Jaffar Khan

Early development of critical illness myopathy and neuropathy in patients with severe sepsis

Objectives: To characterize the prevalence, time of onset, and cause of neuromuscular dysfunction in patients with severe sepsis. Methods: We conducted a prospective cohort study in which participants with severe sepsis underwent weekly neurologic examinations and nerve conduction studies (NCSs) within 72 hours of developing severe sepsis until intensive care unit (ICU) discharge. Electromyography was preformed if clinical weakness developed or if there was a significant reduction in nerve conduction response amplitudes. Results: Abnormal NCS were present upon enrollment in 63% of patients (31/48). The presence of abnormal baseline NCS was predictive of hospital mortality (55% vs 0% for patients with normal baseline NCS; p < 0.001). Development of acquired neuromuscular dysfunction could be predicted by NCS done on day 7. Twenty patients remained in the ICU long enough to have serial NCSs; 50% of these patients developed acquired neuromuscular dysfunction. Most patients with acquired neuromuscular dysfunction had electrophysiologic evidence of both critical illness myopathy and critical illness neuropathy. Conclusion: Changes in nerve conduction studies occur in the majority of patients early in the course of severe sepsis and predict the development of acquired neuromuscular dysfunction and mortality in intensive care unit patients. Most patients with acquired neuromuscular dysfunction after sepsis have both critical illness myopathy and critical illness neuropathy.

Inactivation of sodium channels underlies reversible neuropathy during critical illness in rats

Neuropathy and myopathy can cause weakness during critical illness. To determine whether reduced excitability of peripheral nerves, rather than degeneration, is the mechanism underlying acute neuropathy in critically ill patients, we prospectively followed patients during the acute phase of critical illness and early recovery and assessed nerve conduction. During the period of early recovery from critical illness, patients recovered from neuropathy within days. This rapidly reversible neuropathy has not to our knowledge been previously described in critically ill patients and may be a novel type of neuropathy. In vivo intracellular recordings from dorsal root axons in septic rats revealed reduced action potential amplitude, demonstrating that reduced excitability of nerve was the mechanism underlying neuropathy. When action potentials were triggered by hyperpolarizing pulses, their amplitudes largely recovered, indicating that inactivation of sodium channels was an important contributor to reduced excitability. There was no depolarization of axon resting potential in septic rats, which ruled out a contribution of resting potential to the increased inactivation of sodium channels. Our data suggest that a hyperpolarized shift in the voltage dependence of sodium channel inactivation causes increased sodium inactivation and reduced excitability. Acquired sodium channelopathy may be the mechanism underlying acute neuropathy in critically ill patients.

Toward more efficient clinical trials for amyotrophic lateral sclerosis

Abstract More than 30 phase II or III clinical trials have been carried out in amyotrophic lateral sclerosis (ALS). Only riluzole, however, has been shown to extend survival and/or time to tracheostomy. Many early ALS trials lacked solid pharmacodynamic and pharmacokinetic data for the treatment being tested, challenging the interpretation of the efficacy and pathway relevance. Understanding of the genetics and pathophysiology of ALS has improved considerably in the past decade, but biomarkers of disease activity remain lacking. A more efficient approach to early phase clinical trials is needed to accelerate the identification of useful agents for ALS. Here we summarize our current thinking about phase II design options and the potential benefits of a clinical trial network for phase II trials in ALS.

Mechanisms of Neuromuscular Dysfunction in Critical Illness

The development of neuromuscular dysfunction (NMD) during critical illness is increasingly recognized as a cause of failure to wean from mechanical ventilation and is associated with significant morbidity and mortality. At times, it is difficult to identify the presence of NMD and distinguish the etiology of the weakness in patients with critical illness, but subtle clinical findings and bedside electrophysiologic testing are helpful in establishing the diagnosis. This article describes the clinical spectrum of acquired neuromuscular weakness in the setting of critical illness, provides an approach to diagnosis, and discusses its pathogenesis. Finally, a defective sodium channel regulation as a unifying mechanism underlying NMD in critically ill patients is proposed.

Behavior Matters—Cognitive Predictors of Survival in Amyotrophic Lateral Sclerosis

Background It is difficult to longitudinally characterize cognitive impairment in amyotrophic lateral sclerosis (ALS) due to motor deficits, and existing instruments aren’t comparable with assessments in other dementias. Methods The ALS Brief Cognitive Assessment (ALS-BCA) was validated in 70 subjects (37 with ALS) who also underwent detailed neuropsychological analysis. Cognitive predictors for poor survival were then analyzed in a longitudinal cohort of 171 ALS patients. Results The ALS-BCA was highly sensitive (90%) and specific (85%) for ALS-dementia (ALS-D). ALS-D patients had shorter overall survival, primarily due to the poor survival among ALS-D patients with disinhibited or apathetic behaviors after adjusting for demographic variables, ALS site of onset, medications, and supportive measures. ALS-D without behavioral changes was not a predictor of poor survival. Conclusion ALS-D can present with or without prominent behavioral changes. Cognitive screening in ALS patients should focus on behavioral changes for prognosis, while non-behavioral cognitive impairments may impact quality of life without impacting survival.

Reduced motoneuron excitability in a rat model of sepsis.

Many critically ill patients in intensive care units suffer from an infection-induced whole body inflammatory state known as sepsis, which causes severe weakness in patients who survive. The mechanisms by which sepsis triggers intensive care unit-acquired weakness (ICUAW) remain unclear. Currently, research into ICUAW is focused on dysfunction of the peripheral nervous system. During electromyographic studies of patients with ICUAW, we noticed that recruitment was limited to few motor units, which fired at low rates. The reduction in motor unit rate modulation suggested that functional impairment within the central nervous system contributes to ICUAW. To understand better the mechanism underlying reduced firing motor unit firing rates, we moved to the rat cecal ligation and puncture model of sepsis. In isoflurane-anesthetized rats, we studied the response of spinal motoneurons to injected current to determine their capacity for initiating and firing action potentials repetitively. Properties of single action potentials and passive membrane properties of motoneurons from septic rats were normal, suggesting excitability was normal. However, motoneurons exhibited striking dysfunction during repetitive firing. The sustained firing that underlies normal motor unit activity and smooth force generation was slower, more erratic, and often intermittent in septic rats. Our data are the first to suggest that reduced excitability of neurons within the central nervous system may contribute to ICUAW.

Is it time already to revise the Neurology Milestones

The Accreditation Council for Graduate Medical Education (ACGME) has mandated a transition from competency-based to milestone-based assessment of residents.1 As of 2014, each accredited US neurology program must track resident progress toward 240 specific achievements or anchor statements in 29 domains. Collectively, these are called the Neurology Milestones.2

Defining the Role of the Academic Neurohospitalist in Residency Education

Objective: We sought to better understand the potential impact of the burgeoning neurohospitalist model of inpatient care on education of neurology residents and to better define possible roles for “neurohospitalists” in residency education. Method: We designed a brief qualitative open-ended survey directed toward academic leaders in neurology and distributed it by e-mail to every academic neurology department in the United States and Canada. Results: Of 83 respondents, 36 (43%) had an active neurohospitalist program and only 10% felt certain they would not have 1 within the next 5 years. All respondents expected to have residents continue to be involved with inpatient care. The main perceived advantage for resident education associated with neurohospitalists was inpatient care expertise, and the main expected disadvantage was decreased exposure to subspecialty attendings. The majority anticipated positive impact on all Accreditation Council for Graduate Medical Education core competencies predominantly based on neurohospitalists’ expertise in the inpatient setting. Conclusion: The majority of academic neurology departments are expected to have a neurohospitalist program within the next 5 years. There are several perceived advantages and disadvantages to such a program for education of neurology residents. In general, the impact of these programs is expected to improve resident education. Regardless of expectations, neurohospitalists will likely play a prominent role in the education of the next generation of neurologists.

Preventing burnout increases the desirability of neurology as a career

Neurologic diseases comprise a major percentage of disease burden in the United States, and one that is predicted to increase as our population ages. The need for physicians with expertise in the recognition, diagnosis, and management of neurologic diseases also will increase. Over the next decade, the number of neurologists in the United States will grow from the current 16,000 to 18,000. However, even this number represents a predicted 20% shortfall in number of neurologists needed by 2025.1,2 Our neurology workforce therefore must increase to address this current and future need.

Expectations of Medical Student Neuroradiology Education: A Survey of Practicing Neuroradiologists and Neurologists

The purpose of this study is to evaluate which neuroradiological diseases neuroradiologists and neurologists believe medical students should be exposed to during their neuroradiology rotation. Members of the American Society of Neuroradiology (ASNR) and the American Academy of Neurology (AAN) were surveyed. Respondents were presented 32 diseases with neuroimaging findings and asked which ones medical students should be exposed to during a neuroradiology rotation. Using a 50% response threshold per disease entity, results were tabulated into 3 groups: diagnoses that (1) more than 50% of neuroradiologists and neurologists felt medical students should see radiologically by rotation completion, (2) less than 50% of respondents in both the groups felt were important, and (3) both the groups disagree are important. Both the groups thought medical students should be exposed to imaging of intraparenchymal hemorrhage (ASNR = 80.4% vs AAN = 84.3%; P = 0.346) and subarachnoid hemorrhage (ASNR = 74% vs AAN = 78%; P = 0.394). Both the groups (>50%) thought subdural hematoma, acute ischemic stroke, epidural hematoma, and spinal cord compression are important. Conditions such as spine fractures, nonacute stroke, arteriovenous malformation, and ear-nose-throat pathology showed varied results between both the groups. Varying degrees of similarity and differences exist between the expectations of neuroradiologists and neurologists regarding medical student neuroradiology education, presenting a positive opportunity for greater consensus, dialogue, and joint curriculum formation.