What is New? - Kaleida Health

3/11/2013
Definitions of Encephalitis and Meningitis
Acute Encephalitis: What is New?
Howard Faden and Osman Farooq
Distinguishing Characteristic of Encephalitis and Meningitis
Encephalitis
Meningitis
Change in level of
consciousness
Change in behavior
EEG changes
CSF normal or abnormal
Stiff neck
CSF abnormal
Basic Work‐Up
• Signs and Symptoms: Characteristic of specific diseases
• Physical examination: Fever, rash including insect bites, nuchal rigidity, red throat, cervical adenopathy, splenomegaly, seizures, etc
• Bottom Line: Is there anything in the history or physical examination that suggests a specific etiology?
Encephalitis
Meningitis
Inflammation of the
brain parenchyma
Inflammation of the
meninges
Basic Work‐Up
• History
• Age
• Season: Summer and Fall‐arboviruses and enteroviruses
• Ill contacts: Enteroviruses and EBV
• Animal contact: Cats, bats, rodents, etc.
• Travel: Regional outbreaks
Basic Laboratory Work‐Up
• CBC with differential
• CSF for cells, glucose protein
• Acute (IgG and IgM) specific antibodies and convalescent antibody titers (IgG, +/‐ IgM)
• Respiratory screen (<3years)/ Throat culture(>3 years) for respiratory viruses
• NP/Throat for enterovirus PCR
• Stool culture for enteroviruses
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Basic Laboratory Work‐Up
• CSF PCR for HSV 1 and 2 and enteroviruses
• Anti‐N‐Methyl‐D‐Aspartate Receptor Antibody
California Encephalitis Project,1998‐
2011 (Confirmed or Probable Cases)
Etiology
1998‐2005 a
HSV 1, 2a
40, 5
2007‐2011 b
7, 0
VSV
23
5
Mycoplasma b 2c
0
Enteroviruses b
43
30
SLE, WEE
0
0
WNV
19
5d
EBV
17
0
Bartonella
13
0
Anti‐NMDAR
ND
32
aCID 2006:43, 1565
bCID 2012:54, 899
cPediatrics 2007:120,305, additional 109 possible cases
D2012 ‐
Map of WNV Cases 11/6/2012
238 epidemic cases
West Nile Virus 11/6/2012
State
Texas
California
New York
All States
West Nile Virus
CNS cases
765
238
55
2559
Total Cases
1684
395
98
5054
Lyme Disease 2012
• Clinical manifestations in children: 80% asymptomatic, 20% fever and <1% CNS disease (adults >30%). • CNS manifestations: meningitis, encephalitis (may resemble HSV) and flaccid paralysis (anterior horn neurons destroyed as in polio)
• CNS outcomes: 60% of adults persist with issues such as weakness, confusion and light headedness at 1 year
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Neurological Diseases of Lyme Disease
•
•
•
•
•
Facial nerve palsy
Meningitis
Other cranial nerve palsy
Radiculopathy
Cognitive deficits
Post‐Lyme Disease Syndrome (PLDS)
PLDS includes fatigue, musculoskeletal pain, headache, cognitive difficulty changes; however,
No evidence of Lyme disease causing PLDS if treated appropriately
________________________________ Medical letter 2007,49:49
Pediatric Infectious Disease Journal 2008, 27:1089
Pediatrics 2012, 130:256
Case
Anti‐N‐Methyl‐D‐Aspartate Receptor (NMDAR) Encephalitis
• 17y previously healthy female presents with confusion, agitation, auditory hallucinations and suicidal ideation
• PE and lab parameters were normal
• Discharged home with a diagnosis of Brief Psychotic Disorder
Case: Work up
• Symptoms progressed Æ admitted to psych hospital
• On admission, was noted to have hyperventilation
• Days later: apnea, seizure Æ transferred to tertiary care center
• Brain CT & MRI normal
• CSF showed mildly elevated lymphocytes and protein Æ Rx acyclovir presumed viral enceph
Case: Hospital Course
• 4 days later: 2nd seizure, decreased LOC Æ
intubated, ICU
• Developed orofacial dyskinesias and involuntary movements of the upper extremities
• EEG: non‐convulsive status epilepticus
• Repeat labs & CSF unchanged
• Paraneoplastic antibody panel revealed Anti‐
NMDA‐R antibodies in the serum and CSF
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Case: treatment
• Search for a primary tumor: right ovarian teratoma
• Right oophorectomy performed
• Rx: plasma exchange followed by IVIG
• No improvement in neurological status
NMDAR Encephalitis
Case: Outcome
• ICU course complicated by diabetes insipidus, Staph aureus pneumonia, C diff colitis and bacteremia
• 3 months after initial presentation: 3rd degree heart block with hypotension
• Pace maker
• >14 weeks following admission: cardiac arrest Æ death despite aggressive resuscitation attempts
N‐Methyl‐D‐Aspartate Receptor(NMDAR)
• Autoimmune disorder characterized by:
– Neuropsychiatric disturbances
• changes of mood, behavior, and personality, resembling acute psychosis
– Progresses to include seizures, decreased level of consciousness, dyskinesias, autonomic instability, and hypoventilation
• The NMDA receptor is a glutamate and aspartate receptor found throughout the brain. • It participates in learning, memory and is responsible, in large part, for the plasticity of the brain. Diamond B et al. Immunity and acquired alterations in cognition and emotion
lessons from SLE. Adv Immunol 2006;89:289–320
Historically
• Initially identified in young women with ovarian teratoma who presented with psychosis or memory problems, rapidly progressing to multiple neurological deficits
OVERVIEW
• Frequency : Unclear
• Several features
– Involvement of relatively young women. (20‐50 yrs, median 25.8)
– Unusual presentation with prominent psychiatric manifestations.
– Normal or atypical MRI findings. • (75% of cases consist of mild, transient T2 of FLAIR abnormalities outside the • 59% had tumor
medial temporal lobes, sometimes with cortical enhancement)
– Benign appearance of the ovarian tumors. (About 59% of the patients)
• Despite severity Æ patients often recovered after tumor removal and immunotherapy, suggesting an immune‐mediated pathogenesis
Dalmau et al. Anti‐NMDA‐receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7:1091‐98
– High prevalence of prodromal viral‐like symptoms (part of early immune reaction)
Dalmau et al. Paraneoplastic Anti–N‐methyl‐D‐aspartate Receptor Encephalitis
Associated with Ovarian Teratoma Ann Neurol. 2007 January ; 61(1): 25–36.
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NMDAR Encephalitis in Children
• 40% of cases <18 years
– 25% had tumor (all ovarian teratomas)
– The younger the pt, the less likely a tumor present
• Sx: Behavior and speech problems, seizures, abnormal movements
– Dysautonomia and hypoventilation are less frequent or severe
• Recognition of psychosis in children is challenging
– Tantrums, aggression, agitation, speech problems
Florence et al. Anti–N‐methyl‐D‐aspartate Receptor (NMDAR) Encephalitis in Children and Adolescents. Ann Neurol. 2009 July; 66(1): 11‐18.
Florence et al. Anti–N‐methyl‐D‐aspartate Receptor (NMDAR) Encephalitis in Children and Adolescents. Ann Neurol. 2009 July; 66(1): 11‐18.
Clinical Presentation
Clinical Presentation
II. Psychotic phase: I. Prodromal phase – Nonspecific cold or viral‐like symptoms (fever, fatigue or headache) and, after a mean period of 5 days, developed psycho‐behavioral Within 2 weeks (mean 6.8 days) of developing symptoms
– Emotional disturbance (apathy, lack of emotion, depression, loneliness, fear)
– Cognitive decline – (difficulty in using a cellular phone or passing through an automatic ticket gate)
– Prominent schizophrenia like symptoms symptoms.
– (disorganized thinking, compulsive ideation, delusions, hallucinations, and loss of self‐awareness)
– Amnesia (not prominent at onset)
– Strange behavior: staring at their reflection in a mirror with an odd smile
T. Lizuki et al. Anti‐NMDA receptor encephalitis in Japan: Long‐term outcome
without tumor removal Neurology. 2008 February 12; 70(7): 504–511
Clinical Presentation
T. Lizuki et al. Anti‐NMDA receptor encephalitis in Japan: Long‐term outcome
without tumor removal Neurology. 2008 February 12; 70(7): 504–511
Clinical Presentation
IV.Hyperkinetic phase
III.Unresponsive phase
– All patients gradually develop orolingual dyskinesias such as lip – Catalepsy‐like symptoms licking or chewing, and athetoid dystonic postures of the fingers.
– (Mute, akinetic, unresponsive to verbal commands while keeping their eye open)
– Intractable bizarre orofacial‐limb dyskinesias
• Sustained jaw movements, bruxism, jaw‐opening dystonia, grimacing, – Bizarre and inappropriate smiling
– Athetoid dystonic postures, echo phenomenon
– (mimicking the examiner’s movement)
– Normal Brainstem reflexes, but no eye movement with intermittent ocular deviation or disconjugation, athetoid choreaform
movements of the limbs.
• Varied in speed, distribution, and motor pattern (like psychogenic movement disorder)
– All patients had symptoms of autonomic instability
• Labile blood pressure, bradycardia or tachycardia, hyperthermia, and diaphoresis.
visual threat
T. Lizuki et al. Anti‐NMDA receptor encephalitis in Japan: Long‐term outcome
without tumor removal Neurology. 2008 February 12; 70(7): 504–511
T. Lizuki et al. Anti‐NMDA receptor encephalitis in Japan: Long‐term outcome
without tumor removal Neurology. 2008 February 12; 70(7): 504–511
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Clinical Presentation
V. Gradual recovery phase
– Typically slow, symptoms may relapse, especially in patient with undetected or recurrent tumors and patients with no associated tumors.
– Duration of the hospital stay: 2‐14 month (mean 7 months)
– Spontaneous progressive improvement until recovery
– Characteristic features of patients who recovered from encephalitis
• Persisting amnesia of the entire process
• Compatible with disruption of the mechanism of synaptic plasticity – thought to underlie learning and memory
Florence et al. Anti–N‐methyl‐D‐aspartate Receptor (NMDAR) Encephalitis in Children and Adolescents. Ann Neurol. 2009 July; 66(1): 11‐18.
Dalmau et al. Anti‐NMDA‐receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7:1091‐98.
Antibody Titer
• Correlation between antibody titers and neurological outcome and by the decrease in number of postsynaptic clusters of NMDA receptors caused by patient’s antibodies
T. Lizuki et al. Anti‐NMDA receptor encephalitis in Japan: Long‐term outcome
without tumor removal Neurology. 2008 February 12; 70(7): 504–511
Diagnosis
• Characteristic clinical features – psychotic symptoms, pelvic tumor…
• Antibodies to NR1/NR2B heteromers of the NMDAR in the serum and CSF
• Diagnostic Brain Imaging
• Reversed by removing the antibodies from the cultures, explaining the potential reversibility of patient’s symptoms
– MRI : Less predictable (about 55% has abnormality) – SPECT, FDG‐PET
• Others : CSF pleocytosis, EEG…
– EEG: diffuse delta activity without paroxysmal discharges (usually)
Dalmau et al. Anti‐NMDA‐receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7:1091‐98.
Dalmau et al. Paraneoplastic Anti–N‐methyl‐D‐aspartate Receptor Encephalitis
Associated with Ovarian Teratoma. Ann Neurol. 2007 January ; 61(1): 25–36.
Management
• Decrease antibody titer : NMDA receptor antagonist
– MK801, Ketamine, Phencyclidine • Immune modulating therapy – Corticosteroids, Plasma exchange, IVIG – rapid & sustained control of the immune response within CNS
• Long lasting dyskinesia : responded to propofol and midazolam
• Conservative management : hypoventilation, autonomic instability
Dalmau et al. Anti‐NMDA‐receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7:1091‐98.
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Prognosis
• Better prognosis than most other paraneoplastic encephalitis.
– Despite the severity of the disorder, 25% of the patients had severe deficits or died.
• Resection of the tumor appeared important to attain final recovery or sustain the improvement that in some cases started soon after immunotherapy (Corticosteroid, Plasma exchange, IVIG).
Dalmau et al. Paraneoplastic Anti–N‐methyl‐D‐aspartate Receptor Encephalitis
Associated with Ovarian Teratoma. Ann Neurol. 2007 January ; 61(1): 25–36.
References
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Armangue T, et al. Pediatric anti‐N‐methyl‐D‐aspartate receptor encephalitis – clinical analyis and novel findings in a series of 20 patients. J Pediatr. 2012 Nov 16. pii: S0022‐3476(12)01181‐X. doi: 10.1016/j.jpeds.2012.10.011. [Epub ahead of print]
Dalmau et al. Anti‐NMDA‐receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7:1091‐98
Dalmau et al. Paraneoplastic Anti–N‐methyl‐D‐aspartate Receptor Encephalitis Associated with Ovarian Teratoma. Ann Neurol. 2007 January ; 61(1): 25–36.
Diamond B et al. Immunity and acquired alterations in cognition and emotion: lessons from SLE. Adv Immunol 2006;89:289–
320
Darnell R. NMDA receptor as a target in paraneoplastic encephalitis. Ann Neurol. 2007;61(1):3‐4
Florence et al. Anti–N‐methyl‐D‐aspartate Receptor (NMDAR) Encephalitis in Children and Adolescents. Ann Neurol. 2009 July; 66(1): 11‐18.
Florence NR, et al. Update on anti‐N‐methyl‐D‐aspartate receptor encephalitis in children and adolescents. Curr Opin Pediatr. 2010;22:739‐744
Lizuki T, et al. Anti‐NMDA receptor encephalitis in Japan: Long‐term outcome without tumor removal Neurology. 2008 February 12; 70(7): 504–511
Luca N, et al. Anti‐N‐anti‐N‐methyl‐D‐aspartate receptor encephalitis: a newly recognized inflamatory brain disease in children. Arth Rheum. 2011;63(8):2516‐2522
Vincent A, et al. Anti‐NMDA receptor encephalitis: a cause of psychiatric, seizure and movement disorders in young adults. Lancet Neurol. 2008;7:1074‐1075
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