Review of the Diagnostic Challenges of Lambert-Eaton Syndrome Revealed Through Three Case Reports.

Lambert-Eaton syndrome (LES) is a rare immune-mediated disorder characterized by proximal leg weakness, autonomic symptoms and hypoactive tendon reflexes. The paraneoplastic form is associated with small-cell lung cancer in 50-60% of cases, whereas the remaining cases are found in younger adults with a higher likelihood of coexisting autoimmune disease. The early recognition of LES is crucial for improving clinical outcomes but remains a major challenge. In this review, we analyze the clinical characteristics and diagnostic considerations in treating LES through a series of three case studies, one of which showed definitive response to pyridostigmine and corticosteroid combination therapy, followed by spontaneous remission. Patients were assessed by image-based screening, serological testing and electrophysiological evaluations, which included respiratory and autonomic testing. A better understanding of the common pitfalls in the clinical, serological and neurophysiologic diagnosis of LES through assessment of typical LES dysfunction throughout the nervous system should enable improved recognition and treatment of this syndrome.

Proficiency of nerve conduction using standard methods and reference values (Cl. NPhys Trial 4).

INTRODUCTION: The Cl. NPhys Trial 3 showed that attributes of nerve conduction (NC) were without significant intraobserver differences, although there were significant interobserver differences. METHODS: Trial 4 tested whether use of written instructions and pretrial agreement on techniques and use of standard reference values, diagnostic percentile values, or broader categorization of abnormality could reduce significant interobserver disagreement and improve agreement among clinical neurophysiologists. RESULTS: The Trial 4 modifications markedly decreased, but did not eliminate, significant interobserver differences of measured attributes of NC. Use of standard reference values and defined percentile values of abnormality decreased interobserver disagreement and improved agreement of judgment of abnormality among evaluators. Therefore, the same clinical neurophysiologist should perform repeat NCs of therapeutic trial patients. CONCLUSIONS: Differences in interobserver judgment of abnormality decrease with use of common standard reference values and a defined percentile level of abnormality, providing a rationale for their use in therapeutic trials and medical practice.

A trial of proficiency of nerve conduction: greater standardization still needed.

INTRODUCTION: The aim of this study was to test the proficiency (accuracy among evaluators) of measured attributes of nerve conduction (NC). METHODS: Expert clinical neurophysiologists, without instruction or consensus development, from 4 different medical centers, independently assessed 8 attributes of NC in 24 patients with diabetes mellitus (DM) on consecutive days. RESULTS: No significant intraobserver differences between days 1 and 2 were found, but significant interobserver differences were seen. Use of standard reference values did not correct for these observed differences. CONCLUSIONS: Interobserver variability was attributed to differences in performance of NC. It was of sufficient magnitude that it is of concern for the conduct of therapeutic trials. To deal with interrater variability in therapeutic trials, the same electromyographers should perform all NC assessments of individual patients or, preferably, NC procedures should be more standardized. A further trial is needed to test whether such standardization would eliminate interobserver variability.

Signs and symptoms versus nerve conduction studies to diagnose diabetic sensorimotor polyneuropathy: Cl vs. NPhys trial.

The purpose was to test whether physicians can validly and reproducibly diagnose diabetic sensorimotor polyneuropathy (DSPN). Twelve physicians assessed 24 patients with diabetes mellitus (DM) on consecutive days (576 examinations) with physical features and voice disguised. Results were compared to gold standard 75% group diagnosis (dx) and a nerve conduction score (Sigma5 NC nds). Masking of patients was achieved. Reproducibility measured by the kappa coefficient and compared to Sigma5 NC nd varied considerably among physicians: median and ranges: signs 0.8 (0.32-1.0); symptoms 0.79 (0.36-1.0), and diagnoses 0.47 (0.33-0.84), both low and high scores indicating poor performance. There was substantial agreement between 75% group dx and confirmed NC abnormality (abn). As compared to Sigma5 NC, individual physicians' clinical dx was excessively variable and frequently inaccurate. Study physician dx from signs and symptoms were excessively variable, often overestimating DSPN. Specific approaches to improving clinical proficiency should be tested.

Guillain-Barre syndrome following cardiac surgery. Difficult diagnosis in the intensive care unit.

Weakness of limb and respiratory muscles developing in the course of treatment in the intensive care unit (ICU) is commonly due to critical illness polyneuropathy, a complication of sepsis, or critical illness myopathy, a complication of the use of neuromuscular blocking agents and steroids. Guillain-Barre syndrome may rarely occur in this setting. We report 2 patients identified in our ICU in the last 20 years. Surgery was an apparent precipitating event in both patients. The clinical, electrophysiological, and cerebrospinal fluid features were consistent with this diagnosis. Both patients responded to treatment; the first case was treated with plasmapheresis while the other with intravenous immune globulin. Thus, while rare, it is important to identify this disorder in the ICU because of its response to specific treatment.

Dyspnea as the predominant manifestation of bilateral phrenic neuropathy.

Phrenic neuropathy associated with brachial neuritis has been well described; however, bilateral phrenic neuropathy with minimal or no involvement of the brachial plexus has not. We review the clinical features, as well as the results of radiographic studies, pulmonary function tests, and electrodiagnostic studies, of 3 patients in whom dyspnea was the presenting manifestation of bilateral phrenic neuropathy. All 3 patients had acute-onset dyspnea, which led to consideration of a pulmonary or cardiac etiology. Phrenic nerve conduction studies showed bilateral axonal degeneration of the phrenic nerves. Diaphragmatic paralysis should be considered in the differential diagnosis of acute-onset dyspnea. Dyspnea increases typically when the patient lies down, and paradoxical respiration may be present. Neck, shoulder, or upper limb pain may occur at onset. Inspiratory pressures may be reduced, but a comparison of the forced vital capacity when the patient is standing and supine is more specific for diaphragmatic weakness. Phrenic nerve conduction studies and diaphragmatic electromyography may provide evidence of bilateral involvement. Subclinical evidence of brachial plexus involvement may be present. The prognosis for patients with bilateral phrenic neuropathy may be more favorable than reported previously.

"Unequivocally Abnormal" vs "Usual" Signs and Symptoms for Proficient Diagnosis of Diabetic Polyneuropathy: Cl vs N Phys Trial.

OBJECTIVE To repeat the Clinical vs Neurophysiology (Cl vs N Phys) trial using "unequivocally abnormal" signs and symptoms (Trial 2) compared with the earlier trial (Trial 1), which used "usual" signs and symptoms. DESIGN Standard and referenced nerve conduction abnormalities were used in both Trials 1 and 2 as the standard criterion indicative of diabetic sensorimotor polyneuropathy. Physician proficiency (accuracy among evaluators) was compared between Trials 1 and 2. SETTING Academic medical centers in Canada, Denmark, England, and the United States. PARTICIPANTS Thirteen expert neuromuscular physicians. One expert was replaced in Trial 2. RESULTS The marked overreporting, especially of signs, in Trial 1 was avoided in Trial 2. Reproducibility of diagnosis between days 1 and 2 was significantly (P = .005) better in Trial 2. The correlation of the following clinical scores with composite nerve conduction measures spanning the range of normality and abnormality was improved in Trial 2: pinprick sensation (P = .03), decreased reflexes (P = .06), touch-pressure sensation (P = .06), and the sum of symptoms (P = .06). CONCLUSIONS The simple pretrial decision to use unequivocally abnormal signs and symptoms-taking age, sex, and physical variables into account-in making clinical judgments for the diagnosis of diabetic sensorimotor polyneuropathy (Trial 2) improves physician proficiency compared with use of usual elicitation of signs and symptoms (Trial 1); both compare to confirmed nerve conduction abnormality.

Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis.

Critical illness polyneuropathy (CIP) and myopathy (CIM) are complications of critical illness that present with muscle weakness and failure to wean from the ventilator. In addition to prolonging mechanical ventilation and hospitalisation, CIP and CIM increase hospital mortality in patients who are critically ill and cause chronic disability in survivors of critical illness. Structural changes associated with CIP and CIM include axonal nerve degeneration, muscle myosin loss, and muscle necrosis. Functional changes can cause electrical inexcitability of nerves and muscles with reversible muscle weakness. Microvascular changes and cytopathic hypoxia might disrupt energy supply and use. An acquired sodium channelopathy causing reduced muscle membrane and nerve excitability is a possible unifying mechanism underlying CIP and CIM. The diagnosis of CIP, CIM, or combined CIP and CIM relies on clinical, electrophysiological, and muscle biopsy investigations. Control of hyperglycaemia might reduce the severity of these complications of critical illness, and early rehabilitation in the intensive care unit might improve the functional recovery and independence of patients.

Brief review: Nondepolarizing neuromuscular blocking drugs and critical illness myopathy.

PURPOSE: Critically-ill patients who receive nondepolarizing neuromuscular blocking drugs (NMBDs) may be at risk of developing profound muscle weakness that may last for months after the NMBD is discontinued, especially when large cumulative doses of NMBDs and corticosteroids are co-administered to septic, mechanically ventilated patients. This review focuses on the etiology and clinical features of critical illness myopathy (CIM), summarizes specific risk factors for its development, and discusses strategies that might be used to attenuate or even prevent the development of this potentially devastating syndrome. CLINICAL FEATURES: The etiology of CIM is unknown. Whether it can develop in at-risk patients who undergo lengthy operations during which they receive NMBDs is also unknown. In some patients following exposure to NMBDs their motor systems are impaired secondary to loss of thick (myosin) filaments that render the muscle unexcitable to direct electrical stimulation, while the sensory system is spared. Management of patients who develop NMBD myopathy is supportive, consisting of nutritional support, physical therapy, and daily trials of decreased ventilatory support. CONCLUSION: Recent guidelines recommend that NMBDs be used in critically ill patients only when absolutely necessary, that the depth of muscle paralysis be monitored to avoid overdosing and metabolite accumulation, and that drug administration be curtailed periodically to allow interruption of sustained NMBD effect.

Neuromuscular manifestations of critical illness.

Critical illness, more precisely defined as the systemic inflammatory response syndrome (SIRS), occurs in 20%-50% of patients who have been on mechanical ventilation for more than 1 week in an intensive care unit. Critical illness polyneuropathy (CIP) and myopathy (CIM), singly or in combination, occur commonly in these patients and present as limb weakness and difficulty in weaning from the ventilator. Critical illness myopathy can be subdivided into thick-filament (myosin) loss, cachectic myopathy, acute rhabdomyolysis, and acute necrotizing myopathy of intensive care. SIRS is the predominant underlying factor in CIP and is likely a factor in CIM even though the effects of neuromuscular blocking agents and steroids predominate in CIM. Identification and characterization of the polyneuropathy and myopathy depend upon neurological examination, electrophysiological studies, measurement of serum creatine kinase, and, if features suggest a myopathy, muscle biopsy. The information is valuable in deciding treatment and prognosis.

Cajal's contribution to the neurology of breathing.

Cajal, through his pioneering investigations, was able to characterize the location and connections of several brainstem nuclei. This, coupled with previous investigations by others, allowed him to formulate a concept of the microscopic anatomy of automatic respiration.

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.