Neuro-AIDS

Christian Kamallan
Neurology Department
Faculty of Medicine
Wijaya 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

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 : 3-10
3) Vago et al., AIDS. 2002;16:1925-8.

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
persons 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 infections
2. As a result of HIV related
malignancies
3. As a result of autoimmune disorders
4. 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 with

neuro involvement
Primary lymphoma (most common)
Kaposis 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 with

neuro involvement
Guillain-Barr 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
Bells 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

Acute viral illness

Asymptomatic

Aseptic meningitis

Chronic meningitis

Encephalitis

Minor Cognitive/motor Vacuolar myelopathy

ADC

Distal symmetrical
polyneuropathy

Time

Immuno-suppression

Secondary neurologic
complications

Opportunistic infections
Neoplasms
Vascular disease
Nutritional and
metabolic disorders
Drug toxicity

Time

Drug toxicity

Drug toxicity

Immuno-suppression

Immunological complications

AIDP
CIDP
Mononeuropathy
Myopathy

Time

Immuno-suppression

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 nonspecific 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 antiretrovirals, 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

DISTAL SYMMETRICAL
POLYNEUROPATHY ( 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

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 nave
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.

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:
TUBERCULOSIS
Clinical: Fever, headache, nucchal
rigidity, cranial neuropathy
Caveat: Meningitis due to atypical
species more likely to present as nonfocal 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 Xray 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 Kaposis
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 nondiagnostic 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

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