What have we learned about cognition in myasthenia gravis?: a review of methods and results.

Most individuals with myasthenia gravis (MG) complain of cognitive impairment, but empirical studies of cognition in MG have produced mixed results. In the present review, we critically examined the methodology and results of previous studies that investigated cognition in MG. Results from our review revealed that none of the studies met at least 50% of criteria under review. The most common shortcomings of previous studies included small sample size, no exclusion for visual difficulties in patients, inadequate assessment of mood, and poor control for prednisone use. Despite these methodological difficulties, mild impairments on measures of learning have been identified. These findings need to be replicated with adequate control of potential confounds before any conclusions can be made regarding cognition in this disease. Suggestions for design of future studies are provided.

Autosomal dominant humeroperoneal myopathy.

Emery-Dreifuss muscular dystrophy is a syndrome with five salient features: early and unusual contractures; humeroperoneal muscle wasting; the slow progression of weakness, beginning in childhood; cardiac conduction defects; and X-linked inheritance. We present two cases and detail other reports with a similar constellation of findings with apparent autosomal dominant inheritance. We postulate separate genetic disorders with similar phenotypic expression.

Duchenne muscular dystrophy manifesting carriers.

Seven unrelated women were manifesting carriers of Duchenne muscular dystrophy. A manifesting carrier of Duchenne muscular dystrophy is defined as a female with a history of Duchenne muscular dystrophy in her pedigree who has symptomatic weakness. All were characterized by slowly progressive weakness that began in the second or third decade of life. Asymmetric weakness was present in only three of the seven patients. Serum creatine kinase values were elevated in all patients and none had an electrocardiogram indicating ventricular hypertrophy. The electromyogram and muscle biopsy specimens were reported as myopathic in all patients studied. In the absence of a male relative with Duchenne muscular dystrophy, clinical distinction from cases of autosomal recessive limb girdle muscular dystrophy may not be possible. The development of new techniques in molecular genetics should allow precise identification of manifesting carriers of Duchenne muscular dystrophy in the near future.

Distal vacuolar myopathy with complete heart block.

We describe a 26-year-old man with a predominantly distal myopathy and complete heart block. A muscle biopsy specimen demonstrated numerous vacuoles, which, by electron microscopy, contained membranous whorls. Filamentous inclusions characteristic of inclusion body myositis were not seen. It is important to be aware that life-threatening cardiac disease may occur in this setting.

Arrhythmogenic seizures: diagnosis by simultaneous EEG/ECG recording.

We studied a young man with presumably idiopathic seizures that were refractory to phenytoin therapy. Sick sinus syndrome was found after an episode of unconsciousness, but seizures continued despite the insertion of a demand ventricular pacemaker. Evaluation revealed a left temporal seizure focus, and combined EEG and ECG monitoring during a seizure revealed a left temporal paroxysmal discharge and an ictal cardiac arrhythmia. Detailed EEG and cardiac evaluation is necessary for all patients with "idiopathic" seizures.

Clinical and genetic investigation in autosomal dominant limb-girdle muscular dystrophy.

Limb-girdle muscular dystrophy is a syndrome of progressive myopathic weakness affecting shoulder and hip girdle and proximal arm and leg muscles. The disease occurs either sporadically or inherited as an autosomal recessive trait. Autosomal dominant inheritance is rare. We report a large family with apparent autosomal dominant inheritance. Sixteen members were affected with a disease characterized by proximal weakness, leg greater than arm, onset in the third decade, elevated CK and CK MB levels, and myopathic EMGs and muscle biopsies. Linkage analysis revealed no conclusive linkage.

Multifocal motor neuropathy with conduction block and Campylobacter jejuni.

We describe a patient with acute multifocal motor neuropathy with conduction block (MMNCB) and high titers of immunoglobulin G anti-GM1 antibodies after Campylobacter jejuni enteritis. Treatment with intravenous immune globulin led to rapid improvement with return of normal function by 6 weeks. This is the first report of C. jejuni enteritis preceding MMNCB.

Isolated deficiency of vitamin E with progressive neurologic deterioration.

We studied a 19-year-old man with vitamin E deficiency without intestinal fat malabsorption. In addition to recognized neurologic complications of vitamin E deficiency, he had dystonic posturing and bradykinesia.

Confirmation of linkage of oculopharyngeal muscular dystrophy to chromosome 14q11.2-q13 in American families suggests the existence of a second causal mutation.

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset, autosomal dominant disorder characterized by progressive ptosis, dysphagia, and extremity weakness. Linkage of OPMD to 14q11.2-q13 has been reported in a series of French-Canadian families. Tightly linked markers have been defined and haplotype analysis in these data show a single segregating disease chromosome throughout the OPMD French-Canadian families. We have ascertained and sampled five multigenerational outbred American OPMD families. Four of the five families have known French-Canadian ancestry while the fifth is of English/Scottish origin. Linkage analysis was performed using standard likelihood methods. A peak multipoint lod score of 6.30 was obtained for the marker MYH7.1 in the OPMD families. The English/ Scottish family exhibited a different chromosomal haplotype for the OPMD alleles than the families of French-Canadian origin. These data suggest this family may represent a second, possibly independent mutation in this disorder. Linkage was confirmed to chromosome 14q11.2-q13 with no evidence of genetic heterogeneity.

Development of a microsatellite genetic map spanning 5q31-q33 and subsequent placement of the LGMD1A locus between D5S178 and IL9.

Limb-girdle muscular dystrophy (LGMD) is a genetically and clinically heterogeneous group of disorders. We previously localized an autosomal dominant form of the disorder (LGMD1A) to chromosome 5q22-31 by linkage analysis in a single large pedigree. After developing a microsatellite genetic map incorporating six loci in q31-33 of chromosome 5 and spanning 35 cM, we have refined the original localization. Using multipoint analysis, LGMD1A is localised to a 7 cM region between the markers IL9 and D5S178 with odds > 1000:1.

Treatment of antenatal myasthenia gravis.

Maternal myasthenia gravis has been associated with the presence of neonatal myasthenia and sometimes fatal congenital anomalies. As a result, antenatal therapy directed at fetal sequelae may be indicated. We present the case of a pregnant myasthenic woman whose two previous pregnancies had ended in neonatal deaths from fetal deformations that were presumably due to maternal myasthenia. Serial plasmaphereses and oral prednisone therapy were used in an attempt to depress maternal anti-acetylcholine receptor antibody titers. As anti-acetylcholine receptor antibody titers fell, fetal breathing movements became apparent by ultrasound, and as these titers rose, no fetal breathing movements were apparent. Our patient delivered an infant with transient neonatal myasthenia but normal pulmonary development and no deformations. We suggest that the therapy given may have improved the outcome of this pregnancy compared with her two previous pregnancies.

Cognitive dysfunction in individuals with myasthenia gravis.

In the present study we administered a battery of cognitive measures that examined attention, response fluency, information processing, and verbal and visual learning and retention to 28 individuals with generalized myasthenia gravis (MG) and 18 demographically similar control subjects. Results revealed that MG patients performed significantly more poorly than control subjects on the measures of response fluency, information processing and most measures of verbal and visual learning. Significant group differences were not evident on the measure of attention span or on the indices of retention of information. Cognitive performances of the MG group were not related to mood disturbance, disease duration, or daily dose of prednisone. While these results suggest central involvement in MG, previous studies have not provided evidence that MG antibodies bind to central nicotinic receptors. Possible alternative mechanisms underlying cognitive dysfunction in MG are discussed.

Markers of keratinocyte differentiation in snuff-induced leukoplakia.

Biopsy specimens from 12 patients who used snuff and had leukoplakia in the mucosa of the oral cavity were studied and compared with specimens from their own nonleukoplakic oral mucosa, as well as with biopsy specimens from corresponding areas of the oral cavity in 12 nonsmoking, nontobacco-using control subjects. The biopsy specimens were processed using standard immunohistochemical rabbit antibody to human involucrin and mouse antibody to human transglutaminase type I as the primary antibodies. A computer-driven light absorbance image analysis system was used to determine the optical density of each of the marker-stained specimens. Optical density measurements were compared using a one-way analysis of variance. The expression of involucrin was significantly higher in the epithelium of the nonsmoking, nontobacco-using control subjects (0.2937 +/- 0.0725 optical density) in comparison with the normal-appearing mucosa (0.2283 +/- 0.0488 optical density) and the leukoplakic mucosa of the snuff-using patients (0.2007 +/- 0.0669 optical density) (p < 0.05). The expression of transglutaminase type I was also significantly higher in the epithelium of the nonsmoking, nontobacco-using controls (0.2308 +/- 0.1381 optical density) than in the patients with leukoplakic mucosa (0.1310 +/- 0.0472 optical density) (p < 0.05). However, there was no difference when compared with the normal-appearing mucosa of the patients in the snuff-using group (0.1686 +/- 0.0323 optical density). This study has shown that involucrin and transglutaminase type I are expressed differently in leukoplakic oral mucosa of snuff users and in normal oral mucosa and that this difference can be measured objectively.

Congenital myopathy with cleft palate and increased susceptibility to malignant hyperthermia: King syndrome?

Six children of similar ethnic origin with congenital myopathy, cleft palate, malignant hyperthermia (or susceptibility to malignant hyperthermia), and skeletal anomalies are presented. The findings are remarkably consistent among our patients, 3 of whom were related. This syndrome is likely to be inherited as an autosomal recessive trait. Children with this disorder are likely to undergo surgery with general anesthesia for facial or skeletal deformities and should be recognized as predisposed to developing malignant hyperthermia.