Andrew McKeon

CNS aquaporin-4 autoimmunity in children.

Background: In adult patients, autoantibodies targeting the water channel aquaporin-4 (AQP4) are a biomarker for a spectrum of CNS inflammatory demyelinating disorders with predilection for optic nerves and spinal cord (neuromyelitis optica [NMO]). Here we describe the neurologic, serologic, and radiographic findings associated with CNS AQP4 autoimmunity in childhood. Methods: A total of 88 consecutive seropositive children were identified through service evaluation for NMO-IgG. Sera of 75 were tested for coexisting autoantibodies. Clinical information was available for 58. Results: Forty-two patients (73%) were non-Caucasian, and 20 (34%) had African ethnicity. Median age at symptom onset was 12 years (range 4–18). Fifty-seven (98%) had attacks of either optic neuritis (n = 48; 83%) or transverse myelitis (n = 45; 78%), or both. Twenty-six (45%) had episodic cerebral symptoms (encephalopathy, ophthalmoparesis, ataxia, seizures, intractable vomiting, or hiccups). Thirty-eight (68%) had brain MRI abnormalities, predominantly involving periventricular areas (in descending order of frequency): the medulla, supratentorial and infratentorial white matter, midbrain, cerebellum, thalamus, and hypothalamus. Additional autoantibodies were detected in 57 of 75 patients (76%), and 16 of 38 (42%) had a coexisting autoimmune disorder recorded (systemic lupus erythematosus, Sjögren syndrome, juvenile rheumatoid arthritis, Graves disease). Attacks were recurrent in 54 patients (93%; median follow-up, 12 months). Forty-three of 48 patients (90%) had residual disability: 26 (54%) visual impairment and 21 (44%) motor deficits (median Expanded Disability Status Scale 4.0 at 12 months). Conclusions: Aquaporin-4 autoimmunity is a distinctive recurrent and widespread inflammatory CNS disease in children.

Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study

BACKGROUND Complement activation after binding of an IgG autoantibody to aquaporin 4 (AQP4) is thought to be a major determinant of CNS inflammation and astrocytic injury in neuromyelitis optica. The aim of this study was to investigate the use of eculizumab--a therapeutic monoclonal IgG that neutralises the complement protein C5--in neuromyelitis optica spectrum disorders. METHODS Between Oct 20, 2009, and Nov 3, 2010, we recruited patients from two US centres into an open-label trial. Patients were AQP4-IgG-seropositive, aged at least 18 years, had a neuromyelitis optica spectrum disorder, and had at least two attacks in the preceding 6 months or three in the previous 12 months. Patients received meningococcal vaccine at a screening visit and 2 weeks later began eculizumab treatment. They received 600 mg intravenous eculizumab weekly for 4 weeks, 900 mg in the fifth week, and then 900 mg every 2 weeks for 48 weeks. The coprimary endpoints were efficacy (measured by number of attacks [new worsening of neurological function lasting for more than 24 h and not attributable to an identifiable cause]) and safety. Secondary endpoints were disability (measured by expanded disability status scale), ambulation (Hauser score), and visual acuity. At follow-up visits (after 6 weeks and 3, 6, 9, and 12 months of treatment; and 3 and 12 months after discontinuation), complete neurological examination was undertaken and an adverse event questionnaire completed. This trial is registered with ClinicalTrials.gov, number NCT00904826. FINDINGS We enrolled 14 patients, all of whom were women. After 12 months of eculizumab treatment, 12 patients were relapse free; two had had possible attacks. The median number of attacks per year fell from three before treatment (range two to four) to zero (zero to one) during treatment (p<0·0001). No patient had worsened disability by any outcome measure. Median score on the expanded disability status scale improved from 4·3 (range 1·0-8·0) before treatment to 3·5 (0-8·0) during treatment (p=0·0078). Two patients improved by two points and three improved by one point on the Hauser score; no change was recorded for the other patients. Visual acuity had improved in at least one eye by one point in four patients, and by two points in one patient; no change was recorded for other patients. One patient had meningococcal sepsis and sterile meningitis about 2 months after the first eculizumab infusion, but resumed treatment after full recovery. No other drug-related serious adverse events occurred. Eight attacks in five patients were reported within 12 months of eculizumab withdrawal. INTERPRETATION Eculizumab seems to be well tolerated, significantly reduce attack frequency, and stabilise or improve neurological disability measures in patients with aggressive neuromyelitis optica spectrum disorders. The apparent effects of eculizumab deserve further investigation in larger, randomised controlled studies. FUNDING Alexion Pharmaceuticals.

The Alcohol Withdrawal Syndrome

The alcohol withdrawal syndrome (AWS) is a common management problem in hospital practice for neurologists, psychiatrists and general physicians alike. Although some patients have mild symptoms and may even be managed in the outpatient setting, others have more severe symptoms or a history of adverse outcomes that requires close inpatient supervision and benzodiazepine therapy. Many patients with AWS have multiple management issues (withdrawal symptoms, delirium tremens, the Wernicke–Korsakoff syndrome, seizures, depression, polysubstance abuse, electrolyte disturbances and liver disease), which requires a coordinated, multidisciplinary approach. Although AWS may be complex, careful evaluation and available treatments should ensure safe detoxification for most patients.

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

Insights From LGI1 and CASPR2 Potassium Channel Complex Autoantibody Subtyping

OBJECTIVE To determine, in patients identified as seropositive for neuronal voltage-gated potassium channel (VGKC) complex autoantibodies, the spectrum of clinical presentations and frequency of leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) as defined antigenic neuronal targets in the VGKC macromolecular complex. DESIGN Retrospective cohort study. SETTING Clinical practice, Mayo Clinic Neuroimmunology Laboratory and Department of Neurology. PATIENTS A total of 54 853 patients were evaluated, of whom 1992 were found to be VGKC complex IgG positive. RESULTS From June 1, 2008, to June 30, 2010, comprehensive service serologic evaluation performed on 54853 patients with unexplained neurologic symptoms identified 1992 patients (4%) who were positive for VGKC complex IgG (values ≥ 0.03 nmol/L). Among 316 seropositive patients evaluated clinically at our institution, 82 (26%) were seropositive for LGI1 IgG and/or CASPR2 IgG. Of these 82 patients, 27% had low (0.03-0.09 nmol/L), 51% had medium (0.10-0.99 nmol/L), and 22% had high (≥ 1.00 nmol/L) VGKC complex IgG values. Leucine-rich glioma-inactivated protein 1 IgG positivity was associated with higher VGKC complex IgG values (P< .001) and cortical presentations (P< .001); CASPR2 IgG was associated with peripheral motor excitability (P= .009). However, neither autoantibody was pathognomonic for a specific neurologic presentation or correlated significantly with cancer. Neurologic phenotypes were diverse. Cerebrocortical manifestations (including cognitive impairment and seizures) were recorded in 76% of patients with LGI1 IgG alone (n=46) and 29% with CASPR2 IgG alone (n=28). Peripheral motor hyperexcitability was found in 21% of patients with CASPR2 IgG alone and 6.5% of patients with LGI1 IgG alone. CONCLUSIONS The study emphasizes diverse and overlapping neurologic phenotypes across a range of VGKC complex IgG values and varying LGI1 IgG and CASPR2 IgG specificities. The frequent occurrence of LGI1 IgG and CASPR2 IgG in serum samples with low and medium VGKC complex IgG values supports the clinical significance of low values in clinical evaluation. Additional antigenic components of VGKC macromolecular complexes remain to be defined.

Glycine receptor autoimmune spectrum with stiff-man syndrome phenotype.

OBJECTIVES To determine whether glycine receptor α1 subunit-specific autoantibodies (GlyRα1-IgG) occur in a broader spectrum of brainstem and spinal hyperexcitability disorders than the progressive encephalomyelitis with rigidity and myoclonus phenotype recognized to date, and to ascertain disease specificity. DESIGN Retrospective, case-control study. SETTINGS Mayo Clinic, Rochester, Minnesota, and University of Barcelona, Spain. PATIENTS Eighty-one patients with stiff-man syndrome phenotype, 80 neurologic control subjects, and 20 healthy control subjects. INTERVENTION Glycine receptor α1-transfected cells to test serum or cerebrospinal fluid from cases and control subjects. MAIN OUTCOME MEASURES Frequency of GlyRα1-IgG positivity among stiff-man syndrome phenotype cases and control subjects. Comparison of GlyRα1-IgG seropositive and seronegative cases. RESULTS Seropositive cases (12% of cases) included 9 with stiff-man syndrome (4 classic; 5 variant; 66% were glutamic acid decarboxylase 65-IgG positive) and 1 with progressive encephalomyelitis with rigidity and myoclonus. Immunotherapy responses were noted more frequently in GlyRα1-IgG-positive cases (6 of 7 improved) than in seronegative cases (7 of 25 improved; P= .02). The single seropositive control patient had steroid-responsive vision loss and optic atrophy with inflammatory cerebrospinal fluid. CONCLUSIONS Glycine receptor α1-IgG aids identification of autoimmune brainstem/spinal cord hyperexcitability disorders and may extend to the glycinergic visual system.

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.

Current concept of neuromyelitis optica (NMO) and NMO spectrum disorders

Neuromyelitis optica (NMO) has been described as a disease clinically characterised by severe optic neuritis (ON) and transverse myelitis (TM). Other features of NMO include female preponderance, longitudinally extensive spinal cord lesions (>3 vertebral segments), and absence of oligoclonal IgG bands . In spite of these differences from multiple sclerosis (MS), the relationship between NMO and MS has long been controversial. However, since the discovery of NMO-IgG or aquaporin-4 (AQP4) antibody (AQP4-antibody), an NMO-specific autoantibody to AQP4, the dominant water channel in the central nervous system densely expressed on end-feet of astrocytes, unique clinical features, MRI and other laboratory findings in NMO have been clarified further. AQP4-antibody is now the most important laboratory finding for the diagnosis of NMO. Apart from NMO, some patients with recurrent ON or recurrent longitudinally extensive myelitis alone are also often positive for AQP4-antibody. Moreover, studies of AQP4-antibody-positive patients have revealed that brain lesions are not uncommon in NMO, and some patterns appear to be unique to NMO. Thus, the spectrum of NMO is wider than mere ON and TM. Pathological analyses of autopsied cases strongly suggest that unlike MS, astrocytic damage is the primary pathology in NMO, and experimental studies confirm the pathogenicity of AQP4-antibody. Importantly, therapeutic outcomes of some immunological treatments are different between NMO and MS, making early differential diagnosis of these two disorders crucial. We provide an overview of the epidemiology, clinical and neuroimaging features, immunopathology and therapy of NMO and NMO spectrum disorders.