30 y.o. ICU assistant

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30 y.o. ICU assistant

• 2 Weeks prior to admission--fever, chills,
  myalgias along with bad headaches
• St. Paul ER--diagnosed with UTI and started on
  Levaquin
• 1 Week prior to admission seen in PHD ER and
  diagnosed with flu
• On day of admission (9/6/03), found on floor
  unable to get up with shaking, and ?seizures

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Exam

• Unresponsive. Eyes tended to deviate downward and
  to the right. Corneals intact. Followed no
  commands. On a respirator
• Marked increased tone in the extremities, with
  flexion at the elbows and extension of the legs
• DTRs increased. Plantars flexor.
• LP done 34 WBCs, mostly lymphs, protein 179,
  glucose 34
• Fungal antigens, cultures, PCR for herpes, etc.
  all negative in CSF

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• Initially started on Rocephin had also been
  started on acyclovir
• After MRI, started on 1gm solu medrol per day
• No change in neuro exam and brain biopsy done on
  9/10/03
• Biopsy initially read as meningitis and possible
  encephalitis, and even a diagnosis of vasculitis
  entertained.
• No improvement and antibiotics discontinued and
  solu medrol tapered.
• Then because of worsening changes on MRI, IV solu
  medrol increased again and given a course of IVIG
  around 10 days after admission
• Never any improvement and after a few weeks, she
  remained unresponsive with posturing of the
  extremities and marked increased tone

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Brain Biopsy Findings

• Light microscopy
• perivascular chronic inflammation
• Predominant white matter findings of macrophage
  infiltrate consistent with demyelination
• chronic inflammation in leptomeninges
• no granulomas, vasculitis or viral cytopathic
  changes
• stains for bacteria, fungi, AFB, HSV, varicella,
  CMV, measles, adenovirus, EBV and bacilli
  associated with Whipples Disease negative
• Electron microscopy
• evidence of myelin breakdown
• no viral organisms identified

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Differential Diagnosis

• Acute disseminated encephalomyelitis
• viral encephalitis
• subacute sclerosing panencephalitis
• PML (progressive multifocal leukoencephalopathy)
• Whipples Disease
• multiple sclerosis
• metabolic leukodystrophy

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Viral Encephalitis

• neuronophagia with microglial nodules
• perivascular lymphocytes
• nonsuppurative leptomeningitis
• intranuclear inclusions
• predominantly gray matter
• parenchymal necrosis with macrophage infiltrate

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Subacute Sclerosing Panencephalitis

• chronic progressive encephalitis past exposure to
  measles virus by several years
• patchy demyelination, IN inclusions, gliosis

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Progressive Multifocal Leukoencephalopathy

• caused by JC, polyoma virus
• immunocompromised patients
• demyelination, IN inclusions in oligodendrocytes

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Whipples Disease

• chronic multisystem disorder
• gram positive bacillus Tropheryma
• heavy macrophage infiltrate in organs with PAS
  rods (small bowel, CNS)

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Multiple Sclerosis

• chronic progressive demyelinating disorder
• plaques of different ages
• usually associated with persistent oligoclonal
  bands of immunoglobulins

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Metabolic Leukodystrophy

• inherited metabolic disorders affecting white
  matter
• usually infants, children
• demyelination and macrophage accumulation

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Acute Disseminated Encephalomyelitis (ADEM)

• Immune mediated inflammatory demyelinating
  encephalomyelitis
• Usually preceded days to weeks before by an
  antecedent event such as viral illness or
  inoculation
• Acute onset of fever, headache, and rapidly
  followed by meningeal signs, altered
  consciousness, and focal central neurological
  signs
• Young adults and children most commonly affected

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Acute Necrotizing Hemorrhagic Encephalopathy
(ANHE)

• Similar to ADEM
• Much more explosive in onset
• Characterized by hemorrhage which can be
  extensive
• Usually fatal

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Differential Diagnosis

• Viral encephalitis as well as other infectious
  etiologies
• The history of a period of relative well-being
  following a febrile illness suggests ADEM
• In this case, the distribution of the
  abnormalities predominantly in the white matter
  would be unusual for viral encephalitis
• Negative serologies and cultures would favor ADEM
• Even biopsy may not always be conclusive
• Vasculitis
• Usually see multiple areas of infarction evident
  on diffusion weighted images and FLAIR
• Diagnosis suggested by Agram and confirmed by
  biopsy

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Relationship to Multiple Sclerosis
ADEM
Multiple Sclerosis

• Inciting antigenic stimulus
• Monophasic illness though relapses in up to 20
• Alteration of consciousness common
• Oligoclonal bands absent
• 14/40 adult patients developed MS
• 0/31, 10/25 children developed MS

• No causal relationship to infection or
  inoculation
• Polyphasic with relapses and remittances or slow
  progression
• Alteration of consciousness rare and coma unheard
  of
• Oligoclonal bands present
• Fever/meningismus rare

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Optic Neuritis

• Occurs in 90 of multiple sclerosis patients
• 13-85 progress to multiple sclerosis.
  Predictors
• More than 4 lesions on MRI of brain (85)
• Presence of oligoclonal bands RR 5.2
• HLA-DR2 RR 3.2
• Unilateral optic neuritis more likely to progress
  to MS

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Transverse Myelitis

• 1/3 of idiopathic give history of URI or flu-like
  illness
• Less than 10 progress to multiple sclerosis
• Devics disease (neuromyelitis optica)

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Other Demyelinating Disease

• Leukodystrophies
• Progressive multifocal leukoencephalopathy
• Immunocompromised individuals
• JC virus or polyoma SV40
• Heavy involvment of U fibers evident on MRI

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Viral Infections

• ADEM in 1/1000 measles infections
• Mortality 25 25-40 of survivors permanent
  neurological impairment
• Myoclonus common
• Must be distinguished from SSPE
• Rubella
• 1/500
• Varicella-zoster
• 1/10,000
• An acute cerebellar syndrome common
• Mumps
• Hemiplegia common
• Others herpes simplex, influenza, HIV, EB virus

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Bacterial Infections

• Most commonly mycoplasma
• Others
• Streptococcus
• chlamydia
• legionella
• campylobcter

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Vaccines

• Rabies--common in the past(1/400), almost
  non-existent now with human diploid cell vaccine
• DTP
• Smallpox 1/4,000
• Measles 1-2/million
• Japanese B encephalitis
• Polio
• Hepatitis B
• Influenza

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Treatment

• Methylprednisolone
• IVIG
• Plasmapharesis

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Prognosis

• 40 adult patients
• 14 developed MS
• Of remaining 26
• 2 died
• 9 had minor residual deficits and 3 modt.
  Deficits
• 12 were completely recovered
• 31 Children
• 81 recovered completely
• In the remaining 5 patients, only mild
  neurological sequelae
• 4 had relapses