Saturday, April 21, 2007

History of descriptions

The first description was by T. Clifford Allbutt in Lancet . On the opthalmic signs of spinal disease. Lancet. 1870; 1:76-78. However the Frenchman Devic gets credit, even though his protege did the research. Devic E. Myelite subaigue compliquee de nevrite optique. Bull Med 1894;8: 1033-34. Next up was Stansbury FC. Neuromyelitis optica (Devic's disease) Arch Opthalmol 1949; 42:292-335. Beck commented in 1927 on the longitudinally extensive transverse myelitis, cavitation, perivascular infiltration in CNS,

Confirmation of antibody tests

Jarius S et al. NMO-IgG in the diagnosis of neuromyelitis optica. Neurology 2007;68:1076-77.

NMO IgG was studied in 36 patients with Wingerchuk confirmed clinical criteria for NMO and 80 patients meeting McDonald criteria for MS. 22/36 with NMO and 4/5 with LETM (longitudinally extensive transverse myelitis) had positive antibodies and only one control with MS was positive. Fisher exact test< 0.001. The authors studied a specific pattern of staining in layers of cerebellum including pia and others.

Sunday, April 8, 2007

NMO bibliography: recent important papers

Lennon VA; Wingerchuk DM; Kryzer TJ; Pittock SJ; Lucchinetti CF; Fujihara K; Nakashima I; Weinshenker BG. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis.Lancet. 2004; 364(9451):2106-2112.

Weinstock-Guttman B; Ramanathan M; Lincoff N; Napoli SQ; Sharma J; Feichter J; Bakshi R. Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic disease).Arch Neurol. 2006; 63(7):957-63.

Pittock SJ; Lennon VA; Krecke K; Wingerchuk DM; Lucchinetti CF; Weinshenker BG. Brain abnormalities in neuromyelitis optica. Arch Neurol. 2006; 63(3):390-6.

Correale J; Fiol . Activation of humoral immunity and eosinophils in neuromyelitis optica. Neurology. 2004; 63(12):2363-70

Pittock SJ; Weinshenker BG; Lucchinetti CF; Wingerchuk DM; Corboy JR; Lennon VA. Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression.Arch Neurol. 2006; 63(7):964-8 .

Watanabe S; Nakashima I; Misu T; Miyazawa I; Shiga Y; Fujihara K; Itoyama Y. Therapeutic efficacy of plasma exchange in NMO-IgG-positive patients with neuromyelitis optica.Mult Scler. 2007; 13(1):128-32.

Wingerchuk DM; Pittock SJ; Lucchinetti CF; Lennon VA; Weinshenker BG. A secondary progressive clinical course is uncommon in neuromyelitis optica.Neurology. 2007; 68(8):603-5

NMO Treatment

Again, NMO typically lacks secondary progression and therapy is designed to address acute attacks and limit destruction thereof. For acute attacks, an initial course of Solumedrol is standard consisting of 5-7 days of treatment. Refractory cases are often highly responsive to plasma exchange. Weinshenker studied exchange v. sham exchange in a group of patients with neurologic disease many of whom had NMO, and 42 % responded. His protocol is seven phereses QOD over 14 days. For attack prevention, standard MS therapies are ineffective. Standard immunosuppression consists of a combination of azathioprine and prednisone. As in other neurologic diseases, azathioprine has a long latency to effect and relapses can occur in the interinm that are prevented with prednisone. Mycophenolate can be substituted for azathioprine, but cannot be titrated based on MCV and WBC making it a blind therapy. Frohmann's IV MTX case used 2.5 gram / meter squared wiuth leukovorin rescue. Rituximab is an anti CD20 MAB that eliminates pre B and mature B cells. 4 weekly infusions each involving 375 mg/m(2); 7/8 had had breakthrough disease and 6/8 remained relapse free with an EDSS improvement from mean 7.5 to 5.5. After B Cell recovery 2 more infusions of 1000 mg 2 weeks apart are given. Mmitoxantrone is also an option. The protocol in theonly study done was changed to give more MTX upfront, due to patients relapsing early if every 3 month therapy was chosen. IVIG stabilized 2 patients with active disease despite azathioprine and steroid therapy

More clinical information about NMO

In Cree's summary of NMO in Seminars in Neurology, women predominated by 2.3:1, the mean age of onset was 37, 45 % presented with ON, 38 % with myelitis, 17 % with both, 76 % had a normal brain MRI, more than half had a CSF pleocytosis, and had PMN's in the CSF . The ratio of polyphasic to monophasic disease was 1.8 : 1. Although the prognosis was poor , there were benign cases. Galetta stressed that although LETM (Long extensive transverse myelitis) was characteristic, skip areas also occurred in the cord.

Although the brain lesions were unique according to the Mayo article, a certain percentage has ovoid or periventricular lesions indistinguishable from MS. In patients with NMO with transverse myelitis, recurrence was more common (vice versa). Hiccups and nausea imply a medullary lesion and occur in 17 %. NMO is positive from the very earliest stage. Rarely, patients are NMO negative or have antibodies to another antigen such as MUSK. The complement mediation of destruction is characteristic.

A spectrum of disease probably exists including idiopathic recurrent isolated LETM, recurrent ON with a negative brain MRI, and Asian optic-spinal MS. Standard MS therapies are not effective but specific NMO therapies can be not only effective but occassionally dramatically so in seemingly hopeless cases. Elliott Frohmann described a patient who was limited to movement of one finger, who was treated with high dose IV methotrexate, and recovered completely including driving, living independently, raising her children.

More on NMO Pathology and Aquaphorin story

100 percent of the lesions in NMO are perivascular around the microvessels. The perivascular staining to C9neo is far greater than in multiple sclerosis. Rosettes form. The specific antigen is aqp4 which is a membrane protein involved in water transport in NMO. AQP4 co-localizes with the NMO IgG precipitate . Staining is in pial, not endothelial and was described by Lennon and Weinshenker. AQP4 is not localized elsewhere in CNS but has been localized in crypts in gastric mucosa and distal renal tubules.

Is NMO different than a form of MS? No, but..

The following is based on presentations at a conference including Elliott Frohmann, Brian Weinshenker, Stephen Galetta and others. Officially, it is not yet established as a different disease, but is different based on demographic, clinical, MRI, pathological, immunologic, prognostic, and therapeutic criteria.

Clinical differences between NMO and MS abound. The spinal cord lesions in the two diseases are different. In NMO, the lesions are in the central gray, extend over many segments, and may be necrotic. Eosinophils and neutrophils are abundant. The inflammation is extensive in perivascular areas especially in the micro-vessels. In MS, spinal cord lesions are non-necrotic, smaller, macrophages predominate, and inflammation occurs at the edge of the plaque and along myelin sheaths, not nearly as much along the perivascular edges. Unlike NMO, rosettes do not form.

In NMO, oligoclonal banding is absent, unlike MS. Clonal expansion is not important in NMO, suggesting that the blood brain barrier is not integral to the process. NMO IgG is present in 70 % of cases, v. < 10 % in MS. Systemic autoimmune disease suchas Sjogren's and lupus are abundant, whereas there is only a slight increase in autoimmunity in MS. Many cases of myelitis in patients with SLE or Sjogren's previously thought to be vasculitis are NMO positive, suggesting a different diagnosis. Recurrent transverse myelitis is often NMO positive, suggesting a subset of patients with that condition have that diagnosis. In MRI, brain lesions are "uncommon" in NMO but can occur. They usually are located around the hypothalamus, thalamus and third ventricle, and around the periphery of the cerebellum. However, 8% or so are atypical and can mimic the lesions in multiple sclerosis, with hemispheric lesions. Brain lesions, like cord lesions, can present as long linear lesions in the medulla especially in area postrema and the solitary tract. In one series, 17 %of patients presented with hiccups, correalting with the above pathology. Similarly, optic nerve lesions may be long and centrally located in NMO and extend all the way back to the chiasm. CSF often has a pleocytosis. Asian demyelinating variants may in some cases represent NMO.

Unlike MS, in NMO a secondary progressive course is rare and damage is done during the attacks themselves. If the attacks can be controlled, so can the disease. Plasmapheresis works extremely well in this condition.Rituxan works well as a chronic treatment to control attacks. Beta interferon does not work well.

Diagnostic Criteria-- Wingerchuk criteria

Neurology 2006

* Clinical events involving optic nerve(s) and spinal cord and (2) of (3) of following
* Long extensive spinal cord lesions (> 3 segments common)
* Brain MRI normal or not meeting criteria for multiple sclerosis
* NMO IgG seropositive status