A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis.

OBJECTIVE: To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS. METHODS: A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival. RESULTS: Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis). CONCLUSIONS: At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.

Spinal accessory mononeuropathy following posterior fossa decompression surgery.

Isolated injury of the spinal accessory nerve is a well-recognized complication of surgeries involving the posterior triangle of the neck. The procedures most commonly implicated are lymph node biopsy and carotid endarterectomy. We present a patient with isolated injury to the spinal accessory nerve, localized proximal to the innervation of the sternocleidomastoid muscle, which was noted following suboccipital decompression for an Arnold-Chiari malformation. To our knowledge, this association has not been previously reported.

A pilot randomized trial of oxandrolone in inclusion body myositis.

BACKGROUND: Inclusion body myositis (IBM) remains without effective therapy. As anabolic steroids have myotrophic properties, the authors studied whether a synthetic androgen, oxandrolone, would have efficacy in IBM. METHODS: A double-blind, placebo-controlled, crossover design was used. Patients received oxandrolone or placebo for 12 weeks followed by a minimum 2-month washout period, followed by 12 weeks of the alternative treatment. Maximal voluntary isometric contraction testing (MVICT), manual muscle testing (MMT), and functional performance testing were obtained before and after each treatment period, with the whole-body MVICT score as the primary outcome measure. RESULTS: Of 19 patients enrolled, 16 (14 men, 2 women; median age 68.5 years) had complete data for at least the first treatment period, with 13 completing the entire study. Whole-body MVICT improved by a median of 15.5 kg with drug and 4.1 kg with placebo (p = 0.06), whereas MMT demonstrated a median increase of 2.0 Medical Research Council points with drug and 0.9 point with placebo (p = 0.33). Upper-extremity MVICT demonstrated a significant treatment effect, with strength increasing a median 6.3 kg with drug vs 2.5 kg with placebo (p = 0.006). Stair climbing also increased a median of 1 step on average with drug versus no change with placebo (p < 0.001). Minimal adverse effects occurred. CONCLUSIONS: Oxandrolone had a borderline significant effect in improving whole-body strength and a significant effect in improving upper-extremity strength as measured by MVICT. Given these findings, further study of this drug, possibly in combination with an immunomodulating agent, is warranted.

Unusual clinical presentations in patients harboring the facioscapulohumeral dystrophy 4q35 deletion.

Facioscapulohumeral dystrophy (FSHD) is a dominantly inherited myopathy usually associated with a deletion at locus 4q35. Typically, FSHD patients present with a recognizable constellation of signs including weakness of facial, shoulder and pelvic girdle, humeral, and anterior foreleg muscles; preservation of some muscles including the deltoids; and other characteristic features including prominent scapular winging, anterior axillary folds, and horizontally positioned clavicles. We performed clinical and FSHD genetic studies on four patients with atypical clinical features who were cared for at a regional neuromuscular center. The four patients, each harboring 4q35 deletions, presented with atypical phenotypes including facial-sparing scapular myopathy, limb-girdle muscular dystrophy, distal myopathy, and asymmetric brachial weakness. This report demonstrates the expanding clinical heterogeneity in patients harboring the 4q35 deletion.

Adult-onset MLD: a gene mutation with isolated polyneuropathy.

A 22-year-old man presented with recurrent ulnar mononeuropathies and diffusely slow nerve conduction velocities. Arylsulfatase A (ASA) activity from leukocytes and fibroblasts was reduced, and urinary sulfatides were increased. Sural nerve biopsy revealed a reduction in myelinated fibers and Schwann cell inclusions. Results of studies of CNS integrity, including cranial MRI, evoked potentials, and neuropsychologic tests, were normal. Molecular genetic analyses revealed a novel homozygous missense mutation (Thr286Pro) in the ASA gene.

Autosomal dominant Emery-Dreifuss dystrophy due to mutations in rod domain of the lamin A/C gene.

BACKGROUND: Autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD-AD) is a disorder characterized clinically by humeropelvic weakness, contractures, and cardiomyopathy, and genetically by mutations in the lamin A/C gene on 1q21.2-q21.3. Of the 14 lamin A/C gene mutations reported thus far, the four involving the rod domain have been associated with isolated cardiomyopathy and conduction-system disease. This is the first report of rod domain mutations in patients with the full EDMD-AD phenotype. METHODS: Clinical, pathologic, and genetic data are provided on two families with EDMD-AD. RESULTS: In both families, the full clinical spectrum of EDMD-AD was demonstrated. For the proband in family 1, sequence analysis detected a mutation within exon 2 of the lamin A/C gene. The missense mutation was due to a A448C base substitution causing a Thr150Pro amino acid change. For the proband of family 2, sequence analysis detected an in-frame 3-bp deletion (AAG 778-780 or 781-783) removing one of two adjacent lysine residues (K 260 or 261) of exon 4. Both mutations were in the central rod domain of the lamin A/C gene. CONCLUSIONS: Mutations in the rod domain of the lamin A/C gene may cause the full clinical spectrum of EDMD-AD.

FSH dystrophy 4q35 deletion in patients presenting with facial-sparing scapular myopathy.

OBJECTIVE: To evaluate the incidence of the facioscapulohumeral dystrophy (FSHD) 4q35 deletion in patients with facial-sparing scapular myopathy. BACKGROUND: Scapular winging is typical of FSHD but may also be prominent in other muscle disorders including scapuloperoneal syndromes. With DNA testing, it is possible to determine if patients with facial-sparing scapular myopathy have FSHD. METHODS: Fourteen of 17 unrelated patients with facial-sparing scapular myopathy, seen over a 7-year period at a regional neuromuscular center, agreed to have DNA testing for FSHD. The clinical and laboratory features of these patients were also noted. RESULTS: Of the 14 patients, 10 (71%) had restriction fragments consistent with the 4q35 deletion. The mean size of the smaller fragment following EcoRI digestion was 29.5 kb (range 20 to 39). The mean age at onset was 19.9 years; at presentation, 44.7 years. Except for the absence of facial weakness, most patients had clinical and laboratory features otherwise consistent with FSHD. Five patients (50%) had a positive family history of similar weakness. Following removal of outliers, the Pearson correlation coefficient (r) value between EcoRI fragment size and age at onset was 0.64, and between fragment size and limb muscle strength, 0.64. CONCLUSION: The FSHD 4q35 deletion was found in 71% of the facial-sparing scapular myopathy patients. They otherwise resemble typical FSHD patients in age at onset, physical characteristics, and association between fragment size and disease severity.

Late-Onset Friedreich's Ataxia Presenting as a Spastic Paraparesis.

A 55-year-old woman presented with a 10-yeai history of a progressive gait disorder. Her examination showed a spastic paraparesis with brisk deep tendon reflexes, but only minimal limb ataxia and no evidence for a sensory neuropathy The patient was found to be homozygous for the GAA trinucleotide repeal diagnostic of Friedreich's ataxia The presentation of Friedreich's ataxia as a spastic paraparesis reinforces the appreciation of the variable phenotype of this disease.

Treatable lower motor neuron disease due to vitamin D deficiency and secondary hyperparathyroidism.

Vitamin D deficiency and osteomalacia are frequently associated with muscle weakness and atrophy. We present a 78-year-old man with complaints of progressive painless weakness who was referred to us with a diagnosis of suspected motor neuron disease. Results of the neurological examination were remarkable, showing diffuse limb weakness and atrophy, rare fasciculations, normal sensory examination, no bulbar weakness, and no upper motor neuron signs. Electromyography revealed mild chronic changes, denervation and re-innervation, without fibrillations or positive waves. Serum laboratory studies showed an elevated serum parathyroid hormone and markedly reduced vitamin D level. Although the etiology of the vitamin D deficiency was not determined, the patient made a substantial clinical improvement following vitamin D therapy. Vitamin D deficiency and secondary hyperparathyroidism need to be included in the differential diagnosis of patients presenting with a progressive lower motor neuron disease.

Hereditary neuropathy with liability to pressure palsies in children.

The clinical and neurophysiologic findings of two children presenting with focal weakness and atrophy in unusual nerve distributions and no apparent antecedent injuries are reported. Patient 1 presented with a droopy left shoulder that was initially attributed to scoliosis. Patient 2 presented with right biceps brachii atrophy that was first brought to his parent's attention during a routine physical examination. In addition to documenting focal spinal accessory and musculocutaneous mononeuropathies as the cause of weakness in Patients 1 and 2, respectively, nerve conduction studies also revealed evidence of superimposed diffuse demyelinating polyneuropathy in both children. The latter findings suggested the diagnosis of hereditary neuropathy with liability to pressure palsies and led to definitive DNA diagnoses.

Cervical root stimulation in a case of classic neurogenic thoracic outlet syndrome.

We performed C8 nerve root stimulation in addition to other electromyographic (EMG) studies in a surgically proven case of classic thoracic outlet syndrome (TOS). The patient was a 19-year-old woman with a 2-year history of right hand cramps and progressive weakness and atrophy of hand muscles, especially the thenar eminence. Routine EMG studies showed evidence for an axon-loss lower trunk brachial plexopathy. Stimulation studies of the C8 nerve roots demonstrated proximal conduction block on the affected side only. The diagnosis was further supported by cervical spine radiographs, which demonstrated a cervical rib, and surgical exploration of the brachial plexus, which demonstrated upward compression and stretching of the lower trunk by a fascial band extending from the anomalous cervical rib to the first thoracic rib. The patient noted a modest improvement in hand function postoperatively. Root stimulation studies can help in the diagnosis of classic TOS by providing more precise localization and information regarding the degree, if any, of proximal motor conduction block.

Congenital end-plate acetylcholinesterase deficiency caused by a nonsense mutation and an A-->G splice-donor-site mutation at position +3 of the collagenlike-tail-subunit gene (COLQ): how does G at position +3 result in aberrant splicing?

Congenital end-plate acetylcholinesterase (AChE) deficiency (CEAD), the cause of a disabling myasthenic syndrome, arises from defects in the COLQ gene, which encodes the AChE triple-helical collagenlike-tail subunit that anchors catalytic subunits of AChE to the synaptic basal lamina. Here we describe a patient with CEAD with a nonsense mutation (R315X) and a splice-donor-site mutation at position +3 of intron 16 (IVS16+3A-->G) of COLQ. Because both A and G are consensus nucleotides at the +3 position of splice-donor sites, we constructed a minigene that spans exons 15-17 and harbors IVS16+3A-->G for expression in COS cells. We found that the mutation causes skipping of exon 16. The mutant splice-donor site of intron 16 harbors five discordant nucleotides (at -3, -2, +3, +4, and +6) that do not base-pair with U1 small-nuclear RNA (snRNA), the molecule responsible for splice-donor-site recognition. Versions of the minigene harboring, at either +4 or +6, nucleotides complementary to U1 snRNA restore normal splicing. Analysis of 1,801 native splice-donor sites reveals that presence of a G nucleotide at +3 is associated with preferential usage, at positions +4 to +6, of nucleotides concordant to U1 snRNA. Analysis of 11 disease-associated IVS+3A-->G mutations indicates that, on average, two of three nucleotides at positions +4 to +6 fail to base-pair, and that the nucleotide at +4 never base-pairs, with U1 snRNA. We conclude that, with G at +3, normal splicing generally depends on the concordance that residues at +4 to +6 have with U1 snRNA, but other cis-acting elements may also be important in assuring the fidelity of splicing.

Autosomal dominant distal myopathy not linked to the known distal myopathy loci.

The distal myopathies are clinically, pathologically and genetically heterogenous. Thus far, seven types of distal myopathy have been linked to four chromosome loci. We recently examined four affected members from three generations of an autosomal dominant distal myopathy kindred. A muscle biopsy was performed on the index case. Muscle histopathology showed non-specific myopathic findings including increased variation in fiber size and increased internalized nuclei. No abnormal inclusions or vacuoles were present. Microsatellite markers for the four distal myopathy loci on chromosomes 2, 9 and 14 were studied on affected and several unaffected family members. Affected patients developed distal weakness in anterior foreleg muscles followed by progressive distal upper and proximal lower extremity involvement. Chromosome 2, 9 and 14 regional markers were informative and demonstrated recombinations with affected individuals in the pedigree. The resulting LOD scores obtained from the multipoint analyses gave no evidence of positive linkage to any of the regions and positively excluded (LOD score less than -2) all, or virtually all, of the candidate regions examined. This autosomal dominant distal myopathy family does not show evidence of linkage to any of the known distal myopathy loci, suggesting the existence of at least one more distal myopathy locus. Furthermore, the clinical and pathological features appear distinct from other previously described but genetically-undetermined autosomal dominant distal myopathies.

Cervicomedullary astrocytoma simulating a neuromuscular disorder.

A 12-year-old male developed progressive proximal upper extremity weakness over a 3- to 4-year period. The clinical findings of proximal upper extremity weakness and atrophy, prominent scapular winging, and no sensory deficits or upper motor neuron signs suggested a neuromuscular disorder. Electromyography was consistent with a chronic denervating disorder involving the upper cervical anterior horn cells or their axons. A cervical magnetic resonance image revealed a large intramedullary mass extending from the inferior aspect of the fourth ventricle down to the level of T2. A biopsy of the lesion was consistent with a low-grade astrocytoma.

Creatine kinase values in amyotrophic lateral sclerosis.

Serum creatine kinase (CK1) values were recorded while or soon after the diagnosis of amyotrophic lateral sclerosis (ALS) was established in 140 of 217 (65%) consecutive patients seen in the Motor Neuron Disease Clinic at this center during a 5-year period. Second creatine kinase (CK2) determinations were recorded on 48 of 140 (34%) ALS patients later in the course of the disease. The mean CK1 and CK2 values (unit, times the upper limit of normal) were 1.22 (range, 0.1 to 3.0; median, 0.80) and 1.34 (range, 0.1-9.2; median, 0.80) (P=0.11, r=0.92, mean difference=28.2%). Of the 140 ALS patients, 58 (41%) (male:female ratio: 2.9:1.0) had elevated CK1 values ranging from 1.03 to 13.0 (mean, 2.21; median, 1.67). Twelve patients (8.6%) had CK1 values greater than 3.0. Mean CK1 values were significantly greater (P=0.001) in male (mean, 1.56) versus female (mean, 0.80) ALS patients, and significantly greater (P=0.009) in limb-onset (mean, 1.34) versus bulbar-onset (mean, 0.80) disease. CK1 values correlated poorly with and were not predictive of age of onset or survival.

Nerve conduction velocities of single thenar motor axons based on the automated analysis of F waves in amyotrophic lateral sclerosis.

The motor unit number estimate (MUNE), motor unit size, and conduction velocity (CV) of thenar surface-recorded motor unit action potentials (S-MUAPs) as collected by the automated F-wave technique were analyzed in 13 patients with amyotrophic lateral sclerosis (ALS) (aged 29-78 years, mean: 61) and 10 age-matched normal subjects (aged 49-81 years, mean: 64). Totals of 96 and 100 thenar S-MUAPs were collected from ALS patients and normal subjects, respectively. There were significant differences (P < 0.001) in the mean estimated numbers and sizes of motor units between the ALS patients (MUNE: 41.9, S-MUAP size: 699.6 microV/ms) and normal subjects (MUNE: 151.2, S-MUAP size: 244.1 microV/ms). The mean S-MUAP CV was 46.3 m/s (range: 32-59) for ALS patients and 56.5 m/s (range: 43-69) for normal subjects (P < 0.001). Mean median motor nerve CVs, measured in the forearm segment, were not significantly different (P = 0.79) between ALS patients (53.4 m/s) and normal subjects (52.9 m/s), however. Thenar motor unit CVs are significantly reduced in ALS patients as compared to normal controls, and this may be due to proximal motor nerve slowing.

Further observations on forearm flexor weakness in inclusion body myositis.

In order to further characterize and provide a possible mechanism for the asymmetrical involvement of forearm muscles in inclusion body myositis (IBM), we measured isometric hand and pinch grip strength, and forearm muscle girth on 15 IBM patients. Forearm muscle strength and girth were significantly greater on the dominant versus nondominant side: mean grip strength, 173.9 vs. 98.8 N; mean pinch strength, 47.6 vs. 29.7 N; and mean forearm girth, 22.5 vs. 19.9 cm. This observation may suggest a role for exercise in delaying the disease progression in IBM.