30 y.o. ICU assistant

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. 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 Relationship to Multiple Sclerosis ADEM Multiple Sclerosis

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 • 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 • 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