Wednesday, August 22, 2007

Asian/African populations

have overrepresentation in NMO cohorts with a small genetic component. Clinically it is slightloy different in Japanese.


Lennon et al. applied indirect immunofluorescence to mouse CNS tissue and found that 33/45 patients with NMO (73%) were seropositive with no false positives. The target antigen is aquaphorin 4 the dominant water channel in the CNS. It is located on the astrocyte foot processes ("glia limitans") right on the blood brain barrier. Several studies have shown aquaphorin loss in lesions in NMO patients. You get immune complex deposition, necrosis and cavitation that are vasculocentric. Aquaphorin-4 is not lost in MS.

Trigger antigen-- unknown. Binds aquaphorin, activates complement, which together with IL 8 and Il-17 recruit additional inflammatory cells and cause an intense inflammatory necrosis. There is no clonal expansion as antibody circulates in blood and notgenerated in CSF unlike MS. This may explain why NMo responds so well to plasmapheresis.

Transverse myelitis

Kaplin AI et al. The Neurologist. Diagnosis and management of acute myelopathies. 2005; 11:2-18. Review article

Incidence: 1-8 cases per million per year.

Nosology: idiopathic (most) v. associated with a known inflammatory disease (MS, SLE, Sjogren's, NMO, neurosarcoidosis). In the JHTMC only 20 % recurred, 80 % were monophasic. Regional specificity helps the diagnosis eg. cord plus ON is c/w ON, whereas brain involvement suggests ADEM.

Pathology- depends on process, but all have focal monocyrtic infiltration, into perivascular spaces and astroglial and microglial activation. Gray and white matter of cord both are affected and central cord is often affected. Lupus cases may be associated with a CNS vasculitis OR thrombotic infarct of the cord. Sarcoid has noncaseating granulomas whereas MS has perivascular lymphocyte cuffing mononuclear cell infiltration. Postvaccination TM is described with influenza vaccine and booster hepatitis B. Postinfectious causes have numerous and growing numbers of bacteria and viruses associated including Listeria and HSV. Molecular mimicry, analagous to that seen in GBS after Campylobacter infection, is described with Enterobium vermicularis (pinworm) infection. Superantigen mediated infection (eg. Strep B infection with polyclonal expansion of T cells) is postulated.

NMO and recurrent TM involves humoral abnormal immune function that then activate other components of the immune system. It indicates polyclonal derangement of the immune system. It may not be just autoantibodies, but high levels of circulating antobodies that cause recurrent TM. They may form immune complexes. This occurred with hepB sAg. Several Japanese patients had very high IgE levels (360 v. 52 in MS and 85 in normal controls). They had high IgE to household mites (Dermatophagoides farinae) with antibody deposition in the spinal cord, perivascular lymphocyte cuffing and eosinophilic migration. The recruited eosinophils are thought to have induced the neural injury.

In the JHTMC, elevated IL-6 correlated strongly with disability (unlike MS). IL-6 correlated with nitrous oxide that also correlated with disability.

Predictors of recurrence are multifocal lesions in cord or brain, OCB's in CSF, presence of 14,3,3protein


Stadelman C, BruckW. Lessons from the neuropathology of atypical forms of multiple sclerosis. NeurolSci. 25: S319-S322 2004

This is an "old" paper since itg describes NMO as "idiopathic." It cites a Brain paper (1999) authored by A Bitsch (that is first initial A, last name.)The lesions are destructive and necrotic with cavitation, acute axonal pathology (spheroids), decreased oligodendrocytes within lesions, many macrophages andgranulocytes and eosinophils. Only sparse CD3+ and CD8+ T lymphocytes are detectable. There was perivascular IGm deposition and the terminal complement component (C9neo antigen) within lesions. There was prominent vascular fibrosis and hyalinization seen. Theyt resemble the antibody-complement mediated pattern of MS suggesting a role for humoral antibodies. Antibody deposition, complement activation and eosinophilic granulocytes suggest a TH2 based immune response.