OBJECTIVE: To report the clinical characteristics, type and frequency of hydrocephalus in aquaporin-4 (AQP4)-IgG seropositive neuromyelitis optica (NMO) spectrum disorders. BACKGROUND: Neuromyelitis optica (NMO) is an inflammatory demyelinating autoimmune disease of the central nervous system that is characterized by relapsing attacks preferentially involving the optic nerves and spinal cord. The disease-specific autoantibody marker of NMO, NMO-immunoglobulin G (IgG), binds to the extracellular domain of the AQP4 water channel which is concentrated in polarized foot processes of astrocytes at CNS tissue -fluid interfaces (blood-brain and brain-cerebrospinal fluid) and encircling glutamatergic synapses and nodes of Ranvier. DESIGN/METHODS: Obstructive hydrocephalus was identified in the index case. We therefore reviewed, with a study neurologist and neuroradiologist, all available head MRIs from AQP4-IgG-seropositive cases identified in the Mayo Clinic NMO clinical biospecimens database (125 fulfilled NMO diagnostic criteria; 45 had an NMO spectrum disorder). RESULTS: Hydrocephalus was identified in 2 of 177 AQP4-IgG positive patients (frequency 1.1%), in addition to the index case. In all three patients, imaging findings were consistent with obstructive hydrocephalus: third and lateral ventricles were enlarged, and the fourth ventricle and aqueduct were relatively small. CONCLUSIONS: Obstructive hydrocephalus is encountered in NMO spectrum disorders more frequently than observed in the general adult population. This likely reflects the vulnerability of the cerebral aqueduct of Sylvius to stenosis in the setting of immunopathology targeting AQP4-rich periventricular and periependymal tissues. Study Supported by: Supported by the National Institutes of Health (R01 NS065829) and the Guthy Jackson Foundation.
It is my great pleasure to introduce this issue of Seminars in Neurology on Multiple Sclerosis and the Spectrum of CNS Inflammatory Demyelinating Diseases. Inflammatory demyelinating diseases of the central nervous system (CNS) occur throughout the world and are the foremost cause of nontraumatic neurological disability in young adults. Multiple sclerosis (MS) is the most common of these disorders. The last decade has seen a resurgence of interest in MS, fueled by scientific advances in the epidemiology, genetics, immunology, pathology, neuroimaging, and treatment of the disease. However, MS represents only one member of a family of CNS idiopathic inflammatory demyelinating diseases, which include transverse myelitis, acute disseminated encephalomyelitis (ADEM), and neuromyelitis optica (NMO). Although these disorders are all similarly characterized by focal CNS demyelination, they vary in their clinical course, prognosis, regional distribution, pathology, and pathogenesis. In this issue of Seminars in Neurology, the authors provide a comprehensive, clinically-relevant update on MS and the heterogeneous spectrum of CNS inflammatory demyelinating disorders.
D ISEASE-MODIFYING agents approved for treatment of patients with multiple sclerosis (MS) are glatiramer acetate, interferon beta-1b and -1a, and mitoxantrone hydrochloride. Natalizumab was Food and Drug Administration approved in November 2004, but the manufacturers suspended marketing and clinical trials in 2005 because of safety concerns. Interferon beta-1a is approved for individuals with clinically isolated syndromes (CISs) who are at relatively high risk to “convert to MS.” Opinions vary about whom and when to treat. On one hand, the Medical Advisory Board of the National Multiple Sclerosis Society consensus statement (updated in February 2005) recommends initiation of a disease-modifying agent “as soon as possible following definite diagnosis of MS with a relapsing course, and in selected patients with first attack who are at high risk for MS (CIS).” Alternatively, the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines suggest “it is appropriate to consider” treatment with approved therapies in these patients. We do not believe that all patients with MS or CIS should begin indefinite treatment at the time of diagnosis. Until it is clear that the patient has continuing disease activity clinically and/or radiologically, in which case the need for treatment is clear to the physician and to the patient, it is advisable to observe a period of no treatment while monitoring for inflammatory disease activity. The final decision about whether and when to initiate treatment should be shared by the patient and physician after an unbiased review of the relevant information with the patient. Our current approach is predicated on the following: (1) MS often has a favorable natural history; (2) disease-modifying drugs are only partially effective in the short-term and prevention of disability in the long-term is unproven; (3) with prolonged treatment, it is hard to distinguish whether a favorable outcome reflects a favorable natural history or successful treatment in an individual patient, especially if treatment is started without a period of observation; (4) expense, adverse effects, and neutralizing antibodies are a concern and patients may be reluctant to commit to long-term parenteral medications, especially within the first few months following diagnosis; and (5) prospective clinical and magnetic resonance imaging (MRI) monitoring may allow identification of patients who need treatment. Because disease-modifying agents do not benefit patients with primary progressive MS (approximately 10% of all patients with MS) and their benefit in secondary progressive MS (approximately 30% of all patients with MS) remains questionable, this discussion is limited to patients with a diagnosis of relapsing-remitting MS and CIS. Patients with MS often do well without any treatment. A recent Olmsted County, Minnesota, study found that patients with minimal or nodisability(ExpandedDisabilityStatus Scale [EDSS] score 2) at more than 10 years from onset have a 90% chanceofremainingfullyambulatory (EDSSscore 3.0)10yearslater. This group accounted for 17% of all patients with MS or 33.3% (28/94) of patientswith relapsing-remittingMS in that population-based cohort. Kurtzke et al reported similar findings. Extrapolating these data to all patientswith“destined tobebenign” MS in the United States would result in approximately 35 870 individuals (17% of 211 000 patients with MS in the United States) unnecessarily receiving a potentially lifelong medication. Currently available approved treatments offer a mild to moderate short-term benefit in individuals with active recent disease who are most likely to respond. However, long-term efficacy is unproven. One needs to treat 5.6 patients with interferon beta-1b, 6.3 with interferon beta-1a, and 14.3 with glatiramer acetate to generate 1 person free of relapse for 2 years. Reduction in relapse rate is most evident in the first year and then declines. Number needed to treat (NNT) estimates for natalizumab are more favorable; early results suggest that the NNT to render 1 patient relapse free after 2 years of therapy is 2 to 2.4. However, serious safety concerns have led to voluntary cessation of natalizumab production. Author Affiliations: Department of Neurology, Mayo Clinic, Rochester, Minn (Drs Pittock, Weinshenker, Noseworthy, Lucchinetti, Keegan, and Rodriguez), Scottsdale, Ariz (Drs Wingerchuk and Carter), and Jacksonville, Fla (Dr Shuster).
To determine the prognostic value of neuromyelitis optica (NMO)-immunoglobulin G (IgG) in patients with recurrent optic neuritis (ON). The aquaporin-4-specific serum autoantibody, NMO-IgG, is a biomarker for NMO and relapsing transverse myelitis. Recurrent ON may herald multiple sclerosis (MS) or NMO, or it may occur as an isolated syndrome. The prognosis and response to therapy differs in each of these contexts.We evaluated 34 patients who were tested for NMO-IgG between 2000 and 2007 and who had two or more episodes of ON without satisfying a diagnosis of MS or NMO prior to serologic testing. Clinical data were available for 25 Mayo Clinic patients (5 NMO-IgG positive and 20 NMO-IgG negative) and for an additional 9 seropositive patients whose serum was referred to the Mayo Clinic Neuroimmunology laboratory for testing.Twenty percent of the patients with recurrent ON seen at Mayo Clinic were seropositive. All NMO-IgG-positive patients (vs 65% NMO-IgG-negative patients) had at least one attack with visual acuity in the affected eye worse than 20/200 (p = 0.05). In seropositive patients for whom long-term follow-up was possible (median 8.9 years after the initial ON), 6 of 12 (50%) experienced an episode of myelitis and fulfilled criteria for NMO. In contrast, 1 of 15 seronegative patients (6.7%) fulfilled McDonald criteria for MS (p = 0.03). Seropositive patients had a final visual score which was worse than that of seronegative patients (p = 0.02).Neuromyelitis optica (NMO)-immunoglobulin G seropositivity predicts poor visual outcome and development of NMO. Seropositive recurrent optic neuritis is a limited form of NMO.
To characterize the neuropathologic features of neuromyelitis optica (NMO) at the medullary floor of the fourth ventricle and area postrema. Aquaporin-4 (AQP4) autoimmunity targets this region, resulting in intractable nausea associated with vomiting or hiccups in NMO.This neuropathologic study was performed on archival brainstem tissue from 15 patients with NMO, 5 patients with multiple sclerosis (MS), and 8 neurologically normal subjects. Logistic regression was used to evaluate whether the presence of lesions at this level increased the odds of a patient with NMO having an episode of nausea/vomiting.Six patients with NMO (40%), but no patients with MS or normal controls, exhibited unilateral or bilateral lesions involving the area postrema and the medullary floor of the fourth ventricle. These lesions were characterized by tissue rarefaction, blood vessel thickening, no obvious neuronal or axonal pathology, and preservation of myelin in the subependymal medullary tegmentum. AQP4 immunoreactivity was lost or markedly reduced in all 6 cases, with moderate to marked perivascular and parenchymal lymphocytic inflammatory infiltrates, prominent microglial activation, and in 3 cases, eosinophils. Complement deposition in astrocytes, macrophages, and/or perivascularly, and a prominent astroglial reaction were also present. The odds of nausea/vomiting being documented clinically was 16-fold greater in NMO cases with area postrema lesions (95% confidence interval 1.43-437, p = 0.02).These neuropathologic findings suggest the area postrema may be a selective target of the disease process in NMO, and are compatible with clinical reports of nausea and vomiting preceding episodes of optic neuritis and transverse myelitis or being the heralding symptom of NMO.
Although historically considered a disease primarily affecting the white matter of the central nervous system, recent pathological and imaging studies have established that cortical demyelination is common in multiple sclerosis and more extensive than previously appreciated. Subpial, intracortical and leukocortical lesions are the three cortical lesion types described in the cerebral and cerebellar cortices of patients with multiple sclerosis. Cortical demyelination may be the pathological substrate of progression, and an important pathologic correlate of irreversible disability, epilepsy and cognitive impairment. Cortical lesions of chronic progressive multiple sclerosis patients are characterized by a dominant effector cell population of microglia, by the absence of macrophagic and leukocytic inflammatory infiltrates, and may be driven in part by organized meningeal inflammatory infiltrates. Cortical demyelination is also present and common in early MS, is topographically associated with prominent meningeal inflammation and may even precede the appearance of classic white matter plaques in some MS patients. However, the pathology of early cortical lesions is different than that of chronic MS in the sense that early cortical lesions are highly inflammatory, suggesting that neurodegeneration in MS occurs on an inflammatory background and raising interesting questions regarding the role of cortical demyelination and meningeal inflammation in initiating and perpetuating the disease process in early MS.
Studies focused on recurrent longitudinally extensive transverse myelitis (rLETM) are lacking.To determine the aquaporin 4 (AQP4) IgG detection rate using recombinant human APQ4-based assays in sequential serum specimens collected from patients with rLETM categorized as negative by first-generation tissue-based indirect immunofluorescence (IIF) assay and to define the clinical characteristics and motor disability outcomes in AQP4-IgG-positive rLETM.A search of the Mayo Clinic computerized central diagnostic index (October 1, 2005, through November 30, 2011), cross-linked with the Neuroimmunology Laboratory database, identified 48 patients with rLETM, of whom 36 (75%) were positive and 12 (25%) negative for neuromyelitis optica (NMO) IgG (per IIF of serial serum specimens). Stored serum specimens from "seronegative" patients were retested with recombinant human AQP4-based assays, including enzyme-linked immunosorbent, transfected cell-based, and fluorescence-activated cell-sorting assays. Control patients included 140 AQP4-IgG-positive patients with NMO, of whom a subgroup of 20 initially presented with 2 attacks of transverse myelitis (rLETM-onset NMO).AQP4-IgG serostatus, clinical characteristics, and Expanded Disability Status Scale score.Six patients with negative IIF results were reclassified as AQP4-IgG positive, yielding an overall AQP4-IgG seropositivity rate of 89%. Fluorescence-activated cell-sorting, cell-based, and enzyme-linked immunosorbent assays improved the detection rate to 89%, 85%, and 81%, respectively. The female to male ratio was 2:3 for AQP4-IgG-negative rLETM and 5:1 for AQP4-IgG-positive patients. The AQP4-IgG-positive patients with rLETM or rLETM-onset NMO were similar in age at onset, sex ratio, attack severity, relapse rate, and motor disability. From Kaplan-Meier analyses, 36% of AQP4-IgG-positive patients with rLETM are anticipated to need a cane to walk within 5 years after onset. For patients with rLETM-onset NMO, the median time from onset to first optic neuritis attack (54 months) was similar to the median disease duration for AQP4-IgG-positive patients with rLETM (59 months). The median number of attacks was 3 for AQP4-IgG-positive patients with rLETM (range, 2-22), and the first optic neuritis attack for those with rLETM-onset NMO followed a median of 3 myelitis attacks (range, 2-19). Immunosuppressant therapy reduced the relapse rate in both AQP4-IgG-positive and AQP4-IgG-negative patients with rLETM.Recombinant antigen-based assays significantly increase AQP4-IgG detection in patients with rLETM, and AQP4-IgG-negative adults with rLETM are rare. Evolution to NMO can be anticipated in AQP4-IgG-positive patients. Early initiation of immunotherapy may result in a more favorable motor outcome.
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