Showing papers by "David Burke published in 2013"

Pathophysiology of spasticity in stroke

Abstract: Spasticity is defined clinically by increased muscle tone and tendon jerk hyperreflexia in patients who are at rest. However, the excitability of spinal circuits changes during movement, and this definition provides no insight into the extent to which spasticity and associated motor disturbances cause disability. Only a few spinal circuits have been shown to underlie the abnormalities of patients at rest. Movement can be restrained by pathologically enhanced muscle tone, and there is defective control of the feedback to active motoneurons through virtually all spinal reflex pathways. Spasticity does not necessarily require treatment: in fact, some patients rely on the increased muscle tone to help support otherwise weak muscle contractions for stance and locomotion. In addition, much of the increase in muscle tone arises from changes in muscle and motor units, independent of reflex mechanisms. Managing a patient with impairment after a stroke requires therapy tailored to that particular patient because the mechanisms contributing to the disability experienced by one patient may differ from those affecting another.

Clinical, genetic, neurophysiological and functional study of new mutations in episodic ataxia type 1

Abstract: Background and objective Heterozygous mutations in KCNA1 cause episodic ataxia type 1 (EA1), an ion channel disorder characterised by brief paroxysms of cerebellar dysfunction and persistent neuromyotonia. This paper describes four previously unreported families with EA1, with the aim of understanding the phenotypic spectrum associated with different mutations. Methods 15 affected individuals from four families underwent clinical, genetic and neurophysiological evaluation. The functional impact of new mutations identified in the KCNA1 gene was investigated with in vitro electrophysiology and immunocytochemistry. Results Detailed clinical documentation, dating back to 1928 in one family, indicates that all patients manifested episodic ataxia of varying severity. Four subjects from three families reported hearing impairment, which has not previously been reported in association with EA1. New mutations (R167M, C185W and I407M) were identified in three out of the four families. When expressed in human embryonic kidney cells, all three new mutations resulted in a loss of K v 1.1 channel function. The fourth family harboured a previously reported A242P mutation, which has not been previously described in association with ataxia. Conclusions The genetic basis of EA1 in four families is established and this report presents the earliest documented case from 1928. All three new mutations caused a loss of K v 1.1 channel function. The finding of deafness in four individuals raises the possibility of a link between K v 1.1 dysfunction and hearing impairment. Our findings broaden the phenotypic range associated with mutations in KCNA1 .

Re: HCN channels: function and clinical implications.

Abstract: Dr. Benarroch1 highlighted the function of HCN channels. Studies of axonal excitability using threshold tracking techniques allow HCN function to be quantified indirectly in human peripheral nerve in vivo.2 These physiologic studies may clarify the activity of different voltage-dependent channels expressed on the studied axons, even in CNS disease. For example, abnormalities have been shown in benign familial neonatal epilepsy, a condition due to mutation of the KCNQ2 gene encoding Kv7.2. The abnormalities in axonal excitability were those appropriate for loss of slow K+ channel function.3 Current protocols for studying the accommodation to hyperpolarization produced by HCN currents now use strong long hyperpolarizing currents as conditioning stimuli to alter membrane potential.4 This has allowed further insight into the nature of HCN current in human myelinated axons; specifically, that HCN1 is probably expressed on large myelinated axons, but that isoform expression may differ for myelinated afferent and efferent axons.5 In defined patient groups with epilepsy, these techniques could help clarify whether there is abnormal HCN function. In neuropathic pain, the situation is less certain because the action potentials of small nociceptive afferents can only be characterized with microneurography.

Excitability and the safety margin in human axons during hyperthermia

Abstract: Hyperthermia challenges the nervous system's ability to transmit action potentials faithfully. Neuromuscular diseases, particularly those involving demyelination have an impaired safety margin for action potential generation and propagation, and symptoms are commonly accentuated by increases in temperature. The aim of this study was to examine the mechanisms responsible for reduced excitability during hyperthermia. Additionally, we sought to determine if motor and sensory axons differ in their propensity for conduction block during hyperthermia. Recordings of axonal excitability were performed at normal temperatures and during focal hyperthermia for motor and sensory axons in six healthy subjects. There were clear changes in excitability during hyperthermia, with reduced superexcitability following an action potential, faster accommodation to long-lasting depolarization and reduced accommodation to hyperpolarization. A verified model of human motor and sensory axons was used to clarify the effects of hyperthermia. The hyperthermia-induced changes in excitability could be accounted for by increasing the modelled temperature by 6°C (and adjusting the maximum conductances and activation kinetics according to their Q10s; producing a 2 mV hyperpolarization of resting membrane potential), further hyperpolarizing the voltage dependence of Ih (motor, 11 mV; sensory, 7 mV) and adding a small depolarizing current at the internode (motor, 20 pA; sensory, 30 pA). The modelling suggested that slow K(+) channels play a significant role in reducing axonal excitability during hyperthermia. The further hyperpolarization of the activation of Ih would limit its ability to counter the hyperpolarization produced by activity, thereby allowing conduction block to occur during hyperthermia. Language: en

Pathophysiology of HNPP explored using axonal excitability

Abstract: Objective Hereditary liability to pressure palsies (HNPP) is an autosomal dominant disorder of myelination resulting in susceptibility to pressure palsies from compression or stretching of peripheral nerves. Patients and methods This study examined axonal excitability at two sites (one distal and one proximal) in five patients with biopsy and genetically proven HNPP to understand the pathophysiology of the disease. Comparisons were made with age-matched control subjects as well as five Charcot-Marie-Tooth type 1A patients to contrast the findings and explain the different phenotypes of diseases affecting the same gene. Results Changes in axonal excitability were found in HNPP subjects, but these were not uniform along the nerve: at the wrist there were prominent alterations in threshold electrotonus, whereas at the elbow there were only subtle alterations in the recovery cycle and the response to strong long-lasting hyperpolarisation. Threshold was raised at both sites, but the nerves were probably not hyperpolarised. Not unexpectedly, changes in CMT1A subjects were more marked than those in HNPP subjects and were uniform along the nerve. Conclusions Structural abnormalities at the node of Ranvier are sufficient to explain the changes in axonal excitability in HNPP, and these abnormalities would predispose the nerves to conduction block when subjected to pressure or stretch.

Late-onset neurological symptoms in thalidomide-exposed subjects: a study of an Australasian cohort.

Abstract: Background and purpose Thalidomide was marketed for the treatment of morning sickness and resulted in foetal death and physical deformities. The exact mechanism of action of thalidomide in its teratogenicity is still actively debated in the literature. Methods This study reviewed 16 of the confirmed Australasian victims of in utero exposure to thalidomide who now presented with new-onset neurological symptoms in the fourth and fifth decades. Results Clinical neurological examination and neurophysiological investigations revealed that new symptoms were due in part to compressive neuropathies, often exacerbated by the adaptations made to accommodate the disability and poor mobility arising from the limb deformities. Other subjects were found to have musculoskeletal symptoms due to compensatory postures employed to perform tasks of daily living. Conclusions The study provides no evidence of ongoing loss of neurons or late reactivated neural degeneration and no evidence of a generalized peripheral neuropathy. Rather, the development of new symptoms in subjects can be explained by compressive neuropathies and compensatory postures employed to perform tasks of daily living.

Self-sustained motor activity triggered by interlimb reflexes in chronic spinal cord injury, evidence of functional ascending propriospinal pathways.

Abstract: The loss or reduction of supraspinal inputs after spinal cord injury provides a unique opportunity to examine the plasticity of neural pathways within the spinal cord. In a series of nine experiments on a patient, quadriplegic due to spinal cord injury, we investigated interlimb reflexes and self-sustained activity in completely paralyzed and paretic muscles due to a disinhibited propriospinal pathway. Electrical stimuli were delivered over the left common peroneal nerve at the fibular head as single stimuli or in trains at 2–100 Hz lasting 1 s. Single stimuli produced a robust interlimb reflex twitch in the contralateral thumb at a mean latency 69 ms, but no activity in other muscles. With stimulus trains the thumb twitch occurred at variable subharmonics of the stimulus rate, and strong self-sustained activity developed in the contralateral wrist extensors, outlasting both the stimuli and the thumb reflex by up to 20 s. Similar behavior was recorded in the ipsilateral wrist extensors and quadriceps femoris of both legs, but not in the contralateral thenar or peroneal muscles. The patient could not terminate the self-sustained activity voluntarily, but it was abolished on the left by attempted contractions of the paralyzed thumb muscles of the right hand. These responses depend on the functional integrity of an ascending propriospinal pathway, and highlight the plasticity of spinal circuitry following spinal cord injury. They emphasize the potential for pathways below the level of injury to generate movement, and the role of self-sustained reflex activity in the sequelae of spinal cord injury.

Different mechanisms underlying changes in excitability of peripheral nerve sensory and motor axons in multiple sclerosis.

Abstract: Introduction: Subtle involvement of peripheral nerves may occur in multiple sclerosis. Motor excitability studies have suggested upregulation of slow K+ currents, probably secondary to altered motoneuron properties resulting from the central lesion. This study concentrates on sensory axons. Methods: Excitability of median nerve axons at the wrist was studied in 26 patients. Results: Sensory recordings were possible in 22 patients, and reduced superexcitability was the sole abnormality. There was no evidence for changes in membrane potential or demyelination. The decrease was significant in patients taking immunomodulatory therapy. These findings could be reproduced in a computer model by changing the gating of fast K+ channels. Motor axon findings were consistent with previously reported increased slow K+ current. Conclusions: The sensory findings differ from motor findings. They can be explained by a humoral factor, possibly cytokines, which can penetrate the paranode and have been documented to alter the gating of K+ channels. Muscle Nerve, 2013

Axonal excitability during ischemia in MELAS.

Abstract: Introduction In mitochondrial disease, it is likely that energy substrate depletion leads to paralysis of ATPase-dependent pumps, resulting in membrane depolarization. Axonal depolarization has been demonstrated in a crisis, but not in the resting state. We, therefore, stressed axons using ischemia to see if this would reveal abnormal responses, as occurs in diabetes mellitus. Methods Excitability of median nerve axons at the wrist was studied in 13 patients with MELAS (6 with glucose intolerance) and 17 control subjects in response to ischemia due to inflation of a cuff around the arm for 10 min. Results There were no significant differences in preischemic measures of axonal excitability or in the intra- and postischemic responses. Conclusions Although depolarization has been noted to occur spontaneously during a crisis, we could not demonstrate a defect of axonal ATP-dependent mechanisms. The mechanisms underlying axonal excitability and neuropathy in diabetes may not apply to MELAS. Muscle Nerve 47: 762–765, 2013