Etiology Central Nervous System Infections Bacteria Viruses Warren L. Felton III, MD Fungi Professor and Associate Chair of Clinical Parasites Activities, Department of Neurology Associate Professor of Ophthalmology Prions Chair, Division of Neuro-Ophthalmology Virginia Commonwealth University School of Medicine 1 2 Background Diagnosis Pathogenesis – initial entry: respiratory tract, GI tract, skin Meningeal inflammation is the – path to CNS: bloodstream, peripheral nerves, hallmark of CNS infection adjacent bone, adjacent sinus Time course varies by etiology 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 CNS possesses less immune protection than rest of body – prions: years 3 4 Diagnosis Major Sites Diagnostic steps – determine site of infection Meningitis: meninges – obtain culture and sensitivity: blood, CSF, Encephalitis: brain diffusely other tissue Brain abscess: brain locally – treat expectantly, when indicated – brain parenchyma – determine specific etiology and microbial – epidural abscess sensitivity and modify therapy – subdural empyema 5 6 1 Meningitis: Clinical Features CSF Gram stain detects bacteria Early 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 Latex agglutination antegen tests: H. neurologic signs or papilledema influenza, Strep pneumionae, N. Late meningitidis, group A betahemolytic – stupor or coma strepococci – seizures PCR: M tuberculosis, enteroviruses, – focal neurologic signs, CN palsies herpes simplex virus 7 8 CSF Profiles in CNS Infections Bacteria, WBC Protein Glucose Fungal Culture Viral Meningitis Bacterial 50-10,000 (polys) increased low + 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 - 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 Prognosis is usually good 9 10 Bacterial Meningitis Bacterial Meningitis Treatment 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 Prognosis fatal if untreated: 5-25% – corticosteroids provide modest benefit mortality Immunization: H. influenzae, N. meningitidis (some strains) 11 12 2 Postcontrast CT, Bacterial Meningitis: Complications H. influenzae meningitis Seizures develop in 1/3 of patients Focal neurologic signs in 25% – CN VIII (hearing loss), III, VI – in children: language disorders, developmental delay, mental retardation Cerebral infarct Hydrocephalus Brain abscess Note: some bacterial meningitis requires prophylactic treatment of family or close contacts; rifampin – N. meningitidis – H. influenzae 13 14 Tuberculosis and Fungal Tuberculosis and Fungal Meningitis Meningitis Subacute meningitis Pulmonary source, <50% have active pulmonary infection Fungal etiology: Coccidiodes CSF culture, PCR, serologic tests immitis, Histoplasma capsulatum, Treatment Cryptococcus neoformans, – TB: rifampin, isoniazid, pyrazinamide, and Aspergillis, Candida streptomyoin or ethambutol – fungal: amphotericin B or fluconozole At risk: immunosuppressed, – cryptococcal: amphotenein B, plus flucytosine debilitated, malnourished Mortality 20-50% 15 16 T1W Contrast MRI T1W and T2W MRI Right tuberculoma Tuberculous Meningitis 17 18 3 T1W MRI without and with contrast Spirochete Meningitis Lyme disease: Borrelia burgdorferi – Chronic meningitis – CN palsies, esp CN VII – CSF Lyme titer Syphilis: Treponema pallidum – Chronic meningitis – CSF VDRL Treatment: penicillin, ceftriaxone Cryptococcal meningitis with basal ganglia cysts 19 20 Encephalitis Encephalitis – Other causes of encephalitis • other viruses including cytomegalovirus, 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 Pathogenesis • Flaviviruses including Japanese B, St. Louis, Murray Valley, West Nile – hematogenesis • Bunyaviruses including California virus – neuronal necrosis, glial cell lysis, cerebral edema 21 22 Encephalitis: Clinical Features Encephalitis: Evaluation Fever Imaging: Headache – brain MRI T2: early hyperdense areas of – meningismus minimal to absent edema – head CT or brain MRI: later signs of brain Obtundation and coma necrosis and hemorrhage Focal neurologic signs – herpes simplex encephalitis: mesial Seizures temporal lobar lesions 23 24 4 T2W MRI Encephalitis: Evaluation EEG: diffuse bilateral slowing, seizures CSF 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 Symptomatic Prognosis depends on etiology – seizures – mumps and Venezuelan equine encephalitis: excellent – increased ICP – West Nile, western equine, St. Louis, Corticosteroid use is controversial California encephalitis: 2-15% mortality, 25% morbidity (dementia, seizures, focal 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 29 30 5 Brain Abscess Brain Abscess Pathogenesis 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 31 32 Brain Abscess: Clinical Features Brain Abscess: Evaluation Symptoms subacute Imaging HA, lethargy – head CT: lesion with hypodense center and contrast-enhancing capsule with Fever surrounding edema Seizures, focal or generalized – brain MRI: similar Focal neurologic signs EEG: localized slowing, seizures Increased ICP Note that LP is potentially dangerous due to risk of brain herniation 33 34 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 Broad spectrum antibiotics for both anaerobic and aerobic bacteria Protozoa – cefotaxime, ceftriaxone plus metronidazole, chloramphenicol • Plasmodium falciparum (malaria) – staphylococci: nafcillin • Toxoplasma gondii Surgical aspiration • Naegleria fowleri (primary amebic – gram stain and culture meningoencephalitis) Cerebral edema: corticosteroids, • Acanthamoeba or Hartmanella species mannitol (granulomatous amebic encephalitis) Prognosis: 30-65% mortality, 50% morbidity 39 40 Parasites Prion diseases Helminths Creutzfeldt-Jacob disease (CJD) • Taenia solium (cysticercosis) – most common prion disease, • Angiostrongylus cantonensis 1/1,000,000/year (eosinophilic meningitis) Gerstmann-Straussler syndrome Rickettsia Fatal familial insomnia • Ricketssia rickettsii (Rocky Mountain Kuru spotted fever) 41 42 7 Prion Diseases Prion Diseases Clinical presentation – do not present with typical signs of 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 43 44 Prion Diseases: Transmission Prion Diseases: CJD variant (vCJD) Prions present: CSF, brain, pituitary gland, peripheral nerves inervate dura and cornea United Kingdom Prions not present: saliva, perspiration, urine, Transmitted from infected cattle with stool bovine spongiform encephalopathy Blood considered infectious, but no human case from blood transfusion (BSE, mad cow disease) Transmission: cornea, dura, pituitary, surgical instruments, heredity (GSS, FFI) Most cases sporadic, with transmission