Andrew J. Waclawik

Mutations in the sarcoglycan genes in patients with myopathy.

BACKGROUND Some patients with autosomal recessive limb-girdle muscular dystrophy have mutations in the genes coding for the sarcoglycan proteins (alpha-, beta-, gamma-, and delta-sarcoglycan). To determine the frequency of sarcoglycan-gene mutations and the relation between the clinical features and genotype, we studied several hundred patients with myopathy. METHODS Antibody against alpha-sarcoglycan was used to stain muscle-biopsy specimens from 556 patients with myopathy and normal dystrophin genes (the gene frequently deleted in X-linked muscular dystrophy). Patients whose biopsy specimens showed a deficiency of alpha-sarcoglycan on immunostaining were studied for mutations of the alpha-, beta-, and gamma-sarcoglycan genes with reverse transcription of muscle RNA, analysis involving single-strand conformation polymorphisms, and sequencing. RESULTS Levels of alpha-sarcoglycan were found to be decreased on immunostaining of muscle-biopsy specimens from 54 of the 556 patients (10 percent); in 25 of these patients no alpha-sarcoglycan was detected. Screening for sarcoglycan-gene mutations in 50 of the 54 patients revealed mutations in 29 patients (58 percent): 17 (34 percent) had mutations in the alpha-sarcoglycan gene, 8 (16 percent) in the beta-sarcoglycan gene, and 4 (8 percent) in the gamma-sarcoglycan gene. No mutations were found in 21 patients (42 percent). The prevalence of sarcoglycan-gene mutations was highest among patients with severe (Duchenne-like) muscular dystrophy that began in childhood (18 of 83 patients, or 22 percent); the prevalence among patients with proximal (limb-girdle) muscular dystrophy with a later onset was 6 percent (11 of 180 patients). CONCLUSIONS Defects in the genes coding for the sarcoglycan proteins are limited to patients with Duchenne-like and limb-girdle muscular dystrophy with normal dystrophin and occur in 11 percent of such patients.

Phase II/III randomized trial of TCH346 in patients with ALS

Background: TCH346 exerts antiapoptotic effects by binding to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and blocking the apoptotic pathway in which GAPDH is involved. Apoptosis is considered to be a key pathogenic mechanism in neurodegenerative diseases including ALS. Methods: Patients were randomly assigned in a double-blind fashion to receive either placebo or one of four doses of TCH346 (1.0, 2.5, 7.5, or 15 mg/day) administered orally once daily for at least 24 weeks. The primary outcome measure was the rate of change in the revised ALS functional rating scale (ALSFRS-R). The trial design included a 16-week lead-in phase to determine each patients rate of disease progression. The between treatment comparison was adjusted for the individual pretreatment rates of progression. The study was powered to detect a 25% reduction in the rate of decline of the ALSFRS-R as compared with placebo. Secondary outcome measures included survival, pulmonary function, and manual muscle testing (MMT). Results: Five hundred ninety-one patients were enrolled at 42 sites in Europe and North America. There were no differences in baseline variables. There were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures (survival, pulmonary function, and MMT). Conclusion: The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS.

Iliac Artery Pseudoaneurysm Following Renal Transplantation Presenting As Lumbosacral Plexopathy

A renal transplant patient developed chronic and progressive back and lower extremity pain followed by foot weakness. The correct diagnosis of lumbosacral plexopathy was made after electromyography and nerve conduction studies and the etiology of radiculopathy due to nerve root compression was excluded. This prompted further investigations that led to the discovery of a large internal iliac artery pseudoaneurysm. We emphasize the use of electrodiagnostic studies to investigate patients with back and limb pain for correctly localizing responsible pathology. In this case a potentially lethal situation was correctly identified in a transplant patient.

INFANTILE BOTULISM : PITFALLS IN ELECTRODIAGNOSIS

Botulism in infants, unless recognized early, is associated with high mortality and morbidity. The diagnosis is suspected when infants present with sudden onset of weakness, respiratory failure, and constipation and is confirmed by demonstration of botulinum toxin in stool several weeks later. Electrodiagnosis allows quick and reliable confirmation of botulism. Low-amplitude compound muscle action potentials, tetanic or post-tetanic facilitation, and the absence of post-tetanic exhaustion support the diagnosis. Two infants with confirmed botulism did not exhibit the characteristic electrodiagnostic features, demonstrating the pitfalls in electrodiagnosis of infantile botulism. (J Child Neurol 1999;14:156-158).

Sarcoidosis of the spinal cord with extensive vertebral involvement: A case report

We report on a patient with systemic sarcoidosis who was presented with myelopathy and backache. Plain spinal films were normal, CT scan showed sclerotic lesions within the vertebrae. MRI showed more extensive involvement of the spine with multiple vertebral lesions which were hypointense on both T1W1 and T2W1 and did not enhance with gadolinium. MRI also showed high signal lesions within the cervical and lumbar spinal cord on T2-weighted images (T2W1) which were isointense on T1-weighted images (T1W1) and did not enhance. Vertebral biopsy results were consistent with the diagnosis of sarcoidosis. MRI is very sensitive in detecting sarcoidosis of bone but non-specific and other types of sclerotic or lytic bone lesions (notably metastases) need to be excluded.

The Effects of Lingual Intervention in a Patient With Inclusion Body Myositis and Sjögren's Syndrome: A Longitudinal Case Study

OBJECTIVE To report the 5-year course of a patients swallowing disorder in the context of progressive neuromuscular disease and the effectiveness of a lingual strengthening treatment program. DESIGN This is a case report that describes a lingual treatment protocol that was repeated 3 times over a 5-year period with and without maintenance periods. SETTING The study was completed in 2 settings-an outpatient swallowing clinic at an acute care hospital and the patients home. PARTICIPANT The subject was a 77-year-old woman who was diagnosed with inclusion body myositis and Sjögrens syndrome. INTERVENTION The patient participated in an intensive 8-week lingual strengthening protocol 3 times (at years 1, 4, and 5) and a subsequent maintenance program twice (at years 4 and 5). MAIN OUTCOME MEASURES Three outcome measures were collected during the study: (1) lingual manometric pressures at the anterior and posterior tongue, measured by using a lingual manometric device, (2) airway invasion measured by using an 8-point Penetration-Aspiration Scale, and (3) clearance of the bolus measured by using a 3-point residue scale. RESULTS Isometric lingual strengthening was effective in maintaining posterior tongue lingual pressure and Penetration-Aspiration Scale scores during the treatment periods. Residue scale scores did not significantly change during treatment. CONCLUSIONS We conclude that, in this patient, lingual strengthening slowed the progression of disease-related lingual strength loss and extended functional swallowing performance. Thus, this type of intervention may hold promise as an effective swallowing treatment option for patients with neurodegenerative inflammatory diseases such as inclusion body myositis and Sjögrens syndrome.

Nerve root hypertrophy in CMT type 1A

A 21-year-old man undergoing workup for surgical treatment of scoliosis was referred for evaluation of possible neurofibromatosis due to abnormal imaging studies of the spine. No evidence of neurofibromatosis was …

Plasma exchange after initial intravenous immunoglobulin treatment in Guillain-Barré syndrome: critical reassessment of effectiveness and cost-efficiency.

Objectives: To assess whether intravenous immunoglobulin (IVIG) followed by plasma exchange (PE) is more effective for patients with Guillain-Barré syndrome compared with IVIG alone. Methods: Retrospective chart review of 46 patients treated for Guillain-Barré syndrome between 1995 and 2005 was performed. Patients were divided into four subgroups based on treatment received (IVIG, PE, IVIG + PE, or neither). Disability grade on admission, after completion of IVIG, and on the day of discharge from hospital (DGD) were assessed. DGD was the primary outcome measure. Duration of hospitalization, costs, duration of symptoms before treatment, and interval between IVIG and initiation of PE were analyzed. Results: Mean disability grade on admission was similar for all groups. DGD was significantly lower for the IVIG group (P < 0.001) than other groups. Compared with admission, patients treated with IVIG + PE had more severe impairment after completion of IVIG (P = 0.044) but did not show significant improvement after PE. Disability grade on admission and DGD scores for patients treated earlier (less than 14 days after onset of symptoms) versus later (greater than 14 days) were not significantly different. Duration of hospitalization was longer in patients receiving IVIG + PE versus IVIG alone (P < 0.001). The cost of treatment was significantly higher in the IVIG + PE subgroup (P < 0.001). No correlation between interval from IVIG to PE onset and DGD score was found. Conclusions: We found no association between PE after IVIG and improved short-term outcomes of patients with Guillain-Barré syndrome, but there was an association with an increase in cost and duration of hospitalization. There was no association between the timing of PE after IVIG and the short-term outcome. Prospective studies are needed to clarify whether the cost/benefit ratio favors the routine use of this therapeutic approach.

Myopathic dropped head syndrome: an expanding clinicopathological spectrum.

Liao JP, Waclawik AJ, Lotz BP, Salamat SM, Beinlich BR, Brooks BR: Myopathic dropped head syndrome: an expanding clinicopathological spectrum. Am J Phys Med Rehabil 2007;86:970–976. Objective:A number of neuromuscular conditions may lead to a dropped head syndrome (DHS), with some patients developing a late onset noninflammatory myopathy affecting only, or predominantly, neck extensor muscles (NEM). The cause, pathogenesis, and nosological classification of this condition are unclear. To further investigate this condition, the authors evaluated the clinical, electrodiagnostic and pathologic findings in seven patients with a myopathic DHS. Design:Analysis of clinical data, electrodiagnostic studies, and muscle biopsies of seven patients, including one set of identical twins, who developed a very late onset myopathy with severe NEM weakness. Results:Age of onset was 61–79 yrs, with the pair of identical twins developing NEM weakness within 1 yr of each other (ages 63 and 64, respectively). Seven patients developed weakness (six slight weakness and one more severe) in muscles other than NEM. The group was characterized by the electromyography (EMG) showing a “myopathic” pattern in cervical paraspinal muscles (7/7), muscle biopsies with nonspecific myopathic changes on histologic stains (7/7), marked abnormalities in NADH dehydrogenase–reacted sections (6/7), desmin-positive sarcoplasmic deposits (1/7), low carnitine levels by biochemical assays (2/7), and mitochondrial changes (3/7). Conclusions:Myopathic DHS encompasses a wide spectrum of conditions that strongly affect NEM; however, as documented in the monozygotic twins, some patients may suffer from a distinct, genetically determined form of late-onset restricted myopathy leading clinically to DHS.

Clinical Utility of Videofluorography with Concomitant Tensilon Administration in the Diagnosis of Bulbar Myasthenia Gravis

Myasthenia gravis (MG) classically presents with ocular, bulbar, and predominantly proximal muscle weakness. Isolated bulbar symptoms occur in less than 25% of cases and can mimic stroke (1–3). If left untreated, MG can lead to significant morbidity and mortality, including myasthenic crisis and recurrent aspiration pneumonia. We describe a case of a 68-year-old man who presented with isolated bulbar symptoms. We used a novel approach to diagnosis which included a videofluorographic swallow study with concomitant Tensilon (edrophonium) injection.