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Biomedical subjects

Matthew C Kiernan

Publications and source records attributed to Matthew C Kiernan.

At least 37 records · Page 2Linked to original sources
PubMed2005

Hypokalemic weakness in hyperaldosteronism: activity-dependent conduction block.

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.

Action Potentials↗
PubMed2005

Altered motor nerve excitability in end-stage kidney disease.

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.

Action Potentials↗
PubMed2005

Mutation in the Na+ channel subunit SCN1B produces paradoxical changes in peripheral nerve excitability.

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.

Action Potentials↗
PubMed2005

Altered nerve excitability properties in established diabetic neuropathy.

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.

Action Potentials↗
PubMed2005

Acute tetrodotoxin-induced neurotoxicity after ingestion of puffer fish.

This study documents the effects of puffer-fish poisoning on peripheral nerve. Excitability measurements investigated membrane properties of sensory and motor axons in four patients. The median nerve was stimulated at the wrist, with compound muscle potentials recorded from abductor pollicis brevis and compound sensory potentials from digit 2. Stimulus-responses, strength-duration time constant (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.

Action Potentials↗
PubMed2005

Excitability differences in lower-limb motor axons during and after ischemia.

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.

Action Potentials↗
PubMed2005

Oxaliplatin-induced neurotoxicity and the development of neuropathy.

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.

Adult↗
PubMed2005

Neurotoxic marine poisoning.

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.

Animals↗
PubMed2005

Assessment of disease progression in motor neuron disease.

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.

Algorithms↗
PubMed2005

Segmental facial anhidrosis and tonic pupils with preserved deep tendon reflexes: a novel autonomic neuropathy.

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.

Adie Syndrome↗
PubMed2004

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

The present study was undertaken to determine whether activity-dependent changes in axonal excitability are greater in motor axons than cutaneous afferents for the same impulse load. In nine healthy subjects, supramaximal stimulation at 8 Hz was delivered to the median nerve at the wrist. Changes in the threshold current required to generate compound motor and sensory potentials 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.

Action Potentials↗
PubMed2004

Nerve excitability properties in lower-limb motor axons: evidence for a length-dependent gradient.

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.

Adult↗
PubMed2004

Cytoplasmic body myopathy masquerading as motor neuron disease.

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.

Action Potentials↗
PubMed2004

Mitochondrial dysfunction and rod-like lesions associated with administration of beta2 adrenoceptor agonist formoterol.

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.

Actinin↗
PubMed2002

Wernicke's encephalopathy presenting with upbeating nystagmus.

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.

Anorexia Nervosa↗