Neuromyelitis Optica (aka Devic Disease)Definition:- Once thought to be an MS variant it is now its own disorder characterized by optic neuritis and acute myelitis with MRI changes that extend over at least three segments of the spinal cord. Note that an isolated myelitis or optic neuritis may also occur- NMO is associated with a specific Ab marker (NMO-IgG), which targets aquaporin-4 channels

- NOTE: AQP4 is expressed in the principal collecting duct cells in the kidney and is also expressed in astrocytes

- one proposed set of dx guidelines:- One episode of ON and myelitis + 2 out of 3:

- MRI lesions contiguous over 3+ segments- Brain MRI does not meet Patys’ criteria for MS- anti-NMO seropositive

- NMO Spectrum Disorders:- note that in some studies up to 87% of pts did not present with both ON and myelitis, were AQP4

Ab positive, but developed both later on in the disease process- One type is Longitudinal extensive transverse myelitis: has AQP4 Ab but only has the 3+ segment

lesions, isolated or recurrent ON and diencephalon/medulla involvement- Subacute Myelo-Optico-Neuropathy

- clioquinol, an intestinal antiseptic shown to be related to the development of subacute myelo-optico-neuropathy which may clinically be similar to NMO, but lack a peripheral neuropathy

Pathogenesis:- likely autoimmune, with both T-Cell and B-Cell involvement and likely astrocyte destruction with perivascular complement activation

Clinical Features:- sporadic, age range from childhood to late adulthood with tapering off after 5th decade, can be monophasic or polyphasic with variable recovery - ~1/3 in one study show that death comes by resp failure in relapsing NMO- present with myelopathy, visual deficits or both(more rare), but both usually involved within 3 months-years after first presentation

- Sx vary and can include: visual impairment with possible decreased visual acuity, or visual field defects, or loss of color vision. Muscle weakness, various sensory changes, loss of bladder and bowel control.

- 1/3 preceded by prodrome of fever, myalgia, headache, sorethroat- Ophthalmoscopic examination may be normal or find signs of optic neuritis with blurring of the disc with some having papilledema. May present with a central scotoma- Lhermitte's symptom is frequently present

Lab Findings:- CSF: mild elevation in protein and pleocytosis (lymphocytic). Rarely oligoclonal bands are present (up to 30% of cases in some studies)

- When ordering CSF studies include: cell count, cytology, protein, lactate, albumin CSF/serum ratio, IgG, IgA, and IgM CSF/ serum ratios, oligoclonal bands (OCB), and the MRZ (measles, rubella, and varicella zoster virus) reaction.- MRZ reaction (intrathecal IgG synthesis versus at least two of the three) as it is positive in MS but

not in NMOElectrophysiology:

- Visual evoked potentials, median and tibial somatosensory evoked potentials, and motor evoked potentials- VEP especially useful as P100 latencies in around 40 % and reduced amplitudes or missing potentials in around 25 % of patients

- other labs to consider: CBC with Diff, Coag studies, chemistry panel, ESR, blood glucose, vitamin B12 folic acid, antibodies associated with connective disorders (ANA/ENA, anti-ds-DNA antibodies, lupus anticoagulant, antiphospholipid antibodies, ANCA, etc.), UA, Treponema pallidum hemagglutination assay, and paraneoplastic antibodies (in particular, anti-CV2/CRMP5 and anti-Hu

- Test for Cu deficiency and Zn poisoning. Antibodies to myelin oligodendrocyte glycoprotein (MOG) especially in seronegative peds patients

MRI findings:- three or more vertebral segment cervicothoracic cord lesions, which preferentially involve spinal central gray matter and acutely expand the cord - One can also find CST lesions that are frequently bilateral and involve the posterior limb of the internal capsule and the cerebral peduncle, and extend down the pyramidal tract from subcortical area to the mesencephalon or pons.- Short segment gadolinium enhancement may be seen in these long segments during clinical relapse- 80% have asymptomatic brain lesions and many of these mirror the AQP distribution- Gadolinium-enhanced lesions with heterogeneous intensity and poor-defined borders (cloud-like lesions)- Involve the lining the ependymal surface of the lateral ventricles, sometimes involving the corpus callosum or the cerebrum described as pencil-thin ependymal enhancement- cavitation following periventricular inflammationhttp://radiopaedia.org/images/2395389

vs MS:- does not develop brainstem, cerebellar, or cerebral demyelinating lesions, - NMO-IgG- no cerebral white matter lesions typical of MS on MRI- no oligoclonal bands in the CSF- Spinal cord lesions become necrotizing and cavitary nature of the spinal cord lesion, affecting white and gray matter alike with prominent thickening of vessels but with minimal inflammatory infiltrates. - involves several contiguous longitudinal segments of the spinal cord which MS does not- perivascular complement deposition- acute fragmentation and loss of perivascular glial fibrillary acid protein (GFAP)-positive astrocyte foot processes and their cell bodies in early postmortem which does not happen in MS- myelin preserved in early lesion – likely shows astrocytes being killed first- vs MS where demyelination is primary

TREATMENT:- No cure exists and strategy revolves around inducing remission, improving relapse symptoms, preventing relaps and treating residual symtomsACUTE TX:- Mainstay is steroids – 1gm Methylprednisone daly IV x 5 days, with concomitant PPI and thrombosis PPX- May consider oral taper depending on dz severity- If unresponsive – 5-7 cycles of therapeutic plasma exchange can be attempted

- if CI to TPE – 2g MP daily up to 5d- note TPE was shown to be effective in seroneg NMO also

- IVIg also shown to

LONG TERM:- most studies center around Azathioprine and Rituximab and these have become first line although many immunosuppressant combinations can be used

Prognosis:- varies – the more serious and frequent the attacks – the worse the morbidity and mortality is- there is some recovery of function between attacks, but there is always residual unrepairable damage- relapsing course has worse prognosis- female gender, old age of onset(>30), high frequency of relapses, residual motor deficit and other autoimmune dz have unfavorable course- 80+% have polyphasic course- ~90% 5 yr survival for monophasic and 68% with polyphasic- but studies before long term immunosuppression. So no so clear what prognosis is now