Transcript Encephalitis in childhood

Encephalitis in
childhood
Roderic Smith, MD, Ph.D
Pediatric Neurology Clinic
Problems with studies
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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
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Defined by significant CNS
dysfunction
High rate of mortality
 Higher rate of morbidity
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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 postinfectious
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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
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
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Summary of California
experience 1998
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Total Explained 21%
Not Infectious 7%
Infectious 14%
Viral: 8%
Bacterial: 3%
Prion 1%
Parasitic: <1%
Fungal <1%
Unknown: 79%
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~7% later determined to be
nonencephalitis:
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Neoplastic
paraneoplastic (“limbic
encephalitis”)
Vascular; strokes, thrombosis
mitochondrial diseases
Autoimmune (Hashimoto’s
encephalopathy, Lupus
cerebritis)
Viral causes
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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
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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
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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
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Optic neuritis with or without
papillitis
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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
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Mixed peripheral and central
demyelination
Brainstem encephalitis
Higher risk for direct infection
(arbovirus, HSV, Listeria)
 Minimal imaging findings
 Slow recovery
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Multiple sclerosis
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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
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“Non-specific” respiratory virus
Influenza A, B<acute necrotizing
encephalitis>
Smallpox, small pox vaccination
Measles, rarely vaccine-associated
“Pasteur vaccine”
Family history, genetics
Treatment
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Largely supportive
High dose steroids can shorten
course
In refractory forms, IVIG has been
used
Association with MS is slight, but
not zero
Viral causes
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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
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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
“Common specific
disorders”
HSV
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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)
Treatment
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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
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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
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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
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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
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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
XLP
LYMPHOPROLIFERATIVE DISEASE, XLINKED; XLPD
LYP
DUNCAN DISEASE
EPSTEIN-BARR VIRUS INFECTION,
FAMILIAL FATAL
EBV SUSCEPTIBILITY; EBVS
INFECTIOUS MONONUCLEOSIS,
SUSCEPTIBILITY TO
IMMUNODEFICIENCY, X-LINKED
PROGRESSIVE COMBINED VARIABLE
IMMUNODEFICIENCY 5; IMD5
PURTILO SYNDROME
Other EBV-related
disorders
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“Chronic fatigue” --controversial
often with atypical development of
immune response
Postural orthostatic tachycardia
syndrome
Arboviruses
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World wide-the most common
cause of encephalitis
Transmitted via mosquito
Asymptomatic or mild infection
Extremely common
Aseptic meningitis/encephalitis
Arbovirus
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In US, most cases West Nile
St Louis encephalitis
California encephalitis
Eastern equine encephalitis
Western equine encephalitis
Measles
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Acute measles encephalitis—
secondary process
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Rarely vaccine associated
SSPE—Clinical reactivation of a
latent form of the virus
SSPE
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Subacute sclerosing
panencephalitis
Myoclonus, seizures, behavior
changes
CSF changes, findings on MRI
Usual a progressive, lethal
disorder
Mycoplasma pneumonia
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Recent studies--significant role in
encephalitis clinical presentation
widely varied
Headaches, ADEM-like process,
encephalitis
mechanisms;
direct invasion (acute)
 indirect/autoimmune
 toxin-mediated
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Mycoplasma (cont)
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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
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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
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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:
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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
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Borrelia species—Lyme disease
and a growing number of regional
Borrelia.
Neurocystocercosis
TB
Cryptococcal
Nocardia
Non-infectious causes
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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
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Neuroblastoma
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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
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Focal intractable epilepsy
Leading edge of inflammation on
neuroimaging
Role of anti-GLu R3 vs heteroclitic
antibody response vs other
NOMID/CINCA
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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
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AICARDI-GOUTIERES SYNDROME 1;
AGS1
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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
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Encephalitis
classification
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“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
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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
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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