Joseph Y. Matsumoto

Clinical correlations of antibodies that bind, block, or modulate human acetylcholine receptors in myasthenia gravis

Acetylcholine receptor (AChR) binding and AChR modulating antibodies were found with approximately the same frequency (86%) in 349 patients with myasthenia gravis (MG). However, the total yield of positive serological results was significantly improved (90%) by assaying AChR modulating antibodies when AChR binding antibodies were not detected, because in 27 patients (8%) only one of the two tests was positive. The immunoprecipitation test for AChR blocking antibodies yielded fewer positive results (52%), but there was a significant correlation between the degree of AChR blockade and generalization of muscle weakness. In no patient was this the only positive test, because the test for AChR modulating antibodies in this study detected both AChR blocking and modulating antibodies. Human muscle AChR was used as antigen in all tests. False positive results were rare and were attributed to unexplained antibodies to 125I-alpha-Bgt (AChR binding antibody assay) and recent general anesthesia using muscle relaxants (AChR blocking and AChR modulating antibody assays). Unexplained positive results, documented previously in 5% of patients with the Lambert-Eaton myasthenic syndrome and amyotrophic lateral sclerosis (ALS), were found in this study in two of 22 patients with ALS, but in none of 427 patients with miscellaneous neurological diseases. Patients with severe generalized MG and/or thymoma tended to have higher titers of AChR binding antibodies and greater AChR modulating antibody activity. However, some patients with severe muscle weakness had low titers of antibodies, and some patients in remission or with only ocular manifestations had high titers. These seemingly paradoxical results reflect heterogeneity in the specificities, affinities, and isotypes of anti-AChR antibodies. To effect pathogenicity, antibodies must have access in vivo to extracellular antigenic sites on the AChR. One would anticipate that antibodies with greatest pathophysiological potential would be of an IgG with greatest pathophysiological potential would be of an IgG subclass that activates complement, or of a specificity that competes for acetylcholines binding site on the receptor or readily cross-links two AChR molecules to trigger receptor modulation (e.g., by binding to sites on the duplicated alpha-subunit). In patients with suspected MG who lack serological evidence of anti-AChR antibodies, motor endplate biopsy is required for microelectrophysiological, immunochemical, and ultrastructural studies to establish with certainty whether or not the condition is acquired MG.

A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor

Objective: To evaluate the safety and efficacy of botulinum toxin type A injection in essential tremor of the hand. Background: Botulinum toxin type A is an effective treatment for dystonia, spasticity, and other movement disorders and has been found to be useful in open-label studies and one double-masked study of essential hand tremor. Methods: One hundred thirty-three patients with essential tremor were randomized to low-dose (50 U) or high-dose (100 U) botulinum toxin type A (Botox) or vehicle placebo treatment. Injections were made into the wrist flexors and extensors. Patients were followed for 16 weeks. The effect of treatment was assessed by clinical rating scales, measures of motor tasks and functional disability, and global assessment of treatment. Hand strength was evaluated by clinical rating and by a dynamometer. Results: Both doses of botulinum toxin type A significantly reduced postural tremor on the clinical rating scales after 4 to 16 weeks. However, kinetic tremor was significantly reduced only at the 6-week examination. Measures of motor tasks and functional disability were not consistently improved with botulinum toxin type A treatment. Grip strength was reduced for the low- and high-dose botulinum toxin type A groups as compared with the placebo group. Adverse reactions consisted mainly of dose-dependent hand weakness. Conclusion: Botulinum toxin type A injections for essential tremor of the hands resulted in significant improvement of postural, but not kinetic, hand tremors and resulted in limited functional efficacy. Hand weakness is a dose-dependent significant side effect of treatment at the doses used in this study.

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.

Stiff-Man Syndrome and Variants: Clinical Course, Treatments, and Outcomes

BACKGROUND Little information is available about the incidence of stiff-man syndrome (SMS) (the classic form or its variants) or about long-term treatment responses and outcomes. OBJECTIVE To comprehensively describe the characteristics of a cohort of patients with SMS. DESIGN Observational study. SETTING Mayo Clinic, Rochester, Minnesota. PATIENTS Ninety-nine patients with classic SMS vs variants of the disorder, both glutamic acid decarboxylase 65 kD isoform (GAD65) antibody seropositive and seronegative. MAIN OUTCOME MEASURES Neurological, autoimmune, serological, and oncological findings; treatments; and outcomes between January 1984 and December 2008. RESULTS The median follow-up duration was 5 years (range, 0-23 years). Seventy-nine patients (59 having classic SMS, 19 having partial SMS, and 1 having progressive encephalomyelitis with rigidity and myoclonus [PERM]) were GAD65 antibody seropositive. Sixty-seven percent (53 of 79) of them had at least 1 coexisting autoimmune disease, and 4% (3 of 79) had cancer. GAD65 antibody values at initial evaluation were significantly higher among patients with classic SMS (median value, 623 nmol/L) than among patients with partial SMS (median value, 163 nmol/L) (P < .001). The initial GAD65 antibody value was positively correlated with the last follow-up Rankin score (P = .03). Among 20 patients who were GAD65 antibody seronegative (6 with classic SMS, 12 with partial SMS, and 2 with PERM), 15% (3 of 20) had at least 1 coexisting autoimmune disease, and 25% (5 of 20) had cancer (3 with amphiphysin autoimmunity and breast carcinoma and 2 with Hodgkin lymphoma). Excluding patients with PERM, all patients but 1 had sustained improvements with at least 1 γ-aminobutyric acid agent, usually diazepam; the median dosage for patients with classic SMS was 40.0 mg/d. Additional improvements occurred among 14 of 34 patients (41%) who received immunotherapy (intravenous immune globulin, azathioprine, prednisone, mycophenolate mofetil, or cyclophosphamide). Sixteen of 25 patients (64%) with extended follow-up duration remained ambulatory. CONCLUSIONS Recognition of classic SMS vs variants is important because appropriate therapy improves symptoms in most patients. Classification by anatomical extent and by GAD65 antibody serostatus gives important diagnostic and prognostic information.

Ulnar neuropathy in surgical patients

BackgroundThe goal of this project was to study the frequency and natural history of perioperative ulnar neuropathy.MethodsA prospective evaluation of ulnar neuropathy in 1,502 adult patients undergoing noncardiac surgical procedures was performed. Patients were assessed with a standard questionnair

Pathological and physiological high-frequency oscillations in focal human epilepsy.

High-frequency oscillations (HFO; gamma: 40-100 Hz, ripples: 100-200 Hz, and fast ripples: 250-500 Hz) have been widely studied in health and disease. These phenomena may serve as biomarkers for epileptic brain; however, a means of differentiating between pathological and normal physiological HFO is essential. We categorized task-induced physiological HFO during periods of HFO induced by a visual or motor task by measuring frequency, duration, and spectral amplitude of each event in single trial time-frequency spectra and compared them to pathological HFO similarly measured. Pathological HFO had higher mean spectral amplitude, longer mean duration, and lower mean frequency than physiological-induced HFO. In individual patients, support vector machine analysis correctly classified pathological HFO with sensitivities ranging from 70-98% and specificities >90% in all but one patient. In this patient, infrequent high-amplitude HFO were observed in the motor cortex just before movement onset in the motor task. This finding raises the possibility that in epileptic brain physiological-induced gamma can assume higher spectral amplitudes similar to those seen in pathologic HFO. This method if automated and validated could provide a step towards differentiating physiological HFO from pathological HFO and improving localization of epileptogenic brain.

Dopamine agonist-triggered pathological behaviors: Surveillance in the PD clinic reveals high frequencies☆

BACKGROUND Compulsive behaviors provoked by dopamine agonists often go undetected in clinical series, especially if not specifically inquired about. AIM To determine the frequency of compulsive behaviors in a Parkinsons disease (PD) clinic where agonist-treated patients were routinely asked about such aberrant behaviors. METHODS We utilized the Mayo Health Science Research database to ascertain all PD patients taking a dopamine agonist over a two year period (2007-2009). All were seen by a Mayo-Rochester Movement Disorders Staff specialist who routinely inquired about behavior compulsions. RESULTS Of 321 PD patients taking an agonist, 69 (22%) experienced compulsive behaviors, and 50/321 (16%) were pathologic. However, when the analysis was restricted to patients taking agonist doses that were at least minimally therapeutic, pathological behaviors were documented in 24%. The subtypes were: gambling (25; 36%), hypersexuality (24; 35%), compulsive spending/shopping (18; 26%), binge eating (12; 17%), compulsive hobbying (8; 12%) and compulsive computer use (6; 9%). The vast majority of affected cases (94%) were concurrently taking carbidopa/levodopa. Among those with adequate followup, behaviors completely or partly resolved when the dopamine agonist dose was reduced or ceased. CONCLUSIONS Dopamine agonist treatment of PD carries a substantial risk of pathological behaviors. These occurred in 16% of agonist-treated patients; however, when assessing patients whose dose was at least minimally in the therapeutic range, the frequency jumped to 24%. Pathological gambling and hypersexuality were most common. Carbidopa/levodopa therapy taken concurrently with a dopamine agonist appeared to be an important risk factor.

DPPX potassium channel antibody Frequency, clinical accompaniments, and outcomes in 20 patients

Objective: To describe the detection frequency and clinical associations of immunoglobulin G (IgG) targeting dipeptidyl-peptidase-like protein-6 (DPPX), a regulatory subunit of neuronal Kv4.2 potassium channels. Methods: Specimens from 20 patients evaluated on a service basis by tissue-based immunofluorescence yielded a synaptic immunostaining pattern consistent with DPPX-IgG (serum, 20; CSF, all 7 available). Transfected HEK293 cell-based assay confirmed DPPX specificity in all specimens. Sixty-nine patients with stiff-person syndrome and related disorders were also evaluated by DPPX-IgG cell-based assay. Results: Of 20 seropositive patients, 12 were men; median symptom onset age was 53 years (range, 13–75). Symptom onset was insidious in 15 and subacute in 5. Twelve patients reported prodromal weight loss. Neurologic disorders were multifocal. All had one or more brain or brainstem manifestations: amnesia (16), delirium (8), psychosis (4), depression (4), seizures (2), and brainstem disorders (15; eye movement disturbances [8], ataxia [7], dysphagia [6], dysarthria [4], respiratory failure [3]). Nine patients reported sleep disturbance. Manifestations of central hyperexcitability included myoclonus (8), exaggerated startle (6), diffuse rigidity (6), and hyperreflexia (6). Dysautonomia involved the gastrointestinal tract (9; diarrhea [6], gastroparesis, and constipation [3]), bladder (7), cardiac conduction system (3), and thermoregulation (1). Two patients had B-cell neoplasms: gastrointestinal lymphoma (1), and chronic lymphocytic leukemia (1). Substantial neurologic improvements followed immunotherapy in 7 of 11 patients with available treatment data. DPPX-IgG was not detected in any of the stiff-person syndrome patients. Conclusions: DPPX-IgG is a biomarker for an immunotherapy-responsive multifocal neurologic disorder of the central and autonomic nervous systems.

Prevalence of tremor in multiple sclerosis and associated disability in the Olmsted County population

We applied a clinical tremor rating scale and measures of disability to 200 of 201 multiple sclerosis patients from a prevalence cohort in Olmsted County, Minnesota. In a community‐based sample, tremor was found clinically in 51 (25%) patients, although only 6 (3%) patients had severe tremor. Within the population as a whole, tremor was strongly associated with impairment disability and handicap.

Adult-Onset Opsoclonus-Myoclonus Syndrome

BACKGROUND Little is known about adult-onset opsoclonus-myoclonus syndrome (OMS) outside of individual case reports. OBJECTIVE To describe adult-onset OMS. DESIGN Review of medical records (January 1, 1990, through December 31, 2011), prospective telephone surveillance, and literature review (January 1, 1967, through December 31, 2011). SETTING Department of Neurology, Mayo Clinic, Rochester, Minnesota. PATIENTS Twenty-one Mayo Clinic patients and 116 previously reported patients with adult-onset OMS. MAIN OUTCOME MEASURES Clinical course and longitudinal outcomes. RESULTS The median age at onset of the 21 OMS patients at the Mayo Clinic was 47 years (range, 27-78 years); 11 were women. Symptoms reported at the first visit included dizziness, 14 patients; balance difficulties, 14; nausea and/or vomiting, 10; vision abnormalities, 6; tremor/tremulousness, 4; and altered speech, 2. Myoclonus distribution was extremities, 15 patients; craniocervical, 8; and trunk, 4. Cancer was detected in 3 patients (breast adenocarcinoma, 2; and small cell lung carcinoma, 1); a parainfectious cause was assumed in the remainder of the patients. Follow-up of 1 month or more was available for 19 patients (median, 43 months; range, 1-187 months). Treatment (median, 6 weeks) consisted of immunotherapy and symptomatic therapy in 16 patients, immunotherapy alone for 2, and clonazepam alone for 1. Of these 19 patients, OMS remitted in 13 and improved in 3; 3 patients died (neurologic decline, 1; cancer, 1; and myocardial infarction, 1). The cause of death was of paraneoplastic origin in 60 of 116 literature review patients, with the most common carcinomas being lung (33 patients) and breast (7); the most common antibody was antineuronal nuclear antibody type 2 (anti-Ri, 15). Other causes were idiopathic in origin, 38 patients; parainfectious, 15 (human immunodeficiency virus, 7); toxic/metabolic, 2; and other autoimmune, 1. Both patients with N -methyl-D-aspartate receptor antibody had encephalopathy. Improvements were attributed to immunotherapy alone in 22 of 28 treated patients. CONCLUSIONS Adult-onset OMS is rare. Paraneoplastic and parainfectious causes (particularly human immunodeficiency virus) should be considered. Complete remission achieved with immunotherapy is the most common outcome.