HIV INFECTION AND THE NERVOUS SYSTEM
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Slide 1 :
HIV INFECTION AND THE NERVOUS SYSTEM Carolyn Barley Britton, M.D. Associate Professor of Clinical Neurology Columbia University College of Physicians & Surgeons
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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.
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HIV and the Nervous System All levels of the neuraxis are potential sites of involvement: Meninges Brain Spinal cord Cranial and peripheral nerves Autonomic nervous system Muscle
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HIV and the Nervous System 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.
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HIV and the Nervous System Clinical Syndromes BRAIN SYNDROMES Meningitis Dementia Stroke Seizures Degenerative Disorders
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HIV and the Nervous System Clinical Syndromes SPINAL CORD SYNDROMES Transverse myelitis Progressive myelopathy
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HIV and the Nervous System Clinical Syndromes NERVE AND MUSCLE Bell’s palsy Hearing loss Peripheral neuropathies Autonomic neuropathy Myopathy
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HIV and the Nervous System 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
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HIV and the Nervous System 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
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HIV and the Nervous System 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
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HIV and the Nervous System 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
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HIV and the Nervous System Primary or HIV-related Neurologic Syndromes of Chronic Infection: Infrequent or rare Cerebellar ataxia Multisystem degeneration Anterior horn cell disease
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HIV and the Nervous System 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.
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HIV and the Nervous System 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
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HIV and the Nervous System 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
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HIV and the Nervous System 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.
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HIV and the Nervous System 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
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HIV and the Nervous System 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.
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HIV and the Nervous System 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
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HIV and the Nervous System 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
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HIV and the Nervous System 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
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HIV and the Nervous System 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
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HIV and the Nervous System AIDS Dementia: Differential Diagnosis Toxic/metabolic factors: medication; hypoxia, electrolyte disturbance, B-12 deficiency Secondary opportunistic infection Secondary malignancy Unrelated to HIV
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HIV and the Nervous System 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
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HIV and the Nervous System AIDS Dementia: Treatment Highly active anti-retroviral treatment may have reduced incidence of dementia Clinical trials ongoing to evaluate other potential therapies
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HIV and the Nervous System 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
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HIV and the Nervous System PROGRESSIVE MYELOPATHY Treatment: No known effective treatment. Anecdotal reports of response to anti-retrovirals, immune globulin or supplemental parenteral B12
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HIV and the Nervous System 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
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HIV and the Nervous System NEUROPATHIES OF CHRONIC HIV INFECTION Distal symmetrical polyneuropathy Inflammatory demyelinating polyneuropathy Mononeuritis multiplex Isolated mononeuropathy Progressive polyradiculopathy Autonomic neuropathy
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HIV and the Nervous System 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
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HIV and the Nervous System 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
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HIV and the Nervous System DSPN: DIFFERENTIAL DIAGNOSIS HIV- related Drug or treatment related Metabolic or Nutritional disorder Secondary infection Unrelated to HIV illness
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HIV and the Nervous System 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
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HIV and the Nervous System AUTONOMIC NEUROPATHY Clinical : Orthostatic hypotension; impotence, diarrhea Etiology: Presumed HIV-related sympathetic ganglioneuropathy Important as potential cause of sudden cardiac arrest during procedures
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HIV and the Nervous System 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.
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HIV and the Nervous System 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
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HIV and the Nervous System 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
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HIV and the Nervous System 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
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HIV and the Nervous System NEUROPATHY IN HIV INFECTION: TREATMENT Immune therapy: useful for AIDP/CIDP and may control disabling pain of DSPN Plasmapharesis Immune globulin* Steroids *preferred treatment
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HIV and the Nervous System NEUROPATHY AND HIV INFECTION: TREATMENT Pain treatment Anticonvulsants: Carbamazepine, phenytoin, gabapentin, lamotrigine Tricyclic antidepressants: amitriptyline, nortriptyline Mexilitine Opioids
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HIV and the Nervous System 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
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HIV and the Nervous System 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
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HIV and the Nervous System 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.
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HIV and the Nervous System 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
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HIV and the Nervous System 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.
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HIV and the Nervous System 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
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HIV and the Nervous System 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
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HIV and the Nervous System 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.
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HIV and the Nervous System 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
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HIV and the Nervous System 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.
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HIV and the Nervous System 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)
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HIV and the Nervous System 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
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HIV and the Nervous System 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
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HIV and the Nervous System 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.
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HIV and the Nervous System MENINGITIS: CYTOMEGALOVIRUS MRI of brain +/-gadolinium: meningeal enhancement; periventricular hyperintensities or enhancement. Treatment: Ganciclovir; foscarnet; cidofovir. Outcome: Treatment successful if diagnosis is timely.
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HIV and the Nervous System FOCAL SYNDROMES AND MASS LESIONS Viral: Herpes simplex; Varicella zoster; progressive multifocal leukoencephalopathy Fungal: Abscess due to Cryptococcus, Candida, Zygomycetes, Histoplasma, Aspergillus
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HIV and the Nervous System 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
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HIV and the Nervous System 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.
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HIV and the Nervous System TOXOPLASMOSIS Treatment: sulfadiazine/pyrimethamine; clindamycin/ azithromycin Outcome: Usually excellent. Suppresive therapy indicated after acute treatment.
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HIV and the Nervous System 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.
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HIV and the Nervous System 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
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HIV and the Nervous System 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
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HIV and the Nervous System 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.
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HIV and the Nervous System 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
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HIV and the Nervous System 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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