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Immunology and Infectious Disease
Meeting: Encephalitis
Dr David Tran
Immunology Registrar
John Hunter Hospital
10th of November 2014
Outline
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Encephalitis
What are we missing?
Arbovirus Encephalitis
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Murray Valley Encephalitis Virus
West Nile Virus
Encephalitis Lethargica
Autoimmune Encephalitis
Encephalitis
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Encephalitis is inflammation of the
brain parenchyma.
It is a rare complication following
infection and autoimmune illness
Symptoms include fever, reduced
neurological function, altered
consciousness, seizures,
radiological and histopathological
changes.
Encephalitis can result in fatality
and long term disability and
sequelae.
Microglial Nodule
Perivascular cuff
Murray Valley Encephalitis
MVE Epidemics
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Murray Valley Encephalitis (MVE) has the
potential to cause outbreaks of neurological
symptoms in human
Isolated by E French, MJA, 1952
Causative agent of 1951 and 1974 epidemic
of encephalitis in the Murray Valley district.
Clinical and pathological of links with
Australia X-Disease (1917,1918,1925)1
MVE found in sporadic cases in endemic
locations: central, northern Australia, and
PNG2
1.
Anderson, S (1954) “Murray Valley encephalitis and Australian X disease”, J Hyg 52(4) p445-460
2.
Anderson, S. G., Price Av, N.-K., & Slater, K. (1960). "Murray Valley encephalitis in Papua and New Guinea. II. Serological survey, 1956-1957".
Med J Aust 47(2), 410-3.
Murray Valley Encephalitis
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+ve sense
ss RNA (11kb)
flavivirus,
flaviviridae
family
Japanese
encephalitis
West Nile
Virus
Yellow
Fever
Hepatitis C
Virus
(family)
Diagram: R.McKendall, W Stroop,”Handbook of Neurovirology” 1994 Marcel Dekker Inc NY
p382
Transmission Vectors
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Dead End Host6
 Humans
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Horses
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Dogs
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Fowl (chickens)
Culex
annulirostris
(ARTHROPOD
VECTOR )3
Water Birds4
(VERTEBRATE
HOSTS)
(National MVE Surveillance
Program)5
3. McLean, D. M. (1957). "Vectors of Murray Valley encephalitis". J Infect Dis 100(3), 223-7.
4. Anderson, S. G. (1953). "Murray Valley encephalitis: a survey of avian sera, 1951-1952". Med J Aust 1(17), 573-6.
5. Broom, A. K., et al, (2001). "Australian encephalitis: Sentinel Chicken Surveillance Programme". Commun Dis Intell 25(3), 157-60.
6. Anderson, S. G., Donnelley, M., Stevenson, W. J., Caldwell, N. J., and Eagle, M. (1952). "Murray-Valley encephalitis; surveys of human and
animal sera". Med J Aust 1(4), 110-4.
Murray Valley Encephalitis Virus
1951 and 1974
MVE Outbreak in
the Murray Valley
district.
Australia XDisease
(1917,1918,1925)
Endemic
locations: central,
northern Australia,
and PNG
Public Health
warnings in during
the wet season.
Distribution of Cases
Serology survey (98/114)7
Aboriginal population in the NT
(1956)
Broken Hill (NSW) (1953)8
those born before 1919
increase proportion of
neutralizing antibody
High serological response in
Murray Valley community during
1974 outbreak9
7 Miles, J. A., and Dane, D. M. (1956). "Further observations relating to Murray Valley encephalitis in the northern territory of Australia". Med J Aust 43(10), 389-93.
8 Anderson, S (1954) “Murray Valley encephalitis and Australian X disease”, J Hyg 52(4) p445-460
9 Doherty, R. L., Carley, J. G., Filippich, C., White, J., and Gust, I. D. (1976). "Murray Valley encephalitis in Australia, 1974: antibody response in cases and community". Aust N
Z J Med 6(5), 446-53.
Clinical Manifestations
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N. Bennet “Murray Valley Encephalitis 1974:
Clinical Features” MJA 1976(2)12,p445
 22 cases of MVE admitted to Fairfield Hospital,
Melb
 Incubation period 10-20 days
 Age range (3-74); young > old; male > females
 Prodromal symptoms
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Fever lasting 4-13 days, daily peak 40.5 oC
Associated headache, nausea & vomiting,
photophobia
Early altered consciousness: drowsiness (12);
confusion, disorientation, behaviour changes (7)
Ataxia(6); aphasia(6), grand mal (tonic-clonic)
seizure(8)
Clinical Manifestations
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Severity
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Fatal 4 of 22 pt died (18%)
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Severe (7)
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Residual physical / mental disabilities
(5) respiratory failure (improved with artificial
respiration)
Mild (11)
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LOC, spastic followed by flaccid quadriplegia,
respiratory failure.
Complete recovery (7); mild degree of
imparied motor skills, mental acuity,
Asymptomatic sero-conversion
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Clinical : Sub-clinical infection ratio 1:1000
Neuroradiology: MVE
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Diffusion-weighted image of the Brain
Cervical spine show diffuse hyperintensity of the spinal cord
Einsiedel L 2003
Survillance and Management
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Supportive management
Access to Invasive Ventiliation
Survillance program: Sential groups
Public Health Notification
Vector Control
?Research into vaccinations
Other Emerging Infections
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Japanese Encephalitis
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West Nile Virus
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Affects 20,000-50,000 people pa, Asia
3 cases in Torres Strait Islands 1995
Never been reported in western
hemisphere till Sept 1999: 63 cases
Continued seasonal cases, and spread
of WNV
Niphan Virus; Hendra virus;
West Nile Virus
First reported in
western hemisphere
(Sept 1999) 63
cases NY city
Japanese Encephalitis
- Affects approx 50,000
people per year
- 3 cases in Torres Strait
Islands (1995)
West Nile Virus
Geographic Distribution of WNV in USA 2003
2003 Human Cases
2866 Neurological illness
Total of 9862 human
infections
264 confirm deaths due to
WNV
Geographic Distribution of WNV in USA 2007
WNV Infection 3630; Neurological Illness 1217; Fatal Case 124
Viremic Blood Donor Activity in the United States
2007 WNV
Human Neuroinvasive Disease 2007
(encephalitis and/or meningitis) WNV
West Nile Virus: Clinical presentation
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Most individuals infected with West Nile
virus are asymptomatic.
The incubation period is 2–14 days before
symptom onset.
Prodromal flu-like symptoms
<1% of infected individuals develop
severe neuroinvasive diseases
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West Nile meningitis
West Nile encephalitis
acute flaccid paralysis
West Nile meningitis and encephalitis
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Fever and signs of meningeal
irritation
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headache, stiff neck, nuchal rigidity,
and photophobia
Altered level of consciousness,
disorientation, and focal neurology
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dysarthria, seizures, tremor, ataxia,
involuntary movements, and
parkinsonism
Acute flaccid paralysis
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Main clinical feature was acute
asymmetric flaccid paralysis
Minimal or no sensory disturbance
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Most patients had substantial muscle ache in
the lower back;
Disturbed bowel and bladder functions in some
patients.
Outcomes
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Highly variable recoveries rate
 Complete recovery in weeks
 Ongoing Wheelchair requirements
Asymmetric flaccid paralysis
Lancet Neurology 2007: 6 p171-181
Diagnosis of WNV
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Serum WNV IgM or 4 fold rise in titre
RT-PCR
Pleocytosis on LP
MRI changes
 Pons
 Substantial nigra
 Thalamus
 Anterior Horns – spinal cord
Neuroradiology Findings
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MRI Brain FLAIR: shows abnormal signals in bilateral
thalamus and other areas of basal ganglion.
MRI Spine with Contrast: spinal roots are significantly
enhanced
Lancet Neurology 2007: 6 p171-181
Outcomes in WNV Encephalitis / Meningitis
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Colorado Series
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221 hospitalized patients with WNV
Encephalitis
 18% died (risk factors intubation, previous
stroke, immunosupression)
 25% return home
 46% requiring rehab or long term placement
Meningitis
 No deaths
 90% return home
 9% rehab / placement
Annual of Neurology 2006 60(3),p288
Summary
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Neuroinvasive Flavivirus are an emerging
infection
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WNV Spread in North America
 West Nile meningitis
 West Nile encephalitis
 Acute flaccid paralysis
Similar Clinical presentation, pathology and
radiological findings in MVE
Future risk of MVE outbreak or introduction of
other arbovirus such as Japanese Encephalitis
into the Australia eco-system.
Encephalitis Lethargica
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Between 1917 to 1928, an
epidemic of encephalitis
lethargica spread throughout the
world - “sleepy sickness”.
Associated with 1918 Influenza
pandemic
Post-encephalitic Parkinson's
disease may develop after a bout
of encephalitis
First described by neurologist
von Economo
Ms NM
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21 year old international student from
Indonesia. High achiever on the Dean’s
Honour Role for biomedical science.
No significant past medical history / family
history
Non-smoker, No Alcohol or illicit drug use
No regular medications
Presentation
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Presented to the emergency department
with sister and close family friend
5 day history of declining mental state,
increased anxiety and agitation, poor sleep
and reduced oral intake. Confused, with
bizarre behaviour and thoughts.
Initial CT Brain and Blood Test: Normal
Admitted to the psychiatric unit: Acute
psychosis
Psychosis
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Day 1 of admission: Increased confusion
and agitation. Only muttering single words.
Developed shuffling gait, and incontinence.
? Catatonic Psychosis - Electroconvulsive
therapy ECT
Decline in conscious state - febrile and neck
stiffness.
Transferred to the General Medical /
Neurology unit
Seizures
Increasingly nonresponsive (GCS 10)
Non-Convulsive status
epilepticus on EEG.
Ovarian Cyst noted on US
- benign
PET Scan: normal: no
definite malignancy noted
MRI / LP - no cause found
for reported symptoms
Empirical Management
Intravenous methylprednisolone - 3 days
Intravenous Immunoglobulin - over 5 days
Two week of Acyclovir
Cyclophosphamide considered but deferred due to
patient’s age
Rituximab Infusion (Anti-CD20 therapy)
Progress
Gradual Improvement in mental state and
functional capacity over many months in
rehabilitations
Limbic Encephalitis
Clinical Syndrome
Subacute memory impairment
Disorientation and agitation
Seizure, hallucinations, sleep disturbance
Classification
Infectious
Autoimmune
Paraneoplastic / non-paraneoplastic
mechanisms
Autoimmune
Channelopathies
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Neuronal antibodies against cellsurface antigens
Autoimmune
Channelopathies
Essential roles in the
process of
neurotransmission
Voltage-gated potassium
channels (VGKC)
regulate the release of
neurotransmitters
N-methyl-D-aspartate
receptors (NMDA-Rs) postsynaptic receptors
Ovarian Teratoma & NMDA
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Twelve women (14–44 years) developed
prominent psychiatric symptoms, amnesia,
seizures, frequent dyskinesias, autonomic
dysfunction, and decreased level of
consciousness
Eleven patients had teratoma of the ovary
(six mature) and one a mature teratoma in
the mediastinum
N-methyl-d-aspartate (NMDA)
receptor
All had serum/cerebrospinal fluid antibodies that
predominantly immunolabeled the neuropil of
hippocampus/forebrain, in particular the cell surface of
hippocampal neurons, and reacted with NR2B (and to a
lesser extent NR2A) subunits of the NMDAR.
Mr VG
61 year old man presents with sudden onset
of memory impairment and confusion
Previously high functioning, works as a
lecturer in university
Background
Type I DM
Hypertension
Hyperlipidaemia
Presentation
Co-lateral history from family
Patient awoke in the morning and noted to be
vague
In the afternoon, found at the kitchen table,
still in his pyjamas. Confused, with poor recall
of recent events
Normal neurological exam
Mini-Mental State: Impaired object recall,
short term memory
No evidence of hypoglycaemic episode (BSL
10.5)
Investigations
Classical Neuronal Antibodies (Hu,
Ri, Yo): Negative
Lineblot with Ma/Ta, CV2,
Amphiphysin: Negative
NMDA-Receptor: Negative
CT Neck Chest / Abd / Pelvis:
mesenteric lymph node
Normal Testicular ultrasound
Management
IV Acyclovir
3 days of methylprednisolone
5 days of IVIG
Gradual Improvement in memory
Patient was transferred to rehab
Voltage-gate potassium channel result
available
498 pM (<85)
VGKC autoantibodies
Peripheral nervous system disease
Neuromyotonia
Cramp-fasciculation syndrome
Central nervous system
Morvan syndrome: neuromyotonia,
autonomic, sleep, cognitive dysfunction
Epilepsy
Limbic encephalitis
Radioimmunoassay
Nuclear isotope assay
Requires the use of gamma counters
Process
Radiolabelled (usually I125) antigen (VGPC) mixed and
incubated with patient serum
VGPC antigen-antibody complex (precipitated using
buffering solution) - leaving unbound VGPC antigen in
solution
Precipitated complex is centrifuged and supernatant
aspirated
Residual radioactivity in pellet proportional to level of
VGPC Ab in patient serum
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24 sera from
unselected
patients controls
10 patients with
symptoms of
limbic
encephalitis.
“On the limited evidence available, we suggest that this condition is
treated initially with IvIg or plasma exchange to try to obtain a quick
clinical response, followed by high-dose prednisolone for at least 6
months. If the antibody remains high, alternative immunosuppression
may be useful.”
What is the ideal approach???
Approach to Investigation
Clinical Syndrome
CSF: inflammatory
changes
MRI ⁄ PET: temporal
lobe abnormalities
EEG: temporal lobe
abnormalities
exclude other causes
BIOCHIP Mosaics™ (Brisbane)
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Autoimmune Encephalitis
Mosaic 1 (Euroimmun)
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Glutamate receptor (type NMDA)
Glutamate receptor (type AMPA1
Glutamate receptor (type AMPA2)
Contactin-associated protein 2
(CASPR2)
Leucine-rich glioma-inactivated
protein 1 (LGI1
GABA B receptor
COST??
– Approximately $80-100 a well
Acknowledgements
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Immunology Unit
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A/Prof Michael Boyle
Dr Theo de
Malmanche
Dr Glenn Reeves
Dr Kathryn Patchett
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Hunter Area
Pathology Service
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Immunology
Laboratory
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Karla Lemmert