Neurological Manifestations of Human Immunodeficiency VirusPresenter - 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 NeoplasmsCells affected by HIV - Perivascular Macrophages Monocytes from blood Microglial cells ?Astrocytes
CLASSIFICATION OF NEUROLOGICAL MANIFESTATIONS OF HIVHIV 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 syndromes MENINGES Meningitis SPINAL CORD Myelopathy Radiculopathy PERIPHERAL NERVES Peripheral Neuropathy Inflammatory Demyelinating Polyneuropathies Toxic Neuropathy MUSCLE Polymyosistis , Pyomyositis HIV associated Wasting Syndrome
Neurological Manifestations of HIV involving the BRAIN *AIDS defining illnesses are marked in RED
• CMV Encephalitis • PMLE • HSV , VZV ENCEPHALITIS • Toxoplasma Encephalitis • Aspergillus encephalitisB • • Metabolic Encephalitis IRISR IA • Granulomatous Angitis – AIDS associated • Infectious Vasculitis – Tb, Neurosyphilis, S CI Aspergillus, Mucor • Varicella Zoster Virus Vasculitis H E • Bacterial Endocarditis, non bacterial thromboticN STROKE Like endocarditis M I Syndromes • Venous thrombosis – Hypercoagulable states C • HIV asso. Thrombocytopenia • DIC H • METASTATIC- Kaposi’s Sarcoma, PCNSL E • Coagulopathy M O.
Neurological Manifestations of HIV involving the MENINGES
Neurological Manifestations of HIV involving the SPINAL CORD
M HIV associated • Vacoular MyelopathyYE • CMV Myelopathy • Varicella Zoster VirusL INFECTIONS • Herpes Simplex Virus • HTLV 1 and 2O • NeurosyphilisP NEOPLASTIC • Lymphoma/metastasis associatedA MyelopathyTH METABOLIC • Vitamin B 12 DeficiencyY
Neurological Manifestations of HIV involving the PERIPHERAL NERVES
• AIDP • CIDPN EARLY STAGES- Immune • Vasculitic Neuropathy • Cranial MononeuropathyE Dysregulation • Multiple mononeuropathies • Plexopathy – Brachial, LumbosacralU MID STAGE – HIV • Distal Sensory PolyneuropathyR Replication driven • Autonomic NeuropathyO • CMV polyradiculopathy, Mononeuritis MultiplexP LATE STAGES – • Syphilitic Polyradiculomyelitis Oppurtunistic • Tuberculous PolyradiculomyelitisA Infections, Neopla • Zoster ganglionitis • Lymphomatous Polyradiculopathy smsT • AIDS Cachexic neuropathy • ALS like motor neuropathyH • Nucleoside Reverse Transcriptase Inhibitors – ALL STAGES (TOXIC Didanosine, Zalcitabine, StavudineY NEUROPATHY) • Other Concomittantly used drugs – Vincristine, Isoniazid, Ethambutol, Thalidomide
Neurological Manifestations of HIV involving the MUSCLES
• HIV PolymyositisM • CMV PolymyositisY INFECTION • Pyomyositis • AIDS cachexia- HIV associatedO Wasting SyndromePAT • ZIDOVUDINEH DRUG INDUCED • Others especially NRTISY
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 FEATURESHeadache – 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 VIIIIt 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 IgG3. 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 Minor Cognitive Motor Assymptomatic AIDS Dementia Complex DysfunctionHIV associated NCI, progresses with increased viral load and immunosuppression 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.
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 jerksVegetative 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 ENCEPHALOPATHY STAGE Mental Function Motor Function STAGE 0 Normal NormalSTAGE 0.5 Absent, Minimal or Equivocal Slowed ocular and extremity symtoms movements STAGE 1 Able to perform all but the Unequivocal motor demanding aspects.Unequivocal impairment func. and intellectual impairment Can walk without assistance STAGE 2 Performs basic self care Ambulatory Cannot work or maintain May require a single prop demanding aspects of daily life STAGE 3 Major Intellectual incapacity Major motor disability Cannot walk unassisted STAGE 4 Intellect, social comprehension and Paraparetic or paraplegic with output at rudimentray level bowel, bladder incontinence
INVESTIGATIONS – testing done only to exclude other diagnosis1. 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 Non specific 3.CSF findings – sugar - normal CSF changes 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
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, photophobia Cryptococcomas 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 Complications of Gelatinous pseudocysts Cryptoccal Cryptococcomas meningitis only nonspecific Cerebral Atrophy2. CSF - sugar - decreased D/D TbM protein - elevated protein cells - monomuclear pleocytosis India ink smear – nonspecific D/D Aspergillus, C.immitus, Candida, H.Capsulatum, Naeglaeria CSF cryptococcal antigen (CrAg) – sensitivity 95% Fungal CSF culture for Cryptococcus – gold standard
CT brain showing -1.GelatinousPseudocyst( formed byconfluence of dilatedperivascular spaces).2.Sites: Basalganglia, cerebralcortex, cerebellumand midbrain. No contrastenhancementMRI: Cyst are of CSFintensity
TREATMENT Amphotericin B +/- Flucytosine (0.5 to 0.7 mg/kg/day) ( 75 to 150 mg/kg/day) Renal insufficiency Hematological Hypokalemia x 2 to 3 weeks Toxicity Hypomagnesemia 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
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
INVESTIGATIONS1. CT / MRI – ‘Multiple lesions in Multiple Locations’ Ring Encancing Lesions – inflammation and central necrosis2. 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
TREATMENT Sulfadiazine + 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.lProphylaxis – 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 complicationApprox 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 - Seizures Visual Field defects Aphasia Ataxia, and occ. Sensory deficits With or without mental status changes
INVESTIGATIONS1. CT / MRI – Multiple nonenhancing white matter lesions, may coalesce, predilection for occipital and parietal. MRI – decreased signal intensity on T1 - Hyperintensity on T22. 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 ShowingProgression of ProgressiveMultifocal Leukoencephalopathy a) Multifocal, high-signal-intensity lesions (arrow) in theright hemisphere of a patient TheCSF was positive for JC virus. b) Contrastenhancement is not evident(arrow). c ) 6 weeks later, progressionof the white matter lesions(arrow) shows involvement of theuncinate fibers. d )Patchy enhancement withgadolinium (arrow) is noted (predominantlyin the right hemisphere
T2 flair MRI brain shows White matter hyperintensity of subcortical U fibers, splenium ofcorpus callosum in posterior cerebral hemisphereNo contrast enhancementNo mass effectCommon sites: temporal and occipital white matter, Subinsular region, corpus callosumand subcortical U fibers
TREATMENT No specific therapy available for PMLE Improved survival has been seen with HAART HIV with PMLE without HAART with HAARTMean Survival- 3 – 6 months around 2.5 years (>7years*) Patients on HAART may show paradoxical worsening due to IRISOnly 50% of patients on HAART show any neurological improvement Other therapies tried – Cytosine, acyclovir, Vidrabine, IFN alpha All 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 Corroborative evidence on - CSF – EBV virus DNA amplification PCNSL3. BRAIN BIOPSY – definitve diagnosis - After a failed therapeutic trial for Toxoplasmosis4. SPECT SCAN – may be useful.
A)POST CONTRAST T1WI B) FLAIR T2WI 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) POSTCONTRAST T1WI D) T2WI C-D. 30 year-old man with AIDS show 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
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 DecreasedUsually associated with Distal Sensory Not seen neuropathy 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 etiologies1. MRI SPINE – Cord swelling wtith intramedullary enhancement - T2 signal changes2. CSF – testing for Viral DNA – CMV, VZV, HSV, HTLV 1 & 2TREATMENT 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 cervicalC2 spine- Iintramedullary signal increased signal on T2C5 enhancement extending from C2 though approximately C5. The axial T2 image- Abnormal signal to be symmetric within the posterior columns of the cord.
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. NEUROPATHYDistal Sensory CMV assoc. NRTI assoc. TOXIC AIDP and CIDP PN POLYRADICULOPATHY 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 diagnosticTREATMENT Reduce exposure to NEUROTOXINS – Ethanol, NRTIs, INH, Metronidazole, Dapsone, Vincristine Screen for Vitamin B 12 Deficiency, Diabetes Mellitus HAART Pain control – TCAs – Nortiptyline > Amitriptyline Help relieve - Anticonvulsants – Gabapentin neuropathic pain
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
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