Charles F. Bolton

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. Muscle Nerve, 2005

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.

Sepsis and the systemic inflammatory response syndrome: neuromuscular manifestations.

OBJECTIVE To describe the various conditions of peripheral nerve, neuromuscular junction, and muscle associated with the systemic inflammatory response syndrome (SIRS). DATA SOURCES Publications in the scientific literature and personal observations during the last 15 yrs. DATA EXTRACTION Computer search of the literature and review of patient records relating to polyneuropathy, neuromuscular transmission defects, and myopathies associated with sepsis, the septic syndrome, and SIRS. SYNTHESIS SIRS is a new concept in which infection and trauma induce a systemic inflammatory response affecting the microcirculation to organs throughout the body. The nervous system is commonly affected in the forms of septic encephalopathy and critical illness polyneuropathy. Neuromuscular blocking agents and corticosteroids may have additional toxic effects on the neuromuscular system that are manifest as transient neuromuscular blockade, an axonal motor neuropathy, or a thick filament myopathy. Clinical examination in the critical care unit is often unreliable and electrophysiologic studies, at times accompanied by magnetic resonance imaging of the spinal cord, measurement of the circulating creatine phosphokinase concentration, and muscle biopsy, are often necessary to establish the diagnosis. Variants of critical illness polyneuropathy may occur outside the critical care unit. The precise mechanism of these neuromuscular conditions is not known, and further basic research is needed. CONCLUSIONS A variety of neuromuscular conditions complicates SIRS. The identification of these conditions is important in patient management and in rendering a prognosis.

A quantitative study of Meissner's corpuscles in man

THE MEISSNER corpuscle is an oval, encapsulated nerve ending, approximately 30 by 80 p, that is located almost exclusively in the dermal papillae of nonhairy skin (Fig. 1). The structure and location of this nerve ending strongly suggest that it is a receptor of mechanical stimuli, much in the manner of hair follicle endings in hairy skin;I but, at present, knowledge is lacking concerning the threshold of sensitivity of an isolated Meissner corpuscle to various sensory stimuli. Thus, the specificity of this cutaneous receptor has yet to be elucidated.2 In the few previous attempts in which silver stains were used in quantitating the normal density (number per unit) area of Meissner corpuscles, results were not in good this may have been due partly to the small number of subjects studied. Staining by cholinesterase methods outlines Meissner’s corpuscles in a discrete fashion which allows them to be easily identified and counted (Fig. 2). Recently, Dickens and coworkers5 studied, in 41 patients with sensory loss and in 37 control subjects, the density of Meissner’s corpuscles as demonstrated by this technique. They found that patients with lesions of the central nervous system had a density of Meissner’s corpuscles similar to that of the control group, whereas those with peripheral neuritis appeared to have a decreased density. Therefore, this technique might be useful as another method of investigating and classifying the peripheral neuropathies but before doing this, it was decided to document more thoroughly the normal quantitative variation of Meissner’s corpuscles. This study is concerned with the normal density, distribution, size, and shape of Meissner’s corpuscles and with the variation in these characteristics with age, sex, and occupation of the subject and with the size of the digit.

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.

Prediction of outcome in patients with anoxic coma : a clinical and electrophysiologic study

OBJECTIVE To evaluate and compare the predictive powers of clinical examination, electroencephalography (EEG), and studies of short-latency somatosensory evoked potentials in determining the prognosis in anoxic coma. DESIGN Prospective case series of patients in anoxic coma, whose prognoses were uncertain based on previously established clinical criteria. The clinical features, EEG, and somatosensory evoked potentials results were correlated with outcome. SETTING A 40-bed intensive care unit in a university teaching hospital. PATIENTS Thirty-four consecutive patients admitted over a 2-yr period with anoxic coma as the principal diagnosis. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Twenty-seven (79%) patients never recovered consciousness and seven (21%) patients made a good recovery. One of six patients whose pupillary reflexes were present but whose other cranial nerve reflexes were absent on day 1 recovered, but none of the seven patients with these features still present on day 3 survived. None of the patients with motor responses of extension to painful stimuli or worse on days 1 or 3 recovered. The EEGs were classified into benign, uncertain, and malignant categories. The results of both EEG and somatosensory evoked potentials studies were strongly associated with outcome. With malignant EEG, the sensitivity was 74%, the specificity was 71%, and the positive predictive value was 90% [corrected] for the prediction of no recovery (death or persistent vegetative state). However, two patients with an initially malignant EEG eventually made a good recovery. The sensitivity for low amplitude or absent somatosensory evoked potentials for prediction of no recovery was 66%. There were no falsely pessimistic predictions with somatosensory evoked potentials, as all 18 patients with absent or low-amplitude responses had no recovery (specificity and positive predictive value were 100%). EEG and somatosensory evoked potentials studies were complementary to clinical examination in the determination of prognosis. Using a combined clinical and electrophysiologic approach, 63% of patients who had no recovery could be identified by day 3. Repeat EEG and somatosensory evoked potentials studies were of value in patients whose prognoses were uncertain, as their evolution invariably correlated with outcome. CONCLUSIONS Based on the present data and a literature review, we propose that clinical examination combined with the results of EEG and somatosensory evoked potentials can be used to establish an early, definitive prognosis in a significant proportion of patients in anoxic coma. On day 3 or thereafter, patients with motor response of extension to pain or worse and malignant EEG, or those patients with flexor posturing or worse and bilaterally absent cortical somatosensory evoked potentials invariably have poor outcome. However, some patients with initially malignant EEG and normal somatosensory evoked potentials may recover and should be supported until their prognoses become more definitive.

Severe axonal degeneration in acute Guillain-Barré syndrome : evidence of two different mechanisms ?

Four cases of severe acute Guillain-Barré syndrome (GBS) characterized by severe axonal degeneration are presented. All had electrically inexcitable motor nerves as early as 4 days after onset. The disease was rapid in onset and the residual disability was severe. Two different types of pathology were seen. Nerve biopsies in 3 cases showed severe axonal degeneration without inflammation or demyelination. Autopsy in one of these cases showed that the dorsal and ventral roots were also significantly affected. These cases illustrate the primary axonal form of GBS. Nerve biopsy in the fourth case at day 15 showed marked inflammation and demyelination with axonal degeneration. Contralateral nerve biopsy at day 75 showed almost complete loss of axons. This case illustrates another type of axonal degeneration, that which occurs secondary to inflammation and demyelination.

Neuromuscular disorders associated with failure to wean from the ventilator.

ObjectiveTo determine, by retrospective chart analysis, the frequency, type and significance of neuromuscular disorders in patients whose clinical features suggested a neuromuscular cause of failure to wean.BackgroundFailure to wean is a common and difficult problem in critical care units. While a neuromuscular cause may be suspected in some patients, the frequency and type has not been determined utilizing comprehensive electrophysiological studies of limbs and the respiratory system. Such knowledge may aid in patient management and prognosis.MethodsThe clinical setting was a critical care/trauma centre that admits 1500 patients per year, approximately 500 being on ventilators for longer than five days. We analyzed the hospital charts of 40 patients admitted to the unit during three years, whose respiratory assessment suggested a neuromuscular cause for failure to wean from the ventilator. To investigate this possibility, we performed electrophysiological studies of the limbs and also of the respiratory system by phrenic nerve conduction and needle electromyography of the chest wall and diaphragm. The results were compared to 25 healthy controls.Results38 of 40 patients (95%) had a neuromuscular disorder: 25 — critical illness polyneuropathy, 2 — Guillain-Barré syndrome, 4 — diabetic and critical illness polyneuropathy, 2 — uremic and critical illness polyneuropathy, 10 — an abnormality of central drive, 5 — unilateral phrenic nerve palsy, 3 — a neuromuscular transmission defect, and 5 — a primary myopathy. Fifteen (38%) had a combination of disorders. Patients with more severe polyneuropathy took longer to wean, a mean of 136 versus 52 days (p=0.007).The severity of the polyneuropathy had no effect on mortality.ConclusionsElectrophysiological studies of limbs and the respiratory system are together valuable in confirming the presence, and identifying the specific type of neuromuscular cause for difficulty in weaning from the ventilator. This information is important in patient management and prognosis.

The encephalopathy of sepsis.

Twelve fatal cases of encephalopathy associated with sepsis were examined in a ten-year retrospective study. The sources of infection and organisms isolated were variable. Six of the patients had focal neurologic signs; five had seizures. The level of consciousness varied from drowsiness to deep coma, and electroencephalograms revealed diffuse or multifocal abnormalities. Computed tomographic head scans and cerebrospinal fluid examinations were usually unremarkable. Eight patients had disseminated microabscesses in the brain at autopsy. Four patients had proliferation of astrocytes and microglia in the cerebral cortex, a feature associated with metabolic encephalopathies. Additional findings included cerebral infarcts, brain purpura, multiple small white matter hemorrhages, and central pontine myelinolysis. Although sepsis may cause encephalopathy by producing disturbances in cerebral synaptic transmission and cerebral energy production through a toxic mechanism, bacterial invasion of the brain with the formation of disseminated microabscesses is also an important cause.

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

ABSTRACT: 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.