Etiology Central Nervous System Infections ƒ Bacteria ƒ Viruses

Warren L. Felton III, MD ƒ Fungi Professor and Associate Chair of Clinical ƒ Parasites Activities, Department of Neurology Associate Professor of Ophthalmology ƒ Prions Chair, Division of Neuro-Ophthalmology Virginia Commonwealth University School of Medicine

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Background Diagnosis ƒ Pathogenesis – initial entry: respiratory tract, GI tract, skin ƒ Meningeal inflammation is the – path to CNS: bloodstream, peripheral nerves, hallmark of CNS infection adjacent bone, adjacent sinus ƒ Time course varies by etiology ƒ CNS infection is infrequent due to – viruses: hours to 1 day protective mechanisms – aerobic bacteria: hours to a few days – reticuloendothelial system – anaerobic bacteria, TB, fungi: days to – cellular and humoral immune responses weeks – blood-brain barrier – parasites and syphilis: weeks to years ƒ CNS possesses less immune protection than rest of body – prions: years

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Diagnosis Major Sites

ƒ Diagnostic steps – determine site of infection ƒ Meningitis: meninges – obtain culture and sensitivity: blood, CSF, ƒ Encephalitis: brain diffusely other tissue ƒ Brain abscess: brain locally – treat expectantly, when indicated – brain parenchyma – determine specific etiology and microbial – epidural abscess sensitivity and modify therapy – subdural empyema

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1 Meningitis: Clinical Features CSF ƒ Gram stain detects bacteria ƒ Early ƒ Cultures: bacteria (1-3 days), viruses – prodromal illness, fever (days to weeks), TB and fungi (1-6 – headache, stiff neck weeks) – no alteration of mental status, focal ƒ Latex agglutination antegen tests: H. neurologic signs or papilledema influenza, Strep pneumionae, N. ƒ Late meningitidis, group A betahemolytic – stupor or coma strepococci – seizures ƒ PCR: M tuberculosis, enteroviruses, – focal neurologic signs, CN palsies herpes simplex virus

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CSF Profiles in CNS Infections Bacteria, WBC Protein Glucose Fungal Culture Viral Meningitis Bacterial 50-10,000 (polys) increased low + ƒ Etiology meningitis – most common: enteroviruses (echoviruses, Viral meningitis 20-1,000 (lymphs) Slt increased N - Coxsackie viruses) Fungal/TB 50-10,000 (polys & Increased low + meningitis lymphs) – less common: Herpes simplex type 2, Meningo- 10-1,000 (lymphs) Increased N - mumps, HIV vascular syphilis

Normal or slt Viral encephalitis 10-200 (lymphs) N - ƒ Treatment increased 0-10 (lymphs & – symptomatic Brain abscess Normal N - polys) Normal or slt – acyclovir and related agents for Herpes Epidural abscess 0-20 (lymphs) N - increased simplex Subdural 10-1,000 (polys) Slt increased N - empyema ƒ Prognosis is usually good

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Bacterial Meningitis Bacterial Meningitis ƒ Treatment ƒ Etiology – broad spectrum antibiotics early in course – most common: S. pneumoniae (except • preterm to newborn: ampicillin plus infants), N. meningitidis, H. infleunzae cefotaxime, w/ or w/o gentamicin – 0-3 months: S. agalactiae, E. coli, L. • 2 months to adults: caftriaxone or monocytogenes cefotaxime plus vancomycin, ampicillin for suspected Listeria ƒ Prognosis fatal if untreated: 5-25% – corticosteroids provide modest benefit mortality ƒ Immunization: H. influenzae, N. meningitidis (some strains) 11 12

2 Postcontrast CT, Bacterial Meningitis: Complications H. influenzae meningitis ƒ Seizures develop in 1/3 of patients ƒ Focal neurologic signs in 25% – CN VIII (hearing loss), III, VI – in children: language disorders, developmental delay, mental retardation ƒ Cerebral infarct ƒ Hydrocephalus ƒ Brain abscess ƒ Note: some bacterial meningitis requires prophylactic treatment of family or close contacts; rifampin – N. meningitidis – H. influenzae

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Tuberculosis and Fungal Tuberculosis and Fungal Meningitis Meningitis

ƒ Subacute meningitis ƒ Pulmonary source, <50% have active pulmonary infection ƒ Fungal etiology: Coccidiodes ƒ CSF culture, PCR, serologic tests immitis, Histoplasma capsulatum, ƒ Treatment Cryptococcus neoformans, – TB: rifampin, isoniazid, pyrazinamide, and Aspergillis, Candida streptomyoin or ethambutol – fungal: amphotericin B or fluconozole ƒ At risk: immunosuppressed, – cryptococcal: amphotenein B, plus flucytosine debilitated, malnourished ƒ Mortality 20-50%

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T1W Contrast MRI T1W and T2W MRI

Right tuberculoma Tuberculous Meningitis 17 18

3 T1W MRI without and with contrast Spirochete Meningitis

ƒ Lyme disease: Borrelia burgdorferi – Chronic meningitis – CN palsies, esp CN VII – CSF Lyme titer ƒ Syphilis: Treponema pallidum – Chronic meningitis – CSF VDRL ƒ Treatment: penicillin, ceftriaxone Cryptococcal meningitis with basal ganglia cysts

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Encephalitis Encephalitis – Other causes of encephalitis • other viruses including cytomegalovirus, ƒ Etiology varicella-zoster, adenovirus, herpes simplex (1 and 2), rabies – 90% viral • childhood exanthems including measles, • Arboviruses (togaviruses) most common varicella, mumps, and rubella worldwide, vector born (mosquito, tick) • spirochetes: T pallidum, B Burgdorferi including Eastern, Western, Venezuelan • parasites: toxoplasmosis, falciparum malaria equine ƒ Pathogenesis • Flaviviruses including Japanese B, St. Louis, Murray Valley, West Nile – hematogenesis • Bunyaviruses including California virus – neuronal necrosis, glial cell lysis, cerebral edema

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Encephalitis: Clinical Features Encephalitis: Evaluation

ƒ Fever ƒ Imaging: ƒ Headache – brain MRI T2: early hyperdense areas of – meningismus minimal to absent edema – head CT or brain MRI: later signs of brain ƒ Obtundation and coma necrosis and hemorrhage ƒ Focal neurologic signs – herpes simplex encephalitis: mesial ƒ Seizures temporal lobar lesions

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4 T2W MRI Encephalitis: Evaluation

ƒ EEG: diffuse bilateral slowing, seizures ƒ CSF ƒ Serologic tests: – IgM-antibody-capture enzyme-linked immunoabsorbent assay (MacELISA): serum and CSF arboviruses – CSF PCR: Herpes simplex Lyme Encephalitis 25 26

T2W MRI CT

H. Simplex encephalitis H. Simplex Encephalitis 27 Hemorrhagic transformation 28

Encephalitis: Management Encephalitis: Management

ƒ Symptomatic ƒ Prognosis depends on etiology – seizures – mumps and Venezuelan equine encephalitis: excellent – increased ICP – West Nile, western equine, St. Louis, ƒ Corticosteroid use is controversial California encephalitis: 2-15% mortality, 25% morbidity (dementia, seizures, focal ƒ Antivirals neurologic deficits) – acyclovir for encephalitis of unknown – eastern equine, Japanese B, Murray Valley cause encephalitis: 20-40% mortality – ganciclovir for cytomegalovirus – herpes simplex encephalitis: 20% mortality – famciclovir for varicella-zoster treated with acyclovir, 50% morbidity – rabies encephalitis: fatal

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5 Brain Abscess Brain Abscess

ƒ Pathogenesis ƒ Etiology – extension from within cranium (sinusitis, – bacteria: mastoiditis), following skull fracture or • 50% anaerobic; anaerobic streptococci craniotomy, or blood born matastasis and Bacteroides fragilis – begins as localized encephalitis, necrosis, • S. aureus after head trauma or and inflammation craniotomy – fibroblasts at the periphery form a capsule – fungi wall – parasites: cysticercosis – cerebral edema surrounds the abscess

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Brain Abscess: Clinical Features Brain Abscess: Evaluation

ƒ Symptoms subacute ƒ Imaging ƒ HA, lethargy – head CT: lesion with hypodense center and contrast-enhancing capsule with ƒ Fever surrounding edema ƒ Seizures, focal or generalized – brain MRI: similar ƒ Focal neurologic signs ƒ EEG: localized slowing, seizures ƒ Increased ICP ƒ Note that LP is potentially dangerous due to risk of brain herniation

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Postcontrast CT Postcontrast T1W MRI

Left periventricular bacterial abscess with Right frontal bacterial abscess 35 ventricular rupture and ventriculitis 36

6 T1W MRI T2W MRI

Cysticercosis with scolex Mulitple cysticercosis cysts 37 38

Brain Abscess: Management Parasites ƒ Broad spectrum antibiotics for both anaerobic and aerobic bacteria ƒ Protozoa – cefotaxime, ceftriaxone plus metronidazole, chloramphenicol • Plasmodium falciparum (malaria) – staphylococci: nafcillin • Toxoplasma gondii ƒ Surgical aspiration • Naegleria fowleri (primary amebic – gram stain and culture meningoencephalitis) ƒ Cerebral edema: corticosteroids, • Acanthamoeba or Hartmanella species mannitol (granulomatous amebic encephalitis) ƒ Prognosis: 30-65% mortality, 50% morbidity

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Parasites Prion diseases

ƒ Helminths ƒ Creutzfeldt-Jacob disease (CJD) • Taenia solium (cysticercosis) – most common prion disease, • Angiostrongylus cantonensis 1/1,000,000/year (eosinophilic meningitis) ƒ Gerstmann-Straussler syndrome ƒ Rickettsia ƒ Fatal familial insomnia • Ricketssia rickettsii (Rocky Mountain ƒ Kuru spotted fever)

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7 Prion Diseases Prion Diseases ƒ Clinical presentation – do not present with typical signs of ƒ Pathogenesis infection – no nucleic agent identified – lack fever and elevated WBC – protein normally made by neurons, – subacute to chronic dementia, 6 months to malformed into abnormal infectious particle 2 years – myoclonic jerks common – CSF appears normal by standard tests – prions not killed by ethanol, formalin or boiling – prions killed by autoclaving

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Prion Diseases: Transmission Prion Diseases: CJD variant (vCJD)

ƒ Prions present: CSF, brain, pituitary gland, peripheral nerves inervate dura and cornea ƒ United Kingdom ƒ Prions not present: saliva, perspiration, urine, ƒ Transmitted from infected cattle with stool bovine spongiform encephalopathy ƒ Blood considered infectious, but no human case from blood transfusion (BSE, mad cow disease) ƒ Transmission: cornea, dura, pituitary, surgical instruments, heredity (GSS, FFI) ƒ Most cases sporadic, with transmission not identified

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CJD Diagnosis HIV: History ƒ 1981: CDC reported uncommon ƒ Clinical: rapidly progressive opportunistic infections and dementia, myoclinic jerks, normal malignancies in young homosexual CSF men ƒ CSF electrophoresis: 14-3-3 protein ƒ Later: Acquired Immunodeficiency in many patients Sydrome (AIDS) ƒ Brain MRI atrophy, basal ganglia ƒ 1983: Human immunodeficiency virus, enhancement a retrovirus, isolated; later HIV-1 ƒ EEG: quasiperiodic discharges ƒ Later: HIV-2 identified in West Africa

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8 HIV: Epidemiology HIV ƒ 50% of persons infected with HIV develop symptomatic neurologic disease ƒ 90% of persons dying of AIDS show neuro- ƒ Brain disease without mass effect pathologic abnormalities – HIV encephalopathy ƒ Neurologic disease more frequent when CD4 – cytomegalovirus (CMV) encephalitis < 20 cells/mm³, but may occur at any time – progressive multifocal ƒ Neurologic disease may be a direct effect of leukoencephalopathy (PML) HIV or secondary infection ƒ Any part of the nervous system and muscles may be affected, sometimes resulting in two or more coexisting neurologic conditions

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HIV Dementia HIV Dementia ƒ Nomenclature: AIDS dementia complex (ADC), HIV encephalopathy, HIV-associated major ƒ Neurologic exam cognitive/motor disorder – Impaired mental states ƒ Incidence uncertain, > 1/3 AIDS – Ocular motor saccades and pursuit patients at death abnormal ƒ 3 categories of symptoms, onset – Coordination and rapid alternating insidiousness movements impaired – cognitive: decreased memory and – Frontal release signs common concentration – May progress to akinetic mutism, – behavioral: social withdrawal paraparesis, and incontinence – motor: clumsiness, imbalance, tremor

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HIV Dementia HIV Dementia ƒ Evaluation (cont) ƒ Evaluation – laboratory, exclude other causes: renal, – brain MRI: atrophy, diffuse T2 hyperintense liver, electrolytes, syphilis, vitamin B12 and folate white matter signal – neurophyschological testing – CSF: pleocytosis, mononuclear, < 20 cells/mm³; increased protein, < 65 mg/dl ƒ Treatment – zidovudine (AZT) • HIV-1 30% patients – HAART (highly active antiretroviral • HIV-1 p24 core protein 50% patients therapy) – symptomatic

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9 T2W MRI HIV: Cytomegalovirus

ƒ Pathophysiology – reactivation of latent infection – retinitis most common presentation – any portion of neuraxis may be affected ƒ Symptoms and signs: acute to subacute altered mental status, coma, meningismus, seizures, CN palsies AIDS Dementia 55 56

HIV: Progressive Multifocal HIV: Cytomegalovirus Leukoencephalopathy

ƒ Evaluation ƒ CNS demyelinating disease due to – CSF: normal or pleocytosis (PMN’s), reactivation of JC virus, a increased protein, CMV PCR papovavirus – head CT/Brain MRI: subparenchymal – 5% AIDS patient develop PML enhancement and ventriculitis ƒ Clinical presentation: insidious ƒ Median survival 5 weeks hemiparesis, other focal neurologic ƒ Treatment: ganciclovir, Foscaret symptoms/signs, impaired mental status, visual loss, seizures

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HIV: Progressive Multifocal HIV: Brain disease with mass Leukoencephalopathy affect ƒ Toxoplasma encephalitis – most ƒ Evaluation common – CSF: normal or pleocytosis (PMN’s), ƒ Lymphoma – next most common increased protein, CMV PCR ƒ Opportunistic infections: – head CT/Brain MRI: subparenchymal – Abscess: pyogenic, candida, nocardia, enhancement and ventriculitis cryptococcal, fungal ƒ Median survival 5 weeks – Syphilitic gumma ƒ Treatment: ganciclovir, Foscaret – Parasites ƒ Vascular occlusive disease

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10 HIV: Toxoplasmosis HIV: Toxoplasmosis ƒ Pathophysiology and Epidemiology ƒ Evaluation – CT/MRI: single or multiple, nodular or ring – Toxoplasma gondii: intracellular protozoa enhancing lesions with edema – 5-25% AIDS patients develop toxoplasma – DDx single lesion: primary CNS lymphoma, encephalitis SPECT may distinguish – propensity for basal ganglia, causing chorea – LP contraindicated if mass affect ƒ Clinical presentation: days to weeks – CSF nonspecific: 1/3 mononuclear pleocytosis < 100 cell/mm³, elevated protein 50-200 mg/dl; T. – fever, malaise gondii PCR – focal cortical neurologic symptoms and signs ƒ Treatment: sulfadiazine, pyrimethamine – altered mental status – 90% patients respond in 2-4 weeks

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T2W MRI HIV: Primary CNS Lymphoma ƒ Pathophysiology and Epidemiology – a non-Hodgkins lymphoma arising in and confined to CNS – 2-13% AIDS patients develop PCNSL • 2nd most common brain mass in adults AIDS patients • most common brain mass in pediatric AIDS patients ƒ Clinical presentation: altered mental status, focal neurologic symptoms/signs, Toxoplasmosis seizures, CN palsies Basal ganglia and midbrain 63 64

HIV: Primary CNS Lymphoma HIV: Cerebrovascular Disease

ƒ Evaluation ƒ Pathophysiology – CT/MRI: solitary or multiple, hyperdense ring or – ischemia or hemorrhage nodular enhancement, or isodense and with • 19% autopsy series variable edema – DDx: toxoplasmosis, SPECT may distinguish – due to: underlying infection, marantic – LP contraindicated if mass affect endocarditis, infectious vasculitis (esp • CSF: 25% positive cytology, Epstein-Barr virus syphilis), vasculitis due to HIV, PCR hypercoagulable state ƒ Treatment: radiotherapy ƒ Treatment similar to other patients – leptomeningeal PCNSL, chemotherapy with stroke

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11 HIV: Meningitis HIV: Myelopathy

ƒ HIV-related vascular myelopathy ƒ Cryptococcal: most common – 20% AIDS autopsies – 2-10% AIDS patients – clinical presentation: spastic paraparesis, ƒ Other: TB, syphilis, Listeria, hyperreflexia, bowel and bladder meningeal lymphomatosis incontinence, sensory level uncommon – evaluation: MRI normal or shows spinal cord atrophy or T2 hyperdensities – pathology: loss of myelin, spongy degeneration of dorsal and lateral columns – treatment: none yet proven effective

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HIV: Myelopathy HIV: Neuropathies and Myopathies ƒ Often concomitant with CNS infection ƒ Other: infections including HTLV-1; – Complicates clinical presentation epidural, intradural, and ƒ Neuropathies intramedullary tumors including – Distal symmetric polyneuropathies lymphoma; demyelination; ischemia; – Acute and chronic inflammatory B12 defiency demyelinating polyneuropathy (A/C IDP) – Mononeuropathy multiplex – Autonomic polyneuropathy – Toxic neuropathies – Cytomegalovirus polyradiculopathy

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HIV: Myopathies Summary –Sites affected »Meningitis ƒ Myopathies »Encephalitis – HIV associated myositis »Brain abscess – zidovudine myopathy –Etiologies – HIV wasting syndrome »Viruses including HIV »Bacteria »Fungi »Parasites »Prions 71 72

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