Cindy S.-Y. Lin

Controversies and priorities in amyotrophic lateral sclerosis.

Two decades after the discovery that 20% of familial amyotrophic lateral sclerosis (ALS) cases were linked to mutations in the superoxide dismutase-1 (SOD1) gene, a substantial proportion of the remainder of cases of familial ALS have now been traced to an expansion of the intronic hexanucleotide repeat sequence in C9orf72. This breakthrough provides an opportunity to re-evaluate longstanding concepts regarding the cause and natural history of ALS, coming soon after the pathological unification of ALS with frontotemporal dementia through a shared pathological signature of cytoplasmic inclusions of the ubiquitinated protein TDP-43. However, with profound clinical, prognostic, neuropathological, and now genetic heterogeneity, the concept of ALS as one disease appears increasingly untenable. This background calls for the development of a more sophisticated taxonomy, and an appreciation of ALS as the breakdown of a wider network rather than a discrete vulnerable population of specialised motor neurons. Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease. By contrast, the 90% of apparently sporadic cases and incomplete penetrance of several genes linked to familial cases suggest that at least some forms of ALS arise from the interplay of multiple genes, poorly understood developmental, environmental, and age-related factors, as well as stochastic events.

Chemotherapy‐induced peripheral neurotoxicity: A critical analysis

With a 3‐fold increase in the number of cancer survivors noted since the 1970s, there are now over 28 million cancer survivors worldwide. Accordingly, there is a heightened awareness of long‐term toxicities and the impact on quality of life following treatment in cancer survivors. This review will address the increasing importance and challenge of chemotherapy‐induced neurotoxicity, with a focus on neuropathy associated with the treatment of breast cancer, colorectal cancer, testicular cancer, and hematological cancers. An overview of the diagnosis, symptomatology, and pathophysiology of chemotherapy‐induced peripheral neuropathy will be provided, with a critical analysis of assessment strategies, neuroprotective approaches, and potential treatments. The review will concentrate on neuropathy associated with taxanes, platinum compounds, vinca alkaloids, thalidomide, and bortezomib, providing clinical information specific to these chemotherapies. CA Cancer J Clin 2013;63:419‐437. ©2013 American Cancer Society, Inc.

Acute tetrodotoxin-induced neurotoxicity after ingestion of puffer fish

This study documents the effects of puffer‐fish poisoning on peripheral nerve. Excitability measurements investigated membrane properties of sensory and motor axons in four patients. The median nerve was stimulated at the wrist, with compound muscle potentials recorded from abductor pollicis brevis and compound sensory potentials from digit 2. Stimulus–responses, strength–duration time constant (τSD), threshold electrotonus, and current–threshold relations were recorded. The urine of each patient tested positive for tetrodotoxin. Compared with controls, axons were of higher threshold, compound muscle action potentials and compound sensory nerve action potentials were reduced in amplitude, latency was prolonged, and τSD was reduced. In recovery cycles, refractoriness, superexcitability, and late subexcitability were decreased. Threshold electrotonus of motor axons exhibited distinctive abnormalities with less threshold decline than normal on depolarization and greater threshold increase on hyperpolarization (p < 0.0005 for each patient). The changes in excitability were reproduced in a mathematical model by reducing sodium (Na+) permeabilities by a factor of two. This study confirms that the neurotoxic effects of puffer‐fish poisoning can be explained by tetrodotoxin blockade of Na+ channels. It demonstrates the ability of noninvasive nerve excitability studies to detect Na+ channel blockade in vivo and also the utility of mathematical modeling to aid interpretation of altered excitability properties in disease. Ann Neurol 2005;57:339–348

Clinical evaluation of excitability measures in sensory nerve.

A recently described method for recording multiple excitability parameters of human motor nerves has been adapted to the study of sensory nerves. The protocol measures stimulus–response behavior using two stimulus durations (from which the distribution of strength–duration time constants is estimated), threshold electrotonus to 100 ms polarizing currents, a current–threshold relationship (indicating inward and outward rectification), and the recovery of excitability following supramaximal activation. The method was tested on 50 healthy volunteers, stimulating the median nerve at the wrist and recording the antidromic compound sensory nerve action potential (SNAP) from digit 2. The excitability measurements were similar, where comparisons were possible, with published sensory nerve data, and confirmed differences from motor nerves, particularly in strength–duration behavior and recovery cycle, likely to reflect functional differences between sensory and motor nerves. Although slower than for motor nerves, the sensory nerve recordings were sufficiently quick (16 to 18 min) to allow them to be included in routine clinical studies. We propose that this method, which provides quite different and complementary information about nerve function to conventional conduction studies, provides a useful new approach for exploring the pathophysiology of sensory neuropathies.

Oxaliplatin-induced neurotoxicity: changes in axonal excitability precede development of neuropathy.

Administration of oxaliplatin, a platinum-based chemotherapy used extensively in the treatment of colorectal cancer, is complicated by prominent dose-limiting neurotoxicity. Acute neurotoxicity develops following oxaliplatin infusion and resolves within days, while chronic neuropathy develops progressively with higher cumulative doses. To investigate the pathophysiology of oxaliplatin-induced neurotoxicity and neuropathy, clinical grading scales, nerve conduction studies and a total of 905 axonal excitability studies were undertaken in a cohort of 58 consecutive oxaliplatin-treated patients. Acutely following individual oxaliplatin infusions, significant changes were evident in both sensory and motor axons in recovery cycle parameters (P < 0.05), consistent with the development of a functional channelopathy of axonal sodium channels. Longitudinally across treatment (cumulative oxaliplatin dose 776 +/- 46 mg/m(2)), progressive abnormalities developed in sensory axons (refractoriness P < or = 0.001; superexcitability P < 0.001; hyperpolarizing threshold electrotonus 90-100 ms P < or = 0.001), while motor axonal excitability remained unchanged (P > 0.05), consistent with the purely sensory symptoms of chronic oxaliplatin-induced neuropathy. Sensory abnormalities occurred prior to significant reduction in compound sensory amplitude and the development of neuropathy (P < 0.01). Sensory excitability abnormalities that developed during early treatment cycles (cumulative dose 294 +/- 16 mg/m(2) oxaliplatin; P < 0.05) were able to predict final clinical outcome on an individual patient basis in 80% of patients. As such, sensory axonal excitability techniques may provide a means to identify pre-clinical oxaliplatin-induced nerve dysfunction prior to the onset of chronic neuropathy. Furthermore, patients with severe neurotoxicity at treatment completion demonstrated greater excitability changes (P < 0.05) than those left with mild or moderate neurotoxicity, suggesting that assessment of sensory excitability parameters may provide a sensitive biomarker of severity for oxaliplatin-induced neurotoxicity.

Differences in activity-dependent hyperpolarization in human sensory and motor axons

The present study was undertaken to determine whether activity‐dependent changes in axonal excitability are greater in motor axons than cutaneous afferents for the same impulse load. In nine healthy subjects, supramaximal stimulation at 8 Hz was delivered to the median nerve at the wrist. Changes in the threshold current required to generate compound motor and sensory potentials ∼50% of maximum and other indices of axonal excitability were tracked before and after repetitive stimulation for 10 min. The long‐lasting stimulation produced a prolonged depression in the excitability of both cutaneous afferents and motor axons, with gradual recovery to control levels over 15–20 min. These changes in threshold were associated with a reduction in refractoriness, an increase in supernormality and a decrease in the strength–duration time constant, changes consistent with axonal hyperpolarization. Greater changes in threshold occurred in motor axons: threshold increased by 9.9% and 16.4% for test stimulus durations of 0.1 and 1 ms, respectively, for motor axons and by 5.4% and 8.3% for cutaneous afferents. With higher stimulus frequencies and thereby greater impulse loads, greater threshold changes could be induced in cutaneous afferents. It is argued that the hyperpolarization resulted from activity of the electrogenic Na+–K+ pump, that it requires > 125 ms to restore the resting state following an action potential, and that significant intracellular Na+ accumulation occurs during a steady 8‐Hz train. These findings imply that physiological discharge rates will activate the pump and thereby produce axonal hyperpolarization, the extent of which will vary with impulse load. A plausible explanation is that greater activity‐dependent hyperpolarization in motor axons is due to less inward rectification as a result of less activity of the hyperpolarization‐activated cation conductance (IH) than in cutaneous afferents.

Axonal ion channels from bench to bedside: a translational neuroscience perspective.

Over recent decades, the development of specialised techniques such as patch clamping and site-directed mutagenesis have established the contribution of neuronal ion channel dysfunction to the pathophysiology of common neurological conditions including epilepsy, multiple sclerosis, spinal cord injury, peripheral neuropathy, episodic ataxia, amyotrophic lateral sclerosis and neuropathic pain. Recently, these insights from in vitro studies have been translated into the clinical realm. In keeping with this progress, novel clinical axonal excitability techniques have been developed to provide information related to the activity of a variety of ion channels, energy-dependent pumps and ion exchange processes activated during impulse conduction in peripheral axons. These non-invasive techniques have been extensively applied to the study of the biophysical properties of human peripheral nerves in vivo and have provided important insights into axonal ion channel function in health and disease. This review will provide a translational perspective, focusing on an overview of the investigational method, the clinical utility in assessing the biophysical basis of ectopic symptom generation in peripheral nerve disease and a review of the major findings of excitability studies in acquired and inherited neurological disease states.

Differences in membrane properties of axonal and demyelinating Guillain-Barré syndromes.

Guillain‐Barré syndrome is classified into acute motor axonal neuropathy (AMAN) and acute inflammatory demyelinating polyneuropathy (AIDP) by electrodiagnostic and pathological criteria. In AMAN, the immune attack appears directed against the axolemma and nodes of Ranvier. Threshold tracking was used to measure indices of axonal excitability (refractoriness, supernormality, and threshold electrotonus) for median nerve axons at the wrist of patients with AMAN (n = 10) and AIDP (n = 8). Refractoriness (the increase in threshold current during the relative refractory period) was greatly increased in AMAN patients, but the abruptness of the threshold increases at short interstimulus intervals indicated conduction failure distal to the stimulation (ie, an increased refractory period of transmission). During the 4 week period from onset, the high refractoriness returned toward normal, and the amplitude of the compound muscle action potential increased, consistent with improvement in the safety margin for impulse transmission in the distal nerve. In contrast, refractoriness was normal in AIDP, even though there was marked prolongation of distal latencies. Supernormality and threshold electrotonus were normal in both groups of patients, suggesting that, at the wrist, membrane potential was normal and pathology was relatively minor. These results support the view that the predominantly distal targets of immune attack are different for AMAN and AIDP. Possible mechanisms for the reduced safety factor in AMAN are discussed.

Acute Abnormalities of Sensory Nerve Function Associated With Oxaliplatin-Induced Neurotoxicity

PURPOSE Neurotoxicity is becoming increasingly recognized as the major dose-limiting toxicity of oxaliplatin. Because the mechanism of oxaliplatin-induced neurotoxicity remains unclear, the present study investigated the potential of axonal excitability techniques in identifying pathophysiologic mechanisms and early markers of nerve dysfunction. PATIENTS AND METHODS Measures of sensory axonal excitability were recorded before and after infusion over 88 treatment cycles in 25 patients with colorectal cancer, who received a total oxaliplatin dose of 766 +/- 56 mg/m(2). Neurologic assessment, clinical rating scales, and routine nerve conduction studies were performed. RESULTS By completion of treatment, 16% of patients had developed severe (grade 3) neurotoxicity, and oxaliplatin dose reduction or cessation as a result of neurotoxicity was required in 40% of patients. Changes in axonal excitability occurred after infusion and could be explained on the basis of alterations in axonal membrane sodium (Na+) channel function (refractoriness: 7.6% +/- 1.7% before infusion v 4.5% +/- 1.4% after infusion; P = .03; superexcitability: -22.8% +/- 0.8% before infusion v -20.1% +/- 1.1% after infusion; P = .0002). Changes became less pronounced in later treatment cycles, suggesting that chronic nerve dysfunction and sensory loss masked acute effects at higher cumulative doses. Importantly, patients who demonstrated reductions in superexcitability in early treatment were subsequently more likely to develop moderate to severe neurotoxicity. The findings suggest that the degree of acute nerve dysfunction may relate to the development of chronic neurotoxicity. CONCLUSION Sensory axonal excitability techniques may facilitate identification of Na+ channel dysfunction in oxaliplatin-induced neurotoxicity and thereby provide a method to identify patients at risk for neurotoxicity to target those most likely to benefit from future neuroprotective strategies.

Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory neuropathy, classically characterised by a slowly progressive onset and symmetrical, sensorimotor involvement. However, there are many phenotypic variants, suggesting that CIDP may not be a discrete disease entity but rather a spectrum of related conditions. While the abiding theory of CIDP pathogenesis is that cell-mediated and humoral mechanisms act together in an aberrant immune response to cause damage to peripheral nerves, the relative contributions of T cell and autoantibody responses remain largely undefined. In animal models of spontaneous inflammatory neuropathy, T cell responses to defined myelin antigens are responsible. In other human inflammatory neuropathies, there is evidence of antibody responses to Schwann cell, compact myelin or nodal antigens. In this review, the roles of the cellular and humoral immune systems in the pathogenesis of CIDP will be discussed. In time, it is anticipated that delineation of clinical phenotypes and the underlying disease mechanisms might help guide diagnostic and individualised treatment strategies for CIDP.