuno-deficiency Virus) is a retro-virus that causes AIDS (Acquired Immuno

Deficiency Syndrome). It is one of the deadliest diseases in today’s world. It causes profound

immune-suppression, opportunistic infections and various neurological manifestations.

The neurological impairment that occurs in HIV infected individuals may be either primary

to pathogenic process of HIV infection or secondary to opportunistic infections or

neoplasm’s1 which are very disabling with regards to social, economical, physical, mental

state of that particular patient.

Neurological problem occur throughout the course of disease and may be inflammatory,

demyelinating or degenerative in nature1. Among the more frequent opportunistic diseases

that involve CNS are toxoplasmosis, cryptococcosis, progressive multi-focal leuco-

encephalopathy and primary CNS lymphoma. Other less common are mycobacterial

infections, syphilis and infection with CMV, HTLV-1 and acanthamoeba1.

The diseases, which are produced primarily due to pathogenic process of HIV infection

include aseptic meningitis, HIV encephalopathy (AIDS dementia complex), various

myelopathies, neuropathies and myopathy1.

Among the neoplasm’s are primary CNS lymphoma and Kaposi’s sarcoma1.

The type of neurological disease produced in HIV infected patient depends on age, sex, race,

geographic distribution, type of virus, host response, stage of the disease, viral load, degree

of impairment of cell mediated immunity and genetic predisposition1.

Accurate clinical and investigational diagnosis of these conditions is very important in their

treatment. Nowadays, the diagnostic modalities available are CSF analysis with respect to

CSF biochemistry including sugar and proteins, cytology, staining, cultures, antibody titres in

serum to various infecting organisms, Neuro-imaging studies like CT/MRI Brain & Spinal

cord, PET scan, EMG and NCV. However, the CSF analysis still maintains its place in the era

of modern neuro-imaging modalities such as CT/MRI Brain and PET scan.

The CSF analysis gives both the qualitative and microbiological/cytological information

about the CSF samples of the patients under study.

In this study we present a series of 100 HIV positive patients who presented with

neurological manifestations. For this purpose CSF parameters are essential. This is an

attempt to study the frequency, distribution and co-relating the neurological manifestations

with the CSF parameters and compare this data with various other similar studies conducted

in other parts of India and world.

By this study we come to know that CSF parameters play a very essential role in the

diagnosis of various neurological manifestations in HIV positive patients.

REVIEW OF LITERATURE

The history of HIV is filled with triumphs and failures; living and death. The HIV time line

began early in 1981. In July of that year, the New York Times reported an outbreak of a rare

form of cancer among gay men in New York and California. This "gay cancer" as it was called

at the time was later identified as Kaposi's Sarcoma, a disease that later became the face of

HIV/AIDS. About the same time, emergency rooms in New York City began to see a rash of

seemingly healthy young men presenting with fevers, flu-like symptoms, and a rare

pneumonia called Pneumocystis. This was the beginning of what has become the biggest

health care cancer in modern history. Twenty-five years later the disease still plagues

society.

Here we discuss a few landmarks in the development of HIV/AIDS from the day it first

emerged and now has become one of the dreadful diseases all over the world.

1981

As stated above, 1981 saw the emergence of Kaposi's Sarcoma and Pneumocystis among

gay men in New York and California. When the centres for Disease Control reported the new

outbreak they called it "GRID" (gay-related immune deficiency), stigmatizing the gay

community as carriers of this deadly disease. However, cases started to be seen in

heterosexuals, drug addicts, and people who received blood transfusions, proving that the

syndrome knew no boundaries.

1983

Researchers at the Pasteur Institute in France isolate a retrovirus that they believe is related

to the outbreak of HIV/AIDS. Thirty-three countries around the world had confirmed cases

of the disease that was once limited to New York and California. Controversy arises a year

later when the US government announces their scientist, Dr. Robert Gallo isolates a

retrovirus HTLV-III, that he too claims is responsible for AIDS. Two years later it's confirmed

that HTLV-III and the Pasteur retrovirus are indeed the same virus, yet Gallo is still credited

with its discovery. An international committee of scientists rename the virus HIV.

1985 – ELISA developed

The controversy surrounding HIV/AIDS continues when Robert Gallo’s lab patents an HIV

test that was later approved by FDA. This was the sensitive enzyme-linked immunosorbent

assay (ELISA) was developed, which led to an appreciation of scope and evolution of HIV

epidemic at first in the United States and other developed nations and ultimately among

developing nations throughout the world1.

1987 - A Treatment Arrives

A new treatment emerges that is hailed as the first huge step in beating HIV/AIDS. The drug

Retrovir (AZT, Zidovudine) is FDA approved and begins to be used in high doses to treat

people infected with HIV. Politically, HIV/AIDS is a topic that most avoid. But in response to

public pressure, President Ronald Reagan finally acknowledges the HIV/AIDS problem and

for the first time uses the term "AIDS" in a public speech.

1992 - Combination Therapy Arrives

The FDA approves the first drug to be used in combination with AZT. The addition of the

drug Hivid (Zalcitabine) marks the beginning of HIV/AIDS combination therapies. But a more

disturbing development centres around HIV tainted blood. Three French senior health

officials knowingly sell HIV tainted blood, resulting in the infection of hundreds of

transfusion recipients, most of whom have haemophilia1.

1993

People who are infected and scientists alike are confused and concerned when a British

study, the Concorde Trials, offers proof that AZT monotherapy does nothing to delay

progression to AIDS in asymptomatic patients. As a result, the AZT debate emerges, with

one side proclaiming AZT saves lives and the other denouncing AZT as useless; the

"rethinker" movement is born.

1996 - Protease Inhibitors Arrive

Treatment options take another step forward with the introduction of power HIV-fighting

drugs called Protease Inhibitors. The use of these drugs in combination with existing

HIV/AIDS drugs proves effective in controlling HIV. These new "triple-therapies" give

patients and scientists new hope in eliminating HIV/AIDS. But that hope is dashed when a

year later, scientists find HIV/AIDS "hides" in reservoirs in the body, making total elimination

of the virus virtually impossible.

1997

In late 1996 data from AIDS Clinical Trials Group study 076 (ACTG 076) made it clear that

Retrovir (AZT) used during pregnancy and at the time of delivery drastically reduces

transmission of HIV from mother to child. Those findings led to protocols that now

drastically reduce transmission from mother to child from 1 in 4 to less than 3%.

1998

More than 15 years after the prediction there would be of an AIDS vaccine within 2 years,

the first human trials in the United States of an HIV/AIDS vaccine begins. In a desperate

attempt to get affordable HIV/AIDS drugs to the hardest hit areas of Africa, European drug

companies ignore US patent laws and begin making generic versions of HIV/AIDS

medications. In response, US drug companies file lawsuits to stop such practices.

2000

The AIDS "rethinker" movement gets international attention and support when South

African president Thabo Mbeki questions the use and effectiveness of HIV medications as

well as offering doubt that HIV causes AIDS. In response, the international scientific

community issues the Durban Declaration, offering proof that HIV and AIDS are indeed connected.

2004

As the emphasis on simpler therapies continues, regimen pill burdens are greatly improved

with the release of two new combination drugs, Truvada ([Viread [tenofovir] + Emtriva

[FTC]) and Epzicom (Ziagen [abacavir] + Epivir [3TC]) as well as two new protease inhibitors,

Reyataz and Lexiva. In December, the first generic formulation of an HIV medication is

approved by the FDA, instilling hope that HIV medication prices may soon fall down.

2005

HIV statistics have become sobering to say the least.

4.9 million people were newly infected in 2005

40.3 million people worldwide living with HIV/AIDS.

And as the numbers continue to climb, work on an HIV vaccine has for the most part failed.

Once thought to be "just around the corner" it had become obvious in 2005 that an HIV

vaccine is still years away. Medication advances continue but long term side effects of HIV

medication use are becoming more evident. So much so that experts now agree that for

many patients, waiting to start HIV medications is the best course of action. Finally, 2005

saw a rise in HIV rates on college campuses and risky behaviour among those people already

infected is still a problem.

2006

Experts conclude that HIV has its origin in the jungles of Africa among wild chimps. Experts

go on to report that evidence suggests that the simian form of HIV (SIV) entered the human

species and became HIV by way of monkey bites or ingesting monkey meat and brains.

While the origins of HIV are clearer, the means to pay for HIV care and medications has

become more complicated. India surpasses South Africa as the world's largest HIV

population and in the US infection rates of HIV are steady while STDs are on the rise.

2009

Scientists at the University of North Carolina at Chapel Hill announce they have decoded the

structure of an entire HIV genome. How this will affect the future of HIV treatment,

prevention, and education is not entirely known. What we do know is that the more we

know about HIV, the better we can fight its affects on public health in the US and around the

world.

Neurologic manifestations affecting the nervous system at all levels and stages of HIV

infection are common and increasing with the extended survival of HIV-positive persons.

According to a study done at Nizam’s Institute of Medical Sciences in Hyderabad by Teja VD,

Talasila SR, Vemu L. (Mar,2005)2 revealed not only high prevalence of neurological events

but also their nature, clinical presentations and symptoms. This was necessary for precise

diagnosis and parallel assessment of CD4 count for practical management of a specific

therapy for the HIV infected patient.

A similar study done at Tbilisi, Georgia by Bolokadze N. Et al (Dec,2008)3 provides convincing

evidence that neurological disorders with HIV infection might serve as an indicator for

advanced HIV infection, immunosuppression and decreased CD4+ T cell counts. This data

shows correlation between type of neurological manifestations of HIV infection and CD4+ T

lymphocyte count.

Pandya R, Krentz HB, Gill MJ, and Power C (May, 2005)4 investigated Health Related Quality

of Life (HRQoL) parameters among HIV infected individuals with and without neurological

manifestations. This study indicated that while HIV-related neurological diseases are

associated with reduced HRQoL scores, they suggested enhanced neurological care has a

positive impact on HIV patients overall well-being.

Odiase FE, Ogunrin OA, Ogunniyi AA (May, 2007)5 in their study for Memory Performance in

HIV positive cases found out that, there was no significant memory disturbance among HIV

positive asymptomatic subjects despite the presence of impaired attention and

psychomotor slowing and the severity of immune suppression (as indicated by CD4+ T

lymphocyte count) is a strong determinant of cognitive decline in HIV/AIDS.

Robinson-Papp J. Et al (Aug,2008)6 in their study for motor function and HIV associated

cognitive decline proposed that motor, affective and behavioural abnormalities predict

cognitive impairment in HIV positive patients in this HAART-era cohort. The HIV Dementia

Motor Scale (HDMS) may be useful in the assignment of HIV associated neuro-cognitive

impairment in HIV populations in which normative data or neuro-psychological test design is

not optimal.

HIV infection is associated with autonomic neuropathy which in turn hampers the quality of

life and can have fatal consequences. According to a study done by Compostella C,

Compostella L and D’Elia R (Feb, 2008)7 in Africa the most common autonomic dysfunction

symptoms were: orthostatic intolerance, secretomotor and gastro-intestinal dysfunction.

CD4+ T lymphocyte counts were not related to autonomic symptom scores. Thus they

proposed that African HIV positive patients report symptoms of autonomic dysfunction,

despite normal or borderline autonomic reflex responses.

In a study done at Harare, Zimbabwe by Innocent T. Et al (July, 2000)8 proposed that all the

cases suspected to have meningitis had high HIV sero-positivity irrespective of later whether

they were confirmed to have meningitis or not. Cryptococcal Meningitis was found to be the

most common type with 45% of all cases of meningitis and 100% of HIV sero-positivity.

According to a study done by Jarvis JN et al (Mar, 2010)9 at Cape Town, SA, it was found that

cryptococcal and tuberculous meningitis were the commonest cause of adult meningitis in

the setting of high HIV and TB prevalence. TB Meningitis is probably under-diagnosed by the

laboratory investigations, as evidenced by large numbers presenting with sterile

lymphocytic markedly abnormal CSFs.

Similar results of under-diagnosis of TB Meningitis in HIV patients due to lack of meningism

in elderly and atypical CSF findings were observed in a study conducted by Karstaedt AS et al

in South Africa (Nov. 1998)10.

A study conducted in South Africa by Patel VB, et al (Aug,2010)11 proposed that RD-1

ELISPOT (Enzyme Linked Immunospot) assay, using cerebrospinal fluid mononuclear cells

and in conjunction with other rapid confirmatory tests (Gram stain and cryptococcal latex-

agglutinaqtion test), is an accurate rapid rule-in test for diagnosis of TBM in a TB and HIV

endemic setting.

In a study conducted by Ngo AT et al (June, 2007)12, it was proposed that short-term

mortality of co-infected patients with HIV and Tuberculosis remains high in developing

countries.

According to a study in Argentina by Metta HA et al (Jul-Sept. 2002)13, it was proposed that

manifestations and severity of cryptococcosis maintained its features throughout, in those

cases which were not treated with HAART. All the cases in this study showed neurological

involvement and treatment was not able to modify the mortality in this setting.

In a study conducted at New Delhi, India by Wadhwa A. Et al (July, 2008)14 provides

information about increasing incidence of Cryptococcal meningitis after AIDS pandemic. It

also indicates progression of HIV infection towards AIDS and is useful as a reference in

starting ART in a setting where facilities for determination of CD4 count are not available.

According to a study by Bicanic T. Et al (Mar, 2009)15 it was proposed that aggressive

management of raised opening pressure through repeated CSF drainage appeared to

prevent any adverse impact of raised opening pressure on outcome of patients with

cryptococcal meningitis.

In a study conducted at Bangalore, India by Neelam Khanna, et al (Mar, 1996)16 it was

proposed that comparison of clinical and laboratory parameters between HIV positive and

HIV negative cases showed that CSF cell responses were poor, culture of cryptococci from

non-neural sites was more frequent and mortality was higher in HIV positive group.

According to a study by Martinez Fernandez EM, et al (May, 1999)17, proposed that the

possibility of Cryptococcal infection cannot be ruled out regardless of CSF biochemical

results and immune-suppression levels (CD4+ T cell count).

In a study done by Monaco LS and Tamayo Antabak N. (Oct-Dec, 2008)18 found that of all

the HIV positive cases Cryptococcosis appeared as a first marking disease in 34% cases.

HIV associated polyneuropathy has become the most common neurological complication of

HIV infection and is one of the main risk factors for the development of neuropathy

worldwide.

In a study done by Hahn K. Et al (Apr, 2010)19, proposed that HIV should always be

considered as an underlying cause in patients with neuropathy.

According to a study done by Modi M, Mochan A. and Modi G. (May, 2009)20 In South Africa

it was found that seizures in HIV are a nonspecific manifestation of seizure mechanism.

In patients with HIV infection and AIDS, the most common cause of focal intra-cranial lesion

is Toxoplasma gondii infection. In a study done by Kurne A, et al (Jan-Apr, 2006)21 it was

proposed that until proven otherwise, HIV/AIDS patients presenting with focal neurological

complaints should be accepted as having central nervous system toxoplasmosis.

In a study conducted by von Giesen HJ, et al (Spring 2005)22, proposed that motor

performance correlated significantly with time dependent HDS (HIV Dementia Scores)

subscores for psychomotor speed and construction and HDS subscores. HDS scores also

showed significant correlations to age, premorbid and actual intelligence and duration of

HIV seropositivity. Thus HDS can be used for screening of neuro-AIDS.

According to a study done by Abdulle S, et al (Aug, 2007)23, proposed that the CSF

neurofilament can be used as a useful sensitive marker in evaluating the presence and

activity of ongoing CNS damage in HIV infection.

Le C and DeFreitas D (Dec, 2008)24 reported a case of HIV-infected man who developed

idiopathic intra-cranial hypertension (which is a cause of vision loss in HIV positive patients)

and despite repeated lumbar puncture, acetazolamide and neurosurgical intervention, he

could not regain his vision.

ETIOLOGY/PATHOPHYSIOLOGY/CLINICAL FEATURES/LAB

DIAGNOSIS AND MANAGEMENT

Etiopathogenesis:

HIV infected individuals can experience a variety of neurological abnormalities due to,

Opportunistic infections

Neoplasm’s

Direct effect of HIV or its products

In addition to the lymphoid system, nervous system is also a major target of HIV

infection25.

The main cell types that are infected in the brain in vivo are those of

monocyte/macrophage lineage, including monocytes migrated from the peripheral

blood to brain and resident microglial cells. HIV entry into the brain is facilitated by

ability of the virus infected and immune activated macrophages to induce adhesion

molecules such as E-selectin and Vascular cell adhesion molecules (VCAM-1) on brain

endothelium. HIV gp120 enhances the expression of intra-cellular adhesion

molecule-1 (ICAM-1) in glial cells that facilitate the entry of HIV infected cells into

CNS and promote syncytia formation.1, 25

Galactosyl ceramide is an essential component of the gp120 receptor on neural

cells and antibodies to it inhibit entry of HIV into neural cell lines in vitro.

HIV isolates from the brain are almost exclusively M-tropic i.e R5 strains. HIV

infected individuals who are heterozygous for CCR5D32 appear to be relatively

protected against the development of HIV encephalopathy compared to wild type

individuals.1, 25

Because neurons are not affected by HIV and the extent of neuropathologic

changes is often less than might be expected from the severity of neurological

symptoms25, HIV mediated effects on the brain tissue are thought to be due to a

combination of,

Direct effects, either toxicity or function inhibitory of gp120 on neuronal

cells. The HIV gp120 shed by virus infected monocytes could cause

neurotoxicity by antagonizing the function of vasoactive intestinal

polypeptide (VIP), by elevating intracellular calcium levels and by decreasing

nerve growth factor levels in cerebral cortex.1,25

Indirect effects, either by viral products or by various soluble factors, such as

IL-1, TNF-alpha, IL-6, TGF-beta, IFN-gamma, platelet-activating factor and

endothelin that are produced by infected microglia. In addition nitric oxide,

eicosanoids and quinolinic acid can contribute to neurotoxicity.1,25

The likelihood that HIV or its products are involved in

neuropathogenesis is supported by the observation that neuropsychiatric

abnormalities may undergo remarkable and rapid improvement upon the

initiation of antiretroviral therapy (ART).

The neurological problems that occur in HIV infected individuals are

categorized as follows,

a. Opportunistic infections

- Toxoplasmosis

- Cryptococcosis

- Progressive multifocal leucoencephalopathy

- CMV infection

- Syphilis

- Mycobacterium Tuberculosis

b. Neoplasms

- Primary CNS lymphoma

- Kaposi’s sarcoma

c. Result of HIV-1 infection

- Aseptic meningitis

- HIV Encephalopathy (AIDS dementia complex)

d. Myelopathy

- Vacuolar myelopathy

- Pure sensory ataxia

- Paresthesia / dysesthesia

e. Peripheral Neuropathy

- Acute inflammatory demyelinating polyneuropathy (Gullian-Barre

Syndrome)

- Chronic inflammatory demyelinating polyneuropathy (CIDP)

- Distal symmetric polyneuropathy

f. Myopathy

TOXOPLASMOSIS

CNS toxoplasmosis has been the most common cause of intracerebral mass lesion in HIV-

infected patients. Toxoplasmosis is generally a late complication of HIV and usually occurs in

patients with CD4+ counts < 200/cmm.1

Clinical Features:

The most common clinical features are fever, headache and focal neurological deficits. They

include seizure, hemiparesis, aphasia as a manifestation of these focal deficits or seen as a

picture influenced by accompanying cerebral oedema as confusion, dementia, lethargy

which can later progress to coma1.

Investigations:

CT scan of the brain usually shows multiple-ring enhancing lesions with predilection for

cortex and deep gray-matter structures such as basal ganglia. The cerebellum and brain

stem are less commonly involved. Radiological findings may vary markedly as single lesions

and lesions with diffuse enhancement as well as non-enhancing lesions can appear.

The diagnosis however is suspected on the basis of MRI findings of multiple lesions in

multiple locations in addition to surrounding oedema1.

CSF analysis in these cases is non-diagnostic, it can be normal or may show mononuclear

pleocytosis and elevated protein.

Treatment:

Standard treatment is sulfadiazine (4 to 6 gm/day in r divided doses) and pyrimethamine (a

200 mg loading dose followed by 50-70 mg/day) with leucoverin as needed for minimum of

4-6 weeks.1

Alternative therapeutic regimens include clindamycin in combination with pyrimethamine,

atovaquone plus pyrimethamine, azithromycin plus pyrimethamine plus rifabutin.

Patients with CD4+ T cell counts < 100/cmm and IgG antibody to Toxoplasma should receive

primary prophylaxis with single double strength tablet of sulfadiazine and pyrimethamine.

CRYPTOCOCCOSIS

Cryptococcus neoformans is another CNS opportunistic infection. It is the initial AIDS

defining illness in many cases and occurs in patients with CD4+ T cell count of < 100/cmm1.

It usually presents as acute meningitis but also can have rare presentations like

cryptococcoma and cryptococcal cerebritis.

Clinical Features:

Clinical manifestations can be remarkably benign with vague malaise or nausea alone. More

commonly, headache and fever are presenting features. An acute confusion as cranial nerve

palsies. Stiff neck (meningeal sign) is absent in up to 70% of cases. Cryptococcoma in

addition can have focal neurological deficits where as those with cryptococcal cerebritis

present with seizures or altered mental state. Hence clinicians must maintain a high index of

suspicion for cryptococcal disease, particularly in the setting of new onset of headache.

Investigations:

CSF can be normal or may show mononuclear pleocytosis, elevated proteins, low glucose

and high opening pressure.1,16 The diagnosis can be made by identification of organisms in

CSF with India ink preparation or by the determination of cryptococcal antigen.1

CT/MRI is usually normal or may reveal only atrophy. Uncommonly, cryptococcomas occur,

particularly in the basak ganglia due to spread of organism from basal cisterns by way of the

lenticulostriate arteries. In case of cryptococcal cerebritis and docal meningeal and

parenchymal enhancement is seen in seen on MRI.

Treatment:1

Induction therapy:

- Inj. Amphotericin B in the dose of 0.5-0.7 mg/kg/day preceded by test

dose for a minimum period of 2weeks.

- Flucytosine can be added in the dose of 25mg/kg 6hrly for 2 weeks.

Maintenance therapy:

- Chronic suppressive treatment for life is required with oral

Fluconazole 400 mg once daily for 10 weeks followed by 200 mg/day

until CD4+ T cell count has increased to >200 cells/ul for 6 months in

response to HAART (Highly Active Anti-Retroviral Therapy).

MYCOBACTERIUM TUBERCULOSIS

It is also an opportunistic infection of CNS in HIV patients. The commonest presentations are

tuberculous meningitis and tuberculoma.

Clinical Features:

Tubercular meningitis presents as chronic meningitis with symptoms of fever, vomiting,

headache, visual disturbances, focal neurodeficits, altered sensorium and seizures. On

clinical examination, signs of meningism are present with pappiloedema. Clinical course may

be complicated by involvement of cranial nerve palsies in few cases.

Tuberculomas present as mass lesion, it can be single or multiple.

Investigation:

CSF analysis shows reduced sugar level, markedly elevated proteins and lymphocytic

pleocytosis in the range of 100-150 cells/cmm. CSF PCR for Tuberculosis is highly sensitive

and specific investigation for diagnosis of tubercular meningitis .

CT/MRI of brain chows meningeal enhancement with predominantly basal cisterns and

ependyma. Tuberculomas are seen as ring enhancing lesions mainly in cortical distribution.

Treatment:1

Anti-Tubercular drugs are given for the duration 18 months, with three months of intensive

phase and 15 months of maintenance phase.

Intensive Phase -

Combination chemotherapy including isoniazid (5mg/kg), rifampicin (10 mg/kg),

pyrazinamide (15-30 mg/kg), Inj. Streptomycin (15 mg/kg) are commonly used . Ofloxacin

400 mg/day can be added to the regimen because of its better CNS penetration.

Maintenance Phase –

Isoniazid and rifampicin are continued for the rest of 15 months during this phase.

ASEPTIC MENINGITIS

Many patients with this syndrome have primary HIV meningoencephalitis. The meningitis

can manifest at the time of seroconversion and can recur spontaneously or become chronic.

Clinical Features:

Patients with aseptic meningitis present initially with headache, photophobia, meningismus,

occasionally in association with altered mental status or cranial neuropathies. In

investigating the above symptoms aseptic meningitis must be a diagnosis of exclusion.

Investigation:

Because of high incidence of CSF abnormalities in HIV infected patients, regardless of

symptoms interpretation of CSF in this population can be difficult. CSF analysis shows

lymphocytic pleocytosis, elevated protein levels and normal sugar levels.1

HIV ENCEPHALOPATHY

The role of HIV-1 proliferation itself in the development of AIDS dementia complex (ADC) is

controversial. Although viral strains that are particularly efficient at replicating in brain

macrophages may play a role in the pathogenesis of brain injury, a heavy “viral load” in

brain has not been linked consistently with clinical AIDS dementia. This is generally a late

complication of HIV infection that progresses slowly over months and is seen in patients

with CD4+ T counts > 350 cells/cmm1.

Activated macrophages, whether infected with HIV or not are capable of secreting potent

neurotoxins, including pro-inflammatory cytokines and generating oxygen free radicals that

can damage cells or lead to neuronal dysfunction or death. Soluble factors from these

macrophages were found to be highly neurotoxic.1, 25

Clinical Features:

A major feature is development of dementia, a decline in cognitive ability from a previous

level. It may present as impaired ability to concentrate, increased forgetfulness, difficulty

reading or increased difficulty performing difficult tasks.1 Patients may also present with

motor and behavioural abnormalities.1

Investigations:

There is no specific criteria for diagnosis of HIV encephalopathy and thus it depends upon

demonstrating the decline in cognitive function which can be achieved objectively by

performing a MMSE (Mini Mental Status Examination).1

On CSF analysis of these patients, non-specific finding of an increase in CSF cells and protein

levels is noted. While HIV RNA can be detected in CSF and also HIV can be cultured, this

finding is not specific for HIV encephalopathy. There appears to be no co-relation between

the presence of HIV in CSF and HIV encephalopathy.1

The various molecular and clinical observations regarding ADC are well supported by newer

imaging modalities such as Positron Emission Tomography (PET scan) which show the

metabolic rather than the structural changes in the brains of individuals with early stage of

HIV-associated cognitive impairment.

Treatment:1

Combination ARV (Anti-Retroviral Therapy) is of benefit in patients with HIV

encephalopathy. These patients have an increased sensitivity to the side effects of these

drugs. The use of these drugs for symptomatic treatment is associated with an increased

risk of extrapyramidal side effects and therefore, they must be monitored very carefully.

AIMS AND OBJECTIVES

1. To study the neurological manifestations in HIV positive patients.

2. To study CSF parameters in HIV positive patients.

3. To co-relate CSF study and neurological findings in HIV positive patients.

4. To see the outcome of neurological problem after the treatment.

MATERIALS AND METHODS

In the present study, the clinical profile of 100 HIV positive patients who presented with

neurological manifestations was studied. This is an observational study conducted over a

period from 20th June 2010 to 21st August 2010 in the Department of Medicine, of our

Medical College and Hospital.

Selection criteria

All HIV positive patients presenting with neurological manifestations like

fever, vomiting, headache, altered mental status, decline in cognitive ability, behavioural

problems, focal neurodeficits, gait ataxia, loss of / impaired sensations, bowel / bladder

dysfunction, skin lesions, swellings and signs of meingism like neck stiffness were selected.

The demographical data like name, age, sex, address, occupation, marital

status, socio-economic status were all collected in all patients.

History of high risk behaviours, major surgery and blood transfusions were

asked in all patients.

The diagnosis of HIV was confirmed by 2 HIV ELISA positive reports in the

symptomatic patients.

All patients were subjected to detailed general examination and systemic

examination with special attention to CNS. The CNS examination of the patients included

- Higher function examination

- Cranial nerve examination

- Motor system examination

- Sensory system examination

- Tests for cerebellar dysfunction

- Signs of meningism like neck stiffness etc.

All patients were subjected to routine investigations like haemogram and

blood biochemistry.

Other investigations like CSF analysis, serology and neuro-imaging studies were

undertaken as appropriate to individual patient only when mandatory for the research

project.

The lumbar puncture was done for collection of CSF with all aseptic measures

with written consent from the patient.

The CSF sample was analysed in the Dept. Of Biochemistry, Pathology and

Microbiology of our Hospital, for

1. Biochemistry including sugars and proteins

2. Cytology

3. Staining including Grams staining, Acid fast bacilli and India Ink preparation

The following reference values were considered abnormal

CSF sugar < 40 mg/dl [N/R - 50-80 mg/dl]

CSF protein > 45 mg/dl [N/R - 20-45 mg/dl]

WBC > 10/cmm [N/R - No PMNs and under 6 lymphocytes]

Thus based upon the CSF analysis and neurological examination the patients the

patients were categorised into three groups as follows:

Group I – HIV positive patients with neurological manifestations and abnormal CSF

findings.

Group II – HIV positive patients with neurological manifestations but normal CSF

analysis.

Group III – HIV positive patients without neurological manifestations with abnormal

CSF analysis.

Neuro-imaging techniques like CT scan of the brain and MRI of brain and spinal cord

in patients presenting with focal neuro-deficits, seizures, features of raised ICT,

altered sensorium, paraplegia to aid in diagnosis of conditions like

1. Toxoplasmosis

2. Tuberculoma

3. Progressive multifocal leucoencephalopathy

4. Brain abscess

5. Primary CNS Lymphoma

Guidelines for Diagnosis of Different Neurological manifestations:

1. Meningitis

All HIV positive patients presenting with fever, headache,

vomiting, altered sensorium, visual disturbances and signs of meningism

were subjected to CSF analysis with respect to sugar, proteins, cytology and

staining for organisms in CSF. Depending upon the abnormalities present,

patients were classified into four groups mentioned above

CT/MRI Brain was done to look for evidence of meningitis or

complications associated with it.

2. Neuropathy

All patients presenting with symptoms of tingling, numbness,

paresthesia, dysesthesia, hypoesthesia and anesthesia and weakness

involving distal group of muscles were considered to have peripheral

neuropathy.

3. Intra-cranial space occupying lesions(ICSOL)

This is the radiological diagnosis and differential diagnosis in the

setting of HIV positive cases include Toxoplasmosis, Tuberculoma, Primary

CNS lymphoma, Progressive multifocal leucoencephalopathy and Brain

abscess

The lesions can be single or multiple, with or without

enhancement on injection of contrast material. The characteristic finding is

the presence of mass effect.

The radiological procedures were also helpful in the diagnosis of

various other cases like Cerebrovascular accidents (CVA), Lumbar canal

stenosis, Cerebral Venous Sinus Thrombosis (CVST).

4. HIV Encephalopathy

There are no specific criteria for the diagnosis of HIV

Encephalopathy. The diagnosis depends upon demonstrating the decline in

cognitive function. Mini Mental Status Examination (MMSE) was used to

accomplish this. CSF analysis was done to rule out infective pathology.

CT/MRI Brain in some of the patients show marked cerebral atrophy.

5. Seizure disorders

New onset seizures in HIV infected patients were classified as

isolated seizures when no cause could be arrived at after detailed clinical

evaluation supported by CSF analysis and neuro-imaging studies.

OBSERVATIONS AND RESULTS

A total of 100 cases of HIV positive patients presenting with neurological manifestations

were observed during the study period.

Table I – Sex distribution:

Sex Total %

Male 82 82%

Female 18 18%

Total 100 100%

Fig. 1 – Sex distribution

In the present study the total number of male patients were 82 (82%) and total number of

female patients were 18 (18%).

The Male : Female ratio is found to be 4.55 : 1.

0

10

20

30

40

50

60

70

80

90

Males Females

No

. of

pat

ien

ts

Sex distribution

Table II – Age distribution:

Age group No. of patients Total %

Male Female

11-20 2 2 4 4%

21-30 16 6 22 22%

31-40 42 10 52 52%

41-50 22 0 22 22%

Total 82 18 100 100%

Fig. 2 – Age distribution

Out of the 100 patients,

i. 4% (50% males & 50% females) were in the age-group of 11-20 years,

ii. 22% (72.7% males and 27.3% females) were in the age-group of 21-30 years,

iii. 52% (80.8% males and 19.2% females) cases were found to be in the age-group

of 31-40 years,

iv. 22% (100% males) were in the age-group of 41-50 years of age.

The age-group between 31-40 years contributed the largest percentage of cases. The mean

age at the presentation was found to be 35.8 ~ 36 years.

0

5

10

15

20

25

30

35

40

45

11-20 21-30 31-40 41-50

No

. of

pat

ien

ts

Age distribution

Males

Females

Table III – Neurological manifestation of HIV disease:

Diagnosis Frequency %

Cerebellar ataxia 2 1.92

Cerebrovascular Infarct 5 4.80

Cranial Neuropathy 2 1.92

CVST (Cerebral Venous Sinus Thrombosis) 2 1.92

HIV Encephalopathy 18 17.30

ICSOL (Intra-cranial space occupying lesions) 6 5.76

Lumbar Canal Stenosis 1 0.96

Meningitis 52 50.00

Neuropathy 3 2.88

Seizure Disorder 3 2.88

Unknown 10 9.61

Total 104 100%

Fig. 3 – Distribution of Neurological Manifestations of HIV Disease

In the present study out of 104 neurological events, cerebellar ataxia was present in 2

(1.92%), Cerebrovascular Infarct was seen in 5 (4.8%), Cranial Neuropathy was seen in 2

(1.92%), CVST was seen in 2 (1.92%), HIV Encephalopathy was present in 18 (17.3%), Mass

lesions were present in 6 (5.76%), Meningitis was present in 52 (50%), Neuropathy was

present in 3 (2.88%), Seizures were seen in 3 (2.88%) and Idiopathic were noted amongst 10

(9.61%) of all cases.

0 10 20 30 40 50 60

Cerebellar ataxia

Cerebrovascular infarct

Cranial Neuropathy

CVST

HIV Encphalopathy

ICSOL

Lumbar Canal Stenosis

Meningitis

Neuropathy

Seizure disorder

Unknown

No. of patients

Neurological manifestations in HIV

Of these, the commonest neurological manifestation was found to be Meningitis in 50% of

cases followed by HIV Encephalopathy in 17.3% cases, Idiopathic in 10%, Mass lesions were

present in 5.76% and Neuropathy was seen in 2.88% of all cases.

Table IV – Types of Meningitis in HIV disease

Type of Meningitis no. of cases %

Tuberculous 36 69.23

Croytococcal 8 15.38

Aseptic 6 11.53

Pyogenic 2 3.84

Total 52 100

Fig. 4 – Types of Meningitis in HIV disease

As shown in Fig. 3 Meningitis was seen amongst 50% cases of the study. Fig. 8, shows

different types of Meningitis in the study. In the present study, the most commonest form

of meningitis was found to be Tuberculous meningitis in 69.23% of all cases, followed by

Cryptococcal meningitis in 15.38% cases, Aseptic meningitis in 11.53% cases and Pyogenic

meningitis in 3.84% of all cases.

Types of Meningitis

Tuberculous

Cryptococcal

Aseptic

Pyogenic

Table V – Presenting Complaint’s

Clinical Presentation no.of patients %

Abnormal movements 4 4

Altered Sensorium 32 32

Backache 4 4

Breathlessness 4 4

Chest Pain 2 2

Convulsions 10 10

Diarrhoea 6 6

Diplopia 2 2

Fever 82 82

Gen.Weakness 56 56

Giddiness 2 2

Headache 84 84

Loss of balance 6 6

Pain in abdomen 2 2

Vomiting 48 48

Fig. 5 – Presenting Complaint’s

In the present study, the commonest of the neurological clinical presentations was found to

be Headache in 84% cases, followed by other presenting complaints such as, fever in 82%

cases, Generalised weakness in 56% cases, Vomiting in 48% cases, Altered sensorium in 32%

cases, 10% cases presented with convulsions, 6% with loss of balance and 4% with abnormal

movements.

0102030405060708090

No

. of

pat

ien

ts

Presenting complaints of patients

Table VI – Distribution of CT/MRI findings

Presentation/ Findings no. of cases %

Basal exudates 8 10.25

CVST 2 2.56

Gen. Atrophy 12 15.38

Gen. Oedema 14 17.94

ICSOL 6 7.69

Infarct/Bleed 5 6.14

Mass effect 6 7.69

Meningeal enhancement 6 7.69

Mid line shift 4 5.12

Multiple lesions 8 10.25

Single lesion 6 7.69

Vertebral canal stenosis 1 1.28

Total 78 100%

Fig. 6 – Distribution of CT/MRI findings

In the present study, appropriate cases were subjected to CT/MRI evaluation and the most

frequent cases of Generalised oedema were noted in 17.94% of cases, this was followed by

Generalised atrophy of neuro-parenchyma in 15.38% of cases, Basal exudates and multiple

lesions were found in 10.25% of cases, Mass effect, ICSOL (Toxoplasma?, Tuberculoma?),

Single lesions and meningeal enhancement were noted in 7.69% of cases, Infarcts were

noted in 6.14% of cases, also midline shift was seen in 5.12%, also CVST and Vertebral canal

stenosis was seen in 2.56% and 1.28% respectively of all the cases.

02468

101214

No

. of

pat

ien

ts

CT/MRI findings

Table VII – Distribution of normal and abnormal CSF findings

Total %

Normal CSF 30 30%

Abnormal CSF 70 70%

Total 100 100%

Fig. 7 – Distribution of normal and abnormal CSF analysis

In the present study, 30% cases of HIV presenting with neurological manifestations showed

normal CSF, while 70% cases showed abnormality in their CSF analysis reports.

0

10

20

30

40

50

60

70

Normal CSF Abnormal CSF

No

. of

pat

ien

ts

CSF nature

Table VIII – Distribution of different CSF findings

Findings Total %

Lymphocytosis 31 22.30

India Ink 8 5.75

Increased protiens 36 25.89

Decreased sugar 28 20.14

Acid Fast Bacilli 36 25.89

Total 139 100%

Fig. 8 – Distribution of different CSF findings

Present study shows marked variations on CSF analysis of the patients. As shown in Fig. 6,

70% cases showed abnormality on CSF analysis. The various CSF abnormalities were,

elevated proteins and Acid fast bacilli in 25.89% cases, lymphocytosis in 22.33% cases, India

Ink preparations were positive in 5.75% cases and reduced sugars in CSF were seen in

20.14% of all the cases.

0

5

10

15

20

25

30

35

40

Lymphocytosis India Ink Increased proteins

Decreased sugars Acid fast bacilli

No

. of

pat

ien

ts

Different CSF findings

Table IX – Distribution of cases according to CSF sugars

Sugar in CSF(mg/dl) Cryptococcal Tuberculous

Frequency % Frequency %

Normal 5 62.5 11 30.55

Reduced (<40mg/dl) 3 37.5 25 69.44

Fig. 9 – Comparative analysis of CSF sugars in Cryptococcal and Tuberculous

meningitis

In the present study, out of 8 cases of cryptococcal meningitis, 5 (62.5%) had normal CSF

sugar while it was reduced in 3 (37.5%) of cases.

Out of 36 cases of tuberculous meningitis, 11 (30.55%) had normal CSF sugar and it was

reduced in 25 (69.44%) of all cases.

Thus, patients with Tuberculous meningitis have much lower CSF sugar level to those

compared with cryptococcal meningitis.

0

5

10

15

20

25

30

Normal CSF sugar (50-80mg/dl)

Reduced CSF sugar (<40mg/dl )

No

. of

pat

ien

ts

CSF Sugar levels

Cryptococcal

TB

Table X – Distribution of cases according to CSF proteins

Proteins in CSF(mg/dl)

Cryptococcal Tuberculous

Frequency % Frequency %

Normal (20-45 mg/dl) 1 12.5 4 11.11

Elevated (>45mg/dl) 7 87.5 32 88.89

Fig. 10 – Comparative analysis of CSF proteins in Cryptococcal and

Tuberculous meningitis

In the present study, out of 8 cases of cryptococcal meningitis, only 1 (12.5%) has normal

CSF protein levels while it was elevated in the rest of 7 (87.5%) of the cases.

Out of 36 cases of tuberculous meningitis, 4 (11.11%) cases reported with normal CSF

protein reports and the rest 32 (88.89%) cases reported markedly elevated CSF protein

levels.

Thus, cryptococcal meningitis tend to have much lower rise in CSF proteins than those

compared with tuberculous meningitis in which it is markedly elevated.

0

5

10

15

20

25

30

35

Normal CSF protein (20-45 mg/dl)

Elevated CSF protein (>45 mg/dl)

No

. of

pat

ien

ts

CSF Protein levels

Cryptococcal

Tuberculous

Table XI – Distribution of cases according to WBC count in CSF.

Range of WBCs (cells/cmm.)

Cryptococcal Tuberculous

Frequency % Frequency %

0-50 6 75 5 13.88

50-100 1 12.5 10 27.77

100-150 1 12.5 19 52.77

>150 0 0 2 5.55

Fig. 11 – Distribution of CSF cells in Cryptococcal and Tuberculous meningitis

In the present study, out of 8 patients of cryptococcal meningitis, 6 (75%) had CSF WBC

count between 0-50 and only one case each (12.5%) was found to have counts between 50-

100 and 100-150 groups while none had the cell count of >150 cells/cmm.

Out of 36 patients of tuberculous meningitis, 5 (13.88%) had CSF WBC count between 0-50,

10 (27.77%) had cell counts between 50-100, 19 (52.77%) had cell count between 100-150

and 2 cases (5.55%) had cell count of >150 cells/cmm.

Thus, patients with cryptococcal meningitis had a lesser degree of pleocytosis in their CSF

than those with tuberculous meningitis.

0

2

4

6

8

10

12

14

16

18

20

0-50 50-100 100-150 >150

No

. of

pat

ien

ts

WBC Range in CSF (in cells/cmm.)

Cryptococcal

Tuberculous

Table XII – Outcome of patients

Outcome

Gender

Total % Male Female

Death 22 2 24 24%

Discharged 60 16 76 76%

Total 82 18 100 100%

Fig. 12 – Outcome of the patients

In the present study, 24 out of 100 cases died even after intensive treatment on ambulatory

ventilation, of which 22 were males and 2 were females. However 76 cases were discharged

after their specific treatment, of which 60 were males and 16 were females.

0

10

20

30

40

50

60

Death Discharged

No

. of

pat

ien

ts

Outcome of patients

Male

Female

DISCUSSION

1. Sex Distribution

In this study out of 100 patients, 82 are males and 18 are females. The Male : Female

ratio is estimated to be 4.55 : 1.

Studies show that males are at a higher risk of developing HIV/AIDS due to practice

of high risk behaviour, multiple sexual partners, intravenous drug abuse, homo-

sexuality.

Gongora Rivera F et al, (2000)26 in their study on neurological manifestations of HIV

disease, the male: female ratio was found to be 8.31: 1. In a similar study on 194

patients, by Jacqueline Ferreira de Oliveira et al, (2006)27 the male: female ratio was

found to be 2.28: 1.

2. Age Distribution

The present study shows prevalence of HIV patients with neurological manifestations

more commonly in the age-group of 31-40 years contributing 52% and the mean age

was found to be 35.8 years.

Recent studies suggest that the occurrence of neurological manifestations of HIV is

more common among the younger age group.

Gongora Rivera F et al (2000)26 in their study observed patients ranging from 9 to 75

years of age, with the mean age of 33.8 years. Jacqueline Ferreira de Oliveira et al,

(2006)27 in their study found the mean age to be 35.8 years.

3. Distribution of Neurological manifestations

All the HIV positive patients presenting only with neurological manifestations were

selected for the study. Gongora Rivera F et al (2000)27 in their study found that the

prevalence of HIV with neurological manifestation was 39%

In this study, out of the total of 104 neurological events observed in patients,

meningitis was seen in 50% of the cases with HIV Encephalopathy in 17.3%, few

cases remained un-diagnosed contributing 9.61% of all, Intra-cranial space occupying

lesions (ICSOL)(Toxoplasma?, Tuberculoma?) in 5.76% cases, Cerebrovascular infarct

in 4.8% cases, cranial neuropathies and seizure disorder were seen in 2.88% of the

cases, cerebellar ataxia, cranial neuropathy and CVST (cerebral venous sinus

thrombosis) were seen in 1.92% cases and a single case of lumbar canal stenosis.

The neurological complications that occur in HIV patients may be primary to the

pathogenic process of HIV infection or secondary to opportunistic infections or

neoplasms.

Gongora Rivera F et al (2000)26 in their study on 149 HIV positive patients, 50.3%

cases presented with neurological manifestations, most commonly presented was

brain toxoplasmosis in 32.2% cases, meningitis in 30.2% cases, AIDS dementia

complex in 8.7% cases, 5.4% cases of ischaemic cerebrovascular disease.

4. Distribution of Meningitis

As we can see in Table III meningitis is the most common presentation of HIV

disease, seen in 50% of all cases. Among them, tuberculous meningitis was found to

be the most common variety in 69.23% of the cases of meningitis followed by

cryptococcal in 15.38% cases, aseptic in 11.53% cases and pyogenic in 3.84% cases.

TB meningitis is the most common infectious disease of CNS in India, which is in

contrast to cryptococcal meningitis and toxoplasmosis observed in western

countries. It is because of the fact that here, tuberculosis is the most common

opportunistic infection in HIV disease which has a tremendous affinity to affect CNS.

Gongora Rivera F et al (2000)26, in their study, the most common form of meningitis

was cryptococcal in 21.5% cases followed by tuberculous in 8.7% cases, aseptic in

1.34% cases.

Jacqueline Ferreira de Oliveira et al (2006)27 in their study found toxoplasmosis as

the most common form of CNS infections in HIV patients i.e 42.3%, followed by

cryptococcal meningitis in 12.9% and TB meningitis in 10.8% of the cases.

R. B. Lipton et al (1991)28 in their study on 49 HIV-1 infected patients found

cryptococcal meningitis in 39% and toxoplasmosis in 16% of the cases.

5. Distribution of Clinical presentation

In this study, the clinical presentation of the patients was also taken into

consideration. Headache alone accounted for 84% of all presentation’s, the other

significant clinical presentations were fever in 82% cases, generalised weakness in

56% cases, vomiting in 48% cases and convulsions in 10% of the cases.

R. B. Lipton et al (1991)28 in their study of 49 HIV-1 infected patients found headache

as an identifiable presentation in 82% of the cases.

F. Bissuel et al (1994)29 in their retrospective study of 270 HIV infected patients

found that 21.11% of the patients had developed fever.

David M. Holtzman et al (1989)30 in their study on 100 HIV patients found seizures to

be the presenting symptom in 18 cases.

Fever is a frequent clinical presentation in HIV patients and can occur due to primary

HIV or any other opportunistic infections in HIV. Generalised weakness occurs as a

result of breakdown of the immune system of the patient which causes recurrent

infections. Seizures in HIV may be due to direct effect of HIV on the brain31 or due

to other causes such as cerebral mass lesions, HIV Encephalopathy, cryptococcal

meningitis. Phenytoin is the drug of choice in such cases. However, the prognosis of

such cases depends on the underlying cause.31

6. Distribution of CT/MRI findings

In the present study, the appropriate patients were subjected for CT/MRI evaluation

and generalised oedema was found more frequently in 17.94% cases. Other findings

were generalised atrophy in 15.38% cases, basal exudates and multiple lesions in

10.25% cases, Intra-cranial space occupying lesions, mass effect and meningeal

enhancement in 7.69% of cases, infarct/bleed in 6.14% and mid-line shift in5.12% of

the cases was seen.

M. Whiteman et al (1995)32 in their study on 25 HIV positive patients noted 36%

showed meningeal enhancement, 44% showed enhancing parenchymatous lesions.

MJ Popovich et al (1990)33 verified CT scans of 35 patients with intra-cranial

cryptococcosis and found 43% normal, diffuse atrophy in 34% cases, mass lesions in

11% and diffuse cerebral oedema in 3% cases.

Jose Enrique Cohen et al (1996)34 in their case report mentioned that AIDS related

cerebral atrophy may not only have predisposed the patient to the development of

an extracerebral collection, but may have also favourably influenced the resolution

of haematoma.

7. CSF Analysis

CSF analysis of the HIV patients showed marked variations. CSF was normal in 30%

cases and showed abnormality in 70% cases (Table VII). CSF abnormality was seen in

the form of elevated proteins, reduced sugars, lymphocytosis, positive India ink

preparations and acid fast smears.

In the present study, we make comparative study between cases of cryptococcal

meningitis and tuberculous meningitis as the CSF abnormalities are markedly noticed

among these two groups of patients.

Here, out of 8 cases of cryptococcal meningitis, 62.5% cases had normal CSF sugars

while the rest 37.5% cases reported reduced CSF sugar levels, also CSF protein levels

in these cases were normal in 12.5% cases and showed elevated proteins in 87.5% of

the cases. On CSF cytology reports of these cases, we found 75% cases had CSF WBC

counts between 0-50, 12.5% cases each in the range of 50-100 and 100-150

(WBC ranges in cells/cmm.)

Out of 36 cases of tuberculous meningitis, 30.55% showed normal CSF and reduced

CSF sugars noted in 69.44% of the cases. CSF protein levels in these cases were

normal in 11.11% cases and reported elevated levels in the rest 88.89% of cases. On

CSF cytology of these cases, we found that 13.88% cases had CSF WBC counts

between 0-50, 27.77% between 50-100, 52.77% between 100-150 and 5.5% cases

had counts > 150. (WBC ranges in cells/cmm.)

Thus we can see that,

i. Patients with TB meningitis have lower CSF sugar level as compared to

cryptococcal meningitis.

ii. Patients with TB meningitis have a marked rise in CSF protein levels as

compared to cryptococcal meningitis and

iii. Patients with TB meningitis show a higher degree of pleocytosis in CSF than

those compared with CSF cryptococcal meningitis.

Irina Elovaara et al (2003)35 in their study on HIV infected patients reported that CSF

leucocytes were increased in the early stage of the disease, but later the cellular

reaction subsided.

Lars-Magnus Andersson et al (1999)36 in their study, analysed 52 HIV positive

patients for the CSF tau protein levels and reported significantly higher mean CSF tau

protein concentration in patients with AIDS Dementia Complex (ADC). They also

suggested that CSF tau might be used as a biochemical marker for axonal

degeneration and for the diagnosis of HIV-1 infected patients.

CONCLUSION

1. The neurological manifestations in HIV disease are found to be more commonly in

the younger age-group.

2. Males are affected more frequently than females.

3. Meningitis, HIV Encephalopathy, intra-cerebral mass lesions, cerebrovascular

accidents, neuropathy, seizure disorders are the most common of the neurological

manifestations in HIV infected patients in decreasing frequency. Cases of cerebellar

ataxia, cranial neuropathy, lumbar canal stenosis were also noted.

4. Headache, fever, generalised weakness, vomiting, convulsions, altered sensorium,

meningism are found to be the most frequent clinical findings. Few patients also

presented with breathlessness, backache, loss of balance, giddiness and chest pain.

5. On CT/MRI evaluation of the patients a broad spectrum of intra-cranial

abnormalities were noted. There was generalised oedema, generalised atrophy of

the neuroparenchyma, basal exudates, multiple lesions, intra-cranial mass lesions,

mass effect, mid-line shift, meningeal enhancement were noted in most of the cases.

6. Tuberculous meningitis is found to be the most common meningitis followed by

cryptococcal, aseptic and pyogenic meningitis.

7. 70% of all the cases presented with abnormal CSF findings. The CSF analysis showed

reports of markedly elevated protein levels, reduced sugar levels, lymphocytic

pleocytosis, positive India ink preparations and acid fast smears.

8. It was also found that, the patients with TB meningitis have much lower CSF sugar

levels than those with cryptococcal meningitis and the protein levels in CSF of TB

meningitis patients is markedly elevated as compared to cryptococcal meningitis.

9. On CSF cytology it was observed that, cryptococcal meningitis had a lesser degree of

lymphocytic pleocytosis than TB meningitis.

Thus we conclude with promise that all the HIV infected patients must and should be

suspected to have a neurological manifestations until and unless proved otherwise by

thorough clinical evaluation and relevant investigations as many a times patient present

with subtle symptoms and signs.

HIV patients presenting with neurological manifestations need to be accurately diagnosed

and treated promptly. In today’s world, availability of advanced technologies in the field of

medical sciences such as neuro-imaging studies like CT/MRI, PET scan, EMG, NCV has

become very easy for the physicians and clinicians all over the world. CSF analysis of the

patients under study, has provided the both the qualitative and microbiological/cytological

information. Thus, CSF analysis still maintains its place in the era of modern neuro-imaging

modalities such as CT/MRI Brain and PET scan.

SUMMARY

The present study titled ‘Co-relation of CSF and Neurological Findings in HIV positive

patients’ is a cross-sectional study conducted from 20th June to 21st August 2010. This study

was done with an aim to find out the various neurological manifestations in HIV infected

patients and co-relate them with the CSF analysis of the respective patients.

1. Males were affected more frequently than females. 82% of the study patients were

males and the rest 18% were females. Male: Female ratio was 4.55: 1.

2. The most common age group affected was 31-40 years of age accounting for 52% of

all patients. Mean age was 35.8 ~ 36 years.

3. An overall of 104 neurological manifestations in HIV infected patients were

observed. Meningitis was the most common manifestation in 50% cases, followed by

HIV encephalopathy in 17.3% cases, Idiopathic were 9.61% cases, Intra-cranial mass

lesions were 5.76%, cerebrovascular infarcts in 4.8%, neuropathy and seizures were

in 2.88%, CVST, cranial neuropathy and cerebellar ataxia in 1.92%, lumbar canal

stenosis was also seen in a case (0.96%).

4. Meningitis was seen as the most common neurological manifestation. It was seen as

Tuberculous meningitis in 69.23% of all meningitis cases, cryptococcal in 15.38%,

aseptic in 11.53% and pyogenic in 3.84% of all cases of meningitis.

5. The most common clinical presentation was headache in 84% cases followed by,

Fever in 82%, generalised weakness in 56%, vomiting in 48%, altered sensorium in

32%, convulsions in 10%, diarrhoea and loss of balance in 6%, abnormal movements,

backache and breathlessness in 4%, chest pain, diplopia, giddiness and pain in

abdomen was seen in 6% cases.

6. On CT/MRI evaluation of the patients generalised oedema was seen in 17.94% cases,

atrophy in 15.38% cases, basal exudates and multiple lesions in 10.25% cases, Intra

cranial mass lesions, mass effect, meningeal enhancement in 7.69% cases, Infarct in

6.14%, mid-line shift was seen in 5.12% cases, CVST in 2.56% cases and a single case

of lumbar canal stenosis was also noted.

7. On CSF analysis of the patients, 70% came up with abnormal CSF findings. Among

them, elevated proteins were noted in 25.89% cases, lymphocytosis in 22.3% cases,

reduced sugars in 20.14% cases and acid fast smears wee positive in 25.89% of cases.

8. The CSF analysis of patients with tuberculous meningitis showed that 69.44% cases

had reduced sugars, 88.89% patients had markedly elevated proteins and 52.77%

cases had lymphocytic pleocytosis with cell counts between 100-150 cells/cmm. The

patients with cryptococcal meningitis showed 37.5% cases had reduced sugars,

proteins were elevated in 87.5% cases and lymphocytic pleocytosis with cell counts

between was 50-100 cells/cmm. Was seen in 75% of the cases.

9. Death was seen in 24% of all the cases even after intensive treatment on ambulatory

ventilation of which 22 were males and 2 were females.

SUGGESTIONS

i. All the patients with neurological manifestations must and should be monitored

and treated carefully.

ii. CSF analysis of the HIV patients should be done unless contra-indicated as it

provides both the qualitative and cytological/microbiological profile of the CSF

and is of tremendous importance in the diagnosis of such patients.

iii. CSF analysis with respect to CSF proteins, sugars, CSF cytology, CSF staining

(Gram stain, Acid Fast or Ziehl-Neelsen and India ink preparations), culture and

sensitivity provide a very significant information to aid in the accurate diagnosis

and thereby the treatment of the HIV patients with neurological manifestations.

iv. CSF analysis along with other diagnostic tools such as CT/MRI, PET scan, EMG,

NCV all must be evaluated in the appropriate patients for the correct diagnosis.

The immunological profile of the patient must also be determined as it is helpful

in the treatment and prognosis of the patients.

v. CD4+ T lymphocyte counts of the patients must be determined, they aid in

knowing the appropriate disease and the extent of spread of the HIV into the

body as well as providing treatment course in the patients.

vi. HIV-RNA viral load testing should also be done in patients suspected to have an

acute HIV infection.

vii. The HIV-RNA test and the CD4+ T lymphocyte count are prognostic indicators of

HIV infection and can be used to monitor progression and treatment efficacy.

viii. Even in today’s world of highly advanced medical technologies and

methodologies, the CSF analysis has still maintained its place in providing correct

diagnosis and thereby treatment of the patients.

REFERENCES

1. Anthony S. Fauci, H. Clifford Lane, PART 7 : Infectious Diseases, Chapter 182:

HIV,AIDS and Related Disorders, HARRISON’S, Principles of Internal Medicine, 17th

Edition Volume – 1, pg- 1137-1204.

2. Teja VD, Talasila SR, Vemu L, Neurological Manifestations of HIV infection: an Indian

hospital based study. AIDS read, 2005 March; 15(3):139-43, C3.

3. Bolokadze N, Gabunia P et al, Neurological complications in patients with HIV/AIDS.

Georgian Med News. 2008 Dec; (165):34-8.

4. Pandya R, Krentz HB, Gill MJ, Power C, HIV related neurological syndromes reduce

health-related quality of life, Can J Neurol Sci, 2005 May; 32(2):201-4.

5. Odiase FE, Ogunrin OA, Ogunniyi AA, Memory performance in HIV/AIDS: a

prospective case control study. Can J Neurol Sci, 2007 May; 34(2):154-9.

6. Robinson-Papp J, Byrd D, et al, Motor function and HIV associated cognitive

impairment in a highly active antiretroviral therapy – era cohort. Arch Neurol, 2008

August; 65(8):1096-101.

7. Compostella C, Compostella L, D’Elia R, The symptoms of autonomic dysfunction in

HIV-positive Africans. Clin Auton Res. 2008 Feb; 18(1):6-12. Epub 2007 Dec 15.

8. Hakim, James G, Innocent T et al, Impact of HIV infection on meningitis in Harare,

Zimbabwe: a prospective study of 406 predominantly adult patients. AIDS, 7 July

2000 – Volume 14 – Issue 10, 1401-07.

9. Jarvis JN, Meintjes G et al, Adult meningitis in a setting of high HIV and TB

prevalence: findings from 4961 suspected cases. BMC Infect Dis. 2010 March, 15;

10:67.

10. Karstaedt AS, Valtchanova S et al, Tuberculous meningitis in South African urban

adults. QJM, 1998 No; 91(11): 743-7.

11. Patel VB, Singh R, Connolly C et al, Cerebrospinal T-cell responses aid in the diagnosis

of tuberculous meningitis in a human immunodeficiency virus and tuberculosis

endemic population. Am J Respir Crit Care Med. 2010 Aug 15; 182(4): 569-77. Epub

2010 May 4.

12. Ngo AT, Duc NH, Lan NH et al, Mechanisms and causes of seath in 143 Vietnamese

HIV-Infected patients hospitalised for tuberculosis. Rev Pneumol Clin. 2007

Jun;63(3): 139-46

13. Metta HA, Corti ME et al, Disseminated cryptococcosis in patients with AIDS. Clinical,

microbiological and immunological analysis of 51 patients. Rev Argent Microbiol.

2002 Jul-Sep; 34(3): 117-23.

14. Wadhwa A, Kaur R, Bhalla P, Profile of central nervous system disease in HIV/AIDS

patients with special reference to cryptococcal infections. Neurologist. 2008 Jul;

14(4): 247-51.

15. Bicanic T, Brouwer, Rebe K et al, Relationship of cerebrospinal fluid pressure, fungal

burden and outcome in patients with cryptococcal meningitis undergoing serial

lumbar punctures. AIDS. 2009 Mar27; 23(6): 701-6.

16. Neelam Khanna, A. Chandramuki, Anita Desai, V. Ravi, Cryptococcal infections of the

central nervous system: an analysis of predisposing factors, laboratory findings and

outcome in patients from South India with special reference to HIV infection. J Med

Microbiol 45 (1996), 376-379; DOI: 10.1099/00222615-45-5-376.

17. Martinez Fernandez EM, Lopez-Cortes LF et al, Meningitis by Cryptococcus

neoformans in patients with HIV infection. Neurologia. 1999 May; 14(5): 218-23.

18. Monaco LS, Tamayo Antabak N, Cryptococcosis in AIDS patients: case study from

1996 to 2006 in Paroissien Hospital. Rev Argent Microbiol. 2008 Oct-Dec; 40(4):

218-21.

19. Hahn K, Husstedt IW et al, HIV-associated neuropathies. Nervenarzt. 2010 Apr; 81(4):

409-17.

20. Modi M, Mochan A, Modi G, New onset seizures in HIV – seizure semiology, CD4

counts and viral loads. Epilepsia. 2009 May; 50(5): 1266-69. Epub 2009 Jan 26.

21. Kurne A, Ozkaya G et al, The colourful clinical spectrum of cerebral toxoplasmosis in

five HIV positive cases : What comes out of Pandora’s box?. Mikrobiyol Bul. 2006

Jan- Apr; 40(1-2): 85-92.

22. Von Giesen HJ, Haslinger BA et al, HIV Dementia Scale and psychomotor slowing –

the best methods in screening neuro-AIDS. J Neuropsychiatry Clin Neurosci. 2005

Spring; 17(2): 185-91.

23. Abdulle S, Mellgren A, Brew BJ et al, CSF neurofilament protein (NFL) – a marker of

active HIV – related neurodegeneration. J Neurol. 2007 Aug; 254(8): 1026-32. Epub

2007 Apr 10.

24. Le C, DeFreitas D, HIV-associated pseudotumor cerebri : a case report and literature

review. AIDS Read. 2008 Dec; 18(12): 611-2.

25. Abul K, Abbas, Chapter 6: Diseases of Immunity, Acquired Immunodeficiency

Syndrome (AIDS). Robbins and Cotran, Pathologic Basis of Disease. 7th Edition, pg-

245-58.

26. Gongora-Rivera F, Santos-Zambrano J et al, The clinical spectrum of neurological

manifestations in AIDS patients in Mexico. Arch Med Res. 2000 Jul-Aug; 31(4): 393-8.

27. Jacqueline Ferreira de Oliveira, Dirceu Bartolomeu Greco et al, Neurological disease

in HIV-infected patients in era of highly active antiretroviral treatment: A Brazilian

experience. 2006 Mar-Apr, Rev. Soc. Bras. Med. Trop. Vol.39 no.2 Uberaba.

28. R. B. Lipton, E. R. Feraru et al, Headache in HIV-1 related disorders. 1991 Sep.

Headache: The Journal of Head and Face Pain, Volume 31, Issue 8, pages 518-522.

29. F. Bissuel, C. Leport et al, Fever of unknown origin in HIV-infected patients: a critical

analysis of a retrospective series of 57 cases, Journal of Internal Medicine. 1994 Nov,

Volume 236, Issue 5, pages 529-535.

30. David M. Holtzman, David A. Kaku, Yuen T. So, New-onset seizures associated with

human immunodeficiency virus infection: causation and clinical features in 100

cases. 1989 Jan, Volume 87, Issue 2, pages 173-77.

31. Ravindra Kumar Garg, HIV infection and seizures. Postgrad Med J, 1999 Mar, Volume

75, Issue885, pages- 387-390.

32. M Whiteman, L Espinoza et al, Central nervous system tuberculosis in HIV-infected

patients: clinical and radiographic findings. American Journal of Neuroradiology,

1995, Volume 16, Issue 6, 1319-1327.

33. MJ Popovich, RH Arthur and E Helmer, CT of intracranial cryptococcosis. American

Journal of Roentgenology, 1990, Volume 154, 603-606.

34. Jose Enique Cohen, Katharina Eger, Antonio Montero, Zvi Israel, Rapid spontaneous

resolution of acute subdural haematoma and HIV related cerebral atrophy: case

report. International Journal of Neurosurgery and Neurosciences, 1998 Sep, Volume

50, Issue 3, pages 241-244.

35. Irina Elovaara, Jukka Suni, Timo Tervo et al, CSF protein and cellular profiles in

various stages of HIV infection related to neurological manifestations. Journal of

Neurological Sciences, 1987 May, Volume 78, Issue 3, 331-342.

36. Lars-Magnus Andersson, Kaj Blennow et al, Increased cerebrospinal fluid protein tau

concentration in neuro-AIDS. Journal of Neurological Sciences, 1999 Dec, Volume-

171, Issue 2, pages 92-96.