Marcelo Matiello

Treatment of neuromyelitis optica with rituximab: Retrospective analysis of 25 patients

BACKGROUND Neuromyelitis optica (NMO) is an uncommon, life-threatening inflammatory demyelinating disorder. Recently, much has become known about its immunopathogenesis. However, optimal treatments, with expected outcomes, have not been established. OBJECTIVE To evaluate the use and efficacy of rituximab for treating NMO. DESIGN Retrospective multicenter case series of NMO patients treated with rituximab. SETTING Seven tertiary medical centers in the United States and England. PATIENTS Twenty-five patients (including 2 children), 23 of whom experienced relapses despite use of other drugs before rituximab. Extended follow-up of 7 previously reported patients is included. INTERVENTIONS Infusions of rituximab at median intervals of 8 months. MAIN OUTCOME MEASURES Annualized relapse rate and disability (expressed as Expanded Disability Status Scale score). RESULTS At a median follow-up of 19 months, the median annualized posttreatment relapse rate was lower than the pretreatment rate (0 [range 0-3.2] vs 1.7 [range, 0.5-5] relapses, P < .001). Disability improved or stabilized in 20 of 25 patients (80%, P = .02). Two patients died during the follow-up period, 1 owing to a brainstem relapse and 1 owing to suspected septicemia. Infections were reported in 20% of patients. CONCLUSIONS In NMO, treatment with rituximab appears to reduce the frequency of attacks, with subsequent stabilization or improvement in disability.

NMO-IgG predicts the outcome of recurrent optic neuritis

Objective: 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. Methods: 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. Results: 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). Conclusions: Neuromyelitis optica (NMO)–immunoglobulin G seropositivity predicts poor visual outcome and development of NMO. Seropositive recurrent optic neuritis is a limited form of NMO.

Treatment of neuromyelitis optica with mycophenolate mofetil: Retrospective analysis of 24 patients

BACKGROUND Neuromyelitis optica (NMO) is the first inflammatory autoimmune demyelinating disease of the central nervous system for which a specific antigenic target has been identified; the marker autoantibody NMO-IgG specifically recognizes the astrocytic water channel aquaporin 4. Current evidence strongly suggests that NMO-IgG may be pathogenic. Since disability accrues incrementally related to attacks, attack prevention with immunosuppressive therapy is the mainstay of preventing disability. OBJECTIVE To evaluate the efficacy and safety of mycophenolate mofetil therapy in NMO spectrum disorders. DESIGN Retrospective case series with prospective telephone follow-up. SETTING Mayo Clinic Health System. Patients Twenty-four patients with NMO spectrum disorders (7 treatment-naive). Intervention Mycophenolate mofetil (median dose of 2000 mg per day). MAIN OUTCOME MEASURES Annualized relapse rates and disability (Expanded Disability Status Scale). RESULTS At a median follow-up of 28 months (range, 18-89 months), 19 patients (79%) were continuing treatment. The median duration of treatment was 27 months (range, 1-89 months). The median annualized posttreatment relapse rate was lower than the pretreatment rate (0.09; range, 0-1.5; and 1.3; range, 0.23-11.8, respectively; P < .001). Disability stabilized or decreased in 22 of 24 patients (91%). One patient died of disease complications during follow-up. Six patients (25%) noted adverse effects during treatment with mycophenolate. CONCLUSION Mycophenolate is associated with reduction in relapse frequency and stable or reduced disability in patients with NMO spectrum disorders.

Posterior reversible encephalopathy syndrome in neuromyelitis optica spectrum disorders

Background: Posterior reversible encephalopathy syndrome (PRES) is characterized by vasogenic subcortical edema without infarction. It has been associated with hypertensive crises and with immunosuppressive medications but not with neuromyelitis optica (NMO). Methods: We reviewed the clinical and neuroimaging features of five NMO–immunoglobulin G (IgG) seropositive white women who experienced an episode of PRES and had a coexisting NMO spectrum disorder (NMOSD). We also tested for the aquaporin-4 (AQP4) water channel autoantibody (NMO-IgG) in 14 patients from an independently ascertained cohort of individuals with PRES. Results: All five patients developed abrupt confusion and depressed consciousness consistent with PRES. The encephalopathy resolved completely within 7 days. Comorbid conditions or interventions recognized to be associated with PRES included orthostatic hypotension with supine hypertension, plasma exchange, IV immunoglobulin treatment, and high-dose IV methylprednisolone. Brain MRI studies revealed bilateral T2-weighted (T2W) hyperintense signal abnormalities, primarily in frontal, parieto-occipital, and cerebellar regions. Three patients had highly symmetric lesions and three had gadolinium-enhancing lesions. Follow-up neuroimaging revealed partial or complete disappearance of T2W hyperintensity or gadolinium-enhancing lesions in all five patients. Patients with PRES without NMOSD were uniformly NMO-IgG seronegative. Conclusions: Brain lesions in some patients with neuromyelitis optica spectrum disorder (NMOSD) may be accompanied by vasogenic edema and manifest as posterior reversible encephalopathy syndrome (PRES). Water flux impairment due to aquaporin-4 autoimmunity may predispose to PRES in patients with NMOSD who experience blood pressure fluctuations or who are treated with therapies that can cause rapid fluid shifts. ADC = apparent diffusion coefficient; AQP4 = aquaporin-4; DWI = diffusion-weighted imaging; FLAIR = fluid-attenuated inversion recovery; Gd = gadolinium; IgG = immunoglobulin G; IVIg = IV immunoglobulin; IVMP = IV methylprednisolone; LETM = longitudinally extensive transverse myelitis; NMO = neuromyelitis optica; NMOSD = neuromyelitis optica spectrum disorder; ON = optic neuritis; PLEX = plasma exchange; PRES = posterior reversible encephalopathy syndrome; T2W = T2-weighted.

Azathioprine Tolerability, efficacy, and predictors of benefit in neuromyelitis optica

Objective: To evaluate the efficacy, tolerability, optimal dosing, and monitoring of azathioprine in patients with neuromyelitis optica (NMO). Methods: This was a chart review and telephone follow-up study of 99 patients with NMO spectrum of disorders (NMOSD) treated with azathioprine (1994–2009). NMOSD were NMO (2006 diagnostic criteria) or partial NMO forms (NMO–immunoglobulin G seropositive). Wilcoxon signed rank test was used to compare pretreatment and postinitiation of azathioprine (posttreatment) annualized relapse rates (ARR), Expanded Disability Status Scale (EDSS) score, and visual acuity outcome. Linear regression was used to assess the effects of various factors on ARR change and disability. Results: The median duration of NMOSD symptoms prior to initiation of azathioprine was 2 years (range 1–27); 79 patients were women. Eighty-six patients had NMO and 13 limited NMO versions, including transverse myelitis in 8 and optic neuritis in 5. Median posttreatment follow-up was 22 months. Thirty-eight patients discontinued drug (side effects, 22; no efficacy, 13; lymphoma, 3). Among 70 patients with >12 months follow-up, 48 received ≥2.0 mg/kg/day (ARR: pretreatment, 2.20; posttreatment, 0.52); 22 received <2.0 mg/kg/day (ARR: pretreatment, 2.09; posttreatment, 0.82); 52 received concomitant prednisone (ARR: pretreatment, 2.20; posttreatment, 0.89) and 18 did not (ARR: pretreatment, 1.54; posttreatment, 0.23); p < 0.0001 for each comparison. EDSS was stable or improved despite ongoing attacks in 22 patients (31%). Twenty-six patients tolerated azathioprine and were relapse-free (37%, median follow-up 24 months; range 12–151). Mean corpuscular volume increase influenced ARR change (p = 0.049). Conclusions: Azathioprine is generally effective and well-tolerated. Early initiation, adequate dosing, and hematologic parameter monitoring may optimize efficacy. Classification of evidence: This study provides Class IV evidence that azathioprine is effective for reducing relapse rates and improving EDSS and visual acuity scores in patients with NMO spectrum of disorders. GLOSSARY: AQP4: aquaporin-4 ARR: annualized relapse rate EDSS: Expanded Disability Status Scale IgG: immunoglobulin G MCV: mean corpuscular volume NMO: neuromyelitis optica NMOSD: neuromyelitis optica spectrum of disorders TPMT: thiopurine methyltransferase.Objective: To evaluate the efficacy, tolerability, optimal dosing, and monitoring of azathioprine in patients with neuromyelitis optica (NMO). Methods: This was a chart review and telephone follow-up study of 99 patients with NMO spectrum of disorders (NMOSD) treated with azathioprine (1994–2009). NMOSD were NMO (2006 diagnostic criteria) or partial NMO forms (NMO–immunoglobulin G seropositive). Wilcoxon signed rank test was used to compare pretreatment and postinitiation of azathioprine (posttreatment) annualized relapse rates (ARR), Expanded Disability Status Scale (EDSS) score, and visual acuity outcome. Linear regression was used to assess the effects of various factors on ARR change and disability. Results: The median duration of NMOSD symptoms prior to initiation of azathioprine was 2 years (range 1–27); 79 patients were women. Eighty-six patients had NMO and 13 limited NMO versions, including transverse myelitis in 8 and optic neuritis in 5. Median posttreatment follow-up was 22 months. Thirty-eight patients discontinued drug (side effects, 22; no efficacy, 13; lymphoma, 3). Among 70 patients with >12 months follow-up, 48 received ≥2.0 mg/kg/day (ARR: pretreatment, 2.20; posttreatment, 0.52); 22 received <2.0 mg/kg/day (ARR: pretreatment, 2.09; posttreatment, 0.82); 52 received concomitant prednisone (ARR: pretreatment, 2.20; posttreatment, 0.89) and 18 did not (ARR: pretreatment, 1.54; posttreatment, 0.23); p < 0.0001 for each comparison. EDSS was stable or improved despite ongoing attacks in 22 patients (31%). Twenty-six patients tolerated azathioprine and were relapse-free (37%, median follow-up 24 months; range 12–151). Mean corpuscular volume increase influenced ARR change (p = 0.049). Conclusions: Azathioprine is generally effective and well-tolerated. Early initiation, adequate dosing, and hematologic parameter monitoring may optimize efficacy. Classification of evidence: This study provides Class IV evidence that azathioprine is effective for reducing relapse rates and improving EDSS and visual acuity scores in patients with NMO spectrum of disorders.

Intractable vomiting as the initial presentation of neuromyelitis optica

We report 12 aquaporin‐4 antibody‐positive patients (12% of seropositive Mayo Clinic patients identified since 2005) whose initial presenting symptom of neuromyelitis optica was intractable vomiting. The initial evaluation in 75% was gastroenterologic. Vomiting lasted a median of 4 weeks (range, 2 days–80 weeks). Optic neuritis or transverse myelitis developed after vomiting onset in 11 patients (median interval, 11 weeks; range, 1–156). At last evaluation (median, 48 months after vomiting onset), 7 patients fulfilled neuromyelitis optica diagnostic criteria. Our clinical, pathologic and neuroimaging observations suggest the aquaporin‐4–rich area postrema may be a first point of attack in neuromyelitis optica. Ann Neurol 2010;68:757–761

Coexistence of myasthenia gravis and serological markers of neurological autoimmunity in neuromyelitis optica.

We systematically evaluated the frequency of neurological disorders and muscle and neural autoantibodies in 177 patients with neuromyelitis optica (NMO) and in 250 control subjects (173 healthy; 77 multiple sclerosis, MS, patients). An excess of myasthenia gravis (MG, 2%), and muscle‐type acetylcholine receptor antibody (11%) was detected among NMO patients. The presence of neural or muscle autoantibodies was more common in NMO patients (34%) than in MS patients or healthy controls (7%), P < 0.0001. The coexistence of NMO and MG should be considered in atypical or refractory presentations of either disorder.

HLA-DRB association in neuromyelitis optica is different from that observed in multiple sclerosis

Until recently, neuromyelitis optica (NMO) was considered to be a sub-type of multiple sclerosis (MS), which has a strong predilection for Caucasian populations, whereas NMO is more frequent in non-Caucasian individuals. The objective of this study was to compare the HLA-DRB profile in Brazilian Mulatto patients with NMO spectrum disorders (NMOSDs) with that observed for Mulatto MS patients and healthy Mulatto controls. Twenty seven NMOSD patients (20 women), all seropositive for NMO-IgG, 29 MS patients and 28 Mulatto healthy blood donors were evaluated for HLA-DRB allele groups. HLA-DRB1*03 allele group was overrepresented in NMO patients compared with healthy controls (p = 0.0401; OR = 3.23, 95%CI: 1.07—9.82). In contrast, the HLA-DRB1*15 allele group was overrepresented in Brazilian MS patients (OR = 15.89, 95%CI: 3.51—71.85; p < 0.0001). DRB3 was overrepresented in NMO (p = 0.0064), and DRB5 overrepresented in MS patients (p = 0.0001). The low frequency of HLA-DRB1*15 alleles was associated with the presence of long and central cord lesions at magnetic resonance. In addition, DRB1*15 alleles were associated with the fulfillment of the Barkhof criteria. In conclusion, these results indicate that the DRB profile of NMO patients is different from that observed for MS patients, further corroborating the distinction between NMO and MS.

Paraneoplastic isolated myelopathy Clinical course and neuroimaging clues

Objective: To report the clinical phenotype and outcome of isolated paraneoplastic myelopathy. Methods: We systematically reviewed clinical, serologic, and MRI data for 31 patients (20 female) who presented with an isolated myelopathy and coexisting cancer: carcinoma (lung, 9; breast, 7; kidney, 2; thyroid, 2; ovary/endometrium, 2), melanoma (2), or other cancer (3), or a paraneoplastic autoantibody with strong cancer association (amphiphysin–immunoglobulin G [IgG], 9; collapsin response-mediator protein 5–IgG, 9; Purkinje-cell cytoplasmic autoantibody type 1, 2; antineuronal nuclear autoantibody [ANNA]–1, 1; ANNA-3, 1). Results: Of 31 patients who presented with a progressive myelopathy, symptom onset was subacute in 16 (52%). The median age was 62 years. CSF abnormalities included elevated protein (>45 mg/dL), 22; pleocytosis, 15; excess oligoclonal bands (normal <4), 7. MRI cord abnormalities identified in 20 patients were longitudinally extensive (>3 vertebral segments), 14; symmetric tract or gray matter–specific signal abnormality, 15 (enhancing in 13). Myelopathy preceded cancer diagnosis in 18 patients (median interval 12 months; range 2–44). After myelopathy onset, 26 patients underwent oncologic treatment, immunosuppressive treatment (median delay to commencing immunotherapy 9.5 months [range 1–54]), or both; only 8 improved (31%). At last neurologic evaluation (median interval after onset 17 months; range 1–165 months), 16 patients (52%) were wheelchair-dependent (median time from onset to wheelchair 9 months [range 1–21]). Ten patients died after a median of 38 months from symptom onset (range 7–152). Conclusion: Symmetric, longitudinally extensive tract or gray matter–specific changes on spinal MRI should raise suspicion for a paraneoplastic myelopathy. Resulting disability is often severe. Only a minority of patients improve with treatment.

Familial neuromyelitis optica

Background: Detection of aquaporin-4–specific immunoglobulin G (IgG) has expanded the spectrum of neuromyelitis optica (NMO). Rare reports of familial aggregation have suggested a component of genetic susceptibility but these reports mostly antedated the discovery of the NMO-IgG biomarker and recently updated diagnostic criteria. Methods: We report a case series describing the demographic, clinical, neuroimaging, and NMO-IgG serologic status of 12 multiplex NMO pedigrees with a total of 25 affected individuals. Results: Twenty-one patients (84%) were women. Families were Asian (n = 5), Latino (n = 4), white (n = 1), or African (n = 2). Apparent transmission was either maternal (n = 5) or paternal (n = 2). In 1 family, 3 individuals had NMO; in the others, 2 individuals were affected. Sibling pairs (n = 6), parent-child (n = 4), and aunt-niece (n = 3) pairs were observed. Nineteen patients (76%) were NMO-IgG positive. Twelve (48%) had clinical or serologic evidence of another autoimmune disease. Familial occurrence of NMO occurs in approximately 3% of patients with well-established diagnosis of NMO. Conclusions: A small proportion of patients with NMO have relatives with this condition, but familial occurrence is more common than would be expected from its frequency in the general population. Familial NMO is indistinguishable from sporadic NMO based on clinical symptoms, age at onset, sex distribution, and frequency of NMO-IgG detection. One or 2 generations were affected and affected individuals represented a small fraction of family members. Taken together, these data suggest complex genetic susceptibility in NMO.