The discovery of critical illness polyneuropathy.

In 1892 Osler described 'rapid loss of flesh' in prolonged sepsis. Thereafter, for years, limb weakness was attributed to cachectic myopathy, and difficulty weaning from mechanical ventilation was attributed to diaphragmatic fatigue. In 1961 Mertens described 'coma-polyneuropathies', and in 1971 Henderson and colleagues described polyneuropathy in patients with burns. In 1984 Bolton and colleagues, in a series of reports, defined the clinical, electrophysiological and morphological features of septic encephalopathy and critical illness polyneuropathy. Evidence suggested that polyneuropathy was due to the 'toxic' effects of sepsis. Polyneuropathy was a common cause of difficulty in weaning when lung and cardiac cause had been excluded. Since 1984, cases of critical illness polyneuropathy have been reported from several countries. Moreover, a number of investigators reported instances of critical illness myopathy. Comprehensive studies by Latronico and colleagues indicated that polyneuropathy and myopathy often occurred together in the same patient. With successful treatment of sepsis, improvement often occurred in encephalopathy, polyneuropathy and myopathy, except in very severe cases.

Pathological findings in the x-linked form of Charcot-Marie-Tooth disease: a morphometric and ultrastructural analysis.

Mutations in the connexin 32 gene (Cx 32) are associated with the x-linked form of Charcot-Marie-Tooth disease (CMTX) and segregate with a CMT 1 phenotype. The gap junction protein Cx 32 is expressed in myelinating Schwann cells and has been localized to regions of non-compacted cytoplasm in paranodes and in Schmidt-Lanterman incisures. Mutant Cx 32 myelin proteins are predicted to impair Schwann cell functions. We have studied the resulting pathology in motor and sensory nerves from the probands of 13 CMTX kindreds with precisely defined genotype. This report provides a detailed descriptive and morphometric analysis of 14 CMTX nerve biopsy samples, taken at various stages in the development of the neuropathy and studied by light and electron microscopic examination. Findings indicated unusually prominent changes in paranodal myelin with resulting widened nodes of Ranvier, but with segmental demyelination being less common. In parallel early axonal cytoskeletal abnormalities were noted, which were followed later by axonal atrophy, degeneration and loss of myelinated nerve fibers, occurring in a length-dependent fashion. Regenerative sprouting was also unusually prominent. Ultrastructural abnormalities included a frequent dilatation of the adaxonal spaces, prominence of the adaxonal Schwann cell cytoplasm and widening of the Schmidt-Lanterman incisures. We conclude that mutations in Cx 32 gap junction protein lead to a compromise of Schwann cell functions and to impaired Schwann cell-axon interactions with subsequent pathology in both myelin and axons.

Minimum standards for electromyography in Canada: a statement of the Canadian Society of Clinical Neurophysiologists.

BACKGROUND: Electromyography (EMG) is a widely used diagnostic technique for disorders of the nervous system. The Canadian Society of Clinical Neurophysiologists (CSCN) promotes the education, evaluation and standards of EMG in Canada. A statement of practice standards was needed to clarify the position of the CSCN on several issues relevant to the practice of EMG. METHODS AND RESULTS: A subcommittee of the CSCN reviewed current patterns of practice and established guidelines for review by the CSCN. The guidelines developed by the subcommittee were reviewed by the CSCN and adopted as recommendations for EMG practice. The subcommittee was charged with formulation of a document for publication. CONCLUSIONS: This document deals with minimum standards for electromyographer education, laboratory operation, equipment and a variety of special circumstances relevant to the practice of EMG. The standards can be adopted by EMG laboratories to guide quality assurance.

Impact of plasma exchange on indices of demyelination in chronic inflammatory demyelinating polyradiculoneuropathy.

We studied the impact of plasma exchange (PE) on indices of primary demyelination in patients of the Canadian multicenter trial of PE in chronic inflammatory demyelinating polyneuropathy (CIDP). Individual motor nerves (median, ulnar, peroneal, tibial) were studied: distal motor latencies (DMLs), proximal and distal compound muscle action potential (M-wave) amplitudes, negative peak areas and durations, and motor conduction velocities (CVs). Proximal M-wave amplitudes in individual motor territories, particularly in the ulnar nerve (from below elbow, above elbow, and axillary stimulating sites) demonstrated significant improvement with PE, but not sham exchange. Proximal ulnar M-wave areas also had significant improvement with PE. Trends toward improvement of individual nerve motor CVs, M-wave durations, and DMLs did not achieve statistical significance. Proximal M-wave amplitudes, particularly in the ulnar motor territory, and proximal M-wave areas (providing a measure of conduction block) were the most sensitive indices of improvement conferred by PE in CIDP. In individual patients, these indices may help judge the efficacy of therapy.

Clinical and pathological observations in men lacking the gap junction protein connexin 32.

The X-linked form of Charcot-Marie-Tooth disease has been associated with mutations in the connexin 32 (Cx 32) gene, which encodes a gap junction protein. The majority of identified mutations are missense, but a few nonsense mutations or frame-shifting microdeletions have been encountered. Functional assessments of the mutated gap junction protein have demonstrated altered or simple losses of function. Mutations segregate with a typical clinical phenotype, which is the result of an age-related, progressive neuropathy. The mechanisms that cause the nerve damage are unknown. This report describes the consequences of a unique deletion mutation that eliminates the entire coding sequence of Cx 32, resulting in the absence of the Cx 32 gap junction protein in affected, hemizygous men. The clinical expression of this unique mutation was studied by the clinical, electrophysiological, and pathological evaluation of this kinship of five generations. The resulting severe neuropathy combines features of demyelination, notably in paranodal distribution, and distal accentuated axonal degeneration. The predicted absence of Cx 32 gap junctions is shown to be associated with a severe dysfunction of the axon-Schwann cell unit. Observed changes resemble those of Cx 32-null mice. No central nervous system changes were demonstrated.

Genotype/phenotype correlations in X-linked dominant Charcot-Marie-Tooth disease.

We have studied the relationship between genotype, clinical phenotype, and pathology in 13 families with dominant X-linked Charcot-Marie-Tooth (CMT) neuropathy. Connexin32 (Cx32) gene mutations were spread throughout the coding region and included eight missense mutations, one 8-bp deletion/4-bp insertion frame shifting mutation, two nonsense mutations, and one deletion of the entire coding sequence. One hundred sixteen affected CMTX patients (53 males and 63 females) and 63 unaffected, at-risk individuals were compared by neurological and electrophysiological examinations and analyzed by gender; nerve biopsies were available from seven index cases. It was found that mutations within all regions of the Cx32 gene coding sequence caused an identical clinical phenotype. Male CMTX patients were affected more severely and showed an age-dependent progression of clinical signs and of the pathology; there was, however, variability in the severity of disease expression, irrespective of age, among males within families of defined genotype. All but 10% of female CMTX patients had only mild signs. Motor nerve conduction velocities were moderately slowed (median nerve MNCV: males 34.5 +/- 6.2 m/sec; females 45.8 +/- 7.3 m/sec), and motor and sensory nerve amplitudes were reduced (median nerve CMAP: males 3.7 +/- 3.7 mV; females 7.8 +/- 3.4 mV), with electromyographic evidence of chronic denervation. Differences were significant between gender and between affected and unaffected individuals. In agreement with the electrophysiological observations, pathological studies showed evidence of paranodal demyelination and of a length-related axonal degeneration in motor and sensory nerve fibers. Correlations between genotype and clinical phenotype suggested that missense mutations located within the second transmembrane domain and/or cytoplasmic loop might be associated with milder clinical phenotype, and therefore might be less disruptive of connexin32 gap junction function. Missense, chain-terminating, or deletion mutations in all other locations of the connexin32 protein caused severe forms of CMTX and disease onset in the first decade. Observed variability of disease severity among males within kinships suggests the influence of other modifying factors.

Repetitive phrenic nerve stimulation in myasthenia gravis.

OBJECTIVE: In patients with MG it may be difficult to determine whether respiratory insufficiency is due to a defect in neuromuscular transmission. We therefore studied the clinical value of repetitive electrical stimulation of the phrenic nerve. METHODS: Repetitive phrenic nerve stimulation at 3 Hz was performed in 25 patients with MG. We recorded from the ipsilateral hemidiaphragm with surface electrodes before and after exercising the diaphragm for 10 and 90 seconds. The percent decrement of the negative peak (NP) area between the first and the fifth or sixth diaphragmatic compound muscle action potential (DCMAP) was analyzed and results compared with those from 10 healthy individuals. RESULTS: The mean +/- standard deviation percent change of the NP area in healthy individuals was -2.1 +/- 4.2%, with a normal cutoff of > or = 11%. Twelve patients (48%) had an abnormal decrement of DCMAP--9 had a decrement when the diaphragm was rested, 3 only after fatiguing of the diaphragm. The mean percent change in the 12 patients was 20% at rest, -18% after 10 seconds of exercise, and -23% after 90 seconds of exercise-a pattern consistent with MG. Repetitive stimulation of the accessory nerve with recording of the trapezius CMAP (TCMAP) was abnormal in nine patients (36%). The three patients with abnormal decrement of the DCMAP despite normal TCMAP had symptoms of dyspnea. CONCLUSIONS: Repetitive phrenic nerve stimulation studies are a promising tool in the diagnosis of respiratory muscle weakness in MG and should be part of electrophysiologic studies in patients with undiagnosed respiratory failure.

Genotype/phenotype correlation in affected individuals of a family with a deletion of the entire coding sequence of the connexin 32 gene.

X-linked Charcot-Marie-Tooth disease (CMTX) is a peripheral nerve disorder that has been linked to mutations in the connexin 32 gene (Cx32). These mutations have been shown to be genetically heterogeneous, though recurrences of specific mutations in apparently unrelated families have been seen. The majority of mutations have been shown to be missense, resulting in non-conservative amino acid changes. A few mutations resulting in a premature termination of protein translation, including both nonsense mutations as well as frameshifting microdeletions, have been documented. We would like to report a deletion mutation that appears to eliminate the entire coding sequence of the Cx32 gene, but which has been shown to segregate with a clinical phenotype not unlike that seen in individuals with a less severe alteration of the Cx32 gene. The causes at a cellular level of the CMTX phenotype are still not fully clear, though there has been speculation that these may involve a dominant negative effect where the mutant connexin 32 suppresses the function of other connexins. Studies of kindreds such as this, where in CMTX-affected males the Cx32 gene product is totally absent, will help us to better understand the molecular mechanisms underlying the clinical phenotype associated with this disorder.

Clinical and electrophysiological findings in critical illness polyneuropathy.

Sixty two patients with critical illness polyneuropathy (CIP) were studied prospectively to determine the clinical and electrophysiological profile, to assess the prognostic value of respiratory electrophysiology in determining the duration of ventilation and to analyze the role of neuromuscular blocking agents (NMBA) and steroids. Limb motor and sensory nerve conductions, bilateral phrenic nerve onset latencies, bilateral diaphragmatic compound muscle action potentials (CMAP), unilateral diaphragmatic needle electromyography (EMG), limb muscle EMG, time on the ventilator, time in the intensive care unit (ICU), dosage of NMBA and steroids were analyzed in 62 patients. The diagnosis of CIP was made by clinical criteria, electrophysiological criteria and exclusion of any other condition suspicious of an axonal neuropathy. The results of phrenic nerve conduction studies and diaphragmatic EMG were compared to normal mean values in 25 healthy subjects. The most common finding in our study were reduced CMAPs and abnormal spontaneous activity in muscle, occuring in 100%. Forty per cent had reduced CMAPs but normal sensory nerve action potentials (SNAP). These patients had normal CK-levels and normal findings, unspecific changes, type 2 fibre atrophy or denervation atrophy on muscle biopsy. Seventy seven per cent of patients had abnormal diaphragmatic CMAPs and spontaneous activity in the diaphragm indicating denervation of the diaphragm is common in CIP. There was no statistically significant relationship to the dosage of NMBA and steroids, and the respiratory electrophysiological studies, duration of ventilation and stay in the ICU.

Electromyography of the diaphragm in neuromuscular disease.

We compared the diaphragmatic electromyographic (EMG) recordings from 32 patients with known neuromuscular disease and respiratory symptoms (23 neuropathies, 9 myopathies) to recordings from 23 normal subjects. Turns analysis of 219-ms sections, or epochs, of the EMG demonstrated a significant overlap between diagnostic groups, although some epochs from neuromuscular patients were significantly different from normal. Empirical rules were derived to infer neuropathic and myopathic involvement of the diaphragmatic EMG.

Diagnostic difficulties in myasthenia gravis.

Four patients with myasthenia gravis presented with severe, largely isolated, bulbar and respiratory muscles weakness. Tensilon tests were positive and antiacetylcholine receptor (anti-AChR) antibody titers were negative in all patients. Only 1 patient had a greater than 10% decremental response during the period of respiratory failure. Although routine nerve conduction studies were normal, all had very low-amplitude diaphragmatic compound muscle action potentials. Three patients had abundant fibrillation potentials and positive sharp waves largely restricted to respiratory muscles. Clinical and electrophysiological findings improved with corticosteroids, and surprisingly, decremental responses became positive in all patients. The assessment of patients with largely isolated bulbar and respiratory muscle weakness due to myasthenia gravis may be difficult and misleading, as anti-AChR antibody titers may be negative, decremental responses may be absent, and electrophysiological assessment atypical. Due consideration of clinical symptomatology, a Tensilon test, and a trial of immunosuppression may be necessary to establish the diagnosis.

Novel measurement for automated interference pattern analysis of the diaphragm.

The automated interference pattern analysis for limb muscles was modified to take into account the unique features of the needle EMG of the diaphragm. The modification was successful in recording more accurately the number of small and large segments and the activity levels with inspiratory effort. "Clouds" were generated in ten healthy subjects. The techniques may prove useful in electrophysiological investigations.