Rawiphan Witoonpanich

Randomized Trial of Thymectomy in Myasthenia Gravis

BACKGROUND Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).

Idiopathic hypertrophic cranial pachymeningitis

Idiopathic hypertrophic cranial pachymeningitis is a rare chronic inflammatory process of unknown origin that can cause neurological deficits owing to thickening of the dura. Patients with this condition commonly present with cranial neuropathy accompanied by localized headache. The clinical features, neuroimaging findings, histopathological features and treatment outcomes for three patients with this condition are reported here. The first patient presented with subacute dull headache in the left temporal area followed by left abducens nerve palsy. The second patient suffered from a cranial nerve IX-XII lesion accompanied by an occipital headache and the third patient presented with left optic neuropathy and mild headache in the frontal area. In all patients, MRI of the brain revealed prominent dural thickening, and histopathological study of the dura revealed chronic inflammatory cell infiltration. Combined therapy with corticosteroid and immunosuppressive drugs was effective, resulting in almost complete resolution of the symptoms and signs, except for visual impairment in one patient.

Electrophysiological and immunological study in myasthenia gravis: Diagnostic sensitivity and correlation

OBJECTIVE To determine the diagnostic sensitivity of repetitive nerve stimulation (RNS), single fiber electromyography (SFEMG) and acetylcholine receptor antibody (AChRAb) in myasthenia gravis (MG), and to compare the degree of SFEMG abnormality between ocular and generalized MG and between seronegative and seropositive patients. METHODS The sensitivities of RNS, SFEMG and AChRAb were estimated. SFEMG abnormality was compared between ocular and generalized MG and between seronegative and seropositive patients. RESULTS Abnormal RNS, abnormal SFEMG and AChRAb were detected in 62%, 93% and 38% of 42 ocular, and 80%, 99% and 73% of 70 generalized cases, respectively. The degree of SFEMG abnormality was significantly greater in the generalized than ocular patients and was significantly greater in the seropositive than seronegative patients in both extensor digitorum communis and orbicularis oculi muscles. CONCLUSION SFEMG is a very sensitive and useful test for MG. A correlation between SFEMG abnormality and clinical phenotype or severity and between SFEMG abnormality and AChRAb seropositivity was demonstrated. SIGNIFICANCE The sensitivities of RNS, SFEMG and AChRAb in the diagnosis of MG were documented. The differences in severity between the ocular and generalized MG and between the seronegative and seropositive MG were confirmed and quantitatively determined by SFEMG.

Survival analysis for respiratory failure in patients with food-borne botulism.

Introduction. Botulism is a rare presynaptic neuromuscular junction disorder caused by potent toxins produced by the anaerobic, spore-forming, Gram-positive bacterium Clostridium botulinum. Food-borne botulism is caused by the ingestion of foods contaminated with botulinum toxin. In March 2006, there was a large outbreak of food-borne botulism associated with the ingestion of home-canned bamboo shoots in Thailand. The survival analyses for respiratory failure in these patients were studied and are reported here. Methods. A prospective observational cohort study was conducted on this outbreak. The primary outcome of interest was the time to respiratory failure. The secondary outcome was the time to weaning off ventilator. The prognostic factors associated with respiratory failure and weaning off ventilator are presented. Results. A total of 91 in-patients with baseline clinical characteristics were included. Most cases first presented with gastrointestinal symptoms followed by neurological symptoms, the most striking of which being difficulty in swallowing. Common clinical features included ptosis, ophthalmoplegia, proximal muscle weakness, pupillary abnormality, and respiratory failure. Forty-two patients developed respiratory failure requiring mechanical ventilation and the median duration on ventilator was 14 days. The median length of hospital stay for all patients was 13.5 days. Difficulty in breathing, moderate to severe ptosis, and dilated and fixed pupils were associated with respiratory failure. Among patients who were on ventilators, a short incubation period and pupillary abnormality were associated with a longer period of mechanical ventilation. All patients had antitoxin injection and there was no mortality in this outbreak. Conclusion. The history of difficult breathing and the findings of moderate to severe ptosis and pupillary abnormality were associated with severe illness and respiratory failure. A long incubation time was associated with a better prognosis. Although botulism is a potentially fatal disease, there was no mortality in this outbreak. All patients had antitoxin injection and good intensive care that resulted in good clinical outcomes.

Congestive heart failure with rhabdomyolysis and acute renal failure in a manifesting female carrier of Duchenne muscular dystrophy with duplication of dystrophin gene.

We report a 69-year-old woman who presented with dyspnea, orthopnea, and acute renal failure. She also had proximal muscle weakness suggestive of muscle disease. Her symptoms were alleviated by induced dieresis, although there was high-serum creatine kinase. Investigations for any possible etiologies of rhabdomyolysis were all negative. An X-linked recessive muscle disease was highly suspicious in view of the fact that both of her sons had suffered from muscle disease and died of respiratory failure at the ages of 22 and 29, respectively. Her muscle biopsy showed mosaic pattern with dystrophin antibody against amino-terminal, carboxy-terminal, and rod domain. Her DNA study revealed heterozygous duplication at exon 1 to 6 of the dystrophin gene as well. Therefore, she is a manifesting carrier of dystrophinopathy who was first diagnosed in late adulthood with congestive heart failure, acute episode of spontaneous rhabdomyolysis, and acute renal failure.

Novel DYSF mutations in Thai patients with distal myopathy

Dysferlinopathy refers to a variety of autosomal recessive, skeletal muscle disorders due to the mutations of dysferlin-encoding gene, DYSF. It encompasses limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy (MM), distal myopathy with anterior tibial onset (DMAT), isolated hyperCKemia, rigid spine syndrome and congenital muscular dystrophy. Herein, we report five Thai patients with distal myopathy due to dysferlinopathy including four MM and one DMAT patients. Muscle biopsy from one MM patient depicted numerous ring fibers which is an atypical finding in dysferlinopathy. Mutation analysis of DYSF revealed novel compound heterozygous mutations of p.Tyr309X and c.236+1G>T in two related MM patients, known homozygous mutations, p.Arg89X and p.Gln176X, in two MM patients and a heterozygous missense mutation, p.Arg555Trp, in a DMAT patient. Most of the previously reported DMAT patients were Hispanic. To the best of our knowledge, this is the first report of genetically confirmed patients with dysferlinopathy in Thailand.

Glioblastoma multiforme at the corpus callosum with spinal leptomeningeal metastasis

Glioblastoma multiforme (GBM) often occurs in the supratentorial white matter including corpus callosum. However, spinal leptomeningeal metastasis in cases of supratentorial GBM has been reported to be rare and there is usually a long interval between the cerebral lesion and the spinal seeding. We report here a case of GBM at the corpus callosum and other parts of the brain with simultaneous manifestation of spinal leptomeningeal seeding. The patient exhibited an abnormal motor behavior of the left hand as mirror movement when the right hand was performing a unimanual task (diagonistic dyspraxia) which is a sign of lesion of the posterior part and splenium of the corpus callosum. There were also signs of peripheral nerve or nerve root involvement suggestive of spinal metastasis without any sensory symptoms. He died 3 months after the onset of the symptoms confirming the poor prognosis and short survival time in cases with spinal leptomeningeal metastasis reported previously. The cerebral GBM with spinal seeding was disclosed at autopsy.

Electrodiagnosis of botulism and clinico-electrophysiological correlation

OBJECTIVE An electrophysiological study can help to confirm the diagnosis of botulism. This study was aimed at validating a simple and reliable electrodiagnostic test and at correlating the findings with clinical severity. METHODS Pre- and post-exercise single supramaximal stimulations (SSSs) were performed in 63 patients with botulism. The sensitivity and specificity of amplitude of compound muscle action potential (CMAP) and percentage increment (PI) of SSS were determined. These two parameters were then correlated with respiratory failure. The relationship between the amplitude of CMAP and PI was also studied. RESULTS SSS with a PI of 25% showed a sensitivity of 95.2% and a specificity of 100% in association with botulism. The area under the receiver operating characteristic (ROC) curve of CMAP and PI was associated with the respiratory failure by 0.7 and 0.6, respectively. An inverse relationship between the amplitude of CMAP and PI was also demonstrated. CONCLUSIONS SSS is sensitive and specific in the diagnosis of botulism. There was some correlation of the findings with clinical severity. The inverse relationship between the amplitude of CMAP and PI reflects the pathophysiology of this disorder. SIGNIFICANCE This study has validated SSS as being a simple and reliable electrodiagnostic test for botulism.

Phenotypic heterogeneity in a large Thai slow-channel congenital myasthenic syndrome kinship.

The slow-channel congenital myasthenic syndrome (SCCMS) is an autosomal dominant neuromuscular disorder caused by mutations in different subunits of the acetylcholine receptor (AChR). We here report our clinical findings in three generations of a large Thai kinship suffering from SCCMS and trace the disease to the p.Gly153Ser mutation in the AChR α subunit. The same mutation had previously been reported only in Caucasian but not in Asian patients. The clinical features include ptosis, ophthalmoparesis, and weakness of the cervical and finger extensor muscles as well as marked phenotypic heterogeneity.

Long-term effectiveness of acetazolamide on permanent weakness in hyperkalemic periodic paralysis.

Acetazolamide is commonly used as an empirical treatment for inherited periodic paralyses although some patients may develop deleterious effects. We report a 65 year-old man with hyperkalemic periodic paralysis and late-onset permanent weakness in association with the common T704M mutation in α-subunit, skeletal muscle voltage-gated sodium channel gene. He rapidly recovered from weakness after acetazolamide treatment. Magnetic resonance imaging of thighs comparing pre- and post-treatment revealed a significant increase in muscle bulk. The patient has been without any type of weakness for over 6 years. This data show the remarkable benefit of acetazolamide on permanent weakness of hyperkalemic periodic paralysis in association with the T704M mutation.