Download Post-Vaccinial Encephalitis

Infectious Disease
Clinical Case Presentation
Samina Syed, MS IV
Kees Van Dam, MD
September 12, 2007
CC: Acute mental status changes
“I feel like I’m going crazy”
History of Present Illness
R.S. is a 19 year old white male in the Armed Forces, who
was preparing for deployment to Iraq during the week of
9/3.
The patient’s family visited him over the weekend (9/1-9/2)
and he was in a normal state of health aside from
complaints of a headache.
On Monday, 9/3, his father called him around 1300
and was surprised to find him still in bed. His son
sounded unusually sleepy.
That evening the patient told his mother that he with
felt like he was “going crazy.”
On 9/4 he did not show up for work.
On 9/4 he did not show up for work.
He was found on his bed nude, mumbling
incomprehensible words.
He was taken to AF base facility and then to Wayne
Memorial.
Upon admission, he could state his first name and the
year.
He began showing signs of frontal disinhibition and
rapidly deteriorated.
He underwent lumbar puncture and was
placed on ceftriaxone, vancomycin, and
acyclovir.
He was intubated for airway protection and
transferred to MICU at UNC.
Upon arrival patient was minimally responsive
to noxious stimuli.
Past Medical History: Previously healthy
SOCIAL HX: Active duty stationed at a nearby airforce
base. Deployment week of 9/3/07. Per coworkers, patient
does not drink, smoke, or do illicit drugs.
Travel: Patient trained in Texas November-April
and then moved to North Carolina. He visited
family in NY state in July.
FAMILY HX: No hx of early CAD
HOME MEDICATIONS: mefloquine
ALLERGIES: NKDA
• Review of Systems
• Other than HPI fairly unobtainable.
• Mother had noticed a rash on his feet
bilaterally on Tuesday, 9/5 at Wayne
Memorial. She thought it might have
been due to the boots he had been
wearing.
Vitals Tmax = 39.4 on admission
BP 115/59
RR 20
Physical Exam:
General: Intubated, no response to voice.
Lymphadenopathy: 1 mm left axillary node
Skin: Two to three 1 mm areas with blanching papules
bilaterally on the feet. Similar papules were on the dorsum
of PIP on left hand and DIP of ring finger on left hand.
Physical Exam: Neurological
Comatose, no response to voice
Visual fields show no reaction to threat bilaterally, PERRLA
Normal bulk and tone, bilateral upper extremity extensor posturing with
nail pressure
Slight withdrawal on left lower extremity with nail pressure, slight
movement of right quadricep with right lower extremity naill pressure
Reflexes symmetric and 3+ bilaterally at bicep, tricep, bracheoradialis,
patellar, ankle.
ADMISSION DIAGNOSTIC STUDIES: (WM)
CBC:
WBC 12.7
Gran 10.7 (84.3%)
Lymph 1.5 (11.7%)
Mono 0.5 (3.8%)
Eos 0.0
Chem panel:
Na 138
K 4.2
Cl 102
BUN 27
Creatinine 11
Anion gap 9
Baso 0.0
RBC 4.74
Hemoglobin 13.6
Hematocrit 41
Platelets 215
LFTs normal range
UA: trace protein, ketones 15, rare
WBCs
EKG: NSR, biatrial enlargement
ADMISSION DIAGNOSTIC STUDIES
Toxicology Screen Negative:
Amphetamines
Barbiturates
Benzodiazepines
Cocaine
Opiates
Phencycidine
Cannaboids
TCAs
Methamphetamine
Methadone
Toxicology screen positive:
Acetaminophen
ADMISSION DIAGNOSTIC STUDIES
LP: opening pressure 36
Appearance: colorless clear
RBCs 3,
WBCs 135
28% neutrophils 59% lymphocytes, 13% monocytes,
Glucose 65, Protein 91.
CSF Gram stain: No organisms, few WBCs
ADMISSION DIAGNOSTIC STUDIES
CT with and without contrast: showed “no acute
intracranial process and no enhancing lesions.”
An MRI was performed at Wayne Memorial prior to
transfer.
MRI also performed at UNC on evening of arrival to
MICU.
MRI BRAIN 9/5/07: T2 Images
MRI BRAIN: FLAIR Images
FINDINGS
There are large areas of abnormal T2 and FLAIR signal abnormalities involving the subcortical and
deep white matter in the bilateral frontal, parietal, and occipital lobes.
There is abnormal signal involving the the corpus callosum and periventricular white matter.
There is abnormal increased T2 and FLAIR signal involving the medial portions of the temporal lobes
and right thalamus.
There is similar abnormal signal involving the posterior pons.
There is a somewhat linear area of restricted diffusion in the left frontal region just superomedial to the
sylvian fissure. This correlates with an area of FLAIR and T2 signal abnormality.
There is abnormal FLAIR signal in the subarachnoid spaces bilaterally superiorly. This is nonspecific
but can be seen with proteinaceous fluid or subarachnoid hemorrhage but can also be related to
ventilation.
IMPRESSION
1.Multiple areas of abnormal signal involving predominantly white
matter but also areas of gray matter.
2. Nonspecific increased FLAIR signal in the subarachnoid space as
described above.
DISCUSSION
Additional History: Vaccine
History
• On 8/18 pt received anthrax vaccine #1, as
well as typhoid vaccine IM
• On 8/23 patient received a smallpox
vaccination left deltoid.
• On 8/30 he received anthrax vaccine #2
Course:
• Upon arrival to UNC his smallpox vaccination site
was examined by Dr. Weber and found to be a “8 mm
well scabbed over black eschar on left upper arm.”
• He had no evidence on exam for satellite lesions.
• Patient was placed on contact precautions.
• ICU team added Doxycycline.
• ID and Neurology were consulted.
LABS
HIV negative
RPR NR
Crypto ag serum neg
B12 normal
TSH normal
---------------------------------------------------------------------------------------------------
WNV (CSF)
VZV PCR (CSF) HSV PCR (CSF) Lyme titer (CSF)
Crypto Ag CSF
Fungal and AFB stain and culture (CSF)
VDRL (CSF)
Course:
• We recommended addition of high dose ampicillin to cover
Listeria in addition to continuing vancomycin, ceftriaxone,
acyclovir and doxycycline.
• Asked MICU to check RMSF titers, arbovirus serologies.
• We were most concerned for a post vaccinia encephalitis (PVE).
• Neuro-radiology and Neurology: Imaging, clinical picture c/w
Acute Disseminated Encephalomyelitis (ADEM).
• Neurology recommended high dose steroids and IVIG.
Consultation with the CDC and DOD on 9/5/07:
A second LP at WM had been done on 9/4 with CSF and
serum sent to CDC labs.
Poxvirology Lab:
PCR negative CSF and Blood for poxvirus nucleic acid
Serum and CSF IgG negative for poxvirus
Serum and CSF IgM pending
CDC strongly endorsed adding IVIG to the high dose
steroids.
CDC Conference Call
CDC also recommended several additional tests:
• Pre-IVIG Serum sent to CDC for Poxvirus antibody testing.
• highly sensitive CRP
• complement levels and circulating immune complexes
•EBV, CMV DNA PCR, serologies in blood
•Chlamydia antibodies
•Streptoccoccal antibodies
Conference calls with the CDC were continued to follow the course of
the post vaccinia complication: post vaccinial encephalitis.
CDC Conference Call:
Later that evening the serum and CSF IgM returned
positive.
Despite lack of evidence for disseminated vaccinia,
decided patient might benefit from vaccinia
immunoglobulin and CDC shipped VIG overnight to RDU.
VIG started on Friday afternoon, IVIG resumed afterwards
until pt completed 2g/kg over 4 days.
High dose steroids continued.
Course
• Vancomycin, ceftriaxone, doxcycline dc’d after >48
hrs negative cultures, low susp for RMSF.
• Ampicillin continued until final CSF cultures negative
9/10.
• Acyclovir continued until CSF HSV, VZV PCR
negative 9/11
Course
• West Nile CSF negative
• Lyme antibody CSF negative
• RMSF serum IFA 1:80
• CDC labs: CSF negative for Adenovirus, Enterovirus,
HSV, VZV
• CDC testing of serum: now positive for IgG on pre
IVIG, pre VIG, post VIG serum
Vaccinia virus is a live DNA virus used as the vaccine against
smallpox, which is caused by the Variola virus.
Genus: Orthopoxvirus.
Day 3-5 Papule
Day 5-8 Vesicular
Day 8-10 Pustular
Day 14-21 Scab separation
Adverse events after smallpox vaccination
recommended for report:
Superinfection of the vaccination site or regional lymph nodes
Inadvertent inoculation
Contact transmission
Ocular vaccinia
Generalized vaccinia
Eczema vaccinatum
Progressive vaccinia
Erythema multiforme major or SJS
Fetal vaccinia
Postvaccinial CNS disease
Myo/pericarditis
Dilated cardiomyopathy
Adverse Events
• Inadvertent Inoculation
– Results in a normal vaccinial lesion in an
inappropriate site (most common
complication in 1968 study).
Adverse Events
• Generalized Vaccinia
– Generalized vaccinia is the result of the
systemic spread of virus from the
vaccination site. Despite the appearance of
the lesions, it is usually a benign
complication of primary vaccination that is
self-limited except in some individuals with
underlying immunosuppression
(medications or illnesses).
Adverse Events
• Eczema Vaccinatum
– A local or disseminated vaccinia that
occurs in patients with a hx of eczema or
other types of atopic dermatitis
• Erythema Multiforme
– Pathogenesis thought to be allergic, toxic,
or both.
Adverse Events
• Progressive Vaccinia (Vaccinia
Necrosum)
– Universally fatal prior to VIG
– Occurs in immunodeficient vaccinees
– Progressive destruction of local areas of
skin, subcutaneous tissue, and metastatic
lesions can lead to death
Adverse Events
• Myocarditis and Pericarditis
– Effects range from asx T wave changes to
fatal myocarditis.
– During 2003 civilian first responders
vaccination program, 6 out of 10,000
vaccinees developed myocarditis.
Post-Vaccinial Encephalitis
• Neurological illness is a rare but severe
Vaccine Adverse Event (VAER)
• Post-vaccine Encephalitis (PVE)
• Historically occurred with greater
frequency in first time vaccinees.
Case Definition of PVE for use in Smallpox VAER
(Sejvar et al JAMA 2005)
•
Confirmed PVE:
•
acute cerebral +/- menningeal inflammation or demyelination on histopathology
•
Probable PVE:
•
Encephalopathy (AMS, personality change) >24 hrs
•
AND
•
Additional features suggestive of cerebral inflammation including 2 or more of
following:
•
•
•
•
•
•
•
Fever (>38) or Hypothermia (<35)
Meningismus
Pleiocytosis
Presence of focal neurologic defect
EEG c/w encephalitis
Neuroimaging (MRI) c/w inflammation or demyelination
Seizures
•
AND
•
No alternative etiology
•
Suspected PVE: same as Probable except that only one criteria for cerebral inflammation
or demyelination.
Post-Vaccinial Encephalitis
• Clinicohistopathologic data from the
1920s and 1960s identified 2
clinicopathological forms of PVE:
• Microglial encephalitis
• Post-vaccinial encephalopathy
PVE: Microglial encephalitis:
– More frequent in >2 years of age
– 10-20 days after vaccination
– Fever, vomiting, headache malaise followed by
decreased consciousness, seizures, coma
– Widespread demyelination of subcortical white
matter (prob corresponds to ADEM)
ie MRI etc were not available in 1920s, 1960s.
PVE: Post-vaccinial
encephalopathy
–
–
–
–
More frequent in <2 years of age
6-12 days after vaccination
Fulminant seizures and hemiplegia, elevated ICP.
Diffuse cerebral edema and perivascular
hemorrhages
– At times vaccinial viremia and even vaccinia virus
isolation/detection from brain or CSF.
– A neuroinvasive form of vaccinia virus?
POST VACCINIAL ENCEPHALITIS
European Countries
(1964)
Incidence %
Britain
1.5
Finland
3.1
Sweden
3.5
Switzerland
5.0
Belgium
7.0
Holland
13.0
Germany
11.0
Austria
30.0
The overall incidence in the U.S. was 2.9/million
vaccinees in 1968. The case fatality rate in the U.S. was
25% and 30-50% in Europe (1959-1966). In 2001, the
CDC reported the rate as 1 case per 300,000 vaccinees.
Acute Demyelinating Encephalomyelitis
(ADEM)
• ADEM is an immune mediated inflammatory
disorder of the CNS, primarily of the white
matter, that is typically precipitated by viral
infection or vaccination
ADEM
• Diagnosis of exclusion
• Differential: Infection, MS, Transverse Myelitis
• Based on clinical and radiologic features
(MRI critical)
• Usually monophasic , recurrent ADEM has
been reported
Clinical Features
ADEM
• Rapid onset encephalopathy
• Prodrome with fever, malaise, headache,
nausea, vomiting
• Meningeal signs and drowsiness
• Rapidly progressive, developing over hours to
maximum deficits within days
• Neurologic signs include acute hemiplegia,
ataxia, cranial nerve palsies, seizures,
impairment of speech, mental status changes
MRI Features
ADEM
• Patchy, poorly marginated areas of increased
signal intensity; large, asymmetric, multiple
• Four patterns:
– ADEM with less than 5 mm lesions
– Large, confluent lesions with edema and mass
effect
– ADEM with additional symmetric bithalamic
involvement
– Acute hemorrhagic encephalomyelitis (worst
prognosis)
Epidemiology of ADEM
• More common in pediatric patients
• Recent study of persons less than 20 years
with ADEM showed 5% had a vaccination
within 1 month, 93% had signs of infection in
preceding 21 days
• Post-vaccinial encephalitis usually occur 7-14
days after vaccination
• Incidence varies by country
Pathophysiology of ADEM
• Pathogenesis is not well understood
• Immune pathogenesis supported by
time course between vaccine and
encephalitis
• Similarity in the neuropathology of
ADEM with animal models of
experimental allergic-autoimmune
encephalitis (EAE)
Pathophysiology of ADEM
• EAE is an autoimmune disease mediated by
T cells directed at myelin antigens
• Postulated that phosphorylation of myelin
basic protein, by vaccinia’s viral kinase, may
change the immunogenicity of myelin basic
protein
• Viral epitopes may resemble myelin reactive
T cell clones through molecular mimicry
Treatment of ADEM
• No standard therapy
• Based on case reports and small series
• Most therapies use a form of
immunosuppressant therapy
– Steroids
– IV immunoglobulin
– Plasmapheresis
Treatment of ADEM
• IVIG
– Interaction with Fc receptors
on effector cells
– Anti-idiotypic antibodies
against circulating antibodies
– May alter the number of T
cells and subsets
– Promote clearance of
immune deposits
– May contain neutralizing
antibodies
– May increase clearance of
pathogenic IgG
– May neutralize the
inflammatory actions of
complement
Treatment of ADEM
• High dose steroids
– Gastric perforation, hyperglycemia, hypokalemia,
hypertension, facial flushing
• Plasmapheresis
– Hypotension, bleeding, allergic rxn,
immunosuppresion
• * Vaccinia immunoglobulin
VIG and ADEM due to PVE?
• Vaccinia Immunoglobulin (VIG) not thought to
be useful because PVE thought to be immune
mediated, and not due to vaccinial infection.
• Nanning et al, 1962: Randomized trial of
prophylactic VIG in >106,000 Dutch troops
vaccinated with smallpox vaccine reduced
incidence of PVE from 13 to 3
Prognosis
Case reports
• recovery
• Mild to severe impairment
• Fatalities
• ADEM with 15 cases had a 50% recovery rate
Pooled summary of case fatality rates (CFR)
– For every million primary vaccinations
• 60 cases accidental infection
• 40 cases of generalized vaccinia
• 13 cases eczema vaccinatum
• 3 cases of post-vaccinial encephalitis (CFR
28.9%)
• 1 case of vaccinia necrosum (CFR 15.4%)
Current clinical course
• Patient has no spontaneous extremity
movements
• Patient has opened his eyes, and is
moving his eyes in response to voice
and movement
• Continue tapering dose of steroids and
watch for improvement
References
•
Aragon et al. Risks of serious complications and death from smallpox
vaccination: A systematic review of the United States experience, 19631968. BMC Public Health. Vol.3:26. 2003
•
Casey et al. Adverse Events Associated with Smallpox Vaccination in
the United States, January-October 2003. JAMA. Vol. 294 (21).
December 7, 2005.
•
Isascs, S. and Harvey Friedman.Vaccinia Virus as the smallpox
vaccine. March 16, 2007. UpToDate [On-Campus Access Only]
•
Kretzschmar et al. Frequency of Adverse Events after Vaccination with
Different Vaccinia Strains. PLOS Medicine. Vol 3: 8. August 2006.
•
Lofquist et al. Smallpox: A review of clinical disease and vaccination.
American Journal of Health-System Pharmacists. Vol. 60. April 15,
2003.
References (cont’d.)
•
Menge et al. Acute disseminated encephalomyelitis: an acute hit
against the brain. Current Opinion in Neurology. Vol. 20 (3), 247-254.
June 2007.
•
Miravalle, A. and Karen Ross. Encephalitis Complicating Smallpox
Vaccination. Arch Neurol. Vol. 60; 925-928. July 2003.
•
Sejvar et al. Neurologic Adverse Events Associated with Smallpox
Vaccination in the United States, 2002-2004. JAMA. Vol. 294: 21.
December 7, 2004.
•
Silvergleid, A. General Principles of the use of IVIG. January 4, 2007
UpToDate (On-Campus Only 7/1/2007)
•
Temembaum et al. Acute Disseminated Encephalomyeltis. Neurology.
Vol. 68 (2). April 17, 2007
References (cont’d.)
•
CDC Surveillance Guidelines for Smallpox vaccine adverse reactions.
Vol. 55 (RR01); 1-16. Feb. 3, 2006.
•
CDC Update: Adverse Events Following Civilian Smallpox Vaccination-U.S. 2003. Vol. 52 (20); 475-477. May 23, 2003.
•
CDC Update: Smallpox vaccination and adverse reactions. Vol, 52
(RR04); 1-28. Feb. 21, 2003.
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