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The Neurologic Complications of HIV

The Neurologic Complications of HIV. Stephen Raffanti MD Comprehensive Care Center Vanderbilt University Presentation Prepared for VU Infectious Diseases Fellows Fall 2002. Overview. Epidemiology of Neurologic Disease Neuropathogenesis Clinical Manifestations Opportunistic Infections

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The Neurologic Complications of HIV

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  1. The Neurologic Complications of HIV Stephen Raffanti MD Comprehensive Care Center Vanderbilt University Presentation Prepared for VU Infectious Diseases Fellows Fall 2002 S.Raffanti MD, TNAETC

  2. Overview • Epidemiology of Neurologic Disease • Neuropathogenesis • Clinical Manifestations • Opportunistic Infections • CNS Lymphoma • Progressive motor syndromes • Peripheral Neuropathy • AIDS Dementia Complex S.Raffanti MD, TNAETC

  3. EPIDEMIOLOGY • Pre-HAART era revealed high incidence of neurological disease: 7-20% of initial AIDS diagnoses, 39-70% prevalence in HIV/AIDS, >70% in post mortem studies. • HAART era shows expected decrease in incidence rates of neurologic OI’s, CNS lymphoma and AIDS Dementia Complex (ADC) (which may be occurring at higher CD4 counts). S.Raffanti MD, TNAETC

  4. Risk of Neurologic Disease in At-Risk Patients Condition Incidence • PML 4% • Toxoplasmic Encephalitis 5-15% • Cryptococcal Meningitis 6-10% • CNS Lymphoma 7-10% • CMV encephal./radiculopathy 20-40% post • AIDS Dementia Complex 15-30% • Distal Symmetric Peripheral >30% Neuropathy • What is not known is how prolonged treatment with or without immune response will affect the incidence and manifestations of these diseases. S.Raffanti MD, TNAETC

  5. Neuropathogenesis • HIV is neurovirulent but not neurotropic: • Virus cannot productively infect primary neuronal cell cultures; • In situ hybridization doe not show significant amount of free virus in brain tissue. • HIV can productively infect monocytes, macrophages and possibly some glial cells: • In acute infection meningial macrophages are most involved; • In later disease perivascular macrophages and microglial cells predominate. • Infection results in a cascade of toxic mediators: • Cytokines, arachidonic acid derivatives, IFN, interleukins and gp120 are all associated with virus induced inflammation. S.Raffanti MD, TNAETC

  6. Neuropathology • Neuronal injury occurs as a result of inflammatory process. • In the brain: reactive astrogliosis, myelin pallor, neuronal loss, alterations of dendritic processes with most severe damage seen in the deep gray matter (atrophy). • In the peripheral neuron: degeneration of axons, endoneurial perivascular inflammation (Distal Symmetric Peripheral Neuropathy) or perivascular inflammation with macrophage mediated segmental demyelination (Inflammatory Demyelinating Neuropathy). S.Raffanti MD, TNAETC

  7. Clinical Manifestations • Opportunistic infections: • Four most common account for over 90% of clinically significant CNS infections: Cryptococcal meningitis, Progressive Multifocal Leukoencephalopathy (PML), Toxoplasmic encephalitis (TE), CMV encephalitis/radiculopathy. • All four occur at patients identified “at risk”. • All four have decreased incidence in HAART responders. • All four may have a different long term course with concurrent successful HAART. S.Raffanti MD, TNAETC

  8. Clinical Case #1 • 43 year old bakery truck driver, CD4 88 cells/mm3, VL 16,900 copies/ml, presents with headache, fever, nausea and some general malaise of three weeks’ duration. Course has been waxing and waning. Yesterday he felt relatively well. • PE shows uncomfortable patient, no focal findings. T=100.2. S.Raffanti MD, TNAETC

  9. Clinical Case #1 • CT of head with/without contrast negative. • LP yields: OP of 220 mm H2O, WBC of 4 cells/mm3, glucose 68 (80) mg/dl, protein 45 mg/dl and positive india ink prep. • Serum reveals + cryptococcal antigen 1:256. S.Raffanti MD, TNAETC

  10. Clinical Case #1 • How uncommon is the duration of his complaints? The waxing and waning? • What predictors of a poor outcome does this case have? Of a good outcome? • How common is the lack of classic meningial signs? • Is it likely that an MRI would have been abnormal? If so, would it have changed your work-up? S.Raffanti MD, TNAETC

  11. Cryptococcal Meningitis • C. neoformans is an encapsulated yeast, inhaled into the small airways where it usually causes sub-clinical disease; dissemination to the CNS is not related to pulmonary response. • C. neoformans produces no toxins and evokes little inflammatory response. The main virulence factor is the capsule. S.Raffanti MD, TNAETC

  12. Cryptococcal Meningitis • Clinical manifestations: • headache (70-90%), fever (60-80%), malaise (76%), stiff neck (20-30%), photophobia (6-18%), seizures (5-10%) nausea. • Average duration of symptoms is 30 days. • Predictors of poor outcomes are altered mental status, increased opening pressure, WBC<20 cells/mm3. • Diagnosis made by CSF examination with india ink (74-88%), Crypto Ag serum/CSF (99%), CSF culture. • Level of Crypto Ag is not indicative of severity of disease or a marker of response to therapy. Serum Crypto Ag can rule out clinical disease in HIV positive but not negative patients. S.Raffanti MD, TNAETC

  13. Cryptococcal Meningitis • Therapy: • Acute: Ampho B (0.7-0.8 mg/kg/d) for 14 days with or without 5-FC 25 mg/kg QID, then Fluconazole 400 mg/d for 8-10 weeks. • Maintenance: Fluconazole 200 mg/d. D/C with immune reconstitution (?). • Repeated lumbar puncture for OP > 250 mm. • Alternatives with liposomal preparations. • No controlled trials on stopping maintenance in the setting of immune reconstitution. S.Raffanti MD, TNAETC

  14. Case #1 • Patient was started on Ampho + 5-FU. Received total dose of 1 gram ampho, 1 week 5-FU. LP performed three times to relieve pressure. Pt started on fluconazole 400 mg/day. • Currently on dual PI-based salvage therapy. 4 years out from Crypto. VL 3,435 copies/ml, CD4 468 cells/mm3. Remains on fluconazole. • No further relapses of cryptococcus. S.Raffanti MD, TNAETC

  15. Clinical Case #2 • 31 year old dental hygienist brought to ED with new onset seizures. CD4 122 cells/mm3, VL 22,000 copies/ml. Family reports 10 days of increasing fever, some obtundation, social withdrawal. • PE reveals post-ictal, febrile female with poor dentition, questionable LUE weakness. S.Raffanti MD, TNAETC

  16. Clinical Case #2 • MRI of head shows multiple ring-enhancing lesions in the right basal ganglia and cortico medullary junction. • Toxoplasma IgG serology is positive. • Patient recovers somewhat in ED with marked LUE weakness, slow mentation. S.Raffanti MD, TNAETC

  17. Clinical Case #2 • Is the diagnosis made? Would other studies be appropriate? • Is Toxo IgM likely to be positive? • Would a CT have been as sensitive as an MRI to pick up the lesions? • Is a PET scan warranted? • Is a brain biopsy warranted? S.Raffanti MD, TNAETC

  18. Toxoplasmic Encephalitis • T. gondii is a ubiquitous intracelluar protozoan, definitive host is the cat (millions of oocysts are excreted daily in cat feces during acute infestation!). AIDS pts can become infested either through direct contact with cat feces or ingesting tissue cysts in undercooked meat. • Clinical disease is reactivation disease; 30% of AIDS patients with + baseline serology will develop TE if not given prophylaxis. • Seroprevalence varies greatly nationally and internationally (10-40% US, >70% France, developing countries) • Most clinical disease occurs at below 100 CD4 cells /mm3 but ~ 20% in 100-200 cell range. • Pathology ranges from localized granulomatous process to diffuse necrotizing encephalitis. S.Raffanti MD, TNAETC

  19. Toxoplasmic Encephalitis • Clinical presentation includes focal neurologic deficit (50-89%), seizures (15-20%), fever (56%), generalized cerebral dysfunction, neuropsychiatric abnormalities. • Diagnosis is often presumptive based on characteristic lesions, clinical course, risk strata and positive serology. • Presumptive diagnosis is considered confirmed by tissue sample or response to TOXO therapy in appropriate time frame. • Patients should show clinical response -- neuro deficits, not necessarily fever or headache -- by day 5 (50%), day 7 (70%), and day 14 (90%). In contrast, patients with CNS lymphoma all had worsening of signs or symptoms by day 10 of therapy. S.Raffanti MD, TNAETC

  20. Toxoplasmic Encephalitis Treatment: (for at least 6 weeks, 80-90% response) • Acute: Sulfadiazine (4-8 gm/d) or Clindamycin (600 mg q6h) Plus Pyrimethamine (100-200 mg load then 50-75mg/d) with folinic acid (10-20 mg/d) • Less proven regimens: macrolides (azithromycin, clarithromycin) or atovaquone (750 mg QID) plus pyrimeth and folinic acid • Maintenance: Without maintenance therapy relapse rate is 50-70% per year. Maintenance dose is lower for sulfadiazine therapy, same dose for clindamycin • Maintenance therapy may be discontinued if on HAART with CD4>200 x 3mos for primary and >6 mos for secondary prophylaxis. S.Raffanti MD, TNAETC

  21. Case #2 • Patient initially treated empirically for toxoplasmic and bacterial encephalitis with sulfa and levofloxacin. GI intolerance hampers treatment. Undergoes biopsy which confirms diagnosis of toxoplasmosis. Patient responds to clindamycin-based therapy. • Starts on HAART and responds clinically, virologically, and immunologically. Patient gains weight, well-being and is rechallenged with sulfa which she tolerates. Remains well on maintenance therapy and HAART. S.Raffanti MD, TNAETC

  22. Case #3 • 33 year old unemployed substance abusing male is brought to the ED after he was found wandering near the mission. • PE reveals cachectic, obtunded male with dysarthria. T 100.4, CD4 14 cells/mm3, VL 648,000 copies/ml. S.Raffanti MD, TNAETC

  23. Case #3 • MRI shows single 4 cm enhancing lesion involving the corpus callosum. No peri-lesional edema is present, no mass effect. • Patient is stable but obtunded. • Lumbar puncture is performed. S.Raffanti MD, TNAETC

  24. Case #3 • What studies would you perform on the CSF? • Could a definitive diagnosis be made without brain biopsy? S.Raffanti MD, TNAETC

  25. Primary CNS Lymphoma • B-cell malignancies, high-grade (73%). • Occurs in extremely immunocompromised hosts (CD4 < 50 cells/mm3), unlike systemic NHL. • Common signs include focal neuro deficits (38-78%), altered sensorium (57%), seizures (21%), cranial nerve defects (13%). • 50% of patients will have single lesions, usually in the the gray matter. Toxo lesions are usually multiple, smaller and associated with basal ganglia but the two entities cannot be distinguished by imaging alone. S.Raffanti MD, TNAETC

  26. Primary CNS Lymphoma • Diagnosis is based on clinical presentation, neuroimaging, CSF studies, and brain biopsy. • CSF PCR for EBV is sensitive (66-99%) and specific (60-99%). • Treatment is radiation +/- chemotherapy. • Response is related to stage of disease and control of HIV. S.Raffanti MD, TNAETC

  27. Case #3 • Toxo serology negative. PCR for EBV negative. PET scan hypermetabolic. Neurosurgery confirms that lesion is not accessible. Patient does not respond to empiric therapy for toxoplasmic and bacterial encephalitis. • Patient becomes more obtunded. Family refuses further work-up or treatment. • Patient is enrolled in Hospice where he dies 2 weeks later S.Raffanti MD, TNAETC

  28. Case #4 • 42 year old mechanic is seen in clinic complaining of left side weakness and visual disturbance. CD4 98 cells/mm3, VL 234,000. • PE shows a somewhat slow speaking man, afebrile, with left upper and lower extremity weakness and homonymous hemianopsia. Disc margins are crisp. S.Raffanti MD, TNAETC

  29. Case #4 • MRI of the head shows diffuse white matter lesions affecting subcortical area bilaterally. Parietal-occipital disease is noted on the left side. No enhancement is seen; no mass effect. • CSF shows normal opening pressure, a protein of 50 mg, glucose of 82, WBC 6. S.Raffanti MD, TNAETC

  30. Case #4 • What other test(s) would you order on the CSF? • How typical was this presentation for PML? S.Raffanti MD, TNAETC

  31. Progressive Multifocal Leukoencephalopathy (PML) • PML is a demyelinating disease of the central nervous system caused by infection of oligodendrocytes by JCV, a papovavirus. • JCV does not infect neurons but has been detected in urogenital cells, B lymphocytes in the spleen and bone marrow, and in peripheral blood lymphocytes. • By age ten, 40-60% of the population have antibodies to JCV. Disease occurs only in the severely immunocompromised. Acute disease has not been documented. • Pathology shows multifocal demyelination with hyperchromatic enlarged oligodendroglial nuclei and enlarged bizarre astrocytes. • Lesions can occur anywhere but typically are found in the white matter, most often in the parietal-occipital regions. The gray matter may be involved as well as the cerebellum, brainstem and rarely spinal cord. S.Raffanti MD, TNAETC

  32. Progressive Multifocal Leukoencephalopathy (PML) • Clinical disease occurs in patients with advanced disease and onset may be insidious, over several weeks. • Clinical signs and symptoms include hemiparesis (43%), cognitive defects (22%), speech deficits (28%),visual deficits (16%), sensory deficits (14%), and seizures (5%). • Clinical hallmark of disease is patient with focal neurologic defect, white matter disease and no mass effect. S.Raffanti MD, TNAETC

  33. Progressive Multifocal Leukoencephalopathy (PML) • Diagnosis rests on clinical picture, neuro radiologic findings, CSF findings and tissue histopathology. • PCR for JCV in the CSF is a specific but variably sensitive technique for supporting diagnosis. Sensitivity ranges from 30-61%, specificity ~99%. • Distinguishing PML from ADC may be difficult, but more rapid onset, lack of cognitive dementia findings (slow mental processing), focal neurologic deficits and extensive subcortical disease suggest PML. • Treatment efforts have been largely unsuccessful. HAART may be beneficial. Ongoing trials evaluating cytosine arabinoside (ARA-C) are enrolling patients. Scattered reports have suggested some response. Approximately 7% of patients resolve without any treatment; these patients generally have less compromised immune status. S.Raffanti MD, TNAETC

  34. PET/SPECT SCANS and CNS Lesions in AIDS • 20 patients with AIDS and contrast enhancing lesions: 7/8 Toxo pts. had PET scans, 7 had hypometabolic lesions. 6 pts. with lymphoma had hypermetabolic scans. 7 patients had varied results (Pierce 1995). • SPECT scans in 37 AIDS patients with intracranial lesions: 12 had increased intense focal uptake; all twelve had Bx proven lymphoma. 25 had no uptake; 24 had TOXO by clinical , one had MTB abscess (Ruiz 1996). • 24 patients with AIDS and CNS mass lesions by MRI were evaluated with SPECT. 8 had lymphoma and all had + scans, 7/10 Toxo pts had negative scans. 1 pt. with Blasto and 3 with PML had negative scans. MTB had +/- scan. (Barker 1997) S.Raffanti MD, TNAETC

  35. Brain Biopsy in CNS Lesions in AIDS • Brain biopsy should be considered : • In presumptive TE when empiric therapy fails; • In rapidly progressing single lesion disease; • In patients with a clinical picture of TE but a reliable history of sulfa-based PCP prophylaxis; • In patients receiving corticosteroid therapy. • In patients with unexplained potentially treatable lesions. • Other pathogens/conditions to be considered: lymphoma, bacterial including T. pallidum, BA, PML, MTB. S.Raffanti MD, TNAETC

  36. Case #4 • LP is performed twice, PCR for EBV is negative x 2, PCR for JCV is positive in one lab negative in other. • Brian biopsy reveals findings consistent with PML. • Patient is started on new ART regimen with mother administering meds. Neurological deterioration slows. Patient plateaus at near total care status. CD4 increase to 338 cells/mm3, VL <400 copies/ml. S.Raffanti MD, TNAETC

  37. Case #5 • 41 year old artist from Kentucky presents with rapidly progressing bilateral lower extremity weakness, urinary retention and lower back pain. CD4 33 cells/mm3. • PE shows wasted male c/o back pain, flaccid paralysis of both legs, “saddle anesthesia”, DTR’s in both legs are absent. S.Raffanti MD, TNAETC

  38. Case #5 • What characteristics of this presentation suggest that something relatively rare is occurring? • What diseases are included in the differential? • What is your next few studies and how rapidly should they be done? S.Raffanti MD, TNAETC

  39. Case #5 • Contrasted MRI of the spine shows diffuse enhancement of the cauda equina and the conus and “clumping” of nerve roots (ice storm sign). • CSF reveals 14,000 WBC, 90% PMN, glucose 34mg/dl, protein 240 mg/dl. • Retinal examination shows findings c/w CMV retinitis. • PCR studies are not available. S.Raffanti MD, TNAETC

  40. Progressive Motor Syndromes in HIV • CMV polyradiculomyelitis is a rare (<2%) disease presenting in patients with advanced AIDS as rapidly progressive flaccid paralysis of lower extremities which includes back pain, urinary/fecal retention, sensory abnormalities. • Diagnosis is based on clinical features, characteristic CSF and MRI findings and evidence of CMV disease (retinal, PCR in blood or CSF). • Most patients were described in the pre-HAART era and survival was poor, with variable response to therapy. • Although there are no large controlled studies, scattered reports indicate that treatment with ganciclovir plus foscarnet may be superior to one agent alone. S.Raffanti MD, TNAETC

  41. Progressive Motor Syndromes in HIV • Inflammatory Demyelinating Neuropathy (IDP) can present very early in disease as AIDP (Acute IDP), with rapid progressive involvement of muscles of two or more limbs. Sensory involvement may precede motor. Course may resemble GBS. • Chronic IDP (CIDP) is a slower progressive, principally motor, syndrome of the lower extremities which may have relapsing course over several months. • Nerve conduction study (NCS) shows slow nerve conduction velocities and findings c/w primary demyelination. Some axonal degeneration may be present. AIDP findings may be less pronounced. Sural nerve bx results show perineural edema, perivascular infiltrates and macrophage mediated segmental demyelination. CMV inclusion in Schwann cells have been identified in late stage CIDP. • Treatment options include plasmapheresis, IV Ig, prednisone which have all shown efficacy but are often of temporary benefit. Up to 15% of patients will resolve without specific therapy. S.Raffanti MD, TNAETC

  42. Progressive Motor Syndromes in HIV • HIV associated myelopathy is a rare (<4%) manifestation of advanced disease which presents with leg stiffness, falling, and slowness of gait and slowly progresses to bowel/bladder dysfunction, paraplegia. • Hyperreflexia and spasticity are common. • Imaging and CSF are normal except for mildly elevated protein. • Pathology shows vacuolar myelopathy with little inflammation. • Treatment is supportive and rehabilitative. S.Raffanti MD, TNAETC

  43. Progressive Motor Syndromes in HIV • Other causes of motor weakness include: • Cord lesions caused by infectious/neoplastic processes are usually more fulminant, have discrete sensory levels, include back pain, may involve thoracic or cervical spine and should have imaging or CSF findings c/w diagnosis. • Patients from endemic areas should be tested for HTLV-I co-infection. • Rarely, mononeuritis multiplex may present as motor weakness. S.Raffanti MD, TNAETC

  44. Case #5 • Patient is hospitalized and ganciclovir induction therapy is started. Severe cytopenia results and patient is switched to foscarnet. Neurologic decline rapidly progresses to paraplegia and coma. • Patient expires 8 days later. • Autopsy is refused. S.Raffanti MD, TNAETC

  45. Case #6 • 38 year old real estate agent presents complaining of numbness, tingling and pain in the feet and lower legs progressing over several months. • CD4 424, VL<400, medications include stavudine, didanosine, and nelfinavir. • PE shows relatively well male, motor strength intact, normal light touch perception and vibration. Gait normal. S.Raffanti MD, TNAETC

  46. Case #6 • What other questions would you ask about the pain? What other physical sign might you illicit? • What is the differential for the pain in the lower extremities? • What factors are favoring neuropathy? • What factors argue against Distal Symmetrical Peripheral Neuropathy (DSPN)? • What other tests would you order? S.Raffanti MD, TNAETC

  47. Case #6 • Patient describes pain as burning, starting at the soles and involving the dorsum of both feet. Walking is impaired at times due to pain. He has not bumped into walls or fallen down. • Achilles DTR’s are absent. Patellar reflexes are intact. Babinski is absent. Proprioception is intact. • Serum B12 normal, RPR non-reactive. • EMG/NCS shows mild axonal degeneration. No evidence of demyelination. S.Raffanti MD, TNAETC

  48. Peripheral Neuropathy • Two most frequent types: DSPN and toxic neuropathy. • Clinical manifestations are similar. Both present with sensory symptomatolgy with little sensory dysfunction. Both usually involve the lower extremities, show absent Achilles DTR’s and axonal degeneration on NCS. Patients can have negative NCS/EMG and abnormal findings on skin biopsy and examination of epidermal nerve fibers. Differentiating between the two syndromes is based on history and concurrent meds. S.Raffanti MD, TNAETC

  49. Peripheral Neuropathy • DSPN is a frequent (30%) complication of advanced HIV. Course is gradually progressive and may be severe enough to disable patient. Factors associated with DSPN include low CD4 count, high viral load, concurrent ADC. • Toxic neuropathy is associated with antiretrovirals and other medications. Factors associated with toxic neuropathy include length of time on neurotoxic medications, pre-existing neuropathic syndrome, concurrent administration of multiple neurotoxic agents. • Both syndromes are now thought to be part of a “mitochondrial toxicity” phenomenon. S.Raffanti MD, TNAETC

  50. Peripheral Neuropathy • Medications which cause neuropathy include zalcitabine>didanosine>stavudine, metronidazole, INH, vincristine, dapsone. • Treatment options include: • d/c of offending agents (sx may worsen initially), • Treatment with amitriptyline, mexilitine, carbamazepine, and gabapentin, narcotics, acupuncture. Randomized trials have demonstrated efficacy for lamotrigine and human nerve growth factor. S.Raffanti MD, TNAETC

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