Study of mitoxantrone for the treatment of recurrent neuromyelitis Optica (Devic disease)
ABSTRACT Neuromyelitis optica is a severe demyelinating disease that selectively involves the optic nerves and the spinal cord but usually spares the brain. It is considered to have a B-cell-induced pathogenesis. Mitoxantrone hydrochloride, a synthetic anthracenedione approved for worsening relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis, has been shown to primarily suppress the humoral response.
To evaluate the benefit of mitoxantrone treatment in patients with relapsing neuromyelitis optica.
Prospective 2-year study.
Academic multiple sclerosis center.
Five patients (3 women and 2 men) with an age range of 20 to 51 years and an Expanded Disability Status Scale score of 2.5 to 6.5 (mean +/- SD, 4.40 +/- 1.88).
Monthly intravenous infusions of mitoxantrone hydrochloride, 12 mg/m2, for 6 months followed by 3 additional treatments every 3 months.
Expanded Disability Status Scale score measured every 3 months and during relapses; findings on orbital, brain, and spinal cord magnetic resonance images performed at baseline and at 3, 6, 12, 18, and 24 months; and visual evoked potentials and results of ophthalmologic evaluations performed at baseline and annually.
During the 2 years of treatment, 2 patients each had a relapse once within the initial 5 months of treatment (1 severe and 1 moderate). Improvement was seen clinically and on magnetic resonance images in 4 patients. Patients generally tolerated the treatment well, although 1 patient had a reversible decrease in cardiac ejection fraction.
Our results suggest a beneficial effect of mitoxantrone treatment for relapsing neuromyelitis optica.
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ABSTRACT: Since the discovery of aquaporin 4-IgG, a sensitive and highly specific biomarker of neuromyelitis optica (NMO), a wide range of syndromes have been recognized as being associated with this condition. This observation has led to new proposed terminology for the entire disorder, NMO spectrum disorders (NMOSD). The discovery of a pathogenic autoantibody and its target antigen has also facilitated basic research into the immunopathogenesis of the disease. Key advances include establishment of passive transfer animal models demonstrating the pathogenic potential of the autoantibody and confirming an important role of complement suggested by immunopathology of NMO brain lesions and of B-cell subsets, plasmablasts in particular. These discoveries have led to phase 1 clinical trials of targeted immunotherapy with potential for improved efficacy and less toxicity than current empiric immunosuppressant medications used to treat NMOSD. Randomized clinical trials are beginning to assess the efficacy and safety of a variety of immunotherapies in NMOSD. Therapeutic options are likely to increase, and improved outcomes in NMOSD patients are anticipated.Current Neurology and Neuroscience Reports 09/2014; 14(9):483. DOI:10.1007/s11910-014-0483-3 · 3.78 Impact Factor
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ABSTRACT: Neuromyelitis optica (NMO) is an autoimmune disease of the CNS that is characterized by inflammatory demyelinating lesions in the spinal cord and optic nerve, potentially leading to paralysis and blindness. NMO can usually be distinguished from multiple sclerosis (MS) on the basis of seropositivity for IgG antibodies against the astrocytic water channel aquaporin-4 (AQP4). Differentiation from MS is crucial, because some MS treatments can exacerbate NMO. NMO pathogenesis involves AQP4-IgG antibody binding to astrocytic AQP4, which causes complement-dependent cytotoxicity and secondary inflammation with granulocyte and macrophage infiltration, blood-brain barrier disruption and oligodendrocyte injury. Current NMO treatments include general immunosuppressive agents, B-cell depletion, and plasma exchange. Therapeutic strategies targeting complement proteins, the IL-6 receptor, neutrophils, eosinophils and CD19-all initially developed for other indications-are under clinical evaluation for repurposing for NMO. Therapies in the preclinical phase include AQP4-blocking antibodies and AQP4-IgG enzymatic inactivation. Additional, albeit currently theoretical, treatment options include reduction of AQP4 expression, disruption of AQP4 orthogonal arrays, enhancement of complement inhibitor expression, restoration of the blood-brain barrier, and induction of immune tolerance. Despite the many therapeutic options in NMO, no controlled clinical trials in patients with this condition have been conducted to date.Nature Reviews Neurology 08/2014; 10(9). DOI:10.1038/nrneurol.2014.141 · 15.52 Impact Factor
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ABSTRACT: The recent discovery of several potentially pathogenic autoantibodies has helped identify patients with clinically-distinctive central nervous system diseases that appear to benefit from immunotherapy. The associated autoantibodies are directed against the extracellular domains of cell-surface expressed neuronal or glial proteins such as LGI1, the NMDA-receptor and aquaporin-4. The original descriptions of the associated clinical syndromes were phenotypically well-circumscribed. However, as availability of antibody testing has increased, the range of associated patient phenotypes and demographics has expanded. This, in turn, has led to the recognition of more immunotherapy-responsive syndromes in patients presenting with cognitive and behavioural problems, seizures, movement disorders, psychiatric features, and demyelinating disease. While antibody detection remains diagnostically important, clinical recognition of these distinctive syndromes should ensure early and appropriate immunotherapy administration. We review the emerging paradigm of cell-surface directed antibody-mediated neurological diseases, describe how the associated disease spectrums have broadened since the original descriptions, discuss some of the issues regarding antibody detection and syndrome definitions, and emphasize considerations surrounding immunotherapy administration. As these disorders continue to reach mainstream neurology, and even psychiatry, more cell-surface directed antibodies will be discovered and their possible relevance to other commoner disease presentations should become more clearly defined. ANN NEUROL 2014. © 2014 American Neurological Association.Annals of Neurology 06/2014; 76(2). DOI:10.1002/ana.24200 · 11.91 Impact Factor