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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

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infectious disease clinical case presentation

Infectious DiseaseClinical Case Presentation

Samina Syed, MS IV

Kees Van Dam, MD

September 12, 2007

slide2
CC: Acute mental status changes

“I feel like I’m going crazy”

slide3

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.

slide4

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.

slide5

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.

slide6

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.

slide7

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

slide8
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.
slide9

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.

slide10

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.

slide13

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

slide14

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.

slide43

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.

additional history vaccine history
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
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.
slide47

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)

course48
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.
slide49

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.

slide50

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.

slide51

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.

course52
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
course53
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
slide54

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

slide55

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
Adverse Events
  • Inadvertent Inoculation
    • Results in a normal vaccinial lesion in an inappropriate site (most common complication in 1968 study).
adverse events57
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 events58
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 events59
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 events60
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
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
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 encephalitis63
Post-Vaccinial Encephalitis
  • Clinicohistopathologic data from the 1920s and 1960s identified 2 clinicopathological forms of PVE:
  • Microglial encephalitis
  • Post-vaccinial encephalopathy
pve microglial encephalitis
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
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?
slide66

POST VACCINIAL ENCEPHALITIS

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
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
slide68
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
Clinical FeaturesADEM
  • 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
MRI FeaturesADEM
  • 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
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
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)
slide73

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
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 adem75
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 adem76
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
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
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
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
References
  • Aragon et al. Risks of serious complications and death from smallpox vaccination: A systematic review of the United States experience, 1963-1968. 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
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 d82
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.
search pubmed
Search PubMed
  • Post-vaccinial encephalitis
    • Case Reports
    • Reviews
    • Differential Diagnosis
    • Drug Therapy