A novel autosomal dominant distal myopathy with early respiratory failure: clinico-pathologic characteristics and exclusion of linkage to candidate genetic loci.

We describe a novel autosomal dominant myopathy presenting in mid-adult life with tibialis anterior weakness. We carried out a detailed clinical assessment of 24 individuals spanning three generations, documenting pathologic features of the muscles in 7 of the 11 affected individuals, including an autopsy study on one case. The second generation of affected individuals presented at an earlier age, and the disease progressed more rapidly than in the first generation. Lung function tests revealed progressive global respiratory muscle weakness detectable from the time of presentation, with preferential diaphragmatic involvement in some cases. Hip girdle and shoulder girdle weakness appeared later in the disease course. We observed a striking correlation between the clinical and pathological features. Clinically unaffected muscles had minimal pathologic change. Fiber splitting, eosinophilic inclusions, and vacuoles with basophilic rims were seen in moderately affected muscles, and fat and fibrous connective tissue replaced muscle fibers in the severely involved muscles. The inclusions were Congophilic and reacted with antibodies to desmin, beta-amyloid, and phosphorylated tau protein. The disease was not linked to any of the known loci associated with distal myopathies, confirming that the disorder in this family is both genetically and phenotypically distinct.

Symptomatic lumbar spinal arachnoiditis: fact or fallacy?

It is generally accepted that chronic adhesive lumbar arachnoiditis is a cause of symptoms, notably back pain and/or pain (of almost any type, not necessarily 'anatomical') in the lower limbs, although there is no clearly defined clinical pattern which is clearly associated with this syndrome. There is no doubt that arachnoiditis occurs as a pathological and radiological entity due to a number of causes. In the view of the present authors, the nexus between the pathology and radiology on the one hand, and the patients' symptoms on the other hand, has not been demonstrated with any degree of scientific rigor.

Familial amyotrophic lateral sclerosis with a mutation in exon 4 of the Cu/Zn superoxide dismutase gene: pathological and immunocytochemical changes.

Detailed molecular pathology studies and clinicopathological phenotyping of familial amyotrophic lateral sclerosis (FALS) with characterised mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) will yield important insights into the pathogenesis of motor neuron degeneration. An autopsy case is described with the mutation E100G (exon 4) of the SOD1 gene in which full neuropathological examination including immunocytochemistry of ubiquitin and neurofilament epitopes was performed. The case falls into the category of "amyotrophic lateral sclerosis (ALS) with posterior column involvement." Critical analysis of the findings indicates a truly multisystem disorder in which ascending sensory pathways and components of the efferent cerebellar pathways are at least as severely affected as the motor system. Abnormal neurofilament phosphorylation was not a prominent feature. Ubiquitinated neuronal inclusions were infrequent except in the hippocampal denate granule cells where they were indistinguishable from sporadic cases of ALS-dementia. The motor cortex was preserved despite severe distal axonal loss in the corticospinal tract. These findings suggest a primary failure of axonal maintainance affecting several neuronal groups with long projecting axons. The differences and similarities compared to previously reported case with I113T (exon 4) and A4T (exon 1) mutations are discussed. Findings related to inflammatory cell infiltration, ubiquitination and neurofilament phosphorylation are discussed with reference to the pathogenesis of sporadic ALS.

Phrenic neuropathy in association with diabetes.

We report the case of a 51-year-old man who presented with breathlessness on exertion and orthopnoea in association with Type 2 diabetes mellitus. Investigation showed bilateral diaphragmatic paralysis due to phrenic neuropathy. There was no evidence of neuropathy or microvascular disease elsewhere. Phrenic neuropathy may be an important, albeit rare, complication of diabetes and diaphragmatic function should be considered in any patient with unexplained breathlessness and orthopnoea.

Neuromuscular disease, respiratory failure and cor pulmonale.

Respiratory muscle weakness is an uncommon cause of chronic respiratory failure and a rare cause of cor pulmonale. The problem may not be apparent unless specific physical signs are sought or appropriate investigations performed. We present three patients who presented diagnostic difficulty for prolonged periods until the presence of respiratory muscle weakness was considered. Once the diagnosis was established treatment with nocturnal nasal intermittent positive pressure ventilation produced a dramatic improvement in symptoms and allowed a return to a near normal lifestyle.

Breathing during sleep in patients with myotonic dystrophy and non-myotonic respiratory muscle weakness.

Sleep apnoea and hypopnoea have been reported in myotonic dystrophy, but it is unclear whether this is simply attributable to the respiratory muscle weakness which is common in this condition. We therefore investigated whether breathing and oxygenation during sleep were more abnormal in patients with myotonic dystrophy than in patients with non-myotonic muscle weakness. Seven subjects were studied in each of three groups: normal controls, myotonic dystrophy and non-myotonic weakness. Patients in the latter group were chosen to represent a similar range of severity of respiratory muscle weakness to those with myotonic dystrophy. Detailed polysomnography was performed; the severity of breathing disorders during sleep was quantified in terms of the frequencies of apnoea and hypopnoea and the degree of arterial desaturation. The myotonic patients showed more frequent apnoea and hypopnoea and more severe desaturation than the other two groups; the results in the non-myotonic patients were generally intermediate. The results suggest that abnormal breathing during sleep is common in myotonic dystrophy and is not due solely to the direct effects of respiratory muscle weakness. Somnolence, which is a well recognized symptom of myotonic dystrophy, was not clearly attributable to the sleep apnoea/hypopnoea syndrome nor to abnormal sleep architecture in the myotonic patients.

Clinical, biochemical and histological responses to treatment in polymyositis: a prospective study.

Routine methods of monitoring treatment responses in polymyositis patients, such as clinical strength assessments and measurements of ESR and serum creatine kinase, have been compared with functional strength measurements and assay of serum myoglobin levels, in a prospective study of nine cases followed for up to five years. Seven patients also underwent serial muscle biopsies during the first year of treatment in order to document the nature and chronology of histological changes during therapy. Inflammatory and necrobiotic changes indicating active myositis resolved within six months in all cases and no patient developed histological evidence of steroid myopathy. Scores on functional muscle strength assessments improved more slowly than static manual muscle strength test results, reflecting morphometric and architectural abnormalities in the biopsies which persisted throughout the period of observation. Serum creatine kinase levels returned to normal more rapidly than serum myoglobin. No statistical relationship was found between muscle strength measurements and biochemical or histological changes within the patients as a group, but variations in these indices in individual subjects reflected changes in clinical state.

Mitochondrial myopathies. A clinico-pathological study of cases with and without extra-ocular muscle involvement.

The clinical and pathological features of 28 patients with mitochondrial myopathy were reviewed. The cases were divided into a group with involvement of the extra-ocular muscles alone or with limb muscle involvement, and a group with a facioscapulohumeral syndrome or generalised weakness without extra-ocular muscle involvement. Cardiac and central nervous system manifestations occurred particularly in the first group which included six patients with multisystemic features and two with the complete Kearns-Sayre syndrome. Diabetes mellitus occurred in the second group only. Quantitative histology on limb muscle biopsies showed a higher proportion of fibres with abnormal mitochondrial aggregates in the second group. No one type of mitochondrial inclusion or other ultrastructural change was specific for either group of cases. The findings illustrate the clinical heterogeneity of cases of mitochondrial myopathy and the lack of specificity of any of the myopathological changes for different subgroups of patients.

Central neurogenic hyperventilation in a conscious patient with a primary cerebral lymphoma.

The clinical and neuropathological findings of a patient with central neurogenic hyperventilation are described. The patient had an extensive primary central nervous system lymphoma but no lesions below the level of the superior colliculus. The possible mechanism of central neurogenic hyperventilation is discussed with reference to the present case and those previously described.

Inclusion body myositis: a case with associated collagen vascular disease responding to treatment.

Patients with inclusion body myositis demonstrate characteristic histological and electronmicroscopical abnormalities in muscle and are generally considered refractory to treatment. A patient with inclusion body myositis is described with evidence of associated autoimmune disease, who responded to steroids.