neuro hiv/aids objectives

NEURO HIV/AIDS Objectives

1. Review the various etiological agents that cause neurological disorders

2. Give key points when taking a history 3. Describe the clinical presentation of each

disorder 4. List the recommended diagnostics and

common findings for each disorder 5. Understand the treatment and

management of neurological disorders 6. Discuss preventive measures

Overview

Reported incidence Reported incidence ((16%16% to to 72%72%) ) of neurological of neurological abnormalities varies greatlyabnormalities varies greatly.. A wide range of neurological manifestations is A wide range of neurological manifestations is reportedreported: : cognitive defectscognitive defects, , focal deficitsfocal deficits, , painful feet painful feet syndromesyndrome, , encephalopathyencephalopathy.. Pathogens arePathogens are::

the HIV itselfthe HIV itself several several Ois Ois & & neoplasmsneoplasms drugsdrugs

While 5-year survival after the toxo episode was 8% in 1990-1993, it had climbed to 30 % by 1994-1996. This rate has risen to approximately 80 % since 1997 in countries where HAART is readily available.

1. Epidemiology of HIV/AIDS

INTERNATIONAL CENTRE FOR EYE HEALTH TEACHING SET NO.8 HIV/AIDS

Adults and Children Estimated to be Living with HIV/AIDS (June 2000)

Source UNAIDS / WHO

HIV and AIDS IN CANADA •58,929 from November 1985 up to June 30, 2005. •4,200 New HIV cases every year! • 33% HIV-positive Canadians don't know they are infected! • $36 million funding CIDA gave to HIV/AIDS initiatives in 2001-02 Source: Public Health Agency of Canada

Acute HIV Infection

12%Neuro Sx32%Diarrhea12%Thrush54%Myalgia/arthralgia13%Wt loss70%Rash14%HSM70%Pharyngitis27%N/V74%LAD32%Headache96%Fever

CDC 2002

Neuro: meningoencepalitis or aseptic meningitis; peripheral neuropathy or radiculopathy; facial palsy, Guillain-Barre syndrome; brachial neuritis; cognitive impairment or psychosis

• >12% of Primo Infection & “seroconversion” have neuro Sx! • Problems & Special Cases

• The "diagnostic window“ • Needle-stick injury or other occupational exposure

2. Human Immunodeficiency Virus (HIV) and AIDS

INTERNATIONAL CENTRE FOR EYE HEALTH TEACHING SET NO.8 HIV/AIDS

Major Pathogens

Protozoal infection Toxoplasma Gondii (toxoplasmosis) Mycobacterial infection M. tuberculosis (TB meningitis) Bacterial Strep pneumoniae, Neisseria meningitis (bacterial meningitis) Fungal infection Cryptococcus neoformans (cryptococcal meningitis) Viral infection Cytomegalovirus (CMV) Other: Progressive multifocal leukoencephalopathy (PML)

Primary CNS lymphoma HIV-associated dementia (HAD) Painful sensory and motor peripheral neuropathies Neurosyphilis

1515% % of patients have concurrent of patients have concurrent ((>>22) ) AIDSAIDS--related related CNS CNS OIsOIs..

ProtozoalProtozoal infection infection: : ToxoplasmaToxoplasma gondii gondii ((toxoplasmosistoxoplasmosis)) Presenting Signs and SymptomsPresenting Signs and Symptoms

reactivation of a latent infection

Usually: acute neurological syndrome Clinical symptoms may evolve quickly • Focal neurological deficits • Headache (severe, localized) • Seizures • personality changes, cognitive disorders • Fever • Confusion • Myalgia • Arthralgia

HE

> 85% seropositive for T. gondii antibodies.

PCR (blood or CSF) has little relevance

CSF values • Normal: 20-30% • Protein: 10-150/ml • WBC: 0-40 (monos)

An HIV-infected individual presenting with typical signs

and symptoms and normal cerebrospinal fluid findings should be put on treatment for toxoplasmosis. Response to therapy (within 2 weeks) then confirms the diagnosis.

Diagnostics

tachyzoites within pseudocysts (Grocott's silver)

•• 1 1//3 3 solitarysolitary, , 11//3 3 several several ((22--55) ) or or 11//3 3 multiplemultiple; ; deep or deep or juxtacorticaljuxtacortical lesions wlesions w//oedema oedema ; ; big big or smallor small..

•• 90%90% smooth smooth, , peripheral ring peripheral ring enhancementenhancement

••The more lesions there The more lesions there areare,, the more likely thethe more likely the

immunostaining

Unique FeaturesUnique Features, , CaveatsCaveats

One of the most common HIV-related neurological complications without HAART If patient does not receive maintenance therapy, disease will recur. Usually occurs when CD4<100 Check blood picture regularly for toxicity. Leukopenia, thrombocytopenia and rash are common. Folinic (not folic!) acid reduces the risk of myelosuppression. During treatment, patients should maintain a high fluid intake and urine output. Empirical treatment may be diagnostic, but any lesion that failed to improve after 2-4 weeks biopsy needed! Rare: chorioretinitis (vs CMV)

Mycobacterial Infection: M. tuberculosis (TB Meningitis)

Presenting Signs and Symptoms

Most common feature of extrapulmonary TB is cervical lymphadenopathy, but every organ can be involved.

Gradual onset of headache and decreased consciousness

• Low grade evening fevers • Night sweats, Weight loss • Neck stiffness, Kernig’s, etc • Cranial nerve palsies (III & IV !)

Tuberculoma (rare)

CSF Values

• Normal: 5-10% • Protein: High (40mg/dl-100 mg/dl) • WBC: 5-2000 (average is 60-70% monos) • Glucose: low (<20 mg/dl) • AFB smear : 20% (negative if “no bacteria” after 8 weeks) • PCR sensitivity:95% specificity 40-77%

Diagnostics

Unique featuresUnique features, , CaveatsCaveats

CD4<350, and if <100 circulating CD4 cells/µl, the risk of mortality is high. MAC is rare until <50 CD4s

MTB meningitis in up to 10% of patients who present with TB (from the rupture of a tuberculoma or blood-borne)

Always exclude cryptococcal meningitis by CSF microscopy (India ink stain)

Multidrug-resistant tuberculosis is rising (12-25% now!)

Bacterial Infection: Strep pneumoniae, Neisseria Meningitis (Bacterial Meningitis)


Symptoms tend to present within one week of infection. May be preceded by a prodromal respiratory illness or sore throat.

- Fever - Vomiting

- Headache - Malaise

- Stiff neck - Irritability

- Photophobia - Drowsiness - Coma

CSF Values

• leukocytosis • cerebrospinal fluid shows increased pressure • cell count (100 –10,000/mm3) • protein (>100 mg/dl) • decreased glucose (<40 mg/dl or <50% of the

simultaneous glucose blood level) • gram-stained smear of the spun sediment of the

CSF can reveal the etiologic agent

Diagnostics

Management and Treatment

Penicillin (24 million units daily in divided doses every 2-3 hours)

or Ampicillin (12 gr daily in divided doses every 2-3 hours)

or Chloramphenicol (4 to 6 grams IV/day). Treatment should be continued for 10 to 14 days.

Crystalline penicillin 2-3 mega units and

chloramphenicol 500-750 mg every 6 hours for 10-14 days


Often encountered during late stages of HIV disease. Prompt diagnosis and aggressive management and treatment ensure a quick recovery

Fungal Infection: Cryptococcus neoformans

(cryptococcal meningo-encephalitis)


Presentation usually nonspecific for > 1 month. • Protracted headache and fever may be the only signs • Nausea, vomiting, and stiff neck may be absent and

focal neurological signs are uncommon early on. • Signs of raised ICP? • Extraneural symptoms: pneumonitis, pleural effusions,

skin lesions (rare) and retinitis • Fever, malaise, nuchal pain signify a worse prognosis • Imaging may be unrevealing: cryptococcomas are rare!

Imaging?

LP !!!

CSF Values • Normal 20% • Culture (+) 95-100% • Protein 30-150/dl • WBC: 0-100 (monos) • Glucose decreased: 50-70mg/dl • Crypt Ag nearly 100% sensitive and specific

Diagnostics GMS stain

Cryptoccocal meningitis: CSF

India ink examination positive in > 80%!!!

Triple therapy effective (80% remission) but controversial (flucytosine only IV and is toxic)


If untreated, it is slowly progressive and ultimately fatal

CSF is negative in approximately 60 % of cases after two weeks of successful therapy (< 4 weeks!)

Most common life-threatening fungal infection in HIV/AIDS patients. Also the most common cause of meningitis in patients with HIV/AIDS in Africa and Asia.

Occurs most often in patients with CD4<50

It is better prevented than treated


Headache is secondary to fungal accumulation. Headache increases gradually over time and then follows a recurring pattern. It becomes harder to get rid of, and then becomes continuous. This is what the patient reports.

Requires lifelong suppressive treatment unless immune reconstitution occurs

If there is raised ICP, CSF drainage may become necessary. Steroids are useless here.

Viral Infection: Cytomegalovirus (CMV) Resenting Signs and Symptoms

Fever ± delirium, lethargy, disorientation, malaise, headache most common. Stiff neck, photophobia, cranial nerve deficits less common.

Usually no focal neurological deficits

Other manifestations of disseminated CMV infection are rare (15 %), and can affect every organ. Pneumonia, esophageal ulcers, colitis and encephalitis are most frequently involved. Sinusitis and myelitis may also occur.

Retinal exam to check for changes. Consult an “HIV-experienced” ophthalmologist!

CMV retinitis, characterized by creamy yellow white, hemorrhagic, full thickness retinal opacification, which can cause visual loss and lead to blindness if untreated; patient may be asymptomatic or complain of floaters, diminished acuity or visual field defects. Retinal detachment if disease is extensive

CMV serology (IgG almost always positive, IgM variable) is usually not helpful.

CMV PCR or a blood test for pp65 antigen to detect antibodies against a CMV-specific phosphoprotein may be more useful. CMV retinitis or a recurrence is unlikely with a negative PCR or pp65 result.

Diagnostics


HAART has dramatically improved prognosis. The previously required life-long daily infusions of ganciclovir or foscarnet via port, pumps and nursing service are luckily now a thing of the past. If there are relapses under oral valganciclovir, we recommend re-induction and maintenance therapy with foscarnet or possibly with cidofovir.

Unique featuresUnique features, , caveatscaveats

Evolution occurs in less than 2 weeks Mainly in untreated patients when CD4<100

Although any part of the retina may be involved, there is a predilection for the posterior pole; involvement of the optic nerve head and macula region is common

Characteristically involves the retinal vessels which are always abnormal in areas involved by retinitis. There is minimal or no accompanying uveitis

Rare but devastating illness pre HAART. Treatment is very expensive and usually not available. CMV management needs special care. Therefore, early referral is essential – leads to blindness in 30% patients

Viral Infection: Progressive mulltifocal leukoencephalopathy (PML)


Afebrile, alert, no headache Progressively impaired cognition & behaviour, speech, vision & motor function. Cranial nerve deficit and cortical blindness

JCV was named after the initials of the first patient in 1971 Seroprevalence is high (80 %); latent persistent infection must be assumed often. PML doesn’t always indicate the final stage of HIV infection

CT may be normal or MRI may show some diffuse asymmetrical demyelination PCR of CSF (not sera!) for detection of JC virus

sensitivity 80%; specificity 90% (in good hands) Definitive

diagnosis

Diagnostics

Luxol fast blue EM

ART can improve symptoms and prolong life. Foscarnet, interferon, immune stimulants, cytosine arabinoside and steroids failed!

Cidofovir and camptothecin being tested now The absolute priority should currently be to optimize ART


Unique FeaturesUnique Features, , CaveatsCaveats CD4<100 (but possible with ~200 CD4 T cells)

PML is very rare in the general community, but 2nd most common nowadays in AIDS patients.

Evolution occurs over weeks to months. Always fatal in the pre-HAART era, prognosis is still poor.

peripheral enhancement observed after “immune reconstitution inflammatory syndrome - IRIS” (PML’s ‘inflammatory phase’).

Although lesions are huge, every PML starts small: very discrete, localized, solitary lesions do not exclude the diagnosis! Must differentiate from HHV-6 or HIV encephalopathies.

Diagnosis of PML vs. MS

Typical of PML Clinical Tempo: Sub-acute Location: Sub-cortical, cerebellum

MRI Non-enhancing No mass effect Sub-cortical

CSF JCV DNA detectable

Differentiation vs. MS Clinical Tempo: Acute Location: ON, cord, and other localizations

MRI Gd enhancement Edema, mass effect Not only sub-cortical

CSF JCV DNA negative

Features Suggestive of

• Behavioral and neuropsychological alteration

• Cortical signs and symptoms • Retrochiasmal visual deficits • Hemiparesis • Marked cerebellar findings • Gait/limb abnormalities

• Diplopia • Paraesthesiae • Paraparesis • Optic neuritis • Myelopathy

Typical Clinical Presentation

• Over weeks • Progressive

• Over hours to days • Normally stabilize • May resolve even

spontaneously

Evolution

• Sub-Acute • Acute Onset PML MS

Clinical Features of MS and PML

Unique FeaturesUnique Features, , CaveatsCaveats

Primary CNS lymphoma


Afebrile w/Headache, mental status, personality or behavioral changes over several weeks. Focal and multifocal neuro deficits, seizures.

Severely immunocompromised, constitutional symptoms may mask the actual problem.

Cerebral lymphoma

CT Scan MRI Peri-ventricular in one or more sites Prominent edema, irregular and solid on enhancement.

CSF: • Normal;—30-50% • Protein—10-150/ml • WBC—0-100 (monos) • Cytology positive in <5% • Suspect with negative toxo IgG or failure to

respond to empiric toxo treatment

Diagnostics


There is no cytotoxic chemotherapy for this disease but a treatment attempt with IV MTX can be justified (3 g/m2 every 14 days with leucovorin rescue).

Irradiation (fractionated, 40 Gy total dose) can help some patients, but is considered palliative.

Dexamethasone 8 mg tid can help if raised ICP.

The decisive factor is the best possible immune reconstitution!


PCNSL is rare in the general community, but affects up to 10% of AIDS patients

CD4 <50 Typical end-stage complication of HIV disease EBV-associated in almost 100 % of cases.

HIV-associated dementia (HAD)

HIV encephalopathy (HIVE) AIDS dementia complex; AIDS dementia HIV-associated cognitive motor complex.


10-20% – decreased with HAART but now increasing due to increased life expectancy CD4 <200 Afebrile; general lethargy

Triad of cognitive, motor and behavioral dysfunction

CSF normal/decreased WBC w/ raised protein (OCB(+)!) subcortical dementia MMS not sensitive Memorial Sloan Kettering scale (Price 1988).

Diagnostics

HIV-E Differential diagnoses


Widely controversial and vastly unproven yet! Possible benefit from ARV agents that penetrate the CNS (zidovudine, lamivudine (high concentrations in ventricular CSF), nevirapine and indinavir)

Benefit of early AZT at higher dose for mild cases.

? selegeline, nimodipine, lexipafant and the antioxidant agent CPI-1189

HIVHIV--associated associated myelopathy myelopathy ((HIVHIV--MM))

Clinically progressing with less prominent or no cognitive decline. Cervical/ thoracic w/ lipid-laden macrophages “vacuolar myelopathy” May be sub-clinical. Mainly with advanced immunosuppression Diagnosis: only non-specific findings Treatment: Early observations of significant improvement with zidovudine monotherapy were later confirmed with HAART.

Neurologic AIDS Research Consortium

Other Neurological Syndromes Reported with HCV

• Demyelinating myelitis• Cord biopsy

– Macrophages– Perivascular lymphocytes– Loss of myelin– Reactive gliosis– No HCV antigen

• ?Immune mediated myelitis

Grewal, J N Sci, 2004

Painful Sensory and Motor Peripheral Neuropathies Presenting signs and symptoms

Burning pain and numbness in toes and feet, ankles, calves, fingers in more advanced cases Paraplegia Autonomic dysfunction Poor bowel/bladder control Dizziness secondary to postural hypotension Contact hypersensitivity in some cases Mild/moderate muscle tenderness Muscle weakness Later: Reduced pinprick/vibratory sensation; reduced or absent ankle/knee jerks Sweating

EMG / NCT show predominantly axonal neuropathy CPK usually elevated CSF - look for cytomegalovirus or herpes simplex virus infections—lymphomatous infiltration Spinal fluid to determine etiology Serum B12 and TSH Quantitative sensory testing or thermal thresholds may be helpful

Diagnostics


Exclude neurotoxic drugs, alcoholism, diabetes, B12 deficiency, thyroid problems and treat underlying causes if known.

Discontinue presumed neurotoxic medication (d4T, ddC, ddI, possibly also 3TC) often resolves only very slowly, therefore change treatment quickly!

Severe, progressive muscular weakness (d4T, ddI)

Provide proper nutrition and vitamin supplements

Treatments for neuropathies

HIV myopathies

• Myalgia, fatigue and raised CK are frequently found in HIV infection. • The diagnosis of probable myopathy requires weakness, muscle atrophy or myopathic features demonstrated by electromyography. • Treat w/ Prednisone or IvIg • Stop AZT

Neurosyphilis

Presenting Signs and Symptoms Can be asymptomatic

Headache, fever, photophobia, meningismus ± seizures, focal findings, cranial nerve palsies

Tabes dorsalis—sharp pains, parasthesias, decreased DTRs, loss of pupil response

General paresis— memory loss, dementia, personality changes, loss of pupil response

Meningovascular strokes, myelitis Ocular syphilis—iritis, uveitis, optic neuritis

CT Scan/MRI: Aseptic meningitis—may show meningeal enhancement General paresis—cortical atrophy, sometimes with infarcts

Meningovascular syphilis—deep strokes. Dementia?

CSF: Protein—45-200/ml WBCs—5-100 (monos) VDRL positive—sensitivity 65%; specificity 100% positive Serum VDRL and FTA-ABS are clue in >90%; false neg serum VDRL in 5-10% with tabes dorsalis or general paresis

Definitive diagnosisDefinitive diagnosis: : positive CSFpositive CSF, , VDRL VDRL ((found in found in 6060--70%70%))

Diagnostics


Give Aq penicillin G, 18-24 mil units/day x 10-14 days

Follow-up VDRL every 6 months until negative

Indications to re-treat: • CSF WBC fails to decrease at 6 months or CSF still

abnormal at 2 years • Persisting signs and symptoms of inflammatory

response at 3 months • Four-fold increase in CSF VDRL at 6 months

Failure of CSF VDRL of 1:16 to decrease by two-fold by 2 months or four-fold by 12 months


0.5% of all HIV/AIDS patients

Most common forms in HIV-infected persons are ocular, meningeal, and meningovascular

Some evidence that syphilis progresses more rapidly in the context of HIV infection, so that complications may occur at an unusually early phase.

Recommended that syphilis testing be offered to all in high prevalence areas because it is treatable in early stages, and has an accelerated course in HIV.

CD4<350

Lancet InfectLancet Infect Dis Dis 20042004; ; 44: : 456456––6666

Syphilis and HIVSyphilis and HIV: : a dangerous combinationa dangerous combination.. W A Lynn and SW A Lynn and S Lightman Lightman

Last slides after this brief

announcement ☺

http://www.unaids.org/

42

HIV Risk Factors

“Unprotected” sexual contact, since 1978Any “STD”, HPV/Pap, OCPs…

“Recreational” blood exposureIVDU, tattoos, cocaine straws, etc.

Receipt of tissue or blood productsRisk 1:60,000 / 1985 → 1:675,000 / 1996 (USA)

“PARTNER” with above risksPerson from high prevalence groupNote “6-month” negative window

43

Sexual Risk Assessment“Have you…?”

? Ever had sex since 1978 ?? Used condoms 100% ?

? Used oral contraceptives ?? Ever been pregnant ?

? Ever had:? A sexually transmitted infection ?? An abnormal Pap smear ?

? Had sex with men, women or both ?? Had sex vaginally, orally or rectally ?

Do you know the above for all of your partners ???

neuro hiv/aids objectives

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