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 System Clinical 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.

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

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

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

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)

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

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

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