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Biomedical subjects

Matthew C Kiernan

Publications and source records attributed to Matthew C Kiernan.

At least 19 recordsLinked to original sources
PubMed2026

Characterising the motif composition and allele length distribution of ZFHX3 GGC repeat expansions in amyotrophic lateral sclerosis.

A pathogenic GGC repeat expansion in zinc finger homeobox 3 (ZFHX3), encoding a pure polyglycine (polyG) tract, causes spinocerebellar ataxia type 4 (SCA4). Intermediate expansions of other SCA loci have been implicated in amyotrophic lateral sclerosis (ALS), while repeat motif composition is recognised to influence pathogenicity in neurodegenerative diseases. Given the genetic pleiotropy between ALS and SCA, we evaluated whether ZFHX3 GGC expansions are associated with ALS and characterised repeat motif composition. ZFHX3 GGC repeat sizes were genotyped using ExpansionHunter in short-read whole-genome sequencing data from ALS cases and healthy controls of European ancestry. Repeat sizes were visually inspected using REViewer, and motif configurations were manually derived from a subset. Receiver operating characteristic analysis and Youden's J statistic identified a candidate repeat size threshold. Logistic regression tested associations of repeat length and motif composition with ALS, while regression models assessed clinical phenotypes. Across 5785 ALS cases and 7982 controls, no association was observed between ZFHX3 expansions and ALS risk. Longer alleles showed a nominal association with later disease onset, however this did not remain significant after Bonferroni correction. Among 802 ALS cases and 800 controls, 50 distinct motif compositions were identified, including 11 encoding pure polyG tracts characteristic of pathogenic SCA4 expansions; none were associated with ALS. Although no association with ALS was observed, this study established the dynamic nature of ZFHX3 repeat motif composition and configuration. Variation within and between repeat sizes, including pure polyG repeats, supports consideration of motif composition alongside allele length when evaluating neurodegenerative disease risk.

Journal Article↗
PubMed2007

Abnormalities in cortical and peripheral excitability in flail arm variant amyotrophic lateral sclerosis.

BACKGROUND: 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. METHODS: Cortical and peripheral nerve excitability studies were undertaken in 11 flail arm patients, defined by muscle weakness limited to the proximal aspects of the upper limbs for at least 24 months. RESULTS: Mean age at disease onset (60.3 years) was similar to other ALS phenotypes (58.3 years), with strong male predominance (male:female distribution: flail arm 10:1; ALS 1.5:1; p<0.05) and prolonged disease duration (flail arm 62.5 months; ALS 15.8 months; p<0.05). There was evidence of cortical hyperexcitability in flail arm patients, similar to findings in ALS, with reduction in short interval intracortical inhibition (flail arm 0.8 (0.6)%; ALS 4.1 (1.1)%; controls 8.5 (1.0)%; p<0.0001) and resting motor threshold (flail arm 53.4 (2.8)%; ALS 56.6 (1.8)%; controls 60.7 (1.5)%; p<0.05), along with an increase in motor evoked potential amplitude (flail arm 49.5 (9.0)%; ALS 44.4 (4.9)%; controls 25.8 (2.8)%; p<0.05). Peripheral nerve excitability studies demonstrated changes consistent with upregulation in persistent Na+ currents and reduction of slow K+ conductances, similar to findings in ALS. CONCLUSION: This study has demonstrated the presence of cortical hyperexcitability in flail arm syndrome, along with abnormalities in peripheral nerve excitability, findings consistent with previous studies in other ALS phenotypes. By demonstrating the presence of upper motor neuron dysfunction, the present study suggests that the flail arm syndrome is an unusual variant of ALS.

Age of Onset↗
PubMed2007

Uremic neuropathy: clinical features and new pathophysiological insights.

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.

Axons↗
PubMed2006

Reversible myeloradiculopathy due to Mycoplasma pneumoniae.

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.

Adult↗
PubMed2006

Oxaliplatin and axonal Na+ channel function in vivo.

PURPOSE: 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. EXPERIMENTAL DESIGN: Excitability studies were combined with standard nerve conduction studies and clinical assessment in 22 patients undergoing treatment with oxaliplatin. RESULTS: Excitability studies recorded before and immediately after oxaliplatin infusion for 89 treatment cycles revealed significant increases in refractoriness and relative refractory period postinfusion in all patients, consistent with an effect of oxaliplatin on axonal Na(+) channels. However, those patients that developed chronic neuropathy had significantly greater changes. Following cessation of oxaliplatin treatment, 41% of patients had persistent symptoms and nerve conduction abnormalities consistent with the development of chronic neuropathy. CONCLUSION: The present study provides evidence that oxaliplatin-induced neurotoxicity is mediated through an effect on axonal Na(+) channels. Clinical nerve excitability techniques may prove beneficial in monitoring for early signs of neurotoxicity and in the assessment of future prophylactic therapies.

Adult↗
PubMed2006

Activity-induced weakness in recessive myotonia congenita with a novel (696+1G>A) mutation.

OBJECTIVE: To investigate the cause of the transient weakness that occurs in recessive myotonia congenita (RMC) following sustained muscle contraction. METHODS: Nerve excitability studies were performed on a 35-year-old male with RMC due to a novel 696+1G>A CLCN1 mutation. The median nerve was stimulated at the wrist and compound muscle action potentials (CMAPs) were recorded from abductor pollicis brevis (APB). Stimulus-response behaviour using two stimulus durations, threshold electrotonus to 100-ms polarizing currents, a current threshold relationship and the recovery of excitability following supramaximal stimulation were recorded at rest. Excitability parameters were also recorded before and after maximal voluntary contraction (MVC) of APB against resistance for 60s. Results were compared to data obtained from 12 normal controls. RESULTS: Baseline axonal excitability parameters were all normal, indicating that axonal function was normal at the point of stimulation. Following one minute of MVC, excitability parameters demonstrated a significant increase in threshold when compared to controls (RMC 54.9%; controls 15.5+/-3.1%). In the RMC patient, this increase in threshold was associated with a 39% reduction in the amplitude of the maximal CMAP, which remained unaffected in controls. CONCLUSIONS: The reduction in maximal CMAP is likely to represent muscle activation failure due to depolarization block, with the increase in threshold possibly reflecting a compensatory attempt by motor axons to overcome prolonged contraction-induced changes in the muscle membrane. SIGNIFICANCE: The prolonged recovery of excitability following sustained muscle contraction is likely to be a contributing factor to symptoms of weakness and fatigue experienced by RMC patients.

Action Potentials↗
PubMed2006

Novel threshold tracking techniques suggest that cortical hyperexcitability is an early feature of motor neuron disease.

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.

Action Potentials↗
PubMed2006

Axonal excitability properties in amyotrophic lateral sclerosis.

OBJECTIVE: To investigate axolemmal ion channel function in patients diagnosed with sporadic amyotrophic lateral sclerosis (ALS). METHODS: A recently described threshold tracking protocol was implemented to measure multiple indices of axonal excitability in 26 ALS patients by stimulating the median motor nerve at the wrist. The excitability indices studied included: stimulus-response curve (SR); strength-duration time constant (tauSD); current/threshold relationship; threshold electrotonus to a 100 ms polarizing current; and recovery curves to a supramaximal stimulus. RESULTS: Compound muscle action potential (CMAP) amplitudes were significantly reduced in ALS patients (ALS, 2.84+/-1.17 mV; controls, 8.27+/-1.09 mV, P<0.0005) and the SR curves for both 0.2 and 1 ms pulse widths were shifted in a hyperpolarized direction. Threshold electrotonus revealed a greater threshold change to both depolarizing and hyperpolarizing conditioning stimuli, similar to the 'fanned out' appearance that occurs with membrane hyperpolarization. The tauSD was significantly increased in ALS patients (ALS, 0.50+/-0.03 ms; controls, 0.42+/-0.02 ms, P<0.05). The recovery cycle of excitability following a conditioning supramaximal stimulus revealed increased superexcitability in ALS patients (ALS, 29.63+/-1.25%; controls, 25.11+/-1.01%, P<0.01). CONCLUSIONS: Threshold tracking studies revealed changes indicative of widespread dysfunction in axonal ion channel conduction, including increased persistent Na+ channel conduction, and abnormalities of fast paranodal K+ and internodal slow K+ channel function, in ALS patients. SIGNIFICANCE: An increase in persistent Na+ conductances coupled with reduction in K+ currents would predispose axons of ALS patients to generation of fasciculations and cramps. Axonal excitability studies may provide insight into mechanisms responsible for motor neuron loss in ALS.

Action Potentials↗
PubMed2006

Ischaemia induces paradoxical changes in axonal excitability in end-stage kidney disease.

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.

Adolescent↗
PubMed2006

Paraneoplastic mononeuritis multiplex in non-small-cell lung carcinoma.

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.

Carcinoma, Non-Small-Cell Lung↗
PubMed2006

Neuropathy, axonal Na+/K+ pump function and activity-dependent excitability changes in end-stage kidney disease.

OBJECTIVE: 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). METHODS: Nerve excitability was assessed in 10 ESKD patients before and after a single session of haemodialysis and in 29 age-matched control subjects. Changes in excitability were recorded at baseline and following maximal voluntary contraction (MVC) of abductor pollicis brevis (APB) for 60s. Serum concentrations of putative neurotoxins including potassium, urea, parathyroid hormone and beta-2-microglobulin were also measured. RESULTS: Baseline excitability values were consistent with axonal depolarisation prior to dialysis. Following maximal voluntary contraction (MVC), there was an increase in threshold, which was associated with reduced strength-duration time constant and increased superexcitability, consistent with axonal hyperpolarisation. These changes were quantitatively similar for patients and controls, arguing against any significant reduction in the axonal Na(+)/K(+) pump in ESKD. Following dialysis, activity-dependent changes were less in ESKD, which suggests greater Na(+)/K(+) pump activity prior to dialysis, the opposite of the changes expected with reduced Na(+)/K(+) pump function. The reduced post-contraction threshold change in post-dialysis recordings is likely to be secondary to relative hyperpolarisation of the axonal membrane following dialysis and reduction in K(+) concentration. CONCLUSIONS: Our findings suggest that Na(+)/K(+) pump function is not impaired in patients with ESKD. SIGNIFICANCE: Pre-dialysis excitability changes in ESKD patients may be explained on the basis of hyperkalaemia. Alteration in Na(+)/K(+) pump function does not appear to be a contributing factor to the development of neuropathy in ESKD patients.

Adolescent↗
PubMed2006

Assessment of cortical excitability using threshold tracking techniques.

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.

Action Potentials↗
PubMed2006

Axonal function and activity-dependent excitability changes in myotonic dystrophy.

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.

Action Potentials↗
PubMed2006

Riluzole therapy for motor neurone disease: an early Australian experience (1996-2002).

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.

Adult↗
PubMed2006

Focal and generalized peripheral nerve dysfunction in spinal cord-injured patients.

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.

Action Potentials↗
PubMed2006

The pathophysiology of oxaliplatin-induced neurotoxicity.

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.

Antineoplastic Agents↗