1. 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

2. 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
DTR’s increased. Plantars flexor.
LP done: 34 WBC’s, mostly lymphs, protein 179, glucose 34
Fungal antigens, cultures, PCR for herpes, etc. all negative in CSF

3. 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

20. 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 Whipple’s Disease negative
Electron microscopy:
evidence of myelin breakdown
no viral organisms identified

21. Differential Diagnosis
Acute disseminated encephalomyelitis
viral encephalitis
subacute sclerosing panencephalitis
PML (progressive multifocal leukoencephalopathy)
Whipple’s Disease
multiple sclerosis
metabolic leukodystrophy

22. Viral Encephalitis neuronophagia with microglial nodules
perivascular lymphocytes
nonsuppurative leptomeningitis
intranuclear inclusions
predominantly gray matter
parenchymal necrosis with macrophage infiltrate

24. Subacute Sclerosing Panencephalitis
chronic progressive encephalitis past exposure to measles virus by several years
patchy demyelination, IN inclusions, gliosis

25. Progressive Multifocal Leukoencephalopathy
caused by JC, polyoma virus
immunocompromised patients
demyelination, IN inclusions in oligodendrocytes

26. Whipple’s Disease chronic multisystem disorder
gram positive bacillus Tropheryma
heavy macrophage infiltrate in organs with PAS+ rods (small bowel, CNS)

27. Multiple Sclerosis chronic progressive demyelinating disorder
plaques of different ages
usually associated with persistent oligoclonal bands of immunoglobulins

30. Metabolic Leukodystrophy
inherited metabolic disorders affecting white matter
usually infants, children
demyelination and macrophage accumulation

31. 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

32. Acute Necrotizing Hemorrhagic Encephalopathy (ANHE)
Similar to ADEM
Much more explosive in onset
Characterized by hemorrhage which can be extensive
Usually fatal

33. 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

34. 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

35. 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

36. Transverse Myelitis
1/3 of idiopathic give history of URI or flu-like illness
Less than 10% progress to multiple sclerosis
Devic’s disease (neuromyelitis optica)

37. Other Demyelinating Disease
Leukodystrophies
Progressive multifocal leukoencephalopathy
Immunocompromised individuals
JC virus or polyoma SV40
Heavy involvment of U fibers evident on MRI

38. Viral Infections ADEM in 1/1000 measles infections Rubella
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

39. Bacterial Infections Most commonly mycoplasma Others: Streptococcus
chlamydia
legionella
campylobcter

40. 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

41. Treatment
Methylprednisolone
IVIG
Plasmapharesis

42. Prognosis 40 adult patients 31 Children 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