NEUROLOGIC MANIFESTATION OF HIV/AIDS (INDIA)

Dr PS Deb, MD, DM

NEURO HIV/AIDS: EPIDEMIOLOGY

Post MortemClinical

First SymptomDeath

0

10

20

30

40

50

60

70

80

HOW DOES HIV AFFECT THE NERVOUS SYSTEM?

NEURO HIV/AIDS CLASSIFICATION: ICD10

B20: Oppor. Infection

• (B20.0) HIV disease resulting in mycobacterial infection

• (B20.1) HIV disease resulting in other bacterial infections

• (B20.2) HIV disease resulting in cytomegaloviral disease

• (B20.3) HIV disease resulting in other viral infections

• (B20.8) HIV disease resulting in other infectious and parasitic diseases

• (B20.9) HIV disease resulting in unspecified infectious or parasitic disease

B23: Other

B21: Neoplasm• (B21.0) HIV disease resulting

in Kaposi's sarcom• (B21.2) HIV disease resulting in other

types of non-Hodgkin's lymphoma• (B21.3) HIV disease resulting in

other malignant neoplasms of lymphoid, haematopoietic and related tissue

• (B21.7) HIV disease resulting in multiple malignant neoplasms

• (B21.8) HIV disease resulting in other malignant neoplasms

• (B21.9) HIV disease resulting in unspecified malignant neoplasm

B22: Specific Syndromes• (B22.0) HIV disease resulting

in encephalopathy

B24: NOS

NEURO HIV/AIDS : PATHO-PHYSIOLOGIC

Primary (caused by HIV alone)• AIDS Dementia Complex (brain)• Vacuolar Myelopathy (spinal cord)• Peripheral Neuropathy (nerve)• Meningitis (acute and chronic)

Secondary (opportunistic infections )• Fungal (Cryptococcal Meningitis)• Parasitic (Toxoplasmosis)• Viral (Progressive Multifocal Leukoencephalopathy, CMV,HSV,VZV)• Bacterial (TB, Syphilis)• HIV-Related Tumors (Primary CNS lymphoma, Kaposi Sarcoma, Multiple

lymphoma)

Tertiary (treatment complications)• Autoimmune (GBS)• Immune Reconstitution Inflammatory Syndrome (IRIS)• “Neuromuscular weakness syndrome”• Drug induced peripheral neuropathy/myopathy

NEURO HIV/AIDS: ANATOMICAL

Brain • Meningitis• Dementia• Stroke• Seizures• Degenerative Disorders

Spinal cord• Transverse myelitis• Progressive Myelopathy

(acute/subacute/chronic)

Peripheral neuropathies• Cranial• Peripheral• Sensory• Motor, • Autonomic

Myopathy( +/-inflammatory)

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

EARLY(CD4 > 500/mm3

MIDSTAGE(CD4 = 200-500/mm3)

ADVANCED(CD4 < 200/mm3)

Seroconversion syndromes

MeningitisMeningoencephalitisMyelitisDemyelinating syndromes

AIDPSensory ganglionopathyBrachial plexopathyRhabdomyolysis

HIV related meningitis: aseptic (acute, recurrent, chronic)Asymptomatic CSF abnormalities: elevated protein, lymphocytic pleocytosis, normal glucose

HIV DementiaCryptococcal meningitisToxoplasmosisPMLVacuolar MyelopathyCMV- encephalitis - polyradiculitis - mononeuritis multiplex

Herpes zoster radiculitis

Distal sensory polyneuropathy

Demyelinating polyneuropathiesMononeuritis multiplex

NRTI neuropathy, AZT myopathyPolymyositis

Immune mediated

Immune compromised

NEURO HIV/AIDS: TEMPORAL

NEURO AIDS IN INDIA: NIMHANS BANGALORE 20Y REGISTRY CASES

HIV 1 C Clad (West B) recombinant strain rare.

Mode of Transmission – Hetero 86%, Blood Transfusion 2.04%, IDU 2.34%

Neuro AIDS – 70-85% OpI

• Cryptococcus - 37.2%• TB - 31.9%• Dementia - 1.4% (west 30-

40%)• PML - Rare • Myelopathy - Rare• Neoplasm -

Infrequent, (PCNL) and (Kaposi

sarcoma)•

Pandey A, Reddy DC, Ghys PD, et al. Improved estimates of India’sHIV burden in 2006. Indian J Med Res 2009; 129: 50–58.

NEUROLOGIC MANIFESTATIONS OF HIV INFECTION: NIMS HYDERABAD

Retrospective survey 1993-2003

Total 7091 (OP 5485 -> IP 1606)

Neurological events 25% (411/1606)

Meningitis: 162

• TBM : 25.06%• CRM : 10.95%• Pyogenic: 1.95%• Aseptic: 1.95%• Syphilis: 0.97%

Mass Lesions: 113• Toxoplasma: 9.25%• Tuberculoma: 10.71%• Lymphoma: 6.08%• PML: 1.70%

Neuoropathy : 84• Mononeuritis multiplex• DSP• Progressive PNP• AIDP• CIDP• Sensory neuropathy• Cranial neuropathy• Toxic Neuropathy

Myelopathy + Dementia: 33

Vijay D. Teja, MD, Sudha Rani Talasila, MSc, Lakshmi Vemu, MD :AIDS Read. 2005;15(3):139-145

NEUROLOGIC MANIFESTATIONS OF THE HIV: MUMBAI

300 cases over 3years ART-naive

67 (22.3%) had neurologic manifestations due to the direct effects of HIV-1

Meningitis: 75

• TBM : 51• CRM : 24• Zoster: 01• Aseptic: 03

CMV Encephalitis 1

Mass Lesions: 137 • Toxoplasma: 61• Tuberculoma: 48• Lymphoma: 08• PML: 20

Myelopathy: 2

Neuoropathy : 24 • Peripheral neuropathy: 15• Cranial neuropathy: 09

Dementia: 4

Myopathy: 1

Stroke: 20

Alaka K. Deshpande, Department of Retroviral Medicine, Grant Medical College & Sir JJ Group of Hospitals, Mumbai, India.

ASEPTIC MENINGITIS

May occur in acute infection or sero-conversion or in the chronic stage of HIV infection

Clinical

• Fever, malaise, stiff neck, and photophobia• Clinical course is self-limited, without sequelae• Cranial neuropathy, typically Bell’s palsy, may co-exist• After recovery, underlying HIV may be asymptomatic

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

SYMPTOMATIC NEURO-COGNITIVE DISORDER ASSOCIATED WITH HIV IN INDIA

Rare – 1-4% in various large studies• Early death due to OIs• Under reporting due to poor

evaluation• HIV clad C • Genetic factor of Host

CMV ENCEPHALITIS

Common (IgM 10%) OpI, HSV5 ubiquitous, (IgG 60-80%) asymptomatic, reactivation in immuno-compromised

Confusion, headache, delirium, focal neurology, cranial nerve deficits

IV ganciclovir, valganciclovir, foscarnet,

cidofovir

CRYPTOCOCCOSIS

•Most cases seen in patients with CD4 count <50 cells/µL•30-40% of Neuro AIDS in Developing countries•5-8% in developed countries before widespread use of effective ART , much lower with use of ART

CRYPTOCOCCAL MENINGITIS

•Fever, malaise, headache

•Neck stiffness, photophobia, or other classic meningeal signs and symptoms in 25-35% of cases

•Lethargy, altered mental status, personality changes (less common)

Subacute or Chronic meningitis

•Lymphocytic with raised protein, low sugar

•India Ink•Cr Ag in CSF•Cr culture in

Blood

CSF

CRYPTOCOCCOSIS: TREATMENT

•Induction (≥2 weeks): •Amphotericin B 0.7 mg/kg IV QD + Flucytosine 25 mg/kg PO QID

•Lipid formulation Amphotericin B 4-6 mg/kg IV QD + Flucytosine 25 mg/kg PO QID

•Consolidation (8 weeks): •Fluconazole 400 mg PO QD

•Chronic maintenance:•Fluconazole 200 mg PO QD

First

•Induction: •Amphotericin (deoxycholate or lipid formulation, dosed as preferred therapy) + fluconazole 400 mg PO or IV QD for 2 weeks

•Amphotericin (deoxycholate or lipid formulation, dosed as preferred therapy) for 2 weeks

•Fluconazole 400-800 mg PO or IV QD + flucytosine 25 mg/kg PO QID for 4-6 weeks (inferior efficacy)

•Consolidation: •Itraconazole 200 mg PO BID for 8 weeks

•iChronic maintenance:• Itraconazole 200 mg PO QD

Alternative

CRYPTOCOCCOSIS: ADVERSE EVENTS

•Up to 30% develop IRIS after initiation of ART

•Management: continue ART and antifungal therapy

•If severe IRIS symptoms, consider short course of corticosteroids

•Consider delaying initiation of ART at least until completion of induction therapy

IRIS

•Lifelong suppressive treatment (after completion of initial therapy), unless immune reconstitution on ART

•Preferred: fluconazole 200 mg QD

•Consider discontinuing maintenance therapy in asymptomatic patients on ART with sustained increase in CD4 count to >200 cells/µL for ≥6 months

•Restart maintenance therapy if CD4 count decreases to <200 cells/µL

Secondary prophylaxis:

TUBERCULOSIS IN HIV

•WHO 2006 9.2millioon TB world and 7.7% were HIV +•TB in normal population 5-10% / 5-15 % in HIV +•Role of HIV epidemic on TB epidemic in India is not clear

CLINICAL AND IMMUNO PATHOLOGICAL COURSE OF HIV ASSOCIATED TUBERCULOSIS (DE COCK ET AL 1992).

HIV AND NS TUBERCULOSIS

1/3 of all AIDS related deaths due to Tb. Untreated universally fatal, with low CD4• HIV accelerates the spread of TB and latent to active by 100

fold• Accelerates the course of HIV so needs index of suspicion.• HAART has reduced TB by 80% in Brazil• India Human Mycobacterium is common not avian

Clinical picture of TBM with/without HIV not much difference• Fever less common• Seizure more common• Hydrocephalus more common• Cerebral infarction more common• No difference in CSF picture• No difference in the response to the treatment

TREATMENT OF TB MENINGITIS

Anti TB (HRZ+E/STM)x2 + (HR)x10 months (12-18months)

Steroid: can be used as in non HIV case• Reduce cerebral edema, ICH,

inflammation• Prevent hydrocephalus, vasculitis• Mortality benefit (41->31%) in Vietnam

study

FOCAL SYNDROMES AND MASS LESIONS

•Herpes simplex; Varicella zoster; progressive multifocal leukoencephalopathy

Viral:

•Abscess due to Cryptococcus, Candida, Zygomycetes, Histoplasma, Aspergillus

Fungal:

•Abscess due to pyogenic bacteria, mycobacteria (tuberculoma), Listeria, Nocardia

Bacterial:

•Trypanosoma cruzei; Taenia solium; toxoplasmosis

Parasitic:

•Primary or metastatic lymphoma; glioma; metastatic Kaposi’s sarcoma

Neoplasm:

TOXOPLASMOSIS

TOXOPLASMOSIS

CEREBRAL TOXOPLASMOSIS

20-40% in AIDS with low CD4 (<100)

Reactivation of prior infection

Presentation – Focal mass lesion, altered mentation

Diagnosis• Imaging• Serology (+ >97% for IgG), if –ve likelihood of toxo is <

10%• CSF nonspecific• Biopsy if unresponsive to Rx

CEREBRAL TOXOPLASMOSIS IMAGING

Multiple/single, ring enhancement, surrounding edema• Multiple in 2/3, ring

enhancing-90%• Size < 2cm• Site: Parietal/frontal

lobes, thalamus , BG, Brainstem, Corticomedulary junction, Pituitary

TOXOPLASMOSIS RX

•Pyrimethamine (200mg-L/75C) + Sulfadiazine(6-8g/d -4d/d) till improve CD4 count

•Pyrimethamine + Clindamycine

First Line

•Pyrimethamine+ Azithromycin

•Pyrimethamine+ Atovaquine

•Sulfadiazine+ Atovaquine

Alternative

•Relapse common

•Reduce dose and continue

Maintenance

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

JC virus(Human polyoma virus), reactivation (70% of adult population: Ab to JC virus)

Late manifestation of AIDS ; in ~4% of pts with AIDS

Bilateral, asymmetric, & localized preferentially to periventricular areas & subcortical white matter .

Protracted course +/- Change in mental state, Multifocal deficit:

Uncommon in India

PRIMARY CNS LYMPHOMA

AIDS defining malignancy ~20% cases of lymphoma in HIV

Usually associated with EBV infection , no age predilection.

Median CD4 ~ 50/ul: at later stage and poorer prognosis than systemic lymphoma

Presentation: Focal deficit with cognitive impairment, sub-acute

Radiotherapy (usually palliative) or high dose methotrexate (chemo)Uncommon in India

STROKE IN HIV

Ischemic and hemorrhagic –clinical in 4%, autopsy report 34%.

Ischemic• Bacterial endocarditis • Non bacterial thrombotic• Infectious vasculitis- (VZV, Tb, syphilis, crypto, angioinvassive fungi-asperg & mucor)

• Granulomatous angitis• Procoagulant state

Hemorrhagic• Thrombocytopenia• Coagulopathy-CLD,DIC• PCNSL, KSa, toxo• Drugs- cocaine, amphetamin• TTP

VACUOLAR MYELOPATHY

Vacuolar Myelopathy• - 1/3 (20-55%) in autopsy series

Clinical manifestation is much smaller• Usually late HIV• Develops slowly (months)• Coexisting neuropathy• Sensory symptoms: loss vibration and joint

position sensation with relatively preserve pain sensation.

• No discrete sensory level

AIDS NEUROPATHY

Distal symmetrical polyneuropathy

Inflammatory demyelinating polyneuropathy

Mononeuritis multiplex

Isolated mononeuropathy

Progressive polyradiculopathy

Autonomic neuropathy

AIDS MYOPATHY

Causes: • Drug treatment (AZT/NRTI);• HIV : AIDS cachexia• Secondary infection – Toxo• Rhabdomyolysis, NHL, myasthenia gravis, nemaline (rod)

Clinical:• Progressive proximal limb weakness

Laboratory:• Elevated creatine kinase; myopathic features on EMG; +/-

myoglobinuria• Muscle biopsy

Treatment:• Discontinue AZT; steroids or plasmapharesis; treat infection