neuro aids

Neuro-AIDS

Christian KamallanNeurology Department

Faculty of MedicineWijaya Kusuma University

33th Year of AIDS

World AIDS Day Dec 1, 2014

Principles of HIV Neurology

• Time Locking – Neurological complications are directly related to the duration of HIV disease, degree of advancement of HIV disease

• Parallel Tracking – Existence of multiple pathologies in different parts of the nervous system (cerebral, spinal cord, peripheral nerves)

• Layering – multiple complications in one part of the nervous system

• Unmasking – previously compensated deficits may be unmasked by occurrence of an additional insult

Presentations

• Vary wildly• Often multiple pathologies on different

courses• Often hard to diagnose, especially if already

treated empirically• May not be HIV related!

• 10-15% of AIDS patients present with neurologic symptoms only

• 35-50% of AIDS patients have neurologic symptoms during life1,2

• 75-90% have neuropathologic abnormalities at death3

1) Brouwman et al, Neurology. 1998 ; 50:1814-20. 2) McArthur J Neuroimmunol 2004; 157 : 3-103) Vago et al., AIDS. 2002;16:1925-8.

HIV and the Nervous System

HIV enters the nervous system early, at thetime of initial infection, and may

immediately cause symptoms, or maycause symptoms any time during the

person’s lifetime.

Neurological Complications of AIDS

• Common– Pathological findings (>90%)– Clinically significant problems (40-70%)

• Affecting all parts of the nervous system• Multiple pathological processes

Common neurological condition in non-HIV patients can also be found in HIV patients

Neuropathogenesis

Neurological impairment can occur through several routes:1. As a result of opportunistic infections2. As a result of HIV related malignancies3. As a result of autoimmune disorders4. Directly related to the action of HIV (can be

CNS or PNS related)5. Multifactorial / drug related / not understood

1. Opportunistic infections with CNS involvement

• Cerebral toxoplasmosis• PML (Progressive Multifocal Leucoencephalopathy)• Meningitis (Cryptococcyl meningitis, TB

meningitis)• Encephalitis (CMV, HSV, VZV)• Neurosyphilis

2. HIV related malignancies withneuro involvement

• Primary lymphoma (most common)• Kaposi’s sarcoma with cerebral involvement

(rare)• Multiple lymphomas with either CNS

(including spinal cord compression) or rarely PNS involvement (ie secondary CNS/PNS lymphomas)

3. Autoimmune disorders withneuro involvement

• Guillain-Barré Syndrome (GBS)• Inflammatory Demyelinating Polyneuropathy

(IDP)

4. Direct action of HIV

• AIDS Dementia Complex (ADC) or HIV Associated Dementia (HAD)

• Distal Symmetrical Polyneuropathy (DSPN)• Mononeuritis multiplex• Vacuolar Myelopathy• ?Wasting Syndromes (although cardiac system

now implicated more)

5. Multifactorial / drug related / poorly understood

• “Neuromuscular weakness syndrome”• Role of drugs in peripheral neuropathy

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.

Clinical Syndromes

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

Clinical Syndromes

• SPINAL CORD SYNDROMES– Transverse myelitis– Progressive myelopathy

Clinical Syndromes

• 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

–Sero-conversion–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

Direct action of HIV in the CNS

• HIV can easily cross the blood brain barrier• HIV thought to chiefly target phagocytic

macrophages, but also astrocytes, microglia and monocytes

• Do not affect directly affect CNS neurons or oligodendrocytes

Theories of how HIV crosses the blood brain barrier

Different theories including:• Infected monocytes and lymphocytes traffic

across the BBB as part of their normal immune surveillance role

• Blood brain barrier weakened by this process – leading to increased trafficking

• Monocytes differentiate in to microglia and macrophages

Theories of how HIV crosses the blood brain barrier

• Also theory that meningeal macrophages infiltrate the CNS through the CSF compartment

• May also be a combination of these processes

• Neurotoxic viral proteins released in to CNS by HIV infected cells resulting in neuronal injury / death

How Does HIV Affect the Nervous System?

• HIV indirectly destroys cells in the nervous system

Kaul, Garden & Lipton (2001). Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410, 988-994.

Progression of HIV Infection of the Nervous System

HIV neg HIV positive, but otherwise asymptomatic

Constitutional Symptoms & Severe Immunosuppression,

but no OIs

AIDS

Acute

Chronic Meningitis

HIV-Associated Neurocognitive Disorders

Schematic diagram of HIV-related diseases that affect central nervous system (solid border) and peripheral nervous system (dotted border). Adapted from Johnson et al., 1988.

Pathological Processes

Primary result of HIV

Secondary neurologic complications

Immunological complications

Primary result of HIV

Time Immuno-suppression

Acute viral illnessAseptic meningitis

Encephalitis

AsymptomaticChronic meningitis

Minor Cognitive/motor

ADC

Vacuolar myelopathy

Distal symmetrical polyneuropathy

Secondary neurologic complications


Opportunistic infections

Neoplasms

Vascular disease

Nutritional and metabolic disorders

Drug toxicityDrug toxicityDrug toxicity

Immunological complications


CIDP

Myopathy

Mononeuropathy

AIDP

HIV - ASSOCIATED DEMENTIA

• Classification SystemI. 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


– 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


• 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

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


• 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


• 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.


• 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: 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

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.

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.

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

The Two-Minute HIV NeuroScreen• Abnormality Possible Diagnosis• Memory loss, slow mentation Dementia• Cauda equina syndrome cmv radiculitis• Leg weakness, sensory level Myelopathy, epidural abscess• Ascending paresis Guillain-Barre syndrome, lactic acidosis• Pain in feet, absent ankle jerks Sensory neuropathy• Seizures, focal deficits Toxoplasmosis• Slowly progressive deficits Progressive multifocal

leukoencephalopathy• Cranial neuropathies, intracranial Cryptococcal meningitis

pressure elevation

Thank you for your attention

http://hivinsite.ucsf.edu/InSite?page=kb-04-01-02

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