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Encephalitis in childhood

Encephalitis in childhood. Roderic Smith, MD, Ph.D Pediatric Neurology Clinic. Problems with studies. Encephalitis remains an “orphan” disease Poor model for US style of research support, since it is not hypothesis driven

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Encephalitis in childhood

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  1. Encephalitis in childhood Roderic Smith, MD, Ph.D Pediatric Neurology Clinic

  2. Problems with studies • Encephalitis remains an “orphan” disease • Poor model for US style of research support, since it is not hypothesis driven • Not all conditions are defined within parameters requiring public health reporting-mixture of infectious, immune and other considerations

  3. Encephalitis is a serious disorder • Defined by significant CNS dysfunction • High rate of mortality • Higher rate of morbidity • Specific diagnosis can be made 20-30% of the time. With decrease in common childhood disorders, rate of diagnosis has gone down.

  4. Direct infectious vs post-infectious • Direct effects acts on neuropile or neurons and white matter: HSV, West Nile, Arbovirus • Post-infectious encephalitis is best recognized as a white matter based process: influenza B, other URI • Disputed mechanisms: Mycoplasma, VZV

  5. Unknown encephalitis project: California, Tennesse, New York • Hospitalized w/encephalopathy (depressed or altered consciousness > 24 hrs) AND 1 or more of the following: • fever (38o C) • seizure(s) • focal neurological findings • CSF pleocytosis • EEG findings c/w encephalitis • abnormal neuroimaging • Exclusions: < 6 months old or immunocompromised

  6. Summary of California experience 1998- • Total Explained 21% • Not Infectious 7% • Infectious 14% • Viral: 8% • Bacterial: 3% • Prion 1% • Parasitic: <1% • Fungal <1% • Unknown: 79%

  7. ~7% later determined to be nonencephalitis: • Neoplastic • paraneoplastic (“limbic encephalitis”) • Vascular; strokes, thrombosis • mitochondrial diseases • Autoimmune (Hashimoto’s encephalopathy, Lupus cerebritis)

  8. Viral causes • HSV-1: 16 cases • Enterovirus: 13 cases • EBV : 6 cases • Measles/SSPE; 5 cases • VZV : 4 cases • Rabies: 3 cases • HIV (acute presentation): 2 cases • West Nile : 1 case (imported)

  9. Viruses with unclear role • Influenza: cases with acute infection, all negative CSF PCR • Adenovirus: 1 case with serologic evidence, throat PCR positive, CSF PCR negative • Rotavirus: 2 cases with PCR positive • Hepatitis C: 4 cases with PCR positive

  10. Distinguishing ADEM vs other encephalitis variants • Not always a clear distinction • Can be difficult to distinguish from vasculitis and stroke • Metabolic or even toxic disorders can mimic ADEM

  11. ADEM •History (antecedent infection or immunization) •Physical and neurologic examination •MRI imaging •Cerebrospinal fluid (CSF) analysis •Response to therapy •Clinical and radiographic course over time

  12. Other variants • Optic neuritis with or without papillitis • Clinical features usually allow it be distinguished from papilledema –loss of acuity, color desaturation • Retro-orbital form has some association with latter development of MS—”the patient sees nothing and the physician sees nothing [abnormal]”.

  13. Variants continued • Mixed peripheral and central demyelination • Brainstem encephalitis • Higher risk for direct infection (arbovirus, HSV, Listeria) • Minimal imaging findings • Slow recovery

  14. Multiple sclerosis • Rare cases diagnosed in first years of life, increasing after puberty • Classically defined by “multiple lesions in time and space” • Diagnosis has been changed by complex MRI criteria • Multiple effective drugs for treatment, at least of relapsing remitting.

  15. Triggers • “Non-specific” respiratory virus • Influenza A, B<acute necrotizing encephalitis> • Smallpox, small pox vaccination • Measles, rarely vaccine-associated • “Pasteur vaccine” • Family history, genetics

  16. Treatment • Largely supportive • High dose steroids can shorten course • In refractory forms, IVIG has been used • Association with MS is slight, but not zero

  17. Viral causes • Topavirus EEE/WEE/VEE • Flavivirus: SLE, WN, JV, Dengue • Bunyaviruses: LaCrosse, • Paramyxoviridae: Mumps, measles • Arenaviruses: LCM, Machupo, etc • Enteroviruses: Polio, coxsackie, etc • Reoviruses: CTF • Rhabdovirus: Rabies • Filoviridae: Ebola, Marburg • Retroviridae: HIV • Herpes: HSV1/2,VZV,EBV,CMV,HHV6 • Adenovirus

  18. Non-viral • RMSF/Ehrlichia chaffensis/Typhus/Relapsing fever • Mycoplasma/Listeria/Leptospirosis/Lyme • Nocardia/Actinomyces • Tuberculosis/Cryptococcus/Histoplasma • Naegleria/Acanthamoeba/Toxoplasma • Plasmodium falcipirum/Trypanosomiasis • Whipples/Bechets/CSD/ • Vasculitis/Carcinoma/Drug reactions • Immunization

  19. “Common specific disorders”

  20. HSV • Most common form of sporadic, focal encephalitis in US • accounts for 10% of reported cases • Post-traumatic HSV-1 • beyond neonatal period, HSV1 is most common (>>>HSV2) • (HSV-2 can cause recurrent “Mollaret” meningitis)

  21. Treatment • Acyclovir. (Note recent changes in dose and duration.) Range of dose 10-20mg/kg tid—renal issues at higher doses 15 days of therapy for HSV-2 in neonates

  22. Varicella Zoster • 10 years ago--one of leading causes of encephalitis • acute cerebellar ataxia OR generalized encephalitis +/- rash • diagnosis: classic rash and/or PCR? • permanent sequelae are uncommon even when encephalopathy is severe. Some deaths reported. • VERY DIFFERENT DISORDER IN IMMUNOSUPPRESSION

  23. Enterovirus • Well-established cause of viral meningitis: 60-90% • role in encephalitis controversial • often in summer months • can be generalized or focal • most outcomes benign • experimental therapy: Pleconaril

  24. Rabies • Often begins with non-specific prodrome • Rapidly progressive CNS manifestations • (Almost) invariably progresses to death • Survival for more than 48-72 hours after severe neurologic symptoms develop suggests alternative explanation for mechanism

  25. EBV • CNS involvement in <1% of cases • Diffuse or focal (temporal/cerebellar) • Often in conjunction with fever • Pharnygitis, lymphadenopathy, atypical • Lymphocytes, positive heterophil • Diagnosis: CSF EBV PCR or serology • Generally not treated—controversy regarding steroid use

  26. EBV-triggered progressive disorders XLPLYMPHOPROLIFERATIVE DISEASE, X-LINKED; XLPDLYPDUNCAN DISEASEEPSTEIN-BARR VIRUS INFECTION, FAMILIAL FATALEBV SUSCEPTIBILITY; EBVSINFECTIOUS MONONUCLEOSIS, SUSCEPTIBILITY TOIMMUNODEFICIENCY, X-LINKED PROGRESSIVE COMBINED VARIABLEIMMUNODEFICIENCY 5; IMD5PURTILO SYNDROME

  27. Other EBV-related disorders • “Chronic fatigue” --controversial often with atypical development of immune response • Postural orthostatic tachycardia syndrome

  28. Arboviruses • World wide-the most common cause of encephalitis • Transmitted via mosquito • Asymptomatic or mild infection • Extremely common • Aseptic meningitis/encephalitis

  29. Arbovirus • In US, most cases West Nile • St Louis encephalitis • California encephalitis • Eastern equine encephalitis • Western equine encephalitis

  30. Measles • Acute measles encephalitis—secondary process • Rarely vaccine associated • SSPE—Clinical reactivation of a latent form of the virus

  31. SSPE • Subacute sclerosing panencephalitis • Myoclonus, seizures, behavior changes • CSF changes, findings on MRI • Usual a progressive, lethal disorder

  32. Mycoplasma pneumonia • Recent studies--significant role in encephalitis clinical presentation widely varied • Headaches, ADEM-like process, encephalitis • mechanisms; • direct invasion (acute) • indirect/autoimmune • toxin-mediated

  33. Mycoplasma (cont) • Mycoplasma -- almost as important as HSV1(“leading cause of sporadic encephalitis”) • From California study-2 cases PCR CSF, 11? additional cases w/acute serology positive or throat PCR positive • Mechanism of action ???—most acute serology (IgM and IgG change). Throat PCR positive, but spinal fluid negative • Clinically—wide range of clinical symptoms/outcome

  34. Amebic encephalitis • Naegleria fowleri- swimming in warm freshwater lakes • Acquire via invasion across cribiform plate • CSF profile similar to bacterial meningitis • Wet mount: trophozoite can be seen, but are easily mistaken for polys • Balamuthia mandrillis, granulomatous encephalitis

  35. Chlamydia • Chlamydia species • Chlamydia pneumonia or Chlamydia psittaci • 5 cases with acute infection by serology • PCRs done on only subset—all negative • Wide range of clinical manifestations/outcome

  36. “Cat-Scratch fever”Bartonella henselae: • Relatively important • 9 cases serology positive, all PCR negative • Fairly sterotypic presentation: acute presentation, febrile, often seizures • Normal spinal fluid, h/o cat contact • Rapid recovery to baseline

  37. Other agents • Borrelia species—Lyme disease and a growing number of regional Borrelia. • Neurocystocercosis • TB • Cryptococcal • Nocardia

  38. Non-infectious causes • Autoimmune disorders, Lupus, Hashimoto’s, TTP • Direct or distant effects of tumors • Rasmussen’s encephalitis • Metabolic disorders • Mitochondrial “Leigh syndrome”, MELAS • FAO defects • Leukodystrophies, e.g. ALD

  39. Neuroblastoma • Opsiclonus/ myoclonus • Severe cereballar ataxia • Encephalitis—limbic or posterior fossa syndrome • All result of usually small, well differentiated tumors, i.e. Negative metabolites in urine

  40. Rasmussen’s encephalitis • Focal intractable epilepsy • Leading edge of inflammation on neuroimaging • Role of anti-GLu R3 vs heteroclitic antibody response vs other

  41. NOMID/CINCA • Neonatal Onset Multisystem Inflammatory Disease (NOMID) chronic infantile neurological, cutaneous and arthropathy (CINCA) syndrome. • early onset of urticarial rash, arthropathy, epiphyseal overgrowth, lymphadenopathy, and central nervous anomalies. • CIAS1, a gene located at chromosome 1q44, that is present in about 50% of children with NOMID. • In vitro functional studies have suggested that the genetic defect identified may be directly associated with an increase in IL-1 activity. • Ongoing treatment/diagnostic protocol at NIH-- Anakinra

  42. AGS/Cree encephalopathy • AICARDI-GOUTIERES SYNDROME 1; AGS1 • ENCEPHALOPATHY, FAMILIAL INFANTILE, WITH CALCIFICATION OF BASAL GANGLIA AND CHRONIC CEREBROSPINAL FLUID LYMPHOCYTOSIS • Both have high levels of interferon alpha in CSF • Gene map locus 3p21

  43. Encephalitis classification • “Reye’s like” diffuse edema, szs, acellular CSF • Prominent temporal lobe involvement • Epilepsia partialis continuins • Acquired Myoclonus • Seizures with rapid recovery • Cerebellar involvement • Movement disorders (dyskinesias) • Prominent psychiatric disorders

  44. Lesson for Alaska Bioregionalism—many disorders are environmentally limited Populations with special risk factors; e.g. SSPE, neurocystocercosis, TB meningitis Unique animal populations with risk of human to human spead Specific groups may have risk for neurologic disorders.

  45. Conclusion • Acute encephalopathy/ encephalitis is a diagnostic challenge • Treatable causes need to be addressed rapidly • Treatment, in most cases, will be symptomatic, even if an etiology is suspected • A high level of vigilance is required for new patterns

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