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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

Encephalitis in childhood

Roderic Smith, MD, Ph.D

Pediatric Neurology Clinic


Problems with studies
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


Encephalitis is a serious disorder
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.


Direct infectious vs post infectious
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


Unknown encephalitis project california tennesse new york
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


Summary of california experience 1998
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%



Viral causes
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)


Viruses with unclear role
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


Distinguishing adem vs other encephalitis variants
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


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


Other variants
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]”.


Variants continued
Variants continued

  • Mixed peripheral and central demyelination

  • Brainstem encephalitis

    • Higher risk for direct infection (arbovirus, HSV, Listeria)

    • Minimal imaging findings

    • Slow recovery


Multiple sclerosis
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.


Triggers
Triggers

  • “Non-specific” respiratory virus

  • Influenza A, B<acute necrotizing encephalitis>

  • Smallpox, small pox vaccination

  • Measles, rarely vaccine-associated

  • “Pasteur vaccine”

  • Family history, genetics


Treatment
Treatment

  • Largely supportive

  • High dose steroids can shorten course

  • In refractory forms, IVIG has been used

  • Association with MS is slight, but not zero


Viral causes1
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


Non viral
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



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)


Treatment1
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


Varicella zoster
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


Enterovirus
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


Rabies
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


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


Ebv triggered progressive disorders
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


Other ebv related disorders
Other EBV-related disorders

  • “Chronic fatigue” --controversial often with atypical development of immune response

  • Postural orthostatic tachycardia syndrome


Arboviruses
Arboviruses

  • World wide-the most common cause of encephalitis

  • Transmitted via mosquito

  • Asymptomatic or mild infection

  • Extremely common

  • Aseptic meningitis/encephalitis


Arbovirus
Arbovirus

  • In US, most cases West Nile

  • St Louis encephalitis

  • California encephalitis

  • Eastern equine encephalitis

  • Western equine encephalitis


Measles
Measles

  • Acute measles encephalitis—secondary process

    • Rarely vaccine associated

  • SSPE—Clinical reactivation of a latent form of the virus


SSPE

  • Subacute sclerosing panencephalitis

  • Myoclonus, seizures, behavior changes

  • CSF changes, findings on MRI

  • Usual a progressive, lethal disorder


Mycoplasma pneumonia
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


Mycoplasma cont
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


Amebic encephalitis
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


Chlamydia
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


Cat scratch fever bartonella henselae
“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


Other agents
Other agents

  • Borrelia species—Lyme disease and a growing number of regional Borrelia.

  • Neurocystocercosis

  • TB

  • Cryptococcal

  • Nocardia


Non infectious causes
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


Neuroblastoma
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


Rasmussen s encephalitis
Rasmussen’s encephalitis

  • Focal intractable epilepsy

  • Leading edge of inflammation on neuroimaging

  • Role of anti-GLu R3 vs heteroclitic antibody response vs other


Nomid cinca
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


Ags cree encephalopathy
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


Encephalitis classification
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


Lesson for alaska
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.


Conclusion
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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