Neurological Manifestations of

Human Immunodeficiency Virus

Presenter - Dr.Garima AggarwalModerator - Dr (Brig) Rajesh Kakkar

Dr.Manish Mittal

HIV is the most common viral infection of the nervous system, affecting both the CNS and PNS.

Upto 50% of HIV patients have clinically apparent neurological disease.

Upto 20% of HIV patients present for the first time with neurological manifestations.

Upto 90% of HIV patients have neuropathological changes on autopsy.

India has the second largest burden of HIV related pathology next to sub-Saharan Africa. Neurological complications associated to HIV-1 infections, are very common in our clinical setting.

NEUROPATHOGENESIS

Nervous System effects of HIV infection

DIRECT INDIRECTHIV virus and its products Oppurtunistic infections

HIV associated Neoplasms

Cells affected by HIV - Perivascular Macrophages Monocytes from blood Microglial cells ?Astrocytes

NEUROPATHOGENESIS

CLASSIFICATION OF NEUROLOGICAL MANIFESTATIONS OF HIV

HIV can involve disorders of both the CNS and PNS.

Classification based on the neuroanatomical localization and clinical syndromes associated -

BRAIN Dementia Space occupying lesions Encephalitis Stroke like syndromesMENINGES MeningitisSPINAL CORD Myelopathy RadiculopathyPERIPHERAL NERVES Peripheral Neuropathy Inflammatory Demyelinating Polyneuropathies Toxic NeuropathyMUSCLE Polymyosistis , Pyomyositis HIV associated Wasting Syndrome

Neurological Manifestations of HIV involving the

BRAIN

*AIDS defining illnesses are marked in RED

• HIV Encephalopathy/ ADC• Progressive Multifocal Leuco-

Encephalopathy• Tuberculosis• Neurosyphilis• Lymphoma

DEMENTIA

• Abscesses • Infective Granulomas• Neoplastic• Others

SPACE OCCUPYING

LESIONS

TuberculosisListeriaNocardiaE.Coli

ToxoplasmaAspergillusCandidaCryptococcus

Primary CNS LymphomaSecondary MetastasisMetastatic Kaposi’s SarcomaGlioma

PMLE, Varicella Zoster, CMV

BRAIN

• CMV Encephalitis• PMLE• HSV , VZV• Toxoplasma Encephalitis• Aspergillus encephalitis• Metabolic Encephalitis• IRIS

ENCEPHALITIS

• Granulomatous Angitis – AIDS associated• Infectious Vasculitis – Tb, Neurosyphilis,

Aspergillus, Mucor• Varicella Zoster Virus Vasculitis• Bacterial Endocarditis, non bacterial

thrombotic endocarditis• Venous thrombosis – Hypercoagulable states• HIV asso. Thrombocytopenia• DIC• METASTATIC- Kaposi’s Sarcoma, PCNSL• Coagulopathy

STROKE Like Syndromes

ISCHEMIC

HEMO.

BRAIN

Neurological Manifestations of HIV involving the

MENINGES

• HIV Seroconversion Illness- Aseptic meningitis

• Pneumococcal, Meningococcal• E.Coli• Klebsiella• Listeria

ACUTE

• Mycobacterium tuberculosis• Mycobacterium Avium complex• Cryptococcus• Candida• Syphilis• Nocardia• Metastatic Meningitis - Lymphoma

CHRONIC

MENINGITIS

Neurological Manifestations of HIV involving the

SPINAL CORD

• Vacoular MyelopathyHIV associated

• CMV Myelopathy• Varicella Zoster Virus• Herpes Simplex Virus• HTLV 1 and 2• Neurosyphilis

INFECTIONS

• Lymphoma/metastasis associated Myelopathy

NEOPLASTIC

• Vitamin B 12 DeficiencyMETABOLIC

MYELOPATHY

Neurological Manifestations of HIV involving the

PERIPHERAL NERVES

• AIDP• CIDP• Vasculitic Neuropathy• Cranial Mononeuropathy• Multiple mononeuropathies• Plexopathy – Brachial, Lumbosacral

EARLY STAGES- Immune

Dysregulation

• Distal Sensory Polyneuropathy• Autonomic Neuropathy

MID STAGE – HIV Replication driven

• CMV polyradiculopathy, Mononeuritis Multiplex

• Syphilitic Polyradiculomyelitis• Tuberculous Polyradiculomyelitis• Zoster ganglionitis• Lymphomatous Polyradiculopathy• AIDS Cachexic neuropathy• ALS like motor neuropathy

LATE STAGES – Oppurtunistic

Infections, Neoplasms

• Nucleoside Reverse Transcriptase Inhibitors – Didanosine, Zalcitabine, Stavudine

• Other Concomittantly used drugs – Vincristine, Isoniazid, Ethambutol, Thalidomide

ALL STAGES (TOXIC NEUROPATHY)

NEUROPATHY

Neurological Manifestations of HIV involving the

MUSCLES

• HIV Polymyositis• CMV Polymyositis• Pyomyositis• AIDS cachexia- HIV associated

Wasting Syndrome

INFECTION

• ZIDOVUDINE• Others especially NRTIS

DRUG INDUCED

MYOPATHY

Some commonly encountered Neurological Manifestations

Of HIV

In Clinical Practice

ASEPTIC HIV MENINGITIS 10-15% of patients with Acute HIV Seroconversion illness present

with meningtisPATHPHYSIOLOGY – Immune mediated illnessCLINICAL FEATURES Headache – severe and protracted, isolated persistant headacheSigns of meningeal irritation – nausea, vomiting, photophobiaAcute Seroconversion illness – Flu like febrile illnessPreserved alertness and cognitionMay be associated with features of EncephalitisCranial nerve Involvement may be seen – CN VII, rarely V and/or VIII

It is a diagnosis of exclusion.

ASEPTIC MENINGITIS continued INVESTIGATIONS1. LP – CSF sugar - Normal (40-70mg/dl) protein - Elevated but <100mg/dl (15-50mg/dl) cells - lymphocytic pleocytosis (0-5 Mono/mm3)2. Intrathecal anti HIV IgG 3. Serum P 24 capture assay, HIV RNA level

TREATMENTNo specific therapy is needed.Resolves in 2-4 months without treatment.

HIV ENCEPHALOPATHY/ AIDS DEMENTIA COMPLEX

In the era of HAART, 10-20% of HIV patients are affected by it. It is the first manifestation of AIDS in upto 3 % of HIV patients Associated wth CD4+ T cell count of < 200/mm3 It s considered part of the HIV associated Neurocognitive

Impairment spectrum

PATHOGENESIS – neuropathogenesis as described above.White matter – pallor, multinucleated cell encephaltis, vacoular

changes, focal necrosis and neuronal loss. The cerebral cortex is relatively spared.Areas affected- subcortical structures of brain and spinal cord.

Assymptomatic Minor Cognitive Motor Dysfunction AIDS Dementia Complex

HIV associated NCI, progresses with increased viral load and immunosuppression

HIV ENCEPHALOPATHY continuedCLINICAL FEATURESCognitive impairment – Forgetfulness

Decreased Attention and Concentration Inability to perform complex task Decreased Sexual drive and disrupted Sleep

Mild mania and AgitationMotor Dysfunction- Poor balance

Gait incoordination- slow and rigid gait Slowness of movements

Postural tremors Choreoform movements, myoclonic jerks

Vegetative state- Bowel and Bladder incontinence Unable to Ambulate

lying in bed mute with vacant stare

There are no specific diagnostic criteria for HIV Encephalopathy. Diagnosis of dementia – demonstrating a decline in cognition

CLINICAL STAGING OF HIV ENCEPHALOPATHYSTAGE Mental Function Motor Function

STAGE 0 Normal Normal

STAGE 0.5 Absent, Minimal or Equivocal symtoms

Slowed ocular and extremity movements

STAGE 1 Able to perform all but the demanding aspects.Unequivocal func. and intellectual impairment

Unequivocal motor impairment

Can walk without assistanceSTAGE 2 Performs basic self care

Cannot work or maintain demanding aspects of daily life

AmbulatoryMay require a single prop

STAGE 3 Major Intellectual incapacity Major motor disabilityCannot walk unassisted

STAGE 4 Intellect, social comprehension and output at rudimentray level

Paraparetic or paraplegic with bowel, bladder incontinence

INVESTIGATIONS – testing done only to exclude other diagnosis

1. Neuropsychological testing – MMSEIt is advisabele in all patients with HIV to have a baseline MMSE.2. CT / MRI - Diffuse cerebral atrophy

Patchy or diffusely abnormal signals esp on FLAIR –(Hemispheric white matter +/- basal ganglia and thalamus) Basal Ganglia calcification – in children

3.CSF findings – sugar - normal protein - mildly elevated cells - lymphocytic pleocytosis special tests – HIV IgG synthesis Oligoclonal bands HIV DNA amplification

Quantitative CSF-HIV Burden others MCP1, neopterin, Quin. Acid, Beta2MGThe practical utility of special CSF testing is uncertainNo absolute correlation exists between CSF HIV burden and disease severity

Non specific CSF changes

TREATMENT HAART – HAART improves neuropsychological performance

(Larussa etal 2006) - upto 50% reduction in HIV enceph. since HAART

- simpler regimens with least number of drug side effects - Drugs with high CSF penetration should be used (Zidovudine, Stavudine, Lamivudine, efavirenz, nevirapine) Neuroleptic medication- for patients with psychobehavorial dys.

- they have increased sensitivity to EPS side effects of neurleptic drugs

- TCAs and SSRIs - Clozapine and Haloperidol

Anticonvulsant – Gabapentin and topiramate are preferred Psychological support, assisted living.

CRYPTOCOCCAL MENINGITIS Initial AIDS defining illness in 2% of patients More common with CD4+ T cell count of <100/mic.l CLINICAL FEATURES Subacute onset

Signs of meningeal irritation – fever, stiff neck,vomiting, photophobiaCryptococcomas and Cranial nerve involement rarely

Head to Toe examination for associated infection Skin lesions, like Molluscum contagiosum Palatal and oral ulcers Myocarditis Pulmonary involvement – in 1/3rd of case Gastroenteritis Prostatitis – prostate may serve as reservoir for smoldering infection

INVESTIGATIONS1. CT/MRI – Hydrocephalus

Gelatinous pseudocysts Cryptococcomas

only nonspecific Cerebral Atrophy2. CSF - sugar - decreased

protein - elevated protein cells - monomuclear pleocytosis India ink smear – nonspecific

CSF cryptococcal antigen (CrAg) – sensitivity 95% Fungal CSF culture for Cryptococcus – gold standard

Complications of Cryptoccal meningitis

D/D TbM

D/D Aspergillus, C.immitus, Candida, H.Capsulatum, Naeglaeria

CT brain showing - 1.Gelatinous Pseudocyst( formed by confluence of dilated perivascular spaces).2.Sites: Basal ganglia, cerebral cortex, cerebellum and midbrain. No contrast enhancementMRI: Cyst are of CSF intensity

TREATMENTAmphotericin B +/- Flucytosine

(0.5 to 0.7 mg/kg/day) ( 75 to 150 mg/kg/day)

x 2 to 3 weeks Fluconazole 200mg P/O BD

x upto 3 monthsMaintainence therapy -Fluconazole 200mg P/D OD (1st line)

Amphotericin/Itraconazole weekly (2nd line)

Continue till the CD4+T cell count >200cells/micr.l Increased ICP – Medical- corticosteroids and Acetazolamide Repeated Lumbar punctures, VentriculostomyAcute mortality approaches 30% and is related to inceased ICP

Renal insufficiencyHypokalemiaHypomagnesemia

Hematological Toxicity

TOXOPLASMOSIS of the BRAIN Associaterd with CD4+T cell count < 100cells/micr.l Most commmon cause of focal intracranial masses in patients with

AIDSPATHOGENESISIt almost always occurs as a Recrudescence of previously acquired

infection.It is 10 times times more commmon in patients with Ab to Toxoplas.CLINICAL FEATURES FEVER

HEADACHE FOCAL NEUROLOGICAL DEFICITS (Seizures/Hemiparesis/Aphasia)Rarely patient may have Confusion, Dementia, Lethargy or Coma

2. IgG Ab to Toxoplasma – This should be done for all HIV patients at the time of initial workup.

3. Brain Biopsy – only confirmatory test - patients with failed 2-4 weeks of antitoxoplasma

therapy

INVESTIGATIONS1. CT / MRI – ‘Multiple lesions in Multiple Locations’ Ring Encancing Lesions – inflammation and central

necrosis

D/D of Ring Enhancing Lesions

de

TREATMENTSulfadiazine + Pyrimethamine

(05 to 1.5g P/O q 6th hrly) (200mg loading dose Day 1) ( 75mg P/O OD maintainence)

With Folinic Acid (10mg/day)

Long term Suppressive therapy – Sulfadiazine + Pyrimethamine (2g/day) (25mg/day)

May need to continue maintainence therapy life long in some Or until CD4+T cell count > 200cells/micr.l

Prophylaxis – HIV ,CD4+Tcell count <100c/mi.l, IgG toxoplasma +vePrimary Prevention – HIV , but seronegative for toxoplasma

PROGRESSIVE MULTIFOCAL LEUCOENCEPHALOPATHY It is a late manifestation, seen in 4% of patients with AIDSPATHOGENESISCaused by the JC virus, DNA containing HPV. Only known complication

Approx 90% of general adult population is already exposed to this virus in early childhood, and contains antibodies against it.

Lesions – small foci of demyelination in subortical white matter, which coalesce. Areas – Occipital and parietal lobes, cerebellum, brainstem and rarely Spinal Cord.

CLINICAL FEATURES Protracted course Multifocal Neurological deficits -

With or without mental status changes

SeizuresVisual Field defectsAphasiaAtaxia, and occ. Sensory deficits

INVESTIGATIONS1. CT / MRI – Multiple nonenhancing white matter lesions,

may coalesce, predilection for occipital and parietal.

MRI – decreased signal intensity on T1 - Hyperintensity on T2

2. CSF – non specific changes - CSF PCR for JC virus DNA (sensitivity 76%, specificity 100%)

3. Brain Biopsy – if clinical diagnosis likely, but no viral DNA detected on CSF

Bizarre giant astrocytes with pleomorphic hyperchromic nuclei Altered oligodendrocytes with enlarged nuclei Cells with viral inclusions and myelin loss

FLAIR Images Showing Progression of Progressive Multifocal Leukoencephalopathy

a) Multifocal, high-signal-intensity lesions (arrow) in the right hemisphere of a patient The CSF was positive for JC virus. b) Contrast enhancement is not evident (arrow). c ) 6 weeks later, progression of the white matter lesions (arrow) shows involvement of the uncinate fibers. d )Patchy enhancement with gadolinium (arrow) is noted (predominantly in the right hemisphere

T2 flair MRI brain shows White matter hyperintensity of subcortical U fibers, splenium of corpus callosum in posterior cerebral hemisphereNo contrast enhancementNo mass effectCommon sites: temporal and occipital white matter, Subinsular region, corpus callosum and subcortical U fibers

TREATMENT No specific therapy available for PMLE Improved survival has been seen with HAART

HIV with PMLE

without HAART with HAART

Mean Survival- 3 – 6 months around 2.5 years (>7years*) Patients on HAART may show paradoxical worsening due to IRIS

Only 50% of patients on HAART show any neurological improvement

Other therapies tried – Cytosine, acyclovir, Vidrabine, IFN alphaAll these therapies have shown generally unsatisfactory results

PRIMARY CNS LYMPHOMA Complicate the course of AIDS in upto 5% of patients.PATHOGENESISPCNSL of B cell origin are considered oppurtunistic neoplasms.CLINICAL FEATURESSimilar to Toxoplasmosis – fever, headache , FNDs PCNSL TOXOPLASMA Tempo of evolution slower presents as acute/subacute several days to few weeks Fever usually absent may or maynot be present No response to antitox therapy Show clinical and

neuroimaging imrovement in response to Antitox therapy

INVESTIGATIONS1. MRI > CT – one or more deep lesions

- location – deep, adjacent to lateral ventricle - White matter rather than gray matter

- subependymal extension - predilection for Posterior fossa - Mass effect may be present, surrounding edema rare2. CSF – unhelpful - Monoclonal B lymphocytes by flowcytometry - CSF – EBV virus DNA amplification3. BRAIN BIOPSY – definitve diagnosis

- After a failed therapeutic trial for Toxoplasmosis

4. SPECT SCAN – may be useful.

Corroborative evidence on PCNSL

A-B. 24 year-old man with AIDS Show a solitary large ring-enhancing lesion with mild mass effect and moderate vasogenic edema. The hypointensity of the lesion on T2WI is characteristic of lymphoma. Note that the mass effect and edema is less than expected given the size of the lesion, as is typical for primary brain lymphoma while much more edema and mass effect vs. lesion size is expected in toxoplasmosis.

C-D. 30 year-old man with AIDSshow left temporal lobe vasogenic edema, related to a temporal lobe mass lesion (not shown). There are also bilateral lesions in the caudate nuclei on T2WI (D)(red), with periventricular and ependymal extension of enhancement on the right (C).(green) The ependymal spread is

characteristic of PCNSL

A)POST CONTRAST T1WI B) FLAIR T2WI

C) POSTCONTRAST T1WI D) T2WI

TREATMENT HAART – vigorous attempts to suppress HIV replication are

recommended in all patients with PCNSL

Mass effect – High dose corticosteroid therapy

Radiotherapy – Palliative whole brain radiotherapy

Chemotherapy – Its use remains controversial, trial stages.

VACUOLAR MYELOPATHY VM is the most common cause of spinal cord dysfunction in

untreated patients with AIDS. It is apparent in 25% to 55% of AIDS autopsy series It frequently coexists with HIV Encephalopathy and Distal Sensory

polyneuropathyCLINICAL FEATURES Subacute onset – over weeks or months Gait disturbances, imbalance Ataxia Spasticicity Sphincter dysfunction Examination –Spastic parapareis, Hyperreflexia, Babinski +ve, Loss

of proprioception and vibration sense . No sensory level. Arms are typically spared

VACUOLAR MYELOPATHY VITAMIN B12- sacd

S. Vitamin B12 levels are Normal Decreased

Usually associated with Distal Sensory neuropathy

Not seen

Vacoular changes in myelin sheaths Decreased methylation of histidine and phasphatidylcholine prod.

HIV infected patients may also present with Vitamin B 12 deficiency.

INVESTIGATION nonspecific , to exclude other etiologies

1. MRI SPINE – Cord swelling wtith intramedullary enhancement - T2 signal changes2. CSF – testing for Viral DNA – CMV, VZV, HSV, HTLV 1 & 2

TREATMENT HAART – Viral control can result in improved neurological

function is not well documented in VM. Assistance – Personal

Care of neurogenic bladder, bladder infection Prevention of skin breakdown

Management of limb spasticity, etc.

Sagittal T2-weighted images of the cervical spine- increased signal on T2 extending from C2 though approximately C5.

The axial T2 image- Abnormal signal to be symmetric within the posterior columns of the cord.

C2

C5

Iintramedullary signal enhancement

HIV associated NEUROPATHY Peripheral neuropathies complicate all stages of HIV. Symptomatic neuropathy is seen in 10-15% of patients but

pathological changes of peripheral nerve involvement - almost all AIDS patients

HIV ass. NEUROPATHY

Distal Sensory PN AIDP and CIDP CMV assoc. POLYRADICULOPATHY

NRTI assoc. TOXIC NEUROPATHY

DISTAL SENSORY POLYNEUROPATHYCLINICAL FEATURES Painful burning sensation, with numbness in both feet.Hands spared Depressed or absent ankle jerks, mild pain, temp., vibratory sense loss in

the feet. Symmetrical involvement is a characteristic clinica feature and hands are

usually spared. INVESTIGATIONS – typical clinical features are diagnostic

TREATMENT Reduce exposure to NEUROTOXINS – Ethanol, NRTIs, INH,

Metronidazole, Dapsone, Vincristine Screen for Vitamin B 12 Deficiency, Diabetes Mellitus HAART Pain control – TCAs – Nortiptyline > Amitriptyline - Anticonvulsants – Gabapentin

Help relieve neuropathic pain

Thank you

References1. Neurology in Clinical Practice – 3rd edition(Bradley, Daroff, Fenchal)2. Adams and Victor’s Principles of Neurology- 9th

edition3. Harrison’s principles of Internal Medicine – 17th

edition4. Textbook of neurology- Dounghey5. NACO guidelines for management of AIDS- 20106.WHO guidelines for HIV/AIDS7. World Wide Web