Evidence for Axonal Membrane Hyperpolarization in Multifocal Motor Neuropathy with Conduction Block

Brain : a Journal of Neurology. Mar, 2002  |  Pubmed ID: 11872621

Multiple nerve excitability measurements were used to investigate axonal membrane properties of patients diagnosed with multifocal motor neuropathy (MMN). Six patients were selected, all with evidence of distal focal motor conduction block involving the median nerve in the forearm. In all patients, the median nerve was stimulated at the wrist, just distal to the site of block, and the resulting compound muscle action potentials were recorded from abductor pollicis brevis. Stimulus-response behaviour, the strength--duration time constant, threshold electrotonus to 100 ms polarizing currents, a current-threshold relationship and the recovery of excitability following supramaximal activation were recorded using a protocol described recently. When compared with control values, patients demonstrated significantly greater superexcitability, a 'fanning out' of threshold electrotonus recordings, and a significant change in the slope of the current--threshold relationship. These abnormalities in axonal membrane excitability parameters closely resembled those in normal axons hyperpolarized following release from ischaemia. To test for axonal hyperpolarization, DC depolarizing currents were applied to the nerves of three patients, and all the excitability parameters were normalized by depolarization. Attempts to trace excitability measures proximally towards the site of block were unsuccessful, as the nerve became inexcitable in all cases. It is suggested that the distal hyperpolarization is probably linked to focal depolarization and that the clinical features of MMN are consistent with a depolarizing/hyperpolarizing lesion.

Nerve Excitability Changes in Chronic Renal Failure Indicate Membrane Depolarization Due to Hyperkalaemia

Brain : a Journal of Neurology. Jun, 2002  |  Pubmed ID: 12023325

Multiple nerve excitability measurements were used to investigate axonal membrane properties in patients with chronic renal failure (CRF). Nine patients were studied during routine haemodialysis therapy. The median nerve was stimulated at the wrist and compound muscle action potentials recorded from abductor pollicis brevis. Stimulus-response behaviour, strength-duration time constant, threshold electrotonus, current-threshold relationship and recovery cycle (refractoriness, superexcitability and late subexcitability) were recorded using a recently described protocol. In six patients, sequential studies were performed before, during and after haemodialysis. All patients underwent standard electrolyte and renal function tests before and after haemodialysis. Before dialysis, there were significant abnormalities in axonal excitability: reduced superexcitability; increased accommodation to depolarizing and hyperpolarizing currents; and a steeper current-threshold relationship compared with normal controls. These excitability parameters are the most sensitive to membrane potential and the abnormalities, which were all reduced by haemodialysis, closely resembled those in normal axons depolarized by ischaemia. Before dialysis, the excitability parameters correlated significantly with serum potassium (range 4.3-6.1 mM), but not with other markers of renal dysfunction: patients with normal axonal resting potentials had normal serum potassium, although urea and creatinine were elevated. We conclude that nerves are depolarized in many CRF patients and that the depolarization is primarily due to hyperkalaemia.

Wernicke's Encephalopathy Presenting with Upbeating Nystagmus

Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. Jul, 2002  |  Pubmed ID: 12217687

The case of a 49-year-old woman with Wernicke's encephalopathy is described, in which primary position upbeating nystagmus was the chief ocular sign. Although there was no history of excessive alcohol consumption, Wernicke's encephalopathy was diagnosed on a background of anorexia nervosa. The diagnosis was supported by the patient's symptomatic and clinical recovery following thiamine therapy.

Puffer Fish Poisoning: a Potentially Life-threatening Condition

The Medical Journal of Australia. Dec 2-16, 2002  |  Pubmed ID: 12463990

Puffer fish poisoning has been documented rarely in Australia. It results from ingesting tetrodoxtoxin found in the liver, ovaries, intestines and skin of the fish. Over a recent 16-month period, 11 cases of puffer fish poisoning were reported to the NSW Poisons Information Centre. Symptoms of poisoning may include paralysis, respiratory failure, numbness, paraesthesia, nausea and ataxia. Health professionals should be aware of the condition so as to institute early and appropriate management.

Motor Neurone Disease: a Pandora's Box

The Medical Journal of Australia. Apr, 2003  |  Pubmed ID: 12670269

Has Potassium Been Prematurely Discarded As a Contributing Factor to the Development of Uraemic Neuropathy?

Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. May, 2004  |  Pubmed ID: 14993482

Nerve Excitability Properties in Lower-limb Motor Axons: Evidence for a Length-dependent Gradient

Muscle & Nerve. May, 2004  |  Pubmed ID: 15116367

In this study, nerve excitability protocols were adapted for lower-limb recordings in 25 healthy subjects to enable comparison of excitability parameters between proximal and distal recording sites of the same nerve and between different nerves. Excitability parameters (stimulus-response curves, strength-duration properties, threshold electrotonus, a current-threshold relationship, and the recovery cycle) were recorded from tibialis anterior, extensor digitorum brevis, and abductor hallucis. Excitability recordings were technically possible from each site, and normative values were established for lower-limb nerves. In this process, inter- and intranerve differences in excitability properties were demonstrated: stimulus intensity and rheobase were reduced in recordings from proximal sites; the relative refractory period and late subexcitability were increased; superexcitability was reduced; and a relative "fanning-in" occurred for threshold electrotonus curves recorded from proximal sites. Such a length-dependent gradient in nerve excitability may underlie the greater tendency for ectopic activity to arise from the proximal segments of motor axons and may contribute to the length-dependent involvement of motor axons in the development of peripheral neuropathy.

Mitochondrial Dysfunction and Rod-like Lesions Associated with Administration of Beta2 Adrenoceptor Agonist Formoterol

Neuromuscular Disorders : NMD. Jun, 2004  |  Pubmed ID: 15145339

Formoterol, a selective beta 2-adrenoceptor agonist, has been introduced recently in the treatment of poorly controlled asthma. A patient is presented who developed myalgia and muscle weakness, associated with an elevation of creatine kinase (CK) during treatment with formoterol. Subsequent muscle biopsy demonstrated atrophic fibres lacking cytochrome C-oxidase and succinate dehydrogenase, suggestive of mitochondrial dysfunction. There were no inflammatory changes. Immunocytochemical analysis using antibodies to alpha-actinin-2 and alpha-actinin-3 demonstrated positive staining of 'rod-like' bodies in atrophic fibres. Clinical and biochemical improvement occurred following withdrawal of formoterol. Possible mechanisms involved in the development of myopathy are explored.

Differences in Activity-dependent Hyperpolarization in Human Sensory and Motor Axons

The Journal of Physiology. Jul, 2004  |  Pubmed ID: 15146048

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 approximately 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.

Cytoplasmic Body Myopathy Masquerading As Motor Neuron Disease

Muscle & Nerve. Nov, 2004  |  Pubmed ID: 15389660

Cytoplasmic body myopathy (CBM) is characterized by proteinaceous inclusion bodies in muscle tissue. A 43-year-old woman presented with rapidly progressive weakness and dysphagia. Electromyography (EMG) elsewhere demonstrated lower-limb chronic partial denervation. Muscle biopsy showed fiber size variation without diagnostic features. A diagnosis of possible motor neuron disease was made and the patient was commenced on riluzole. Subsequently, the patient's condition stabilized, prompting reassessment. Repeat EMG demonstrated no features of denervation and was more suggestive of a myopathic process. Review of the original muscle biopsy showed cytoplasmic bodies. The case highlights a further diagnostic possibility in the assessment of patients with "possible" motor neuron disease. The clinical features of CBM are briefly reviewed.

Excitability Differences in Lower-limb Motor Axons During and After Ischemia

Muscle & Nerve. Feb, 2005  |  Pubmed ID: 15609346

Neuropathic diseases typically begin distally and spread proximally. Irrespective of the etiology, pathological investigations often indicate changes consistent with ischemia. In the present study, threshold tracking was used to investigate length-dependent differences in ischemic susceptibility of lower-limb axons in 6 healthy volunteers, with ischemia induced by a sphygmomanometer cuff inflated to 200 mm Hg and maintained for 13 minutes. Following stimulation of the peroneal nerve at the fibula neck, compound muscle action potentials were recorded proximally from tibialis anterior (TA) and distally from extensor digitorum brevis (EDB). During ischemia, excitability changes were consistent with nerve depolarization, with a greater reduction in threshold in EDB than TA. This reduction in threshold was associated with an increase in refractoriness, decrease in superexcitability, and prolongation of strength-duration time constant, consistent with axonal depolarization. With release of ischemia, reversal of these changes was associated with an increase in threshold, greater in EDB than TA, indicating axonal hyperpolarization. The rate of recovery of threshold was similar proximally and distally, arguing against a gradient in Na(+)/K(+) pump function along the peroneal nerve. The greater changes in threshold in EDB during and after ischemia suggest an increased susceptibility of more distal axons to ischemia and are likely to contribute to the length-dependent development of neuropathy.

Acute Tetrodotoxin-induced Neurotoxicity After Ingestion of Puffer Fish

Annals of Neurology. Mar, 2005  |  Pubmed ID: 15732107

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 (tau(SD)), 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 tau(SD) 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.

Segmental Facial Anhidrosis and Tonic Pupils with Preserved Deep Tendon Reflexes: a Novel Autonomic Neuropathy

Journal of Neuro-ophthalmology : the Official Journal of the North American Neuro-Ophthalmology Society. Mar, 2005  |  Pubmed ID: 15756124

A 31-year-old woman had exertional right-sided hemifacial flushing and sweating. Examination demonstrated slightly dilated pupils with absent constriction to light and a tonic near response and redilatation, features consistent with Adie syndrome. Neurological examination was otherwise normal, including preservation of deep tendon reflexes. Magnetic resonance imaging of brain and spine were normal. The combination of unilateral loss of sudomotor and vasomotor activity without loss of ocular sympathetic innervation fulfills the diagnosis of Harlequin syndrome. The combination of Harlequin and Adie syndromes has been called Ross syndrome, but the preservation of deep tendon reflexes precludes a diagnosis of Ross syndrome in our patient. This previously undescribed variant adds further complexity to the spectrum of autonomic neuropathies.

Altered Nerve Excitability Properties in Established Diabetic Neuropathy

Brain : a Journal of Neurology. May, 2005  |  Pubmed ID: 15758031

The underlying cause of diabetic neuropathy remains unclear, although pathological studies have suggested an ischaemic basis related to microangiopathy, possibly mediated through effects on the energy-dependent Na+/K+ pump. To investigate the pathophysiology of diabetic neuropathy, axonal excitability techniques were undertaken in 20 diabetic patients with neuropathy severity graded through a combination of quantitative sensory testing (QST) using a vibratory stimulus, assessment of symptom severity using the Total Neuropathy Symptom Score (T-NSS) and measurement of glycosylated haemoglobin as a marker of disease control. To assess axonal excitability, compound muscle action potentials were recorded at rest from abductor pollicis brevis following stimulation of the median nerve, and stimulus-response behaviour, threshold electrotonus, a current-threshold relationship and the recovery of excitability were recorded in each patient. All patients had established neuropathy, with abnormalities of T-NSS present in all patients and QST abnormalities present in 65%. Compared with controls, diabetic neuropathy patients had significant reduction in maximal CMAP amplitude (P < 0.0005), accompanied by a 'fanning in' of threshold electrotonus. In addition, the strength-duration time constant was decreased in diabetic neuropathy patients and recovery cycles were altered with reductions in refractoriness, the duration of the relative refractory period, superexcitability and subexcitability. It is proposed that while the changes in threshold electrotonus with supportive findings in the current-threshold relationship are consistent with axonal depolarization, possibly mediated by a decrease in Na+/K+ pump activity, the alterations in the recovery cycle of excitability could be explained on the basis of a smaller action potential, reflecting a limitation on the nodal driving current imposed by a reduction in Na+ conductances.

Neurotoxic Marine Poisoning

Lancet Neurology. Apr, 2005  |  Pubmed ID: 15778101

Marine poisoning results from the ingestion of marine animals that contain toxic substances and causes substantial illness in coastal regions. Three main clinical syndromes of marine poisoning have important neurological symptoms-ciguatera, tetrodotoxin poisoning, and paralytic shellfish poisoning. Ciguatera is the commonest syndrome of marine poisoning and is characterised by moderate to severe gastrointestinal effects (vomiting, diarrhoea, and abdominal cramps) and neurological effects (myalgia, paraesthesia, cold allodynia, and ataxia), but is rarely lethal. Tetrodotoxin poisoning and paralytic shellfish poisoning are less common but have a higher fatality rate than ciguatera. Mild gastrointestinal effects and a descending paralysis are characteristic of these types of poisoning. In severe poisoning, paralysis rapidly progresses to respiratory failure. Diagnosis of all types of marine poisoning is made from the circumstances of ingestion (type of fish and location) and the clinical effects. Because there are no antidotes, supportive care, including mechanical ventilation in patients with severe paralysis, is the mainstay of treatment.

Assessment of Disease Progression in Motor Neuron Disease

Lancet Neurology. Apr, 2005  |  Pubmed ID: 15778102

Motor neuron disease (MND) is characterised by progressive deterioration of the corticospinal tract, brainstem, and anterior horn cells of the spinal cord. There is no pathognomonic test for the diagnosis of MND, and physicians rely on clinical criteria-upper and lower motor neuron signs-for diagnosis. The presentations, clinical phenotypes, and outcomes of MND are diverse and have not been combined into a marker of disease progression. No single algorithm combines the findings of functional assessments and rating scales, such as those that assess quality of life, with biological markers of disease activity and findings from imaging and neurophysiological assessments. Here, we critically appraise developments in each of these areas and discuss the potential of such measures to be included in the future assessment of disease progression in patients with MND.

Riluzole: a Glimmer of Hope in the Treatment of Motor Neurone Disease

The Medical Journal of Australia. Apr, 2005  |  Pubmed ID: 15804220

Early experience confirms that riluzole improves survival and is well tolerated.

Mutation in the Na+ Channel Subunit SCN1B Produces Paradoxical Changes in Peripheral Nerve Excitability

Brain : a Journal of Neurology. Aug, 2005  |  Pubmed ID: 15857929

To determine the effect of an established mutation of the beta1 subunit of Na(+) channels on nerve excitability, studies were undertaken in patients diagnosed with generalized epilepsy with febrile seizures plus (GEFS+). Multiple nerve excitability measurements were used to investigate the membrane properties of sensory and motor axons in five patients (aged 18-55 years) who were currently experiencing no seizures and were not on anticonvulsants. There was no history of paraesthesiae, fasciculation or cramps to suggest hyperexcitability of peripheral nerve axons. The median nerve was stimulated at the wrist, and compound muscle action potentials (CMAPs) were recorded from abductor pollicis brevis and the antidromic compound sensory nerve action potential (CSAPs) from digit 2. Stimulus-response behaviour, strength-duration time constant, threshold electrotonus, current-threshold relationship and the recovery of excitability following a supramaximal conditioning stimulus were recorded using threshold tracking. Compared with normal controls (n = 29), the axons of patients were of higher threshold. CMAPs and CSAPs were relatively small, although individual values remained within the normal ranges. Refractoriness and relative refractory period (markers of transient Na(+) channel function) were significantly reduced in GEFS+ patients with established mutations in SCN1B (P < 0.05), and strength-duration time constants (dependent on persistent Na(+) conductances) were reduced. It is suggested that, in peripheral nerve axons, the mutation underlying GEFS+ reduces the number of functioning Na(+) channels at the node of Ranvier and that this rather than any change in gating of individual channels dominates axonal excitability in these patients.

Oxaliplatin-induced Neurotoxicity and the Development of Neuropathy

Muscle & Nerve. Jul, 2005  |  Pubmed ID: 15880395

The pathophysiology of oxaliplatin-induced neurotoxicity remains unclear, although in vitro studies suggest involvement of voltage-gated Na+ channels. In the present study, clinical assessment was combined with nerve conduction studies (NCS) and nerve excitability studies in 16 patients after completion of oxaliplatin therapy. Chronic neuropathic symptoms persisted in 50% of patients. NCS confirmed abnormalities in symptomatic patients: sensory potentials were significantly low, whereas motor studies remained essentially normal. At 12-month follow-up of symptomatic patients, positive sensory symptoms improved but NCS abnormalities persisted. Cumulative oxaliplatin dose was a predictor of neuropathy, and long-term effects appeared to be minimized by low single-infusion dosages. Nerve excitability measures in symptomatic patients established that axons were of high threshold. Refractoriness was significantly greater in patients (symptomatic group, 56.3 +/- 24.9%; entire patient group, 46.3 +/- 12.5%; controls, 27.1 +/- 1.9%; P < 0.05). Thus, although positive sensory symptoms of oxaliplatin-induced neuropathy improved, negative sensory symptoms and abnormalities of sensory nerve conduction persisted. Differences in nerve excitability measures, particularly refractoriness, support in vitro studies indicating involvement of voltage-gated transient Na+-channel dysfunction in the development of oxaliplatin-induced neurotoxicity.

Altered Motor Nerve Excitability in End-stage Kidney Disease

Brain : a Journal of Neurology. Sep, 2005  |  Pubmed ID: 15947058

Although multiple toxins have been implicated in the development of uraemic neuropathy, no causative agent has been identified. In the present study, the excitability properties of lower limb motor nerves in patients with end-stage kidney disease treated with haemodialysis were measured before, during and after a standard 5 h haemodialysis session, in an attempt to explore the pathophysiology of uraemic neuropathy. Compound muscle action potentials were recorded from tibialis anterior and extensor digitorum brevis, following stimulation of the common peroneal nerve in 14 patients. Measures of excitability were assessed in relation to changes in serum levels of potential neurotoxins, including potassium, calcium, urea, uric acid, parathyroid hormone and beta-2-microglobulin. Before dialysis, measures of nerve excitability were significantly abnormal in the patient group for axons innervating tibialis anterior and extensor digitorum brevis, consistent with axonal depolarization: refractoriness was increased and superexcitability and depolarizing threshold electrotonus were reduced. Pre-dialysis excitability abnormalities were strongly correlated with serum K+. Correlation was also noted between the severity of symptoms and excitability abnormalities. Haemodialysis normalized the majority of nerve excitability parameters. In conclusion, lower limb motor axons in uraemic patients are depolarized before dialysis. The correlation between serum K+ and excitability measures indicates that hyperkalaemia is primarily responsible for uraemic depolarization, and a likely contributing factor to the development of neuropathy.

Hypokalemic Weakness in Hyperaldosteronism: Activity-dependent Conduction Block

Neurology. Oct, 2005  |  Pubmed ID: 16247066

The authors describe a 48-year-old man who presented with acute weakness. Serum K+ was 1.7 mmol/L, and investigations established hyperaldosteronism. Nerve excitability studies during hypokalemia demonstrated that axons were of high threshold with a fanning out of threshold electrotonus, consistent with hyperpolarization. Activity-dependent conduction block was induced by voluntary contraction. Excitability abnormalities resolved with K+ replacement. Activity-dependent conduction block induced by normal activity may contribute to weakness and paralysis developing with hypokalemia.

Assessment of Cortical Excitability Using Threshold Tracking Techniques

Muscle & Nerve. Apr, 2006  |  Pubmed ID: 16315324

Conventional paired-pulse transcranial magnetic stimulation (TMS) techniques of assessing cortical excitability are limited by fluctuations in the motor evoked potential (MEP) amplitude. The aim of the present study was to determine the feasibility of threshold tracking TMS for assessing cortical excitability in a clinical setting and to establish normative data. Studies were undertaken in 26 healthy controls, tracking the MEP response from abductor pollicis brevis. Short-interval intracortical inhibition (SICI) occurred up to an interstimulus interval (ISI) of 7-10 ms, with two distinct peaks evident, at ISIs of < or =1 and 3 ms, followed by intracortical facilitation to an ISI of 30 ms. Long-interval intracortical inhibition (LICI) occurred at ISIs of 50-300 ms, peaking at 150 ms. The present study has confirmed the effectiveness of the threshold tracking TMS technique in reliably and reproducibly measuring cortical excitability. Simultaneous assessment of upper and lower motor neuronal function with threshold tracking techniques may help to determine the site of disease onset and patterns of progression in neurodegenerative diseases.

Riluzole Therapy for Motor Neurone Disease: an Early Australian Experience (1996-2002)

Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. Jan, 2006  |  Pubmed ID: 16410201

Riluzole is the only therapy proven in clinical trials to prolong survival in patients with motor neurone disease (MND). Prior to its listing by the Australian Pharmaceutical Benefits Advisory Scheme in June 2003, the aim of the present study was to provide Australian patients with MND early access to riluzole and to expand the safety profile data of this therapy. Patients with MND were referred to the programme by neurologists covering the Sydney metropolitan region. To be eligible to receive riluzole, patients had to be aged between 18 and 75 years and have probable or definite MND based on El Escorial criteria, with a disease duration of less than 5 years and a vital capacity greater than 60% before study entry. Patients were prescribed riluzole 50 mg twice daily. Safety data were collected through documentation of adverse events by clinical history in combination with regular laboratory screening. Full blood count, haematocrit, differential white cell counts and serum liver transaminase levels were obtained monthly for 3 months, and then at each 3-monthly visit for 1 year. In total, 25 patients with MND (17 male, 8 female; age range 40-74 years; mean age 59 years) were commenced on riluzole. Of these, 28% had definite MND and the remaining 72% were diagnosed as probable MND, with the majority (84%) having limb-onset MND. At 12 months, 68% of patients continued on riluzole, 16% had died from their disease and 16% ceased riluzole because of side-effects or other reasons, largely disenchantment owing to a perceived lack of efficacy. Haematological and biochemical assays showed no significant alteration during the initial 12-month period. Long-term survival data for patients in the present series suggest a greater benefit for patients who commenced riluzole early in the course of their illness. In conclusion, riluzole was generally tolerated well by Australian patients with MND. Of the few patients who experienced side-effects attributed to riluzole, all were reversible. Issues related to patient perceptions of efficacy highlight the need for patients and treating physicians to maintain realistic expectations of riluzole therapy.

Axonal Function and Activity-dependent Excitability Changes in Myotonic Dystrophy

Muscle & Nerve. May, 2006  |  Pubmed ID: 16453325

To investigate peripheral nerve function and its potential contribution to symptoms of weakness in myotonic dystrophy type 1 (MD), nerve excitability was assessed in 12 MD patients. Compound muscle action potentials (CMAPs) were recorded at rest from abductor pollicis brevis (APB) following stimulation of the median nerve. Stimulus-response behavior, threshold electrotonus, a current-threshold relationship, and recovery cycles were successfully recorded in each patient. Compared with controls, there was significant reduction in CMAP amplitude in MD patients. This was accompanied by reduction in depolarizing threshold electrotonus and an increase in refractoriness and in the duration of the relative refractory period. To determine whether alteration in axonal resting membrane potential was a factor underlying these changes, axonal excitability was assessed following maximal contraction of APB for 60 seconds. Following contraction, there was reduction in CMAP amplitude for a submaximal stimulus (by 51.5+/-11.8%) and an increase in super-excitability (of 22.2+/-12.0%), consistent with activity-dependent hyperpolarization, with a greater increase in threshold for MD patients compared to controls (MD group, 22.3+/-5.1%; controls, 11.7+/-2.1%; P<0.04) and prolonged recovery to baseline. The present study has established that greater activity-dependent changes in excitability may be induced in MD patients by maximal voluntary contraction when compared to controls. The excitability changes and prolonged recovery of threshold following contraction are likely to contribute to symptoms of fatigue and weakness in MD patients.

Back to the Future: Excitability Studies Take on a New Clinical Role

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Apr, 2006  |  Pubmed ID: 16497553

Neuropathy, Axonal Na+/K+ Pump Function and Activity-dependent Excitability Changes in End-stage Kidney Disease

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. May, 2006  |  Pubmed ID: 16516547

To investigate the mechanisms underlying peripheral neuropathy and to provide insights into axonal Na(+)/K(+) pump function in patients with end-stage kidney disease (ESKD).

Paraneoplastic Mononeuritis Multiplex in Non-small-cell Lung Carcinoma

Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. Jun, 2006  |  Pubmed ID: 16564174

A 60-year-old man developed two selective peripheral mononeuropathies of the peroneal and later the radial nerve, shortly after a diagnosis of large-cell lung carcinoma. Nerve conduction studies and electromyography confirmed isolated lesions in both nerves, and in the case of the peroneal nerve lesion, focal conduction block was localised to the level of the fibula neck. Subsequent magnetic resonance imaging of the lower limb excluded focal compression or malignant infiltration along the course of the peroneal nerve, and there was no signal change within the nerve, prompting a diagnosis of paraneoplastic mononeuritis multiplex. Anti-neuronal antibodies and serological markers of systemic vasculitis were negative. Neither the patient's large-cell lung carcinoma nor mononeuritis multiplex responded to chemotherapy, and he died within 6 months of the initial diagnosis.

Establishment of an Australian Motor Neurone Disease Registry

The Medical Journal of Australia. Apr, 2006  |  Pubmed ID: 16584377

Ischaemia Induces Paradoxical Changes in Axonal Excitability in End-stage Kidney Disease

Brain : a Journal of Neurology. Jun, 2006  |  Pubmed ID: 16636020

Peripheral neuropathy is present in 65% of patients with end-stage kidney disease (ESKD). No cause is yet established: nerve excitability studies have shown that axons are chronically depolarized, primarily owing to hyperkalaemia, but in vitro studies have suggested a role for axonal Na+/K+ pump dysfunction. To investigate Na+/K+ pump activity in vivo, lower limb ischaemia was induced in five ESKD patients and six healthy controls by a sphygmomanometer cuff, inflated to 200 mm Hg and maintained for 13 min. The peroneal nerve was stimulated at the fibular neck and excitability parameters were recorded from tibialis anterior (TA) and extensor digitorum brevis (EDB) before, during and after the ischaemic period. Baseline excitability studies in ESKD patients demonstrated reductions in threshold electrotonus and superexcitability and increased refractoriness, consistent with membrane depolarization. During ischaemia, threshold increased in ESKD patients [by +23.6 +/- 5.0% (TA); +32.1 +/- 7.3% (EDB)] in contrast to the persistent threshold reduction observed in normal controls [-2.4 +/- 5.2% (TA); -13.0 +/- 8.2% (EDB); P < 0.01]. These changes were accompanied by increased refractoriness and reduced superexcitability in both ESKD and control groups, consistent with ischaemic depolarization. Conversely, there was reduction in strength-duration time constant towards the end of ischaemia. Following release of ischaemia, the marked increase in threshold observed in normal controls was not evident in ESKD patients, but the rapid return of threshold to baseline argues against significant Na+/K+ pump dysfunction. The abnormal pattern of response to ischaemia in the ESKD patients was not fully explained by the hyperkalaemic membrane depolarization and suggests that another dialysable factor affects nerve excitability in ESKD patients, most likely H(+) ions, but that this factor only becomes evident during ischaemia. Blockade of persistent Na+ conductances by H+ would also explain the reduction in strength-duration time constant observed during ischaemia.

Focal and Generalized Peripheral Nerve Dysfunction in Spinal Cord-injured Patients

Journal of Clinical Neurophysiology : Official Publication of the American Electroencephalographic Society. Jun, 2006  |  Pubmed ID: 16751729

SUMMARY: The present study was undertaken to quantitate the incidence and clinical patterns of peripheral nerve dysfunction distal to the level of injury in patients with spinal cord injury (SCI). Through retrospective analysis, SCI patients were identified after referral for neurophysiologic investigation of new neuropathic symptoms. In total, peripheral nerve or nerve root lesions developed in 34 SCI patients, most commonly within the first year after SCI. Carpal tunnel syndrome was the most common upper-limb neuropathy (34%); sciatic neuropathy was the most common lower-limb abnormality (8.5%). A significant proportion of SCI patients had neurophysiological evidence of generalized peripheral nerve dysfunction, specifically axonal neuropathy (18%). Tetraplegic patients developed more frequent peripheral nerve lesions than paraplegics. Although most SCI patients presented within 4 years of their original injury, in a more chronic population of SCI patients that developed neuropathy 5 years after injury, 60% had evidence of coexistent syrinx formation. Maintenance of peripheral nerve function is a critical issue in all acute SCI and rehabilitation units, particularly in the context of spinal cord neuronal regeneration projects.

Axonal Excitability Properties in Amyotrophic Lateral Sclerosis

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Jul, 2006  |  Pubmed ID: 16759905

To investigate axolemmal ion channel function in patients diagnosed with sporadic amyotrophic lateral sclerosis (ALS).

Novel Threshold Tracking Techniques Suggest That Cortical Hyperexcitability is an Early Feature of Motor Neuron Disease

Brain : a Journal of Neurology. Sep, 2006  |  Pubmed ID: 16835248

The dying forward hypothesis of motor neuron disease (MND) suggests that corticomotoneurons induce excitotoxic anterior horn cell death, with involvement of the glutamatergic neurotransmitter system. The aim of the present study was to apply novel threshold tracking transcranial magnetic stimulation (TMS) techniques in conjunction with peripheral nerve excitability studies in MND patients to further investigate the dying forward hypothesis and possibly determine the site of disease onset. Studies were undertaken in 23 MND patients using a 90-mm circular coil connected to a BiStim magnetic stimulator for cortical studies and electrical stimulation for peripheral nerve excitability studies. Motor-evoked potentials and compound muscle action potentials (CMAPs) were recorded from the right abductor pollicis brevis in the same setting. Measures of cortical and peripheral nerve excitability were correlated with clinical and neurophysiological parameters of disease severity. Short-interval intracortical inhibition (SICI) was significantly reduced in MND patients compared with controls (MND group = 3.6 +/- 0.8%; controls = 8.5 +/- 1.0%, P < 0.001), most prominently in MND patients with limb-onset disease. Changes in intracortical inhibition were accompanied by alterations in the magnetic stimulus-response curve, cortical silent period duration and resting motor threshold, all indicative of cortical hyperexcitability. Although the reduction in SICI was more pronounced in MND patients with less severe disease, as assessed by the CMAP amplitude, it remained evident even in MND patients with advanced disease. Measures of peripheral disease burden, namely the CMAP amplitude (r = -0.6) and neurophysiological index (r = -0.6), correlated with cortical hyperexcitability changes, as did the strength-duration time constant (r = -0.6), a peripheral marker of axonal excitability. Simultaneous assessment of central and peripheral nerve excitability has established the presence of co-existent upper and lower motor neuron dysfunction, with cortical hyperexcitability an early feature in MND.

Activity-induced Weakness in Recessive Myotonia Congenita with a Novel (696+1G>A) Mutation

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Sep, 2006  |  Pubmed ID: 16854622

To investigate the cause of the transient weakness that occurs in recessive myotonia congenita (RMC) following sustained muscle contraction.

Oxaliplatin and Axonal Na+ Channel Function in Vivo

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Aug, 2006  |  Pubmed ID: 16899592

The aim of the study was to investigate the pathophysiology of oxaliplatin-induced neurotoxicity using clinical nerve excitability techniques that provide information about axonal ion channel function.

The Pathophysiology of Oxaliplatin-induced Neurotoxicity

Current Medicinal Chemistry. 2006  |  Pubmed ID: 17073636

Nerve dysfunction is a common accompaniment of chemotherapy, typically occurring in a dose-dependent manner, so that the higher the dose and the longer the time of exposure, the more likely neuropathy is to occur. With the majority of chemotherapies, the mechanisms of neurotoxicity have not been clearly established. Cessation of therapy may prevent progression to a more severe syndrome and is often necessary even if there has been tumour response. Alternatively dose reduction may slow or halt progression. The clinical investigation of patients with suspected nerve dysfunction related to chemotherapy remains problematic. While routine nerve conduction studies can document the presence of a neuropathy, they do not provide further insight into pathophysiology. In contrast, measurements of nerve excitability by threshold tracking provide complementary information to conventional nerve conduction studies and may be used to infer the activity of a variety of ion channels, energy-dependent pumps and ion exchange processes activated during the process of impulse conduction. The present review will focus on recent developments in clinical rating scales and novel neurophysiological methods for the clinical investigation of chemotherapy-induced neurotoxicity, and will highlight how such methods may prove useful to study the neurological effects of chemotherapy. Specific emphasis will be placed on oxaliplatin, a platinum-based chemotherapy effective for colorectal cancer that exhibits dose-limiting neurotoxicity.

Reversible Myeloradiculopathy Due to Mycoplasma Pneumoniae

Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. Jan, 2007  |  Pubmed ID: 17092721

A 22-year-old man presented with flaccid paraparesis and a thoracic sensory level in the context of a recent respiratory illness. Investigations established cerebrospinal pleocytosis with elevated protein, and subsequent serological testing confirmed raised antibody titres to Mycoplasma pneumoniae. Nerve conduction studies established that H-reflexes were prolonged and somatosensory evoked responses were delayed from the lower limbs bilaterally. Although imaging of the spinal cord revealed no abnormality, clinical and neurophysiological findings were consistent with a myeloradiculopathy. The patient was treated with pulse intravenous methylprednisone and underwent complete recovery over a 4-week period.

Uremic Neuropathy: Clinical Features and New Pathophysiological Insights

Muscle & Nerve. Mar, 2007  |  Pubmed ID: 17195171

Neuropathy is a common complication of end-stage kidney disease (ESKD), typically presenting as a distal symmetrical process with greater lower-limb than upper-limb involvement. The condition is of insidious onset, progressing over months. and has been estimated to be present in 60%-100% of patients on dialysis. Neuropathy generally only develops at glomerular filtration rates of less than 12 ml/min. The most frequent clinical features reflect large-fiber involvement, with paresthesias, reduction in deep tendon reflexes, impaired vibration sense, muscle wasting, and weakness. Nerve conduction studies demonstrate findings consistent with a generalized neuropathy of the axonal type. Patients may also develop autonomic features, with postural hypotension, impaired sweating, diarrhea, constipation, or impotence. The development of uremic neuropathy has been related previously to the retention of neurotoxic molecules in the middle molecular range, although this hypothesis lacked formal proof. Studies utilizing novel axonal excitability techniques have recently shed further light on the pathophysiology of this condition. Nerves of uremic patients have been shown to exist in a chronically depolarized state prior to dialysis, with subsequent improvement and normalization of resting membrane potential after dialysis. The degree of depolarization correlates with serum K(+), suggesting that chronic hyperkalemic depolarization plays an important role in the development of nerve dysfunction in ESKD. These recent findings suggest that maintenance of serum K(+) within normal limits between periods of dialysis, rather than simple avoidance of hyperkalemia, is likely to reduce the incidence and severity of uremic neuropathy.

Abnormalities in Cortical and Peripheral Excitability in Flail Arm Variant Amyotrophic Lateral Sclerosis

Journal of Neurology, Neurosurgery, and Psychiatry. Aug, 2007  |  Pubmed ID: 17210625

While some regard the flail arm syndrome as a variant of amyotrophic lateral sclerosis (ALS), others have argued that it is a distinct clinical entity. Consequently, the present study applied novel central and peripheral nerve excitability techniques to further explore disease pathophysiology in flail arm syndrome.

Axonal Changes in Spinal Cord Injured Patients Distal to the Site of Injury

Brain : a Journal of Neurology. Apr, 2007  |  Pubmed ID: 17264094

It is generally assumed that the peripheral nervous system remains intact following a spinal injury. Accordingly, the electrical thresholds of motor axons in a peripheral nerve below the lesion should be similar to those in intact subjects. Yet in attempts to enter the common peroneal nerve with microelectrodes in 24 quadriplegic or paraplegic individuals it was often found that electrical stimulation over or within the nerve failed to elicit contractions in the pre-tibial flexors. To investigate whether consistent changes in axonal physiology occurred distal to the site of injury in patients with spinal cord injury (SCI), motor nerve excitability was formally tested in 15 of these patients. Threshold tracking techniques were used to measure axonal excitability parameters (stimulus-response curves, strength-duration properties, threshold electrotonus, a current-threshold relationship and the recovery cycle) of motor axons in the median and common peroneal nerves. In these patients motor axons were uniformly of high threshold and consequently, stimulus-response curves were shifted to the right. In some SCI patients, axons were completely inexcitable. Amplitudes of compound motor action potentials were reduced, consistent with axonal loss and strength-duration time constant was significantly reduced in SCI patients (SCI 0.13 +/- 0.02 ms, controls 0.43 +/- 0.02 ms, mean +/- SE, P < 0.0001). Excitability changes were more prominent the more clinically severe the injury, with progressive deterioration over time since the original injury. While compression and traction sustained during the original injury or subsequent hospital rehabilitation may contribute in part to some of these changes, it is difficult to attribute these findings solely to such processes. Changes in axonal structure and ion channel function, but perhaps more critically decentralization and consequent inactivity, are likely to underlie the complex changes observed in axonal excitability in SCI patients.

Riche-Cannieu Anastomosis As an Inherited Trait

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Apr, 2007  |  Pubmed ID: 17317302

To explore the basis for the Riche-Cannieu anastomosis (RCA) and specifically whether this anomaly is an hereditary characteristic.

Fatigue and Activity Dependent Changes in Axonal Excitability in Amyotrophic Lateral Sclerosis

Journal of Neurology, Neurosurgery, and Psychiatry. Nov, 2007  |  Pubmed ID: 17371901

While patients with amyotrophic lateral sclerosis (ALS) may complain of fatigue, the underlying mechanisms appear complex, with dysfunction of central and peripheral nervous systems independently reported as contributing factors. The aim of the present study was to further delineate the mechanisms underlying increased fatigability in ALS by measuring activity dependent changes in axonal excitability following a maximum voluntary contraction (MVC).

Axonal Excitability Properties in Hemifacial Spasm

Movement Disorders : Official Journal of the Movement Disorder Society. Jul, 2007  |  Pubmed ID: 17486620

Hemifacial spasm (HFS) is characterized by involuntary, irregular contractions of muscles innervated by the facial nerve. Whether the facial nerve has a relative predisposition for ectopic activity has not been clarified. Nerve excitability techniques, which provide information about membrane potential and axonal ion channel function, were initially measured in 12 control subjects looking for biophysical differences that may predispose the facial nerve to generate ectopic activity. In a second series of studies, facial nerve excitability was assessed in nine HFS patients. In both series, stimulus-response behavior, threshold electrotonus, a current threshold relationship, and the recovery of excitability following supramaximal stimulation were recorded following stimulation of the facial nerve. When compared to normative data from nerves in the upper and lower limbs, there was a relative "fanning-in" of threshold electrotonus, reduced superexcitability, and increased subexcitability in facial nerve studies from control subjects (P < 0.05), consistent with relative axonal depolarization. These findings may underlie the propensity for the facial nerve to develop ectopic impulse activity in motor axons. In the HFS patient study, there were no significant differences in distal facial nerve excitability properties from the affected side in HFS patients when compared either to the unaffected side or to normative facial nerve data. It is concluded that the impulse generator underlying HFS must consequently be sited more proximally and does not cause a generalized disturbance of motor axon excitability.

Inflections in Threshold Electrotonus to Depolarizing Currents in Sensory Axons

Muscle & Nerve. Dec, 2007  |  Pubmed ID: 17654562

Threshold electrotonus involves tracking the changes in axonal excitability produced by subthreshold polarizing currents and is the only technique that allows insight into the function of internodal conductances in human subjects in vivo. There is often an abrupt transient reversal of the threshold change as excitability increases in response to conditioning depolarizing currents (S1 phase). In recordings from motor axons, it has been recently demonstrated that this notch or inflection is due to activation of low-threshold axons. We report that a notch is frequently seen in sensory recordings (in 33 of 50 healthy subjects) using the standard threshold electrotonus protocol. When large, the notch can distort subsequent phases of threshold electrotonus and could complicate quantitative measurements and modeling studies.

The Pain with Platinum: Oxaliplatin and Neuropathy

European Journal of Cancer (Oxford, England : 1990). Dec, 2007  |  Pubmed ID: 17977714

Pathophysiologic Insights into Motor Axonal Function in Kennedy Disease

Neurology. Nov, 2007  |  Pubmed ID: 17984450

Kennedy disease (KD), or spinobulbomuscular atrophy, is a slowly progressive inherited neurodegenerative disorder, marked by prominent fasciculations that typically precede the development of other symptoms. Although the genetic basis of KD relates to triplet (CAG) repeat expansion in the androgen receptor (AR) gene on the X chromosome, the mechanisms underlying the clinical presentation in KD have yet to be established. Consequently, the present study applied axonal excitability techniques to investigate the pathophysiologic mechanisms associated with KD.

Cortical Excitability Testing Distinguishes Kennedy's Disease from Amyotrophic Lateral Sclerosis

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. May, 2008  |  Pubmed ID: 18313980

Spinobulbomuscular atrophy, or Kennedy's disease (KD), is an X-linked inherited neurodegenerative disorder that clinically may "mimic" amyotrophic lateral sclerosis (ALS). Although KD is regarded as a pure lower motor neuron disorder, recent studies have reported on the presence of corticomotoneuron dysfunction in KD, similar to ALS. To clarify these discordant findings, the present study applied novel threshold tracking transcranial magnetic stimulation (TMS) techniques to gain further insights into corticomotoneuron function and thereby possible pathophysiological processes underlying neurodegeneration in KD.

Axonal Function in a Family with Episodic Ataxia Type 2 Due to a Novel Mutation

Journal of Neurology. May, 2008  |  Pubmed ID: 18338196

Episodic ataxia type 2(EA-2) is a rare, autosomal dominant disorder characterised by recurrent episodes of ataxia and dysarthria,due to mutations in the CACNA1A gene on chromosome 19 encoding voltage-dependent Ca2+ channels. The aim of the present study was to explore whether axonal membrane properties, assessed using nerve excitability techniques, were abnormal in patients with EA-2 . Nerve excitability techniques were applied to the median nerve of three individuals from three generations of a single family, all of whom had typical features of EA-2. This family was found to have a novel mutation at codon 1451 of the Ca2+ channel alpha 1A subunit. Nerve excitability testing demonstrated significant abnormalities,with all patients outside the normal 95 % confidence limits in having a high rheobase and reduced early hyperpolarizing threshold electrotonus. On average there were also significant reductions in refractoriness,late sub excitability and early depolarizing threshold electrotonus. Mathematical modelling indicated that a similar pattern of abnormalities may result from a reduced voltage dependence of slow K+ channels (KCNQ channels). There are significant and distinctive changes in peripheral nerve excitability in EA-2 patients,which are presumably induced indirectly. These findings raise the possibility that excitability testing may prove a convenient screening test for patients with this suspected channelopathy.

Assessment of Nerve Excitability in Toxic and Metabolic Neuropathies

Journal of the Peripheral Nervous System : JPNS. Mar, 2008  |  Pubmed ID: 18346228

Measurement of nerve excitability by threshold tracking provides complementary information to conventional nerve conduction studies and may be used to infer the activity of a variety of ion channels, energy-dependent pumps, and ion exchange processes activated during the process of impulse conduction. This review highlights recent clinical excitability studies that have suggested mechanisms for nerve involvement in a range of metabolic and toxic neuropathies. While clinical nerve excitability studies are still in their infancy, and it is too early to know whether they have diagnostic value, there is growing evidence of their utility to provide novel insights into the pathophysiological mechanisms involved in a variety of neuropathic disturbances.

Activity-dependent Excitability Changes Suggest Na+/K+ Pump Dysfunction in Diabetic Neuropathy

Brain : a Journal of Neurology. May, 2008  |  Pubmed ID: 18362098

The present study was undertaken to evaluate the role of Na(+)/K(+) pump dysfunction in the development of diabetic neuropathy (DN). Nerve excitability techniques, which provide information about membrane potential and axonal ion channel function, were undertaken in 15 patients with established DN and in 10 patients with diabetes who had no evidence of neuropathy (DWN). Excitability parameters were recorded at baseline, and then before and after 1 min of maximal voluntary contraction (MVC) of abductor pollicis brevis. Compared to controls, CMAP amplitude was significantly decreased in DN patients with associated reductions in strength-duration time constant and refractoriness, consistent with a reduction in nodal Na(+) conductances. Following MVC for 1 min, there was an increase in normalized threshold in all diabetic patients and controls, consistent with axonal hyperpolarization. When compared to control values, the increase in threshold following MVC was significantly less in DN patients (DN group 13.1 +/- 2.2%; controls 20.4 +/- 1.9%; P < 0.05) and the rate of recovery was slower (P < 0.01). In DWN patients, CMAP amplitude was preserved, and excitability values following MVC were not significantly different to control values. The reduced threshold change and slower recovery in DN patients following MVC are likely to be secondary to Na(+)/K(+) pump dysfunction. Alteration in Na(+)/K(+) pump function, coupled with reductions in nodal Na(+) currents, may be sufficient to trigger conduction failure in DN patients and are likely to contribute to the clinical symptoms of weakness and fatigue.

Paraspinal Muscles and Amyotrophic Lateral Sclerosis - Getting to the Core?

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Jul, 2008  |  Pubmed ID: 18468484

Cortical Hyperexcitability May Precede the Onset of Familial Amyotrophic Lateral Sclerosis

Brain : a Journal of Neurology. Jun, 2008  |  Pubmed ID: 18469020

Familial amyotrophic lateral sclerosis (FALS) is an inherited neurodegenerative disorder of the motor neurons. While 10-15% of cases are caused by mutations in the copper/zinc superoxide-dismutase-1 (SOD-1) gene, the dying-forward hypothesis, in which corticomotoneurons induce anterograde excitotoxic motoneuron degeneration, has been proposed as a potential mechanism. The present study applied novel threshold tracking transcranial magnetic stimulation techniques to investigate the mechanisms underlying neurodegeneration in FALS. Studies were undertaken in 14 asymptomatic and 3 pre-symptomatic SOD-1 mutation carriers, followed longitudinally for up to 3-years. The pre-symptomatic subjects were asymptomatic at the time of their initial study but developed symptoms during the follow-up period. Results were compared to 7 SOD-1 FALS patients, 50 sporadic ALS patients and 55 normal controls. Short-interval intracortical inhibition (SICI) was significantly reduced in SOD-1 FALS (-1.2 +/- 0.6%) and sporadic ALS patients (-0.7 +/- 0.3%) compared to asymptomatic SOD-1 mutation carriers (9.8 +/- 1.5%, P<0.00001) and normal controls (8.5 +/- 1.0%, P<0.00001). SICI reduction was accompanied by increases in intracortical facilitation, motor evoked potential amplitudes and the slope of the magnetic stimulus-response curve. In two pre-symptomatic SOD-1 mutation carriers SICI was completely absent (SICI patient 1, -3.2%; patients 2, -1.3%), while in one subject there was a 32% reduction in SICI prior to symptom onset. These three individuals subsequently developed clinical features of ALS. Simultaneous investigation of central and peripheral excitability has established that cortical hyperexcitability develops in clinically affected SOD-1 FALS patients, similar to that seen in sporadic ALS patients, thereby suggesting that a similar pathophysiological process in evident in both familial and sporadic ALS patients. In addition, the present study has established that cortical hyperexcitability precedes the development of clinical symptoms in pre-symptomatic carriers of the SOD1 mutation, thereby suggesting that cortical hyperexcitability underlies neurodegeneration in FALS.

Acute Cortical Blindness Due to Posterior Reversible Encephalopathy

Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. Oct, 2008  |  Pubmed ID: 18501611

An acutely hypertensive 55 year-old male experienced seizures and cortical blindness post-operatively. CT scans demonstrated hypointensities in the occipital lobes bilaterally. MRI revealed symmetrical bilateral hyperintense signals in the same region, involving both grey and white matter. Thromboembolic screening investigations including vertebral artery doppler studies were normal and echocardiography demonstrated borderline left ventricular hypertrophy. A diagnosis of posterior reversible encephalopathy syndrome (PRES) was reached and there was complete resolution of blindness with antihypertensive therapy. This case supports the vasogenic theory of PRES which suggests that sustained high grade fluctuations in blood pressure lead to a reduction in cerebral vascular autoregulatory function. The resultant failure of compensatory vasoconstriction to prevent hyperperfusion causes fluid to extravasate into the occipital lobes, which in the present case resulted in cortical blindness.

Changes in Human Sensory Axonal Excitability Induced by an Ischaemic Insult

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Sep, 2008  |  Pubmed ID: 18567535

To identify the sensitivity and the patterns of change in sensory excitability that accompany an ischaemic insult.

Nerve Function and Dysfunction in Acute Intermittent Porphyria

Brain : a Journal of Neurology. Sep, 2008  |  Pubmed ID: 18669508

Acute intermittent porphyria (AIP) is a rare metabolic disorder characterized by mutations of the porphobilinogen deaminase gene. Clinical manifestations of AIP are caused by the neurotoxic effects of increased porphyrin precursors, although the underlying pathophysiology of porphyric neuropathy remains unclear. To further investigate the neurotoxic effect of porphyrins, excitability measurements (stimulus-response, threshold electrotonus, current-threshold relationship and recovery cycle) of peripheral motor axons were undertaken in 20 AIP subjects combined with the results of genetic screening, biochemical and conventional nerve conduction studies. Compared with controls, excitability measurements from five latent AIP patients were normal, while 13 patients who experienced acute porphyric episodes without clinical neuropathy (AIPWN) showed clear differences in their responses to hyperpolarizing currents (e.g. reduced hyperpolarizing I/V slope, P < 0.01). Subsequent mathematical simulation using a model of human axons indicated that this change could be modelled by a reduction in the hyperpolarization-activated, cyclic nucleotide-dependent current (I(H)). In contrast, in one patient tested during an acute neuropathic episode, axons of high threshold with reduced superexcitability, consistent with membrane depolarization and reminiscent of ischemic changes. It is proposed that porphyrin neurotoxicity causes a subclinical reduction in I(H) in AIPWN axons, whereas porphyric neuropathy may develop when reduced activity of the Na(+)/K(+) pump results in membrane depolarization.

Changes in Axonal Excitability and Burst Pattern Behaviour in Synkinesis

Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. Nov, 2008  |  Pubmed ID: 18815044

Synkinesis after severe facial nerve paralysis has been related to the processes of aberrant reinnervation and increased excitability of the facial nucleus. We present the electrophysiological features of synkinesis in a 32-year-old woman who developed grouped 'myokymic-like' discharges with eye blinking in the absence of spontaneous muscle activity. With eye blinks, the interspike intervals of discharges in the orbicularis oris varied between 25-150Hz, overlapping with rates of myokymia and neuromyotonia. Analysis of the discharge patterns in the present case suggests that synkinesis reflects aberrant regeneration with effects mediated by properties of axonal excitability that determine the burst pattern characteristics.

Normal Axonal Ion Channel Function in Large Peripheral Nerve Fibers Following Chronic Ciguatera Sensitization

Muscle & Nerve. Mar, 2008  |  Pubmed ID: 17941032

Although the acute clinical effects of ciguatera poisoning, due to ingestion of ciguatoxin, are mediated by activation of transient Na+ channels, the mechanisms underlying ciguatera sensitization remain undefined. Axonal excitability studies were performed by stimulating the median motor and sensory nerves in two patients with ciguatera sensitization. Excitability parameters were all within normal limits, thereby arguing against dysfunction of axonal membrane ion channels in large-diameter fibers in ciguatera sensitization.

Congenital Myasthenic Syndromes

Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. Jan, 2009  |  Pubmed ID: 19017561

Congenital myasthenic syndromes (CMS) are a heterogeneous group of uncommon, inherited disorders affecting the neuromuscular junction. The defects interfere with presynaptic, synaptic, or postsynaptic function and compromise neuromuscular transmission. Most patients with CMS have similar clinical features regardless of the underlying defect, but attention to clinical and electrodiagnostic parameters can narrow the diagnostic spectrum. Recent advances in our understanding of the cellular mechanisms underlying specific syndromes allow DNA testing for some forms of CMS. Diagnosis of CMS enables a rationale for management to be developed. Two cases of genetically determined CMS as well as an undiagnosed infant are presented to highlight the clinical and electrophysiological difficulties associated with the diagnosis and management of such syndromes.

Plasticity of Lower Limb Motor Axons After Cervical Cord Injury

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Jan, 2009  |  Pubmed ID: 19036634

To assess changes in peripheral motor excitability after traumatic spinal cord injury (SCI).

Threshold Behaviour of Human Axons Explored Using Subthreshold Perturbations to Membrane Potential

The Journal of Physiology. Jan, 2009  |  Pubmed ID: 19047204

The present study explores the threshold behaviour of human axons and the mechanisms contributing to this behaviour. The changes in excitability of cutaneous afferents in the median nerve at the wrist were recorded to a long-lasting subthreshold conditioning stimulus, with a waveform designed to maximize the contribution of currents active in the just-subthreshold region. The conditioning stimulus produced a decrease in threshold that developed over 3-5 ms following the end of the depolarization and then decayed slowly, in a pattern similar to the recovery of axonal excitability following a discharge. To ensure that the conditioning stimulus did not activate low-threshold axons, similar recordings were then made from single motor axons in the ulnar nerve at the elbow. The findings were comparable, and behaviour with the same pattern and time course could be reproduced by subthreshold stimuli in a model of the human axon. In motor axons, subthreshold depolarizing stimuli, 1 ms long, produced a similar increase in excitability, but the late hyperpolarizing deflection was less prominent. This behaviour was again reproduced by the model axon and could be explained by the passive properties of the nodal membrane and conventional Na+ and K+ currents. The modelling studies emphasized the importance of leak current through the Barrett-Barrett resistance, even in the subthreshold region, and suggested a significant contribution of K+ currents to the threshold behaviour of axons. While the gating of slow K+ channels is slow, the resultant current may not be slow if there are substantial changes in membrane potential. By extrapolation, we suggest that, when human axons discharge, nodal slow K+ currents will be activated sufficiently early to contribute to the early changes in excitability following the action potential.

Biomarkers in Amyotrophic Lateral Sclerosis

Lancet Neurology. Jan, 2009  |  Pubmed ID: 19081518

Amyotrophic lateral sclerosis (ALS; motor neuron disease) is a relentlessly progressive disorder. After half a century of trials, only one drug with modest disease-modifying potency--riluzole--has been developed. The diagnosis of this disorder is still clinical and there is a pronounced delay between the onset of symptoms and diagnosis, possibly beyond the therapeutic window. Bedside quantification of the involvement of the corticospinal tract and extramotor areas is inadequate and functional rating scales, forced vital capacity, and patient survival have been the measures of therapeutic response so far. Potential biomarkers that are sensitive to the progression of disease, which might enhance the diagnostic algorithm and provide new drug targets, are now being identified from analysis of the blood and cerebrospinal fluid, as well as from neuroimaging and neurophysiology studies. In combination, these biomarkers might be sensitive to early therapeutic effects and would reduce our reliance on animal models, which have uncertain relevance to sporadic ALS in human beings. Such biomarkers might also resolve complexities of phenotypic heterogeneity in clinical trials. In this Review, we discuss the development of biomarkers in ALS and consider potential future directions for research.

Acute Abnormalities of Sensory Nerve Function Associated with Oxaliplatin-induced Neurotoxicity

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Mar, 2009  |  Pubmed ID: 19164207

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.

Another Cause of Occupational Entrapment Neuropathy: La Main Du Cuisinier (the Chef's Hand)

Journal of Clinical Neurophysiology : Official Publication of the American Electroencephalographic Society. Apr, 2009  |  Pubmed ID: 19279505

Recent studies have raised the possibility of a predisposition to mononeuropathies in a number of professions including musicians, cleaners, and industrial workers. There are, however, no previous reports of increased rates of mononeuropathies in the culinary arts. The authors report three cases of mononeuropathies occurring in professional chefs that presented over a 3-month period in the same outpatient clinic, with a case each of distal ulnar neuropathy, distal median motor neuropathy (thenar motor syndrome) and posterior interosseous neuropathy. There was no history of direct hand trauma in any of the patients. In all three patients, the injuries occurred exclusively in the dominant hand, further strengthening the argument for an occupational link.

Identification of Cognitive Deficits in Amyotrophic Lateral Sclerosis

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Apr, 2009  |  Pubmed ID: 19286420

Assessing the Accuracy of a Combination of Clinical Tests for Identifying Carpal Tunnel Syndrome

Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. Jul, 2009  |  Pubmed ID: 19328695

The aim of the study was to investigate whether a combination of selected provocative manoeuvres and sensory testing could improve the accuracy of clinical diagnosis of carpal tunnel syndrome (CTS). Prospective studies were undertaken in 43 of 296 consecutive patients who were referred with suspected CTS and had undergone nerve conduction studies (NCS). Responses to Phalen's test, a modified carpal compression test (MCCT), and sensory testing over the thenar eminence were assessed for each patient. For each test (Phalen's; MCCT), sensitivity (0.64; 0.14), specificity (0.75; 0.96), positive likelihood ratio (PLR) (2.54; 3.64) and negative likelihood ratio (NLR) (0.49; 0.89) were calculated. The inclusion of sensory testing did not improve sensitivity (0.55; 0.13), specificity (0.75; 0.96), PLR (2.22; 3.29) or NLR (0.60; 0.91). These data indicate that assessment of thenar sensation does not improve the diagnostic accuracy of CTS. However, a positive Phalen's test is more likely to be associated with NCS changes that are consistent with CTS.

The Effects of Alterations in Conditioning Stimulus Intensity on Short Interval Intracortical Inhibition

Brain Research. Jun, 2009  |  Pubmed ID: 19332031

Short interval intracortical inhibition [SICI] is mediated by cortical inhibitory interneurons, with two physiologically distinct phases at interstimulus interval [ISI]<1 ms and 2.5-3 ms. The second phase of SICI is mediated by synaptic mechanisms, while the first phase has been attributed to axonal refractoriness, synaptic mechanisms or both. In the present study, threshold-tracking transcranial magnetic stimulation was used to explore mechanisms underlying SICI. SICI was studied in 10 normal subjects at three different conditioning stimulus [CS] intensities [40%, 70% and 90% of resting motor threshold, RMT, defined as the threshold for a MEP of approximately 0.2 mV]. Motor responses were recorded from abductor pollicis brevis. Maximal SICI developed with CS set to 70% RMT [SICI(70%)], with two phases evident, at ISI 1 ms [12.7+/-3.4%] and ISI 2.5 ms [19.3+/-2.9%]. With CS set to 40% RMT, SICI occurred between 1 ms and 5 ms, peaking at 2.5 ms and was reduced [1.9+/-1.4%, P<0.0001] compared to peak SICI(70%). The small SICI peak at 1 ms was absent. With CS at 90% RMT, SICI developed between 2 and 5 ms, peaking at 4 ms [11.2+/-7.8%]. Facilitation was evident at 1 ms. The findings from the present study suggest that inhibitory circuits with different thresholds underlie the phases of SICI, with synaptic mechanisms also critical to the development of SICI at 1 ms.

Myasthenia Gravis Seven Years After Removal of an Invasive Thymoma

Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. Jul, 2009  |  Pubmed ID: 19342243

This report describes a 59-year-old male who developed myasthenia gravis 92 months following excision of an invasive thymoma, in the absence of tumour recurrence. This report highlights the importance of prolonged clinical surveillance in post-thymectomy patients.

Pathophysiology of Neurodegeneration in Familial Amyotrophic Lateral Sclerosis

Current Molecular Medicine. Apr, 2009  |  Pubmed ID: 19355908

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of the motor neurons in the spinal cord, brainstem, and motor cortex. Ten percent of ALS cases are familial, with both autosomal dominant and recessive modes of inheritance reported. Mutations in the copper/zinc superoxide-dismutase-1 (SOD-1) gene, the first gene linked with ALS, result in the classical ALS phenotype. To date, 135 mutations have been identified in the SOD-1 gene, accounting for approximately 20% of familial ALS cases. Mutations are widely distributed throughout the gene with preponderance for exon 4 and 5. Although mutations result in a toxic gain of function of the SOD-1 enzyme, which normally functions as a free radical scavenger, the mechanisms underlying motor neuron degeneration have not been clearly elucidated. Evidence is emerging of a complex interaction between genetic and molecular factors, with resultant damage of critical target proteins and organelles within the motor neuron. The clinical effectiveness afforded by anti-glutamatergic agents such as riluzole, suggests that glutamate excitotoxicity contributes to neurodegeneration in ALS, with glutamate excitotoxicity mediated via corticomotoneurons that provide a direct link between the motor cortex and the spinal motor neuron. This review provides an overview of the genetics of ALS, and describes recent advances in the understanding of the pathophysiological mechanisms underlying neurodegeneration.

Guillain-Barré Syndrome: an Update

Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. Jun, 2009  |  Pubmed ID: 19356935

Guillain-Barré syndrome (GBS) is an acute polyneuropathy consisting of different subtypes. Acute inflammatory demyelinating polyradiculoneuropathy, the classic demyelinating form of GBS, accounts for 90% of all GBS cases in the Western world. Acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN) are axonal forms of GBS that are more prevalent in Asia, South and Central America, often preceded by infection by Campylobacter jejuni. AMAN and AMSAN may be mediated by specific anti-ganglioside antibodies that inhibit transient sodium ion (Na+) channels. The efficacy of plasmapheresis and intravenous immunoglobulin has been established in large international randomised trials, with corticosteroids proven ineffective. Although axonal demyelination is an established pathophysiological process in GBS, the rapid improvement of clinical deficits with treatment is consistent with Na+ channel blockade by antibodies or other circulating factors, such as cytokines. This review provides an update on the epidemiology, clinical features, diagnosis, pathogenesis and treatment of GBS.

Hyperexcitability, Persistent Na+ Conductances and Neurodegeneration in Amyotrophic Lateral Sclerosis

Experimental Neurology. Jul, 2009  |  Pubmed ID: 19361500

Neuromuscular Disease in the Dialysis Patient: an Update for the Nephrologist

Seminars in Dialysis. May-Jun, 2009  |  Pubmed ID: 19386072

Neuromuscular disease is an extremely common complication of end-stage kidney disease (ESKD), manifesting in almost all dialysis patients, and leading to weakness, reduced exercise capacity, and disability. Recent studies have suggested that hyperkalemia may underlie the development of neuropathy. As such, maintenance of serum K(+) within normal limits between periods of dialysis in ESKD patients manifesting early neuropathic symptoms may reduce neuropathy development and progression. For patients with more severe neuropathic syndromes, increased dialysis frequency or a switch to high-flux dialysis may prevent further deterioration, while ultimately, renal transplantation is required to improve and restore nerve function. Exercise training programs are beneficial for ESKD patients with muscle weakness due to neuropathy or myopathy, and are capable of improving exercise tolerance and quality of life. Specific treatments have recently been evaluated for symptoms of autonomic neuropathy, including sildenafil for impotence and midodrine for intra-dialytic hypotension, and have been shown to be effective and well tolerated. Other important management strategies for neuropathy include attention to foot care to prevent callus and ulceration, vitamin supplementation, and erythropoietin. Treatment with membrane-stabilizing agents, such as amitryptiline and gabapentin, are highly effective in patients with painful neuropathy.

Amyotrophic Lateral Sclerosis and the Neuroprotective Potential of Exercise

The Journal of Physiology. Aug, 2009  |  Pubmed ID: 19648444

Conduction Block and Impaired Axonal Function in Tick Paralysis

Muscle & Nerve. Sep, 2009  |  Pubmed ID: 19670323

Tick paralysis (TP) is an uncommon disorder caused by a neurotoxin secreted by engorged female ticks. The cause of TP remains unclear, although alterations in axonal ion channel function and neuromuscular transmission have been proposed. In the present case, nerve excitability techniques, which provide information regarding axonal ion channel function, were used to elucidate the mechanism underlying weakness in a 45-year-old man who presented with weakness following a tick bite in the lateral aspect of the left axilla. Standard clinical nerve conduction studies were undertaken during the acute phase of symptoms and following clinical recovery. Nerve excitability studies were performed to investigate possible changes in ion channel properties distal to the site of conduction failure. Nerve conduction studies and electromyography suggested the possibility of a lesion involving the lower trunk of the left brachial plexus. Nerve excitability studies distal to the site of the tick bite demonstrated an abrupt increase in refractoriness, a marker of recovery from inactivation of Na(+) channels. There was normalization of both nerve conduction and nerve excitability parameters associated with clinical recovery. The alteration in refractoriness is similar to that noted in disorders involving the terminal portion of the motor nerve. The changes raise the possibility that TP may cause weakness through impairment of distal neural transmission.

Axonal Ion Channels from Bench to Bedside: a Translational Neuroscience Perspective

Progress in Neurobiology. Nov, 2009  |  Pubmed ID: 19699774

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.

Defining the Mechanisms That Underlie Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis

Experimental Neurology. Nov, 2009  |  Pubmed ID: 19716820

Amyotrophic lateral sclerosis [ALS] is a rapidly progressive neurodegenerative disorder of motor neurons, heralded by the development of cortical hyperexcitability. Reduction of short interval intracortical inhibition [SICI] in ALS, a feature linked to the development of cortical hyperexcitability, may be mediated by degeneration of inhibitory circuits or alternatively activation of high threshold excitatory circuits. As such, determining the mechanisms of SICI reduction in ALS has clear diagnostic and therapeutic significance. Consequently, the present study utilized a novel threshold tracking paired-pulse paradigm to determine whether SICI reduction in ALS represented reduced inhibition or excessive excitation. Using a 90 mm circular coil, SICI was assessed at three different conditioning stimulus intensities: 40%, 70% and 90% of resting motor threshold [RMT]. Motor evoked potential responses were recorded over the abductor pollicis brevis muscle. Short interval intracortical inhibition was uniformly reduced across all three levels of conditioning intensities in ALS [40% RMT, ALS -0.6+/-0.7%, controls 2.0+/-0.6%, P<0.01; 70% RMT, ALS 0.6+/-2.7%, controls 12.8+/-2%, P<0.001; 90% RMT, ALS -15.9+/-1.3%, controls 2.2+/-4.1%, P<0.01]. In addition, the resting motor threshold was reduced, while the motor evoked potential amplitude was increased in ALS patients, in keeping with cortical hyperexcitability. These findings establish that SICI reduction in ALS represents degeneration of inhibitory cortical circuits, combined with excessive excitation of high threshold excitatory pathways. Neuroprotective strategies aimed at preserving the integrity of intracortical inhibitory circuits, in addition to antagonizing excitatory cortical circuits, may provide novel therapeutic targets in ALS.

Neurological Complications of Chronic Kidney Disease

Nature Reviews. Neurology. Oct, 2009  |  Pubmed ID: 19724248

Chronic kidney disease (CKD) is a critical and rapidly growing global health problem. Neurological complications occur in almost all patients with severe CKD, potentially affecting all levels of the nervous system, from the CNS through to the PNS. Cognitive impairment, manifesting typically as a vascular dementia, develops in a considerable proportion of patients on dialysis, and improves with renal transplantation. Patients on dialysis are generally weaker, less active and have reduced exercise capacity compared with healthy individuals. Peripheral neuropathy manifests in almost all such patients, leading to weakness and disability. Better dialysis strategies and dietary modification could improve outcomes of transplantation if implemented before surgery. For patients with autonomic neuropathy, specific treatments, including sildenafil for impotence and midodrine for intradialytic hypotension, are effective and well tolerated. Exercise training programs and carnitine supplementation might be beneficial for neuromuscular complications, and restless legs syndrome in CKD responds to dopaminergic agonists and levodopa treatment. The present Review dissects the pathophysiology of neurological complications related to CKD and highlights the spectrum of therapies currently available.

Oxaliplatin-induced Lhermitte's Phenomenon As a Manifestation of Severe Generalized Neurotoxicity

Oncology. 2009  |  Pubmed ID: 20016227

Lhermitte's phenomenon, characterized by 'electric-shock' sensations precipitated by neck flexion, may develop during oxaliplatin treatment. Limited cases have been described previously and the pathophysiology underlying Lhermitte's phenomenon in oxaliplatin-treated patients has not been established.

Oxaliplatin-induced Neurotoxicity: Changes in Axonal Excitability Precede Development of Neuropathy

Brain : a Journal of Neurology. Oct, 2009  |  Pubmed ID: 19745023

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.

Ischaemic Sensitivity of Axons in Carpal Tunnel Syndrome

Journal of the Peripheral Nervous System : JPNS. Sep, 2009  |  Pubmed ID: 19909483

Although carpal tunnel syndrome (CTS) is the most common human entrapment neuropathy characterized by paraesthesiae and numbness with nocturnal exacerbation, the mechanisms underlying the generation of these symptoms remain unclear. Consequently, the aim of the present study was to investigate the relationship between changes in axonal excitability and the development of neurological symptoms in response to an ischaemic insult in CTS patients. Sensory and motor excitability were measured in 10 CTS patients and compared with 10 healthy controls, with participants asked to report symptom generation and intensity during the development of limb ischaemia. To induce ischaemia, a sphygmomanometer was inflated above the elbow and maintained at 200 mmHg for 10 min. During ischaemia there were decreases in axonal threshold, with less overall reduction in CTS patients when compared with controls. Associated with these differences in threshold, both sensory (p < 0.001) and motor (p < 0.05) refractoriness increased dramatically in CTS patients. This prominent increase in refractoriness was accompanied by a significant reduction in compound sensory action potentials and compound motor action potentials amplitudes for CTS patients when compared with controls (p < 0.05). These changes in axonal excitability resulted in a higher intensity of numbness and paraesthesiae reported by CTS patients during ischaemia. The present study has established differences in the nerve excitability and symptom development during ischaemia for patients with mild and moderate CTS, and may suggest that axons in the median nerve of CTS patients have an altered functional capacity to respond to an ischaemic insult, further contributing to nocturnal exacerbation of their symptoms.

INSPIRATIonAL--INSPIRAtory Muscle Training in Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis : Official Publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. Oct-Dec, 2009  |  Pubmed ID: 19922129

Respiratory impairment, due to respiratory muscle weakness, is a major cause of morbidity and mortality in patients with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). Threshold loading may strengthen the inspiratory muscles and thereby improve patient prognosis. A phase II, double-blind, randomized-controlled trial was undertaken to determine whether a 12-week inspiratory muscle training programme attenuated the decline in respiratory function and inspiratory muscle strength in patients with ALS/MND. Nine patients were randomized to inspiratory muscle training and 10 to sham training. Primary endpoints were respiratory function (forced vital capacity, vital capacity), lung volumes and inspiratory muscle strength. Patients were assessed before, during and immediately after a 12-week training period, and at eight weeks follow-up. While improvements in inspiratory muscle strength were observed in both treatment arms, there was a non-significant increase in maximum inspiratory pressure of 6.1% in the experimental group compared to controls (standard error of mean, 6.93%; 95% confidence interval -8.58 -20.79; p=0.39). The gains in inspiratory muscle strength were partially reversed during a period of training cessation. In conclusion, inspiratory muscle training may potentially strengthen the inspiratory muscles and slow the decline in respiratory function in patients with ALS/MND.

FUS Mutations in Amyotrophic Lateral Sclerosis: Clinical, Pathological, Neurophysiological and Genetic Analysis

Journal of Neurology, Neurosurgery, and Psychiatry. Jun, 2010  |  Pubmed ID: 19965854

FUS gene mutations were recently identified in familial amyotrophic lateral sclerosis (ALS). The present studies sought to define the clinical, post-mortem and neurophysiological phenotypes in ALS families with FUS mutations and to determine the frequency of FUS mutations in familial and sporadic ALS.

Acute, Reversible Axonal Energy Failure During Stroke-like Episodes in MELAS

Pediatrics. Sep, 2010  |  Pubmed ID: 20679297

The pathophysiology of stroke-like episodes in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) remains unresolved. Possible mechanisms include mitochondrial angiopathy, cytopathy, or both, collectively resulting in cellular energy depletion. To clarify disease mechanisms, axonal excitability properties were investigated in a 10-year-old child with MELAS. Serial assessments during a stroke-like episode revealed reversible depolarization of the axonal membrane consistent with disruption of energy-dependent processes. Axonal parameters correlated with the clinical assessment of central dysfunction and biochemical measures of acidosis. Novel axonal excitability techniques have established acute, reversible ischemic-like depolarization that may serve as a surrogate marker of central events that develop during stroke-like episodes in MELAS.

Corticomotoneuronal Function and Hyperexcitability in Acquired Neuromyotonia

Brain : a Journal of Neurology. Sep, 2010  |  Pubmed ID: 20736187

Acquired neuromyotonia encompasses a group of inflammatory disorders characterized by symptoms reflecting peripheral nerve hyperexcitability, which may be clinically confused in the early stages with amyotrophic lateral sclerosis. Despite a clear peripheral nerve focus, it remains unclear whether the ectopic activity in acquired neuromyotonia receives a central contribution. To clarify whether cortical hyperexcitability contributes to development of clinical features of acquired neuromyotonia, the present study investigated whether threshold tracking transcranial magnetic stimulation could detect cortical hyperexcitability in acquired neuromyotonia, and whether this technique could differentiate acquired neuromyotonia from amyotrophic lateral sclerosis. Cortical excitability studies were undertaken in 18 patients with acquired neuromyotonia and 104 patients with amyotrophic lateral sclerosis, with results compared to 62 normal controls. Short-interval intracortical inhibition in patients with acquired neuromyotonia was significantly different when compared to patients with amyotrophic lateral sclerosis (averaged short interval intracortical inhibition acquired neuromyotonia 11.3 +/- 1.9%; amyotrophic lateral sclerosis 2.6 +/- 0.9%, P < 0.001). In addition, the motor evoked potential amplitudes (acquired neuromyotonia 21.0 +/- 3.1%; amyotrophic lateral sclerosis 38.1 +/- 2.2%, P < 0.0001), intracortical facilitation (acquired neuromyotonia -0.9 +/- 1.3%; amyotrophic lateral sclerosis -2.3 +/- 0.6%, P < 0.0001), resting motor thresholds (acquired neuromyotonia 62.2 +/- 1.6%; amyotrophic lateral sclerosis 57.2 +/- 0.9%, P < 0.05) and cortical silent period durations (acquired neuromyotonia 212.8 +/- 6.9 ms; amyotrophic lateral sclerosis 181.1 +/- 4.3 ms, P < 0.0001) were significantly different between patients with acquired neuromyotonia and amyotrophic lateral sclerosis. Threshold tracking transcranial magnetic stimulation established corticomotoneuronal integrity in acquired neuromyotonia, arguing against a contribution of central processes to the development of nerve hyperexcitability in acquired neuromyotonia.

Why an Australian Editor for JNNP?

Journal of Neurology, Neurosurgery, and Psychiatry. Jan, 2010  |  Pubmed ID: 20019215

Neurophysiological Methodologies: Diagnosis of Peripheral Nerve Disease and Assessment of Pharmacological Agents

Current Opinion in Investigational Drugs (London, England : 2000). Jan, 2010  |  Pubmed ID: 20047161

Recent developments in the field of neurophysiology have led to the refinement of neurophysiological techniques, enabling clinical investigators to assess neuropathy patients with greater precision. In addition to conventional nerve conduction studies and electromyography, novel axonal excitability techniques and quantitative sensory testing may be used to improve diagnosis and to characterize and serially monitor peripheral nerve disorders. A significant expansion in the number of clinical trials being conducted for neurological indications has increased the impetus to further develop neurophysiological measures that reflect the responsiveness to drug therapies. Measures such as motor unit number estimation and the neurophysiological index may facilitate the advancement of compounds in the drug discovery pipeline. This review summarizes several electrodiagnostic and neurophysiological techniques, both conventional and novel, highlighting recent advances that are relevant to disease diagnosis and the assessment of patient response to treatment strategies.

Fatigue in Multiple Sclerosis: Mechanisms and Management

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Jun, 2010  |  Pubmed ID: 20100665

Multiple sclerosis [MS] is a chronic immune-mediated disorder of the central nervous system [CNS]. Fatigue may be a debilitating symptom in MS patients, adversely impacting on their quality of life. Clinically, fatigue may manifest as exhaustion, lack of energy, increased somnolence, or worsening of MS symptoms. Activity and heat typically serve to exacerbate symptoms of fatigue. There is now strong evidence to suggest that fatigue results from reduced voluntary activation of muscles by means of central mechanisms. Given that axonal demyelination is a pathological hallmark of MS, activity-dependent conduction block [ADCB] has been proposed as a mechanism underlying fatigue in MS. This ADCB results from axonal membrane hyperpolarization, mediated by the Na(+)/K(+) electrogenic pump, with conduction failure precipitated in demyelinated axons with a reduced safety factor of impulse transmission. In addition, Na(+)/K(+) pump dysfunction, as reported in MS, may induce a depolarizing conduction block associated with inactivation of Na(+) channels. These processes may induce secondary effects including axonal degeneration triggered by raised levels of intracellular Ca(2+) through reverse operation of the Na(+)-Ca(2+) exchanger. Restoration of normal conduction in demyelinated axons with selective channel blockers improves fatigue and may yet prove useful as a neuroprotective strategy, in preventing secondary axonal degeneration and consequent functional impairment.

The Case of a 48 Year-old Woman with Bizarre and Complex Delusions

Nature Reviews. Neurology. Mar, 2010  |  Pubmed ID: 20212429

A 48 year-old woman presented with an 18 month history of bizarre and complex delusions on a background of social, behavioral and cognitive decline over several years. Her psychosis progressed despite receiving high doses of antipsychotics. The patient's father also had a psychotic episode in his 40s. He subsequently developed motor neuron disease, which caused his death at 68 years of age.

Changes in Human Sensory Axonal Excitability Induced by Focal Nerve Compression

The Journal of Physiology. May, 2010  |  Pubmed ID: 20351048

The aim of the present study was to establish the changes in nerve excitability and symptom generation associated with the application of focal nerve compression (FNC). FNC was applied at the wrist by means of a custom-designed electrode in 10 healthy subjects, and was maintained for 24 min. Symptoms of paraesthesiae and signs of numbness were recorded every 30 s. Despite apparently minimal changes in axonal threshold, FNC was associated with prolongation in latency by 14.5 +/- 2.1% (P < 0.001) and reduction in compound sensory action potential (CSAP) amplitude by 34.3 +/- 5.1% (P < 0.001), with two subjects developing conduction block. The reduction in CSAP was associated with abolition of superexcitability, and an increase in refractoriness of 295.2 +/- 55.5% (P < 0.005) and strength-duration time constant (SDTC) by 48.1 +/- 10.3% (P < 0.005), all consistent with axonal depolarization. With release of FNC, threshold rapidly increased above pre-compression levels (P < 0.01), consistent with the development of axonal hyperpolarization. Associated with these changes in axonal excitability, paraesthesiae and numbness steadily increased throughout FNC and reached a peak at the termination of FNC, followed by a gradual recovery on release of FNC. When compared to previous studies that utilised the effects of more generalised limb ischaemia, the changes in axonal excitability recorded during FNC were qualitatively and quantitatively alike, suggesting that similar biophysical mechanisms contributed to the changes observed with both manoeuvres.

Corticomotoneuronal Function in Asymptomatic SOD-1 Mutation Carriers

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Oct, 2010  |  Pubmed ID: 20362497

Diffusion tensor imaging (DTI) recently identified structural abnormalities of corticomotoneurons in asymptomatic copper/zinc superoxide-dismutase-1 (SOD-1) gene mutation carriers. The potential existence of longstanding corticomotoneuronal dysfunction would clearly have consequences for the medical management of asymptomatic SOD-1 mutation carriers. To clarify this unexpected finding, DTI techniques were combined with threshold tracking transcranial magnetic stimulation (TMS) to assess the anatomical and functional integrity of corticomotoneurons in asymptomatic SOD-1 mutation carriers.

The 10-metre Gait Speed As a Functional Biomarker in Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis : Official Publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. Dec, 2010  |  Pubmed ID: 20515425

There remains a critical need to develop biomarkers of disease progression in amyotrophic lateral sclerosis (ALS). Mobility is a key determinant of disease status and quality of life. The present study assessed the utility of 10-metre gait speed as a functional biomarker of disability in ALS. The gait speed, ALSFRS-R score, body mass index (BMI) and forced vital capacity (FVC), measured in 50 consecutive ALS patients at the time of diagnosis were assessed. ALS patients were managed in the multidisciplinary clinic for up to three years. 10-metre gait speed was significantly reduced in ALS patients with lower limb-onset disease (0.9 ± 0.1 m/s) compared to those with upper limb (1.3 ± 0.1 m/s, p <0.01) and bulbar onset (1.2 ± 0.1 m/s, p <0.01) disease. The 10-metre gait speed correlated with the total ALSFRS-R score (R = 0.6) and the gross motor subscore (R = 0.8, p <0.001). As such, the 10-metre gait speed may serve as a robust marker of disability and disease progression in ALS.

Corticospinal Tract Dysfunction and Development of Amyotrophic Lateral Sclerosis Following Electrical Injury

Muscle & Nerve. Aug, 2010  |  Pubmed ID: 20589889

The causal relationship between electrical injury and development of amyotrophic lateral sclerosis (ALS) remains controversial. We describe the case of a 25-year-old man who developed ALS after a severe electrical injury. Cerebral magnetic resonance imaging (MRI) demonstrated hyperintensities involving the corticospinal tract. Functional testing with transcranial magnetic stimulation established that the motor cortex was relatively inexcitable. In addition, there were features of denervation on electromyography and muscle biopsy that supported concomitant lower motor neuron findings and the diagnosis of ALS.

Dexpramipexole, the R(+) Enantiomer of Pramipexole, for the Potential Treatment of Amyotrophic Lateral Sclerosis

IDrugs : the Investigational Drugs Journal. Dec, 2010  |  Pubmed ID: 21154151

Dexpramipexole (KNS-760704), the R(+) enantiomer of pramipexole, is under development by Knopp Neurosciences and Biogen Idec as a potential neuroprotective therapy for amyotrophic lateral sclerosis (ALS), a universally fatal neurodegenerative disease. Pramipexole, exclusively the S(-) enantiomer, is a non-ergot dopaminergic autoreceptor agonist that is currently marketed for use in the treatment of Parkinson's disease and restless legs syndrome. Pramipexole has been proposed to exert a broad spectrum of neuroprotective properties, primarily through antioxidant effects, inhibiting apoptotic enzymes and preserving mitochondrial structure and activity. More recent work has suggested that pramipexole possesses anti-excitotoxic properties, raising the possibility of beneficial effects in patients with ALS. However, pramipexole has high intrinsic dopaminergic receptor activity and, consequently, dose-limiting side effects, including orthostatic hypotension and hallucination, are frequent. Dexpramipexole exhibits significantly lower affinity for dopaminergic receptors, thereby making it unlikely to be associated with dopaminergic side effects. In clinical trials to date, dexpramipexole has been safe and well tolerated at doses up to 67-fold higher than the maximum recommended daily dose of pramipexole in patients with Parkinson's disease, and has demonstrated signs of neuroprotective benefit. This report summarizes the chemical and pharmacological properties of dexpramipexole and describes the potential utility of the drug in the pharmaceutical development pipeline.

Scurvy and Stroke - is There an Association?

The Medical Journal of Australia. Nov, 2010  |  Pubmed ID: 21034393

Upregulation of Persistent Sodium Conductances in Familial ALS

Journal of Neurology, Neurosurgery, and Psychiatry. Feb, 2010  |  Pubmed ID: 19726402

Upregulation of persistent Na(+) conductances has been linked to axonal degeneration in sporadic amyotrophic lateral sclerosis (ALS) and has also been reported in the transgenic superoxide dismutase-1 (SOD-1) mouse model. The mechanisms of ectopic activity (fasciculations and cramp) and axonal degeneration still require clarification in familial ALS (FALS) in humans, and specifically whether there are any differences to the processes identified in sporadic patients. Consequently, novel threshold tracking techniques were used to assess whether upregulation of persistent Na(+) conductances was a feature linked to axonal degeneration in FALS.

Dissecting the Mechanisms Underlying Short-interval Intracortical Inhibition Using Exercise

Cerebral Cortex (New York, N.Y. : 1991). Jul, 2011  |  Pubmed ID: 21071618

Recently, 2 physiologically distinct phases of short-interval intracortical inhibition (SICI) have been identified, a larger phase at interstimulus interval (ISI) 3 ms and a smaller phase at ISI 1 ms. While the former is mediated by synaptic processes, the mechanisms underlying the first phase of SICI remain a matter of debate. Separately, it is known that fatiguing hand exercise reduces SICI, a measure of cortical excitability. Consequently, the present study assessed effects of fatiguing hand exercise on the 2 SICI phases, using threshold tracking transcranial magnetic stimulation techniques, to yield further information on underlying mechanisms. Studies were undertaken on 22 subjects, with SICI assessed at baseline, after each voluntary contraction (VC) period of 120 s and 5, 10, and 20 min after last VC, with responses recorded over abductor pollicis brevis. Exercise resulted in significant reduction of SICI at ISI 1 ms (SICI(baseline) 9.5 ± 2.7%; SICI(MAXIMUM REDUCTION) 2.5 ± 2.5%, P < 0.05) and 3 ms (SICI(baseline) 16.8 ± 1.7%; SICI(MAXIMUM REDUCTION) 11.6 ± 2.1%, P < 0.05), with the time course of reduction being different for the 2 phases. Taken together, findings from the present study suggest that synaptic processes were the predominant mechanism underlying the different phases of SICI.

Freud, Neurology and the Emergence of Dynamic Neural Networks

Journal of Neurology, Neurosurgery, and Psychiatry. Feb, 2011  |  Pubmed ID: 21097548

The Realm of Neurology--past, Present and Future

Journal of Neurology, Neurosurgery, and Psychiatry. Jan, 2011  |  Pubmed ID: 21148610

Clinical Diagnosis and Management of Amyotrophic Lateral Sclerosis

Nature Reviews. Neurology. Nov, 2011  |  Pubmed ID: 21989247

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results in progressive loss of bulbar and limb function. Patients typically die from respiratory failure within 3 years of symptom onset. The incidence of ALS in Europe is 2-3 cases per 100,000 individuals in the general population, and the overall lifetime risk of developing the disease is 1:400. ALS is familial in 5% of cases, and shows a Mendelian pattern of inheritance. ALS is recognized to overlap with frontotemporal dementia. Diagnosis is made on clinical grounds, using internationally recognized consensus criteria, after exclusion of conditions that can mimic ALS. The Revised ALS Functional Rating Scale is currently the most widely used assessment tool; scores are used to predict survival, and have been employed extensively in clinical trials. Riluzole remains the only effective drug, and extends the average survival of patients by 3-6 months. Optimal treatment is based on symptom management and preservation of quality of life, provided in a multidisciplinary setting. The discovery of further effective disease-modifying therapies remains a critical need for patients with this devastating condition.

Nerve Compression, Membrane Excitability, and Symptoms of Carpal Tunnel Syndrome

Muscle & Nerve. Sep, 2011  |  Pubmed ID: 21996801

In this study we investigated the changes in axonal excitability and the generation of neurological symptoms in response to focal nerve compression (FNC) of the median nerve in carpal tunnel syndrome (CTS).

Activity-dependent Conduction Failure: Molecular Insights

Journal of the Peripheral Nervous System : JPNS. Sep, 2011  |  Pubmed ID: 22003929

Weakness and fatigue are commonly encountered symptoms in neurological disorders and significantly impair quality of life. In the case of motor axons, conduction block contributes to weakness and fatigue and may be associated with aberrant nerve activity including fasciculations and cramp. These symptoms result from dysfunction of the constituent channels and pumps of the axonal membrane. In critically conducting axons, impulse conduction can be impaired by the effects of activity or by other mechanisms that produce a significant shift in membrane potential. Conduction failure may be accentuated or relieved by maneuvers that manipulate the time course of the driving current, including the administration of agents that interfere with Na(+) channel function. In patients with inflammatory neuropathies, normal activity may be sufficient to precipitate conduction failure at sites of impaired function in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). From a clinical perspective, these features are not assessed adequately by conventional neurophysiological techniques. As weakness and fatigue may only develop following activity or exertion, it is useful to assess the effects of impulse trains to determine the extent of conduction failure and the resulting symptoms in neurological patients. These techniques and the physiological mechanisms underlying the development of activity-dependent hyperpolarization will be critically appraised in this review, with a focus on demyelinating neuropathies, MMN and the neurodegenerative disease, and amyotrophic lateral sclerosis (ALS).

The Effects of Large Artery Ischemia and Subsequent Recanalization on Nerve Excitability

Muscle & Nerve. Nov, 2011  |  Pubmed ID: 22006704

Predicting a Positive Response to Intravenous Immunoglobulin in Isolated Lower Motor Neuron Syndromes

PloS One. 2011  |  Pubmed ID: 22066029

To determine clinically related characteristics in patients with pure lower motor neuron (LMN) syndromes, not fulfilling accepted diagnostic criteria, who were likely to respond to intravenous immunoglobulin (IVIg) treatment.

Who is Really the World's Best Known Neurologist?

Practical Neurology. Dec, 2011  |  Pubmed ID: 22100957

Neurophysiological Index As a Biomarker for ALS Progression: Validity of Mixed Effects Models

Amyotrophic Lateral Sclerosis : Official Publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. Jan, 2011  |  Pubmed ID: 21271790

Our objective was to evaluate the neurophysiological index (NI) as a biomarker for amyotrophic lateral sclerosis (ALS) and to assess the validity of linear mixed effects models for describing longitudinal changes. Functional assessment and nerve conduction studies were undertaken in 58 ALS patients. Neurophysiological data were collected on four occasions over 12 weeks (baseline, weeks 4, 8 and 12). The NI was calculated for the abductor digiti minimi and ulnar nerve at the wrist. NI declined at a rate of 0.04 per week (S.E. 0.006, p < 0.0001). Patients with bulbar-onset disease had 0.88 greater NI than patients with upper limb-onset disease over the follow-up period (S.E. 0.39, p = 0.03). There were no differences in the rates of decline among patients with different disease phenotypes. Rates of change in NI and functional impairment were weakly correlated (Spearman's p = 0.29, p = 0.03). Linear mixed effects models were appropriate for detailing the longitudinal changes in NI. The present findings support incorporation of NI as an outcome measure for ALS clinical trials conducted over short time periods.

Amyotrophic Lateral Sclerosis

Lancet. Mar, 2011  |  Pubmed ID: 21296405

Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal neurodegenerative disease of the human motor system. In this Seminar, we summarise current concepts about the origin of the disease, what predisposes patients to develop the disorder, and discuss why all cases of ALS are not the same. In the 150 years since Charcot originally described ALS, painfully slow progress has been made towards answering these questions. We focus on what is known about ALS and where research is heading-from the small steps of extending longevity, improving therapies, undertaking clinical trials, and compiling population registries to the overarching goals of establishing the measures that guard against onset and finding the triggers for this neurodegenerative disorder.

Early, Progressive, and Sustained Dysfunction of Sensory Axons Underlies Paclitaxel-induced Neuropathy

Muscle & Nerve. Mar, 2011  |  Pubmed ID: 21321953

Paclitaxel is used in the adjuvant treatment of breast cancer. It induces disabling and potentially long-lasting sensory neuropathy. This study systematically and prospectively investigated sensory function, using clinical grading scales, quantitative sensory testing, and neurophysiological and nerve excitability studies in 28 patients with early-stage breast cancer. After administration of 529 ± 41 mg/m(2) paclitaxel, 71% of patients developed neuropathic symptoms by 6 weeks of treatment. Early and progressive increases in stimulus threshold (P < 0.05) and reduction in sensory amplitudes from 47.0 ± 3.3 μV to 42.4 ± 3.4 μV (P < 0.05) occurred by 4 weeks, with a further reduction by final treatment (33.7 ± 3.0 μV, P < 0.001). The majority of patients (63%) did not experience recovery of neuropathic symptoms at follow-up. Axonal disruption did not relate to membrane conductance dysfunction. We found that paclitaxel produces early sensory dysfunction and leads to persistent neuropathy. Importantly, significant axonal dysfunction within the first month of treatment predated symptom onset, suggesting a window for neuroprotective therapies.

The Contribution of SK3 Polymorphisms to Acute Oxaliplatin-induced Neurotoxicity: Direct or Indirect Effects?

Cancer Chemotherapy and Pharmacology. May, 2011  |  Pubmed ID: 21327679

Cortical Excitability Distinguishes ALS from Mimic Disorders

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Sep, 2011  |  Pubmed ID: 21382747

The diagnosis of amyotrophic lateral sclerosis (ALS) relies on stringent clinical criteria, resulting in diagnostic delay and inevitably the institution of appropriate therapy. Cortical hyperexcitability, as assessed by the novel threshold tracking transcranial magnetic stimulation (TTTMS) technique, appears as an early feature of ALS. Consequently, the present study assessed the diagnostic utility of threshold tracking TMS and developed algorithms to aid the diagnosis of ALS.

Long-term Neuropathy After Oxaliplatin Treatment: Challenging the Dictum of Reversibility

The Oncologist. 2011  |  Pubmed ID: 21478275

Oxaliplatin-induced neuropathy is a significant and dose-limiting toxicity that adversely affects quality of life. However, the long-term neurological sequelae have not been adequately described. The present study aimed to describe the natural history of oxaliplatin-induced neuropathy, using subjective and objective assessments.

Dose Effects of Oxaliplatin on Persistent and Transient Na+ Conductances and the Development of Neurotoxicity

PloS One. 2011  |  Pubmed ID: 21494615

Oxaliplatin, a platinum-based chemotherapy utilised in the treatment of colorectal cancer, produces two forms of neurotoxicity--acute sensorimotor neuropathic symptoms and a dose-limiting chronic sensory neuropathy. Given that a Na(+) channelopathy has been proposed as the mechanism underlying acute oxaliplatin-induced neuropathy, the present study aimed to determine specific mechanisms of Na(+) channel dysfunction.

Neuroprotection for Oxaliplatin-induced Neurotoxicity: What Happened to Objective Assessment?

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Jun, 2011  |  Pubmed ID: 21606425

Clarifying Variability of Corticomotoneuronal Function in Kennedy Disease

Muscle & Nerve. Aug, 2011  |  Pubmed ID: 21698646

Although Kennedy disease (KD) is regarded as a pure lower motor neuron disorder, recent transcranial magnetic stimulation (TMS) studies have reported subclinical corticomotoneuronal dysfunction in KD. To clarify these findings, this study applied novel triple stimulation (TST) and threshold tracking TMS techniques to gain further insights into corticomotoneuronal function in KD.

Isolated Bulbar Phenotype of Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis : Official Publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. Jul, 2011  |  Pubmed ID: 21702735

Typical bulbar-onset ALS generally portends a poor prognosis. To determine whether a relatively isolated bulbar phenotype (IBP) may have a better prognosis, patients with bulbar onset presentations were prospectively assessed, with IBP defined by an absence of limb progression over an initial six-month period. Clinical features and neurophysiological characteristics were compared. From a cohort of 300 consecutive referrals, 32 patients with bulbar onset disease (21 females, 11 males) were identified and compared to 23 age-matched control subjects. In total, patients were followed for 54 months. Twelve patients were identified with IBP (nine female, three male) and 20 had more typical bulbar ALS (12 female, eight male). Clinically, IBP was characterized by greater female predominance and upper motor neuron bulbar involvement. Compound motor action potential amplitudes were preserved in IBP compared to bulbar ALS (IBP, 7.1 mV; bulbar ALS, 4.2 mV, p <0.05), as was the neurophysiological index (IBP, 1.2; bulbar ALS 0.5, p <0.05). Furthermore, short interval intracortical inhibition was normal in IBP and reduced in typical bulbar ALS. In conclusion, patients with IBP were typically female with prominent upper motor neuron bulbar features and had normal cortical excitability. Biomarkers of cortical excitability may prove useful for further classifying ALS.

Modulatory Effects on Axonal Function After Intravenous Immunoglobulin Therapy in Chronic Inflammatory Demyelinating Polyneuropathy

Archives of Neurology. Jul, 2011  |  Pubmed ID: 21747028

To investigate the immediate and longitudinal mechanisms of action of intravenous immunoglobulin (IVIg) on axonal function in chronic inflammatory demyelinating polyneuropathy (CIDP).

Maladaptation of Cortical Circuits Underlies Fatigue and Weakness in ALS

Amyotrophic Lateral Sclerosis : Official Publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. Nov, 2011  |  Pubmed ID: 21830989

Although fatigue is frequently reported in amyotrophic lateral sclerosis (ALS), the underlying mechanisms remain to be elucidated. Cortical excitability studies were utilized to determine the contribution of central mechanisms to development of fatigue and weakness in ALS. Threshold-tracking transcranial magnetic stimulation (TMS) studies were undertaken in 16 ALS patients and 22 normal controls using a 90-mm circular coil. TMS studies were performed at baseline, immediately after a voluntary contraction (VC) period of 120 s duration (three VC periods), and at 5, 10 and 20 min after last VC. At baseline, there was a significant reduction of short-interval intracortical inhibition (SICI) at interstimulus interval of 1 ms (ALS 2.3 ± 2.3%; controls 9.5 ± 2.5%, p < 0.01) and 3 ms (ALS5.1 ± 3.4%; controls 16.8 ± 1.7%, p < 0.01) in ALS patients. Although there was a significant reduction of SICI post-VC in controls at ISI 1 ms (p < 0.05) and ISI 3 ms (p < 0.05), there was no significant change in ALS patients at ISI 1 ms (p = 0.15) or 3 ms (p = 0.31). The changes in cortical excitability correlated with fatigue (R = 0.59, p < 0.05). In conclusion, maladaptation of cortical processes related to degeneration of inhibitory GABAergic intracortical circuits, is a feature of ALS that significantly correlates with development of fatigue and weakness.

Motor Neuron Dysfunction in Frontotemporal Dementia

Brain : a Journal of Neurology. Sep, 2011  |  Pubmed ID: 21840887

Frontotemporal dementia and motor neuron disease share clinical, genetic and pathological characteristics. Motor neuron disease develops in a proportion of patients with frontotemporal dementia, but the incidence, severity and functional significance of motor system dysfunction in patients with frontotemporal dementia has not been determined. Neurophysiological biomarkers have been developed to document motor system dysfunction including: short-interval intracortical inhibition, a marker of corticospinal motor neuron dysfunction and the neurophysiological index, a marker of lower motor neuron dysfunction. The present study performed detailed clinical and neurophysiological assessments on 108 participants including 40 consecutive patients with frontotemporal dementia, 42 age- and gender-matched patients with motor neuron disease and 26 control subjects. Of the 40 patients with frontotemporal dementia, 12.5% had concomitant motor neuron disease. A further 27.3% of the patients with frontotemporal dementia had clinical evidence of minor motor system dysfunction such as occasional fasciculations, mild wasting or weakness. Biomarkers of motor system function were abnormal in frontotemporal dementia. Average short-interval intracortical inhibition was reduced in frontotemporal dementia (4.3 ± 1.7%) compared with controls (9.1 ± 1.1%, P < 0.05). Short-interval intracortical inhibition was particularly reduced in the progressive non-fluent aphasia subgroup, but was normal in patients with behavioural variant frontotemporal dementia and semantic dementia. The neurophysiological index was reduced in frontotemporal dementia (1.1) compared with controls (1.9, P < 0.001), indicating a degree of lower motor neuron dysfunction, although remained relatively preserved when compared with motor neuron disease (0.7, P < 0.05). Motor system dysfunction in frontotemporal dementia may result from pathological involvement of the primary motor cortex, with secondary degeneration of lower motor neurons in the brainstem and anterior horn of the spinal cord.

Purple Pigments: the Pathophysiology of Acute Porphyric Neuropathy

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Dec, 2011  |  Pubmed ID: 21855406

The porphyrias are inherited metabolic disorders arising from disturbance in the haem biosynthesis pathway. The neuropathy associated with acute intermittent porphyria (AIP) occurs due to mutation involving the enzyme porphobilinogen deaminase (PBGD) and is characterised by motor-predominant features. Definitive diagnosis often encompasses a combination of biochemical, enzyme analysis and genetic testing, with clinical neurophysiological findings of a predominantly motor axonal neuropathy. Symptomatic and supportive treatment are the mainstays during an acute attack. If administered early, intravenous haemin may prevent progression of neuropathy. While the pathophysiology of AIP neuropathy remains unclear, axonal dysfunction appears intrinsically linked to the effects of neural energy deficits acquired through haem deficiency coupled to the neurotoxic effects of porphyrin precursors. The present review will provide an overview of AIP neuropathy, including discussion of recent advances in understanding developed through neurophysiological approaches that have further delineated the pathophysiology of axonal degeneration.

Nerve Conduction Studies

Australian Family Physician. Sep, 2011  |  Pubmed ID: 21894276

This article forms part of our 'Tests and results' series for 2011 which aims to provide information about common tests that general practitioners order regularly. It considers areas such as indications, what to tell the patient, what the test can and cannot tell you, and interpretation of results.

Dysfunction of Axonal Membrane Conductances in Adolescents and Young Adults with Spinal Muscular Atrophy

Brain : a Journal of Neurology. Nov, 2011  |  Pubmed ID: 21926101

Spinal muscular atrophy is distinct among neurodegenerative conditions of the motor neuron, with onset in developing and maturing patients. Furthermore, the rate of degeneration appears to slow over time, at least in the milder forms. To investigate disease pathophysiology and potential adaptations, the present study utilized axonal excitability studies to provide insights into axonal biophysical properties and explored correlation with clinical severity. Multiple excitability indices (stimulus-response curve, strength-duration time constant, threshold electrotonus, current-threshold relationship and recovery cycle) were investigated in 25 genetically characterized adolescent and adult patients with spinal muscular atrophy, stimulating the median motor nerve at the wrist. Results were compared with 50 age-matched controls. The Medical Research Council sum score and Spinal Muscular Atrophy Functional Rating Scale were used to define the strength and motor functional status of patients with spinal muscular atrophy. In patients with spinal muscular atrophy, there were reductions in compound muscle action potential amplitude (P < 0.0005) associated with reduction in stimulus response slope (P < 0.0005), confirming significant axonal loss. In the patients with mild or ambulatory spinal muscular atrophy, there was reduction of peak amplitude without alteration in axonal excitability; in contrast, in the non-ambulatory or severe spinal muscular atrophy cohort prominent changes in axonal function were apparent. Specifically, there were steep changes in the early phase of hyperpolarization in threshold electrotonus (P < 0.0005) that correlated with clinical severity. Additionally, there were greater changes in depolarizing threshold electrotonus (P < 0.0005) and prolongation of the strength-duration time constant (P = 0.001). Mathematical modelling of the excitability changes obtained in patients with severe spinal muscular atrophy supported a mixed pathology comprising features of axonal degeneration and regeneration. The present study has provided novel insight into the pathophysiology of spinal muscular atrophy, with identification of functional abnormalities involving axonal K(+) and Na(+) conductances and alterations in passive membrane properties, the latter linked to the process of neurodegeneration.

Regional Differences in Ulnar Nerve Excitability May Predispose to the Development of Entrapment Neuropathy

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Jan, 2011  |  Pubmed ID: 20591727

To assess whether there are differences in nerve excitability properties between proximal and distal stimulation sites in the ulnar nerve in healthy controls, which may provide information on whether alteration in ion channel function predisposes to the development of ulnar neuropathy at the elbow.

How Common Are Behavioural Changes in Amyotrophic Lateral Sclerosis?

Amyotrophic Lateral Sclerosis : Official Publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. Jan, 2011  |  Pubmed ID: 20849323

Our objectives were to assess the frequency of behavioural changes in patients with amyotrophic lateral sclerosis (ALS) and to compare the clinical profile of ALS patients with those with behavioural variant frontotemporal dementia (bvFTD). Ninety-two patients with ALS and their carers participated in a postal survey. ALS patients completed self-report measures of motor function and mood. Eighty-one carers of ALS patients and 25 carers of bvFTD patients completed the revised version of the Cambridge Behavioural Inventory (CBI-R). Results showed that reduced motivation was reported in more than 80% of the ALS cases, with almost 41% of them having moderate-severe apathy. Depression was present in 30% of ALS patients and did not contribute significantly to the presence of behavioural symptoms. Bulbar and limb onset ALS patients did not differ. Abnormal behaviour and stereotypical and motor behaviours were present to a moderate-severe degree in around 20%, and 11% reached the criteria for FTD. The rate of behavioural symptoms was significantly higher in the bvFTD group than ALS in all behavioural domains (p <0.001). In conclusion, apathy was the most prominent feature in ALS patients. A substantial proportion of ALS patients manifested behavioural changes of the type seen in FTD, with 11% fulfilling the criteria for FTD.

Adaptation of Motor Function After Spinal Cord Injury: Novel Insights into Spinal Shock

Brain : a Journal of Neurology. Feb, 2011  |  Pubmed ID: 20952380

The mechanisms underlying spinal shock have not been clearly defined. At present, clinical assessment remains the mainstay to describe progression through spinal shock following traumatic spinal cord injury. However, nerve excitability studies in combination with conventional nerve conduction and clinical assessments have the potential to investigate spinal shock at the level of the peripheral axon. Therefore, peripheral motor axon excitability was prospectively and systematically evaluated in more than 400 studies of 11 patients admitted to hospital after traumatic spinal cord injury, with cord lesions above T9 (nine cervical, two thoracic). Recordings commenced within 15 days of admission from the median nerve to abductor pollicis brevis in the upper limb and the common peroneal nerve to tibialis anterior in both lower limbs, and were continued until patient discharge from hospital. Excitability was assessed using threshold tracking techniques and recordings were compared with data from healthy controls. In addition, concurrent clinical measures of strength, serum electrolytes and nerve conduction were collected. High threshold stimulus-response relationships were apparent from the early phase of spinal shock that coincided with depolarization-like features that reached a peak on Day 16.9 (± 2.7 standard error) for the common peroneal nerve and Day 11.8 (± 2.0 standard error) for the median nerve. Overall, changes in the common peroneal nerve were of greater magnitude than for the median nerve. For both nerves, the most significant changes were in threshold electrotonus, which was 'fanned in', and during the recovery cycle superexcitability was reduced (P < 0.001). However, refractoriness was increased only for the common peroneal nerve (P < 0.05). Changes in the spinal injured cohort could not be explained on the basis of an isolated common peroneal nerve palsy. By the time patients with spinal injury were discharged from hospital between Days 68 and 215, excitability for upper and lower limbs had returned towards normative values, but not for all parameters. Electrolyte levels and results for nerve conduction studies remained within normal limits throughout the period of admission. Contrary to prevailing opinion, these data demonstrate that significant changes in peripheral motor axonal excitability occur early during spinal shock, with subsequent further deterioration in axonal function, before recovery ensues.

Utilizing Natural Activity to Dissect the Pathophysiology of Acute Oxaliplatin-induced Neuropathy

Experimental Neurology. Jan, 2011  |  Pubmed ID: 20965170

Oxaliplatin is first-line chemotherapy for colorectal cancer, but produces dose-limiting neurotoxicity. Acute neurotoxicity following infusion produces symptoms including cold-triggered fasciculations and cramps, with subsequent chronic neuropathy developing at higher cumulative doses. Axonal excitability studies were undertaken in 15 oxaliplatin-treated patients before and immediately after oxaliplatin infusion to determine whether the mechanisms underlying acute neurotoxicity altered resting membrane potential or Na(+)/K(+) pump function. Excitability properties were assessed before and after maximal voluntary contraction (MVC) of the abductor pollicis brevis. Following oxaliplatin infusion, abnormalities developed in the recovery cycle with refractoriness markedly increased. Following activity, changes developed consistent with axonal hyperpolarization, with proportional changes pre- and post-oxaliplatin in normalized threshold. However, recovery cycle parameters following activity were significantly and disproportionally enhanced post-oxaliplatin, with partial normalization of the recovery cycle curve post-activity. Patients with the most abnormal change in the recovery cycle after infusion demonstrated the greatest changes post-contraction. Prominent abnormalities developed in Na(+) channel-associated parameters in response to natural activity, without significant alteration in axonal membrane potential or Na(+)/K(+) pump function. Findings from the present series suggest that oxaliplatin affects nerve excitability through voltage-dependent mechanisms, with specific effects mediated through axonal Na(+) channel inactivation.

Cortical Dysfunction Underlies Disability in Multiple Sclerosis

Multiple Sclerosis (Houndmills, Basingstoke, England). Apr, 2012  |  Pubmed ID: 21965421

Background: Gray matter atrophy has been implicated in the development of secondary progressive multiple sclerosis (SPMS). Cortical function may be assessed by transcranial magnetic stimulation (TMS). Determining whether cortical dysfunction was a feature of SPMS could be of pathophysiological significance. Objectives: Consequently, novel paired-pulse threshold tracking TMS techniques were used to assess whether cortical dysfunction was a feature of SPMS. Methods: Cortical excitability studies were undertaken in 15 SPMS, 25 relapsing-remitting MS patients (RRMS) and 66 controls. Results: Short interval intracortical inhibition (SPMS 3.0 ± 2.1%; RRMS 12.8 ± 1.7%, p < 0.01; controls 10.5 ± 0.7%, p < 0.01) and motor evoked potential (MEP) amplitude (SPMS 11.5 ± 2.2%; RRMS 26.3 ± 3.6%, p <0.05; controls 24.7 ± 1.8%, p < 0.01) were reduced in SPMS, while intracortical facilitation (SPMS -5.2 ± 1.9%; RRMS -2.0 ± 1.4, p < 0.05; controls -0.9 ± 0.7, p < 0.01) and resting motor threshold were increased (SPMS 67.5 ± 4.5%; RRMS 56.0 ± 1.5%, p < 0.01; controls 59.0 ± 1.1%, p < 0.001). Further, central motor conduction time was prolonged in SPMS (9.1 ± 1.2 ms, p < 0.001) and RRMS (7.0 ± 0.9 ms, p < 0.05) patients compared with controls (5.5 ± 0.2 ms). The observed changes in cortical function correlated with the Expanded Disability Status Scale. Conclusion: Together, these findings suggest that cortical dysfunction is associated with disability in MS, and documentation of such cortical dysfunction may serve to quantify disease severity in MS.

What is Impact?

Journal of Neurology, Neurosurgery, and Psychiatry. Jan, 2012  |  Pubmed ID: 22166988

Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: A Behavioural and Cognitive Continuum

Amyotrophic Lateral Sclerosis : Official Publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. Jan, 2012  |  Pubmed ID: 22214356

Our objective was to compare the cognitive and behavioural profile of patients with amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD), and to explore the continuum between these disorders according to neuropsychological and behavioural performance using novel methods of testing and analysis. Twenty patients with ALS, 20 bvFTD patients and 20 healthy controls completed a neuropsychiatric and neuropsychological assessment including cognitive screening, working memory, inhibitory control, decision making and emotion recognition. The resulting neuropsychological and behavioural data were analysed by Rasch analysis. ALS patients showed a similar profile to bvFTD patients on tests of working memory, inhibitory control and behavioural measures. Nine ALS patients (45%) had cognitive impairment and five (25%) met criteria for bvFTD. Even in a subset of MND patients with no impairment on the ACE-R, subtle impairment of inhibitory control together with moderate to severe apathy, were found. The Rasch analysis confirmed that all patients could be ranked on the same continuum, based on their neuropsychological performance and behaviour. Thus, the cognitive and behavioural profiles of ALS mirror those seen in bvFTD. Impaired inhibitory control and behavioural changes suggest subtle orbitofrontal dysfunction in ALS. The Rasch analysis revealed a clear overlap between bvFTD and ALS.

Longitudinal Assessment of Oxaliplatin-induced Neuropathy

Neurology. Jan, 2012  |  Pubmed ID: 22232054

Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Journal of Neurology, Neurosurgery, and Psychiatry. Apr, 2012  |  Pubmed ID: 22399791

Does Interneuronal Dysfunction Contribute to Neurodegeneration in Amyotrophic Lateral Sclerosis?

Amyotrophic Lateral Sclerosis : Official Publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. Mar, 2012  |  Pubmed ID: 22424125

Amyotrophic lateral sclerosis (ALS) is typically regarded as a sporadic neurodegenerative disorder that results in a catastrophic failure of the motor system, with characteristically variable involvement of upper and lower motor neuronal populations. A wide range of evidence from clinical, histological, genetic, neurophysiological, neuroimaging and neuropsychological studies, suggests that a loss of central nervous system inhibitory neuronal influence is a contributing factor in ALS pathogenesis. This loss of inhibitory function points intuitively to an 'interneuronopathy', with natural differences in cortical and spinal inhibitory networks reflected in the hitherto unexplained variable compartmentalization of pathology within upper and lower motor neuron populations. An excitotoxic final common pathway might then result from unopposed glutamatergic activity. If correct, therapies aimed specifically at supporting interneuronal function may provide a novel therapeutic strategy.

Impact of Oxaliplatin-induced Neuropathy: a Patient Perspective

Supportive Care in Cancer : Official Journal of the Multinational Association of Supportive Care in Cancer. Mar, 2012  |  Pubmed ID: 22426503

INTRODUCTION: Dose-limiting neurotoxicity is a major side effect of oxaliplatin treatment, producing initial acute neurotoxicity and chronic neuropathy with increasing exposure. The improvement in survival for patients with early-stage colorectal cancer treated with oxaliplatin has highlighted the need for valid and reliable assessment of peripheral neuropathy. OBJECTIVES: The objective of this paper was to explore neuropathic symptoms in oxaliplatin-treated patients as assessed using different methods. METHODS: Consecutive symptomatic patients reporting peripheral neuropathy after oxaliplatin chemotherapy for colorectal cancer were interviewed using a semi-structured clinical interview. Neurotoxicity was also assessed using the National Cancer Institute Common Toxicity Criteria scale (clinician-rated), patient 'self-report' questionnaires (PNQ), nerve conduction and clinical assessment. RESULTS: Twenty patients were assessed, 12.6 ± 2.8 months after treatment cessation (mean cumulative oxaliplatin dose, 789 mg/m(2)). In 40% of patients, neurotoxicity necessitated early cessation of treatment. Only 10% of patients were designated by clinicians with severe neurotoxicity, whilst, in contrast, patient interviews and self-report questionnaires described significant physical limitations due to neuropathic symptoms in 60% of patients. The majority (85%) of patients had objective evidence of sensory neuropathy with nerve conduction studies. Reports from clinical interviews were strongly correlated with patient self-assessment (Pearson coefficient = 0.790, p < 0.0005). CONCLUSION: Given the discrepancies in symptom prevalence highlighted by these findings, the monitoring of oxaliplatin-induced neurotoxicity would benefit from more informative clinical assessment, with inclusion of patient-reported outcome measures. Such an approach would be beneficial in a clinical trial setting to monitor the efficacy of interventions and in prospective studies of survivorship to determine the true burden of peripheral neuropathy in oxaliplatin-treated patients.

Corticomotoneuronal Integrity and Adaptation in Spinal Muscular Atrophy

Archives of Neurology. Apr, 2012  |  Pubmed ID: 22491191

To gain further insight into disease pathophysiologic process and potential adaptations through investigating whether cortical dysfunction or plasticity is a feature of spinal muscle atrophy (SMA).

Hyperexcitability and Amyotrophic Lateral Sclerosis

Neurology. Apr, 2012  |  Pubmed ID: 22517105

Although amyotrophic lateral sclerosis (ALS) was described some 150 years ago, there remain critical questions about the origin and progression of the disease. A recent focus of clinical research has been the potential role of excitotoxicity underlying the pathophysiology of ALS.(1) Several strands of evidence indicate that a net increase in excitatory neurotransmission in ALS results from reduced cortical inhibition. In this issue of Neurology®, Foerster and colleagues(2) add a further piece to this complex pathophysiologic puzzle, by identifying differences in γ-aminobutyric acid (GABA) content in the motor cortex of patients with ALS. Specifically, using a novel magnetic resonance spectroscopy approach, they found reduced cortical GABA in patients with ALS compared to controls. This in vivo characterization of GABA levels in patients with ALS supports the emerging evidence for cortical hyperexcitability in patients with sporadic and familial ALS. The data are also relevant to the urgently needed development of disease-specific biomarkers: while EMG is more sensitive than clinical examination for the detection of lower motor neuronal involvement, a robust biomarker is lacking that may identify subclinical upper motor neuron degeneration and thereby facilitate an early diagnosis of ALS.