Hiv Infection And The Nervous System

HIV INFECTION AND THE NERVOUS SYSTEM

Carolyn Barley Britton, M.D.

Associate Professor of Clinical Neurology

Columbia University

College of Physicians & Surgeons

HIV and the Nervous System

HIV enters the nervous system early, at the

time of initial infection, and may

immediately cause symptoms, or may

cause symptoms any time during the

person’s lifetime.


• All levels of the neuraxis are potential sites of involvement:

» Meninges» Brain» Spinal cord» Cranial and peripheral nerves» Autonomic nervous system» Muscle


• Multiple areas of the nervous system may be involved simultaneously or sequentially.

• Without anti-retroviral treatment, up to 80% of patients are symptomatic and for 30%, neurologic symptoms are the initial clinical problem.

• Neurologic syndromes may be the sole clinical problem or cause of death.

HIV and the Nervous SystemClinical Syndromes

• BRAIN SYNDROMES– Meningitis– Dementia– Stroke– Seizures– Degenerative Disorders


• SPINAL CORD SYNDROMES– Transverse myelitis– Progressive myelopathy


• NERVE AND MUSCLE– Bell’s palsy– Hearing loss– Peripheral neuropathies– Autonomic neuropathy– Myopathy


• The differential diagnosis of a neurologic syndrome is derived from consideration of:– History– Clinical findings or localization– HIV disease stage

– Seroconversion– Early disease– Late disease


• Causes or etiologic considerations for neurologic disorders include:– Primary or HIV-related: Acute or chronic– Secondary opportunistic infections or

malignancy– Metabolic or nutritional derangements– Complications of medical therapy– Unrelated to HIV infection


• Primary or HIV-Related Syndromes of Acute Infection– Meningitis or encephalitis– Seizures, generalized or focal– Transverse myelitis– Cranial or peripheral neuropathy ( Bell’s palsy

or Guillain-Barre-type neuropathy )– Polymyositis +/- myoglobinuria


• Primary or HIV-related Syndromes of Chronic Infection: common disorders – Meningeal pleocytosis +/- symptoms– Dementia and / or psychiatric disturbances

(AIDS dementia complex, ADC )– Strokes– Seizures– Progressive myelopathy– Neuropathy or myopathy


• Primary or HIV-related Neurologic Syndromes of Chronic Infection: Infrequent or rare– Cerebellar ataxia– Multisystem degeneration– Anterior horn cell disease


• PRIMARY SYNDROMES: MENINGITIS– May occur in acute infection or seroconversion

or in the chronic stage of HIV infection– Clinically indistinguishable from non-HIVcases– Symptoms include fever, malaise, stiff neck,

and photophobia– HIV is the usual cause in early infection;

opportunistic infection, malignancy in late infection.


• PRIMARY SYNDROMES: MENINGITIS• Laboratory evaluation

• CSF: lymphocytic pleocytosis; normal glucose and normal or slightly elevated protein

• HIV serology: may be negative; repeat at 3 and 6 months

• HIV antigen and viral determination positive• T cell studies: normal or borderline• EEG, CT or MRI of brain normal or non-

diagnostic


• PRIMARY SYNDROMES: MENINGITIS• Outcome:

• Clinical course is self-limited, without sequelae

• Cranial neuropathy, typically Bell’s palsy, may co-exist

• After recovery, underlying HIV may be asymptomatic


• PRIMARY SYNDROMES: BELL’S PALSY– May be uni- or bi-lateral– Syndrome of seroconversion or early infection– CSF may show lymphocytic pleocytosis– HIV Serology may be negative– Outcome is similar to non-HIV Bell’s palsy

with recovery the rule.


• PRIMARY SYNDROMES: ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY ( AIDP )

– Ascending limb weakness, sensory loss and areflexia

– Differentiated from Guillain - Barre, non-HIV, by lymphocytic CSF pleocytosis

– Recovery dependent on severity; may respond to plasmapharesis or intravenous immune globulin


• PRIMARY SYNDROMES: TRANSVERSE MYELITIS– Limb weakness, sensory loss, bowel and

bladder involvement below a sensory level, usually thoracic

– CSF with lymphocytic pleocytosis– May respond to plasmapharesis, intravenous

steroids or immune globulin with outcome dependent on severity of paresis.


• PRIMARY SYNDROMES: POLYMYOSITIS– Muscle pain and proximal weakness– +/- myoglobinuria– Elevated creatine kinase– Myopathic changes on EMG– Self - limited or steroid - responsive; rare as

seroconversion or early HIV syndrome


• PRIMARY SYNDROMES OF CHRONIC INFECTION: HIV - ASSOCIATED DEMENTIA, Classification System

• I. Severe manifestations– A. HIV-1-Associated Dementia Complex– B. HIV-1-Associated Myelopathy– II. Mild manifestations– HIV-1-Associated minor Cognitive/Motor

Disorder


• AIDS Dementia: Clinical features– Slowed processing and reaction times

(subcortical features indicating white matter involvement)

– Memory loss, subjective if early– Psychiatric symptoms such as anxiety,

psychosis or mania– May co-exist with myelopathy or peripheral

neuropathy


• AIDS Dementia: Laboratory Findings– Risk increases with disease severity, i.e., more

common in AIDS, CD4 < 200– Cerebrospinal fluid: normal or non-specific

pleocytosis , normal glucose and protein. CSF gamma-globulin often elevated

– CT/MRI: cortical atrophy, ventricular dilatation, white matter rarefaction on CT, T2 signal hyperintensity on MRI


• AIDS Dementia: Differential Diagnosis– Toxic/metabolic factors: medication; hypoxia,

electrolyte disturbance, B-12 deficiency– Secondary opportunistic infection– Secondary malignancy– Unrelated to HIV


• AIDS Dementia: Evaluation– Stage infection with CD4 and viral load – CBC, electrolyte and hepatic panel, serum RPR

or FTA, B12 level, thyroid function studies, arterial blood gas where indicated

– Lumbar puncture – Blood culture for MAI, CMV, fungus– MRI of brain +/- gadolinium


• AIDS Dementia: Treatment– Highly active anti-retroviral treatment may

have reduced incidence of dementia– Clinical trials ongoing to evaluate other

potential therapies


• PROGRESSIVE MYELOPATHY– Clinical: Progressive spastic leg weakness,

impotence and sphincter involvement. Dementia or peripheral neuropathy may co-exist

– Diagnosis: Based on exclusion of other causes. Evaluation includes MRI or myelography of spine, B12 level, lumbar puncture for RPR or VDRL and oligoclonal bands


• PROGRESSIVE MYELOPATHY– Treatment: No known effective treatment.

Anecdotal reports of response to anti-retrovirals, immune globulin or supplemental parenteral B12


• MYOPATHY OF CHRONIC INFECTION– Clinical: progressive proximal limb weakness– Laboratory: elevated creatine kinase;

myopathic features on EMG; +/- myoglobinuria– Diagnosis: muscle biopsy– Causes: Drug treatment (AZT); HIV;

secondary infection– Treatment: discontinue AZT; steroids or

plasmapharesis; treat infection


• NEUROPATHIES OF CHRONIC HIV INFECTION– Distal symmetrical polyneuropathy– Inflammatory demyelinating polyneuropathy– Mononeuritis multiplex– Isolated mononeuropathy– Progressive polyradiculopathy– Autonomic neuropathy


• DISTAL SYMMETRICAL POLYNEUROPATHY ( DSPN )

• Clinical: Painful paresthesias of feet and soles, shooting leg pains, numbness; weakness, subjective or mild

• Stocking-glove sensory loss, decreased vibratory sense in ankles, normal position sense, absent or reduced ankle jerks


• DISTAL SYMMETRICAL POLYNEUROPATHY (DSPN)

– Most common neuropathy of HIV infection and may be disabling

– Prevalence increases with disease stage, most prevalent in chronic HIV infection or advanced disease

– Concurrent conditions may include myelopathy, dementia, constitutional symptoms and weight loss


• DSPN: DIFFERENTIAL DIAGNOSIS– HIV- related– Drug or treatment related– Metabolic or Nutritional disorder– Secondary infection – Unrelated to HIV illness


• DSPN: ETIOLOGY– Infectious: HIV, CMV, Hepatitis virus, MAI,

other infections– Nutritional: B12 deficiency, Acetyl carnitine

deficiency– Auto-immune: Anti-sulfatide, anti-Mag and

other auto-antibodies– Neurotoxic drugs: Antiretrovirals, INH,

chemotherapy, others


• AUTONOMIC NEUROPATHY– Clinical : Orthostatic hypotension; impotence,

diarrhea– Etiology: Presumed HIV-related sympathetic

ganglioneuropathy– Important as potential cause of sudden cardiac

arrest during procedures


• PROGRESSIVE POLYRADICULOPATHY• Clinical: Progressive paraparesis, areflexia,

urinary retention, ascending sensory loss• Etiology: Cytomegalovirus• Diagnosis: Polymorphonuclear pleocytosis may

be present in cerebrospinal fluid; EMG/NCV, acute denervation; CSF PCR and positive blood cultures help in diagnosis.


• NEUROPATHY IN HIV INFECTION: EVALUATION– Stage disease: CD4 count; viral load– Family History– Environmental or toxic exposure– Other: Tick bite or exposure risk; malnutrition

and weight loss– Medication history


• NEUROPATHY IN HIV INFECTION: EVALUATION– Serology: Cytomegalovirus (CMV), Lyme,

Hepatitis, MAG, sulfatide, GM1 ganglioside– Cultures: Blood for CMV, MAI; rectal and

throat swab for CMV– Other: B12, thyroid function, heavy metals


• NEUROPATHY IN HIV INFECTION: EVALUATION– Cerebrospinal fluid: cell count; glucose;

protein; VDRL; cultures for bacteria, fungus, viruses and acid fast bacilli (AFB, includes MAI); Lyme serology. Polymerase chain reaction (PCR) for CMV, Lyme or AFB as indicated.

– Electromyography, nerve conduction; nerve biopsy in select cases


• NEUROPATHY IN HIV INFECTION: TREATMENT– Immune therapy: useful for AIDP/CIDP and

may control disabling pain of DSPN• Plasmapharesis• Immune globulin*• Steroids

*preferred treatment


• NEUROPATHY AND HIV INFECTION: TREATMENT– Pain treatment

• Anticonvulsants: Carbamazepine, phenytoin, gabapentin, lamotrigine

• Tricyclic antidepressants: amitriptyline, nortriptyline

• Mexilitine• Opioids


• NEUROPATHY IN HIV INFECTION: TREATMENT– Neuropathy due to secondary infection (CMV,

MAI or Lyme) responds to specific anti-viral or antibiotic therapy

– Failed therapies: Peptide T; nerve growth factor


• SECONDARY NEUROLOGIC SYNDROMES IN CHRONIC HIV INFECTION:– Etiology: Opportunistic infection ( viral,

fungal, bacterial or parasitic ) or malignancy– Prevalence has declined because of more potent

anti-retroviral therapy and prophylaxis– Clinically important in medication naïve and

treatment failures


• MENINGITIS IN CHRONIC HIV INFECTION• Clinical: Fever, headache, nucchal rigidity,

mental confusion; cranial neuropathy in chronic basilar meningitis such as cryptococcus or mycobacterial. Stroke syndromes or mass lesions may occur.


• MENINGITIS IN CHRONIC HIV INFECTION • Etiology

• Viral: CMV, HSV, VZV, EBV, Hepatitis• Fungal: Cryptococcus, Histoplasma,

Coccidioides, Candida• Bacterial: Listeria, T. pallidum, pyogenic

bacteria (Salmonella, S. aureus), atypical or conventional mycobacteria

• Neoplasm: Lymphoma


• MENINGITIS IN CHRONIC HIV INFECTION: EVALUATION– Stage HIV infection: CD 4 count; viral load– Blood culture: bacteria,including Listeria;

atypical mycobacteria (MAI); fungus; viral.– Serology: RPR or FTA, CMV, Epstein Barr

virus, hepatitis, Lyme, toxoplasmosis. Cryptococcal antigen in serum.


• MENINGITIS IN CHRONIC HIV INFECTION: EVALUATION– Cerebrospinal fluid: Cell count; glucose;

protein; VDRL; cultures for bacteria, AFB and MAI, fungus, virus; Lyme serology; cryptococcal antigen; PCR as indicated for AFB, Lyme, CMV, HSV.

– PPD with controls


• MENINGITIS: NEUROSYPHILIS– Clinical: Asymptomatic; headache; stroke– Laboratory: Positive serology in blood (RPR or

FTA) and spinal fluid (VDRL). CSF otherwise normal or pleocytosis, elevated protein.

– Caveat: In acute syphilis with HIV infection, seroconversion may be delayed, resulting in false negative syphilis serology


• MENINGITIS: NEUROSYPHILIS– Treatment: Penicillin G 24 million units in

divided dose per 24 hours X 24 hours.– Outcome: Response is similar to non-HIV

infected. Follow serology after treatment, monthly for three months, then every three months for a year. If titer rises, repeat LP and re-treat for relapse.


• MENINGITIS: CRYPTOCOCCAL– Clinical: Fever, headache, nucchal rigidity,

cranial neuropathy– Laboratory: CSF lymphocytic pleocytosis, low

glucose, elevated protein• Organism cultured from CSF +/- sputum,

blood• Antigen detected in CSF and blood


• MENINGITIS: CRYPTOCOCCAL• Treatment: Amphotericin B +/- flucytosine;

fluconazole; itraconazole.• Outcome: Dependent on clinical severity pre-

treatment. Coma associated with high mortality. Long-term suppression necessary after acute therapy.


• MENINGITIS: TUBERCULOSIS– Clinical: Fever, headache, nucchal rigidity,

cranial neuropathy– Caveat: Meningitis due to atypical species

more likely to present as non-focal confusional state or encephalopathy. Stroke or focal syndromes with conventional species may be due to vasculitis or mass lesion (tuberculoma)


• MENINGITIS: TUBERCULOSIS

– Laboratory:

• CSF - lymphocytic pleocytosis; low glucose; elevated protein. PCR may be useful.

• MRI brain with gadolinium: meningeal enhancement especially basal; some cases, infarct or mass lesions (tuberculomas)

• PPD may be negative if anergic; chest X-ray may be normal

• Screen for extra-CNS TBC, e.g. bone, liver, lung


• MENINGITIS: TUBERCULOSIS– Treatment: Four drug regimen - Isoniazid,

rifampin, ethambutol, pyrazinamide ( streptomycin, an alternate if necessary ) for 18 to 24 months, adjusted for culture results.

– Corticosteroids increased intracranial pressure, incipient herniation.

– Pyridoxine supplement to prevent INH neuropathy


• MENINGITIS: CYTOMEGALOVIRUS– Clinical: subacute, progressive confusional

state; meningeal symptoms or signs may be minimal or mild

– Laboratory: CSF mixed pleocytosis without distinguishing features, normal glucose, normal or slightly elevated protein; PCR may help in diagnosis. Blood cultures usually positive.


• MENINGITIS: CYTOMEGALOVIRUS– MRI of brain +/-gadolinium: meningeal

enhancement; periventricular hyperintensities or enhancement.

– Treatment: Ganciclovir; foscarnet; cidofovir.– Outcome: Treatment successful if diagnosis is

timely.


• FOCAL SYNDROMES AND MASS LESIONS– Viral: Herpes simplex; Varicella zoster;

progressive multifocal leukoencephalopathy– Fungal: Abscess due to Cryptococcus,

Candida, Zygomycetes, Histoplasma, Aspergillus


• FOCAL SYNDROMES AND MASS LESIONS– Bacterial: Abscess due to pyogenic bacteria,

mycobacteria (tuberculoma), Listeria, Nocardia– Parasitic: Trypanosoma cruzei; Taenia solium;

toxoplasmosis– Neoplasm: Primary or metastatic lymphoma;

glioma; metastatic Kaposi’s sarcoma


– TOXOPLASMOSIS• Clinical: Confusion, focal signs, seizures.

Most common mass lesion.• Laboratory: Positive serum serology. CSF

is non-diagnostic but PCR positive in up to 70%.

• MRI brain +/- gadolinium: enhancing lesions with mass effect, typically involving deep structures.


• TOXOPLASMOSIS– Treatment: sulfadiazine/pyrimethamine;

clindamycin/ azithromycin– Outcome: Usually excellent. Suppresive

therapy indicated after acute treatment.


• PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY– Clinical: Progressive focal signs; seizures rare– Laboratory: CSF is normal; PCR positive in

70%– MRI of brain +/- gadolinium: non-enhancing

T2 signal lesion, hypodense on CT.


• PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY– Treatment: Antiretroviral therapy sometimes

effective in treatment naïve patients. Anecdotal reports of response to cytosine arabinoside, cidofovir and interferon alpha.

– Outcome: Rare spontaneous stabilization; if no response to therapy, death in 3 to 6 months


• LYMPHOMA– Cllinical: focal signs, seizures, cranial

neuropathy or confusional state– Laboratory: CSF is usually non-diagnostic but

may show tumor cells indicating seeding.– MRI of brain +/- gadolinium: single or

multiple enhancing lesions that may have similar appearance to toxoplasmosis


• LYMPHOMA– Diagnosis: Brain biopsy – Treatment: Whole brain radiotherapy;

intrathecal chemotherapy for relapse– Outcome: Without treatment, 1 to 2 month

survival. Improved response to treatment and more prolonged survival with highly active anti-retroviral therapy.


• BRAIN BIOPSY FOR CEREBRAL MASS: INDICATIONS– Solitary lesions– Negative serum serology for toxoplasmosis– No clinical or radiographic response to one

week of toxoplasmosis treatment– CSF PCR is helpful only when positive;

negative result does not exclude a potential agent, except for Herpes simplex


• NUTRITIONAL DISORDERS AND COMPLICATIONS OF MEDICAL TREATMENT– Nutritional: vitamin deficiency states -

thiamine, folic acid, glutathione, B12 – Drug toxicity: myopathy due to AZT;

neuropathy due to ddI, ddC and other anti-retrovirals, INH

Hiv Infection And The Nervous System

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