encephalitis and viral persistence - demystifying medicine
TRANSCRIPT
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Encephalitis and Viral Persistence
Bryan Smith, MD. Staff Clinician, NINDS
and
Avi Nath, MD. Clinical Director, NINDS
NINDS Section of Infections of the Nervous System
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• Describe the definition and criteria for encephalitis
• Discuss two common causes of viral encephalitis on the East Coast
• Examine viral persistence in the CNS• How viruses spread between cells in the CNS
• How viruses evade the immune system
• How viruses form reservoirs
Objectives
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Case Presentation
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• 44 yr old former computer programmer
• 2009: Imbalance, dysarthria
• Involuntary movements (dystonia, chorea)
• Cognitive dysfunction- subcortical dementia by 2013
Case Presentation
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Brain MRI done 6.2013
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Date WBC
(cells/mm3
)
RBC
(cells/mm3)
Protein
(mg/dL)
Glucose
(mg/dL)
Total Tau*
(pg/mL)
14-3-3 protein* IgG
index
IgG synthesis
(mg/dL)
Oligoclonal
bands
Normal
ranges
<5 0 15-45 40-70 < 1150
pg/mL
undetected 0.26-
0.62
<8 0
Jun-
2013
3 18 81 58 normal ambiguous 3.74 93.1 15
May-
2014
2 18 71 59 not tested not tested 5.65 102 17
Intrathecal Synthesis of Antibodies
Extensive work up for infections including PCR for arboviruses in CSF was negative
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Brain Biopsy
CD3GFAP
CD8CD20
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IV STEROIDS 1 g x 3 daysLarge volume spinal tap IV Ig 5 day courseSinemet EDTA chelation for mercuryPlasmapheresisCyclophosphamide
No observable benefit.
Died in June 2014
Treatment
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Basal ganglia
100 um
Hemosiderin
AUTOPSY
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EncephalitisPathologic definitionInflammation of brain parenchyma caused by infection or autoimmunity
Clinical DefinitionAltered mental status lasting >24 hours with no alternative cause identified
Supportive featuresFeverSeizuresFocal neurologic deficitCSF pleocytosisAbnormal neuroimaging consistent with encephalitisAbnromal EEG consistent with encephalitis
Adapted from Venkatesan et al. Clinical Infectious Diseases 2013;57:1114-1128.
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EncephalitisWhat is not encephalitis?
Toxic exposuresSystemic infectionsMetabolic derangementsCerebrovascular disease
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Diagnostic Approach
HistoryTravelExposuresOutdoor activitiesExisting medical problems
Physical ExamNeurologic localizationCranial nerves and abnormal movements
LabBlood culturesHIV testingLP with opening pressureNeuroimaging
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Diagnostic Clues: A Sample
Travel to Asia
Japanese encephalitis virusDengueMalariaNipah virus
Cat biteBartonella, especially with seizures
ImmunocompromisedCMVHHV6/7Toxoplasma gondiiTuberculosisFungal infectionsWNV
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Viral EncephalitisAcute
ArbovirusesHerpes virusesEnteroviruses
Filoviruses (Ebola/Marburg)Rhabdoviruses (Rabies)
Paramyxoviruses (Measles)ArenavirusesBunyaviruses
RubellaRotavirusInfluenza
SubacuteHIVPolyoma viruses (JCV, BK)SSPE
No cause found60-70%.
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Causes of specific viral encephalitis syndromesLimbic encephalitis Cerebellar Parkinsonism Rhombencephalitis EncephalomyelitisHSV-1 VZV JEV Listeria WNV
EBV WNV WNV EV71HHV-6 Paraneoplastic St. Louis JEV JEV
St. Louis Nipah EV71Tick-borne encephalitis
TB ZikaRabies
Mumps VZVHSVCMVEBV
Modified from Cho and McKendall, Handbook of Clinical Neurology 2014
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ArbovirusesMosquitoes
ZikaDengueChikungunyaYellow feverWest NileJapanese B encephalitis
St LouisEastern EquineWestern EquineVenezuelan EquineUsutu
La CrosseMurray Valley encephalitisCache ValleyJamestown Canyon
Male Female
Ades
Culex
TicksPowassanColorado tick feverTick-borne encephalitis
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West Nile Virus Epidemiology
• Isolation in 1937, West Nile district of Uganda
• HISTORICALLY (e.g., prior to 1996):• Infrequent outbreaks
• Mild, dengue fever-like illness
• CNS involvement rare
• Wide distribution throughout Asia, Eastern Europe, Africa
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1999 2000
2001 2002
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WNV Activity, 2017
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~80%
Asymptomatic
~20%
“West Nile Fever”
<1%
CNS
disease
WNV Human Infection “Iceberg”
}Asymptomatic
Infection (likely)
~80% of infections
Generation of life-long
immunity (presumed)
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~80%
Asymptomatic
~20%
“West Nile Fever”
<1%
CNS
disease
WNV Human Infection “Iceberg”
}
West Nile Fever
10-30% of infections
Fever, headache, rash,
fatigue
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~80%
Asymptomatic
~20%
“West Nile Fever”
<1%
CNS
disease
WNV Human Infection “Iceberg”
}Neuroinvasive Disease
(ND)
<1% of all infections
Meningitis, encephalitis,
poliomyelitis
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Solomon. N Engl J Med 2004;351:370.
Clinical Manifestations of WNV
Meningitis (fever, headache, vomiting)
Altered mental statusMovement disorders (25%)Cranial nerve deficits (10%)
Anterior Myelitis
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WNV and Movement Disorders
• Tremor• Sometimes associated with other viral infections• Coarse; postural / kinetic• Occasionally functionally impairing
• Myoclonus• Quick, uncontrolled muscle twitching• Upper extremities, face• Bothersome to patients
• Parkinsonism• “Cogwheel” ridigity, bradykinesia, postural instability• Functionally impairing
• OUTCOMES: WNV = 15-20%
Sejvar et al. JAMA 2003
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WNV “Poliomyelitis”
• Involvement of anterior horn cells-- acute, asymmetric paralysis (generally no sensory loss)
• Relatively infrequent - ~12% of cases of WNV
• May be younger in age, previously healthy
Sejvar et al. EID 2006
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Case (Lury et al., Emerg Rad 2004)
8 yr girl in (Florida)(August): Fever, sore throat, seizures x 4 daysDecreased level of consciousnessCSF: 56 neutrophils; 31 Lymphs; 7 monocytes
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Eastern Equine Encephalitis: Key points IgM positive
Most destructive of all arboviruses with necrotic lesions
Spinal cord is spared
Risk FactorsChildrenImmunotherapy (rituximab)
High mutation rate because no proof reading of RNA
Spread by mosquitos, can infect birds
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• 2019: Seven deaths reported• Virus found Maine to Alabama
Eastern Equine Encephalitis (EEE) Epidemiology
Methuen, MA
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Raised intracranial pressure (aggressive management)IV steroidsshuntmannitol (?)
Seizures (status epilepticus)
IVIG (give early)neutralization of virus by preventing viral entry to cellsclearance of virus from infected neuronscytotoxic T cells are not effective in clearing virus from neurons
Treatment
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• There is an unprecedented increase in arboviral infections worldwide
• Neurological Complications are the most dreaded manifestations• Involves the entire neuro-axis
• The young and elderly are the most vulnerable
• Manifestations can be acute or subacute
• Diagnosis can be challenging
• No antiviral drugs are currently available
Conclusions