1

Neurologic Diseases and HIV

HAIVNHarvard Medical School AIDS

Initiative in Vietnam

2

Learning Objectives

By the end of this session, participants should be able to:

Outline the 2 most common causes of headache and fever in PLHIV

Describe how to diagnose, including potential differential diagnoses, a focal neurological deficit

Describe causes and treatment for peripheral neuropathy in PLHIV

3

I. Headache

4

Differential Diagnoses of Headache and Fever

Meningitis: Cryptococcal

Meningitis Tuberculosis

Meningitis Bacterial Meningitis

• Strep pneumoniae, Neisseria meningitidis

Syphilitic Meningitis

Other Infectious Causes:

Toxoplasma Encephalitis

Brain Abscess (Staph aureus especially with IDU)

Sinusitis (bacterial or viral)

Herpes Meningoencephalitis

5

Cryptococcal Meningitis

Occurs in advanced AIDS: CD4<100 Clinical manifestations:

• Headache• Fever• Nuchal rigidity (only 25%)• Vomiting• Confusion • Blurred vision, photophobia

Often associated with elevated intracranial pressure

6

Cryptococcus Neoformans

Disseminated disease may occur• Fungal pneumonias • Skin lesions

10-40% of patients with disseminated cryptococcal disease have no neurological symptoms

7

Cryptococcus Meningitis: Diagnosis (1)

Lumbar Puncture: High CSF pressure WBC often not elevated (usually < 50

cells/μl) Glucose normal to low Protein normal to high

8

Cryptococcus Meningitis: Diagnosis (2)

Positive CSF India Ink in 75% Cryptococcal Antigen (CRAG)

• CSF > 90% positive• Serum > 99% positive

9

Cryptococcus Meningitis:Management

Treatment Dosage

Standard Treatment• Amphotericin B: 0.7-1mg/kg/day

x 14 days, then• Fluconazole 800-900 mg/day for

8 weeks

If symptoms are mild or if amphotericin is not available or not tolerated

• Fluconazole 800-900 mg/day for 8-10 weeks

Maintenance therapy• Fluconazole 150-200 mg/day

until on ARV with CD4 > 200 for 6 months

Vietnam MOH, HIV/AIDS Treatment Guidelines, 2009

10

Cryptococcus Meningitis:Management of High Intracranial Pressure (1)

Normal pressure < 20 cm/H2O (200 mm/H2O)

Elevated pressure causes severe headache and results in increased mortality and morbidity

Visual loss as consequence of high pressure

11

Cryptococcus Meningitis:Management of High Intracranial Pressure (2)

Daily lumbar punctures (LP) Each time remove 15-20 CC CSF or until

the patient’s headache improves Mannitol and corticosteroids not effective

for lowering pressure

12

Tuberculosis Meningitis

Common in HIV, slow chronic onset is usual Typical symptoms: fever, headache,

confusion May be focal signs or cranial nerve palsies

due to space occupying lesions and/or cerebral mass effect

Often other features of TB • examine chest and lymph nodes

Main differential is cryptococcal meningitis

13

TB Meningitis: Diagnosis

CSF: Pressure may be

raised Lymphocytosis or

mixed cells in CSF Typically:

• Protein very high (2-6 g/dL)

• Low glucose (<45 mg/dL)

AFB are difficult to find in CSF

Perform India Ink staining to help exclude or confirm cryptococcal meningitis

Look for TB elsewhere in body by CXR, sputum, and aspiration of lymph nodes where appropriate

14

TB: National Treatment Protocol

Induction Phase2 months

Maintenance Phase

MOH Protocol SRHZ HE x 6 months

Alternate regimens for HIV patients* (S)ERHZ RH x 4 months

Alternate regimens for HIV patients with severe TB disease*

SRHZE

HRZE x 1 month, then

H3R3E3 x 5 months

9-12 month regimens recommended

for TB meningitis

15

TB Meningitis Treatment: Steroids

Concurrent steroid treatment reduces mortality by 31%

Doses:Thwaites, NEJM, 2004; CDC, MMWR 58:RR-4, 2009

Medication Dosing

Dexamethasone • 0.3-0.4 mg/kg/day x 1 week • then taper over 5-7 weeks

Prednisone • 1 mg/kg/day x 3 wks • then taper over 3-5 wks

or...

16

II. Focal Neurological Deficit

17

Focal Neurologic Deficit

Common causes in HIV:Toxoplasma encephalitisTuberculomaProgressive Multifocal Leukoencephalopathy (PML)Primary CNS lymphomaAbscess

• Bacterial brain abscess in active IDUs• Cryptococcoma

Stroke

18

Tuberculoma

Less common than meningitis, but should be considered in any patient with a history of TB

Lesions may present as single or multiple mass lesions

Look for TB elsewhere in body by CXR, sputum, etc

19

Tuberculomas

20

Cerebral Toxoplasmosis

Seen in patients with CD4<100 Manifestations:

• Focal neurological signs (unilateral paralysis)

• Generalized neurological signs (confusion, epilepsy, coma, etc.)

• Meningeal signs are rare

21

Cerebral Toxoplasmosis – Diagnosis (1)

MRI of cerebral toxoplasmosis showing 2 ring enhancing lesions – “lighting up” with intravenous contrast

22

Cerebral Toxoplasmosis – Diagnosis (2)

CT scan of brain done without intravenous contrast showing edema around multiple lesions

23

Cerebral Toxoplasmosis: Treatment

Treatment Type Medication Regimen

Acute Treatmentfor 6 weeks

Cotrimoxazole:

TMP 10 mg/kg/day IV or orally divided into twice daily doses

Pyrimethamine200 mg loading dose, then 50-75 mg once

daily

Sulfadiazine 2-4 g initial dose, then 1- 1.5 g every 6 hours

Maintenance Therapy: Discontinue when patient is on ART with CD4 count > 100 cells/mm3 ≥ 6 months

Cotrimoxazole: 960 mg (SMX 800mg / TMP 160mg) orally once per day

Pyrimethamine25-50 mg/day

Sulfadiazine 1g x every 6 hours

+OR:

OR:

+

24

Progressive Multifocal Leukoencephalopathy (PML) (1)

Etiology: JC Virus (JCV)• Polyomavirus• Most adults colonized

Clinical:• Focal deficit• Gate disturbance, • Visual loss, sensory loss

Diagnosis: CT or MRI• Hypodense white-matter lesions• No mass effect, no contrast

enhancement• CSF examination normal

Treatment: ARV

25

Progressive Multifocal Leukoencephalopathy (PML) (2)

27 year old male patient in HCMC with right arm weakness and dysarthria

26

Bacterial Brain Abscess and Emboli

Etiology:• Endocarditis secondary to IDU• Staphylococcus aureus infection

Clinical:• Signs of recent injecting• Embolic events: subungal hematoma,

Osler’s nodes (palms and feet), hematuria Diagnosis:

• Cardiac ultrasound• Positive blood culture

27

Primary Cerebral Lymphoma (1)

Etiology Associated with

Epstein-Barr Virus (EBV)

CD4 < 100 cells/mm3

Clinical Headache, usually

no fever Onset usually

slower than toxoplasmosis

28

Primary Cerebral Lymphoma (2)

Diagnosis and Treatment:Difficult to distinguish from toxoplasmosis on CT/MRIIncurable

• so rule out and try empiric treatment for treatable causes before making diagnosis

Treatment: radiation, chemotherapy• May show brief initial response to steroids• ARV may improve survival

29

Diagnostic Approach to Focal CNS Deficit

30

III. Peripheral Neuropathy

31

Causes of Peripheral Neuropathy

Vitamin deficiency• B12• Folate• Pyridoxine• Thiamine

Infectious Diseases• Syphilis• CMV• HIV

Metabolic Diseases• Diabetes

Drug induced• Alcohol• ARV: d4T, ddI• TB: INH

32

Clinical Manifestations of Neuropathy

Usually starts distally (toes or finger tips) and progresses towards center

Numbness, burning, cold

Reduced sensation of:• Pain• Temperature• vibration

Reflexes reduced Strength and joint

position usually normal unless severe

With treatment can improve, but very slowly

Can be irreversible if not treated

33

Peripheral Neuropathy: Prevention

Type of Patient

Prevention Management

Patients on ARV

• Switch d4T to AZT after 12 months

Patients on TB treatment

• Ensure that patients are given pyridoxine (B6) 25-50 mg/day

34

Peripheral Neuropathy: Treatment

1. Treat the Cause 2. Treat the pain

Cause Recommendation

d4T •switch to AZT or TDF

Alcohol • stop drinking

INH •vitamin B6 50 mg/day

•consider stopping INH early

Vitamin supplements: B6, folate, B12

Drug Type/Dosing

Analgesics •Paracetamol•NSAIDs

Amitriptyline 25 – 75 mg/day

Carbamazepine

Morphine if very severe

35

Quick Quiz

36

CSF Profile of HIV-related OIs

CSFOpening pressure

Protein content

Cell count Microscopy Culture

TB meningitis

Cryptococcal meningitis

Very high

Toxoplasmal encephalitis

Bacterial meningitis

High Very highGranulocytes predominate +/- +

Lymphoma Normal Normal Normal - -

Normal or slightly

elevated

Slightly elevated or

normal

Slightly elevated to very high

Normal

High or normal

Slightly elevated or

normal

Elevated(lymphocytes predominate)

Normal

+India ink

stain

-

+/- - -

+

+/-

-

37

Key Points

Fever and headache in PLHIV are indications for a lumbar puncture to evaluate for meningitis

The most common causes of focal neurologic deficits are Toxoplasma, TB, and CNS Lymphoma

Medications (d4T, INH) are common causes of peripheral neuropathy

38

Thank you!

Questions?