Strength-duration Time Constant Research Articles

Motor and Sensory Axon Excitability Properties From the Median and Ulnar Nerves and the Effects of Age on These Properties.

Threshold tracking is a new noninvasive approach for detecting axonal excitability changes in vivo. In this study, the authors compared the excitability indices of motor and sensory axons of median and ulnar nerves to determine whether the two nerves behave in a similar or a noninterchangeable way. They also examined whether age affects these indices. Seventy normal subjects aged 22-70 years (mean, 36.7 ± 12.5 years) were recruited. Multiple excitability indices were measured in both motor and sensory axons from median and ulnar nerves. The threshold and rheobase were significantly higher for the ulnar motor axons recorded at the first dorsal interosseous muscle than for the median motor axons at the abductor pollicis brevis muscle. In contrast, the strength-duration time constant was decreased, threshold electrotonus reduction (in both depolarizing and hyperpolarizing directions) was significantly smaller, I/V slope was decreased, and subexcitability was reduced for the ulnar motor axons. Excitability indices measured in the sensory axons of both nerves were not overtly different. In R-square analysis, age had a homogeneous influence on sensory axon excitability but heterogeneous influence on motor axon excitability. The excitability indices may be interchangeable for sensory axons but not motor axons. The authors therefore recommend recording motor axonal excitability in various muscle groups rather than a single muscle group.

Effect of coil orientation on strength–duration time constant and I-wave activation with controllable pulse parameter transcranial magnetic stimulation

ObjectiveTo compare the strength–duration (S–D) time constants of motor cortex structures activated by current pulses oriented posterior–anterior (PA) or anterior–posterior (AP) across the central sulcus. MethodsMotor threshold and input–output curve, along with motor evoked potential (MEP) latencies, of first dorsal interosseus were determined at pulse widths of 30, 60, and 120μs using a controllable pulse parameter (cTMS) device, with the coil oriented PA or AP. These were used to estimate the S–D time constant and we compared with data for responses evoked by cTMS of the ulnar nerve at the elbow. ResultsThe S–D time constant with PA was shorter than for AP stimulation (230.9±97.2 vs. 294.2±90.9μs; p<0.001). These values were similar to those calculated after stimulation of ulnar nerve (197±47μs). MEP latencies to AP, but not PA stimulation were affected by pulse width, showing longer latencies following short duration stimuli. ConclusionPA and AP stimuli appear to activate the axons of neurons with different time constants. Short duration AP pulses are more selective than longer pulses in recruiting longer latency corticospinal output. SignificanceMore selective stimulation of neural elements may be achieved by manipulating pulse width and orientation.

A single blind randomized controlled clinical trial of mexiletine in amyotrophic lateral sclerosis: Efficacy and safety of sodium channel blocker phase II trial

Fasciculations are characteristic features of amyotrophic lateral sclerosis (ALS), and suggest motor nerve hyperexcitability. Recent reports have shown that an increase in persistent nodal sodium current is associated with shorter survival in ALS patients. This objective of this trial is to study the efficacy and safety of mexiletine, a sodium channel blocker, for ALS. Sixty eligible participants were randomly allocated (1:1) to riluzole 100 mg or riluzole plus mexiletine 300 mg. The primary endpoint was change in the revised ALS functional rating scale (ALSFRS-R) scores during six months. We also monitored strength-duration time constant (SDTC, a measure of persistent sodium current) in median motor axons. Results showed that during six months of treatment, changes in the ALSFRS-R score and SDTC were –7.0 ± 7.1 and –0.04 ± 0.1, respectively, in the riluzole group and –6.9 ± 6.4 and 0.04 ± 0.1, respectively, in the mexiletine group (p = 0.96 and 0.049). Adverse events amounted 20% in the riluzole and 33% in the mexiletine groups. In conclusion, the results suggest that daily 300 mg mexiletine has no effects on axonal sodium current and ALSFRS-R deterioration in ALS. We have to attempt another trial using a higher dose of mexiletine or other agents to suppress sodium currents and ALS progression in the future.

Effects of transcranial magnetic stimulation coil orientation and pulse width on short-latency afferent inhibition

Purpose We used a controllable pulse parameter transcranial magnetic stimulation (cTMS) device to assess whether adjusting pulse width and coil orientation would allow more selective stimulation of different neuronal populations. Methods Young healthy subjects participated in experiments involving single pulse stimulation over the hand motor area elicited by a cTMS device connected to a figure-of-eight coil. Experiment 1 (n=10) evaluated the effect of coil orientation (posterior-anterior, PA; anterior-posterior, AP) and pulse width (30, 60 and 120 μs) on the strength-duration curve, the input-output (IO) curve and the latency of the motor evoked potentials (MEPs) in the first dorsal interosseous muscle. Experiment 2 (n=12) evaluated the effect of coil orientations (PA, AP) and pulse width (30 and 120 μs) on short-latency afferent inhibition (SAI), tested with electrical median nerve stimulation at the wrist prior to TMS (inter-stimulus intervals: N20 latency +2 and +4 ms). All tests were completed during background contraction (∼10% maximum). Results The mean strength-duration time constants were shorter for PA than AP directed currents when estimated using motor threshold data (231 vs. 294 μs; t-test, p = 0.008) and IO data (252 vs. 296 μs; t-test, p < 0.001). ANOVA revealed an interaction of pulse width and orientation on MEP latencies (p = 0.001), due mainly to the increase in latencies with short duration AP stimuli. A similar pulse width and orientation interaction was observed for SAI (p = 0.011), resulting from the stronger inhibition with AP stimuli of short duration. Conclusion PA and AP oriented pulses appear to activate neural populations with different time constants. The AP-sensitive neural populations that elicit the longest latency MEPs are more readily stimulated by short than by long duration pulses, and appear more sensitive to SAI. Manipulating pulse width may improve the selectivity of AP stimulation.

Altered axonal excitability properties and nerve edema in POEMS syndrome

ObjectivePOEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome is a rare cause of demyelinating neuropathy with upregulation of vascular endothelial growth factor (VEGF). This study aimed to elucidate axonal excitability properties and their relation to VEGF levels and nerve edema in POEMS neuropathy. MethodsAxonal excitability measurement and nerve ultrasound were performed in the median nerve of 33 patients with POEMS syndrome. Serum VEGF levels were measured by ELISA. ResultsCompared with normal subjects (n=87), POEMS patients showed longer strength-duration time constant, fanning-out of threshold electrotonus curves, and greater threshold changes in a hyperpolarizing current–threshold relationship. Nerve ultrasound showed significant enlargement in POEMS patients. Serum VEGF levels and the extent of nerve edema partly correlated with nerve conduction slowing, as well as persistent sodium currents and inward rectification. ConclusionsIn POEMS syndrome, patterns of changes in excitability properties could suggest increased persistent sodium currents, and impaired potassium and inward rectifying channels. The findings were not consistent with depolarization due to nerve edema and compression ischemia. SignificanceIn addition to demyelination, nerve edema induced by upregulated VEGF, and upregulated inflammatory cytokines could modulate profiles of POEMS neuropathy.

Abnormal gating of axonal slow potassium current in cramp-fasciculation syndrome

ObjectiveCramp-fasciculation syndrome (CFS) is a heterogeneous condition with multiple underlying causes. Although dysfunction of slow K+ channels has been reported in patients with CFS, testing all potential candidates for this problem using conventional in vitro functional analysis would be prohibitively cost- and labor-intensive. However, relatively economical and non-invasive nerve-excitability testing can identify ion channel dysfunction in vivo when combined with numerical modeling. MethodsPatients with CFS underwent nerve conduction study, needle electromyography, and nerve excitability testing. Mathematical modeling of axonal properties was applied to identify the pathophysiology. ResultsFour patients had distinct electrophysiological findings (i.e., fasciculation potentials, doublet/multiplet motor unit potentials, and sustained F responses); excitability testing showed the following abnormalities: reduction of accommodation during prolonged depolarization, lack of late sub excitability after a supramaximal stimulation, and reduction of the strength–duration time constant. Mathematical modeling showed a loss of voltage-dependence of a slow K+ current. None of these patients had a mutation in the KCNQ2, 3, or 5 genes. ConclusionsThis study showed that patients with CFS might have abnormal kinetics in a slow K+ current. SignificanceNerve-excitability testing may aid the decision to start therapeutic intervention such as administration of slow K+ channel openers.

Sensory axonal dysfunction in cervical radiculopathy

ObjectiveThe aim of this study was to evaluate changes in sensory axonal excitability in the distal nerve in patients with cervical radiculopathy.MethodsThe patients were classified by the findings of cervical...

Theoretical predications of the effects of temperature on simulated adaptive processes in human motor nerve axons at 20°C-42°C.

The effects of temperature on conducting and accommodative processes in the myelinated human motor nerve fiber were previously studied by us in the range of 20°C-42°C. To complete the cycle of our studies on adaptive processes in the fiber, the temperature effects on strength-duration time constant, rheobasic current and recovery cycle are investigated. The computations use our temperature dependent multi-layered model of the fiber and the temperature is increased from 20°C to 42°C. The results show that these excitability parameters are more sensitive to the hypothermia (≤ 25°C) and are most sensitive to the hyperthermia (≥ 40°C), especially at 42°C, than at temperatures in the range of 28°C-37°C. With the increase of temperature from 20°C to 42°C, the strength-duration time constant decreases ~ 8.8 times, while it decreases ~ 2.7% per °C in the range of 28°C-37°C. Conversely, the rheobasic current increases ~ 4.4 times from 20°C to 42°C, while it increases ~ 2.3% per °C in the range of 28°C-37°C. The behavior of relative refractory period and axonal superexcitability in a 100 ms recovery cycle is complex with the increase of temperature. The axonal superexcitability decreases with the increase of temperature during hypothermia. However, it increases rapidly with the increase of temperature during hyperthermia, especially at 42°C and a block of each applied third testing stimulus is obtained. The superexcitability period is followed by a late subexcitability period when the temperatures are in the physiological range of 32°C-37°C. The present results are essential for the interpretation of mechanisms of excitability parameter changes obtained here and measured in healthy subjects with symptoms of cooling, warming and fever, which can result from alterations in body temperature. Our present and previous results confirm that 42°C is the highest critical temperature for healthy subjects.

P850: Electrophysiological pattern in GLUT1 deficiency syndrome (A275T mutation)

s of Poster Presentations / Clinical Neurophysiology 125, Supplement 1 (2014) S1–S339 S269 Figure 2. The relationship between muscle strength and transcranial stimulation motor evoked potential. Conclusions: There is the positive relation between the MEP amplitude and the muscle strength. So, the fixed quantity evaluation method using the statistical technique makes TCS-MEP reliable. And TCS-MEP may enhance us to remove tumors in central nervous system and at the same time preserve motor functions. Moreover this relation between MEP and muscle strength is useful for understanding the motor control system. P850 Electrophysiological pattern in GLUT1 deficiency syndrome (A275T mutation) C. Giliberto1, V. Sofia1, R. Barone2, R. Guerrini3, M. Zappia1 1University of Catania, Department G.F. Ingrassia, Section of Neurosciences, Catania, Italy; 2University of Catania, Pediatric Neurology, Department of Pediatrics, Catania, Italy; 3University of Florence, Pediatric Neurology, Unit and Laboratories, Children’s Hospital A. Meyer, Florence, Italy Question: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is characterized by impaired glucose transport across the blood-brain barrier due to SLC2A1-gene mutation. GLUT1DS infancy onset shows epileptic encephalopathy, ataxia and microcephaly although paroxysmal exerciseinduced dyskinesia and epilepsy may also be observed. Exercise and recovery-induced modifications of GLUT4 and GLUT1 expression in human muscle have been reported.We describe clinical and electromyographyc correlates of a GLUT1DS patient with adult-onset of exercise-induced dystonia. Patients and methods: A 19 year old male with mild mental retardation presented with a two-year history of episodic stiffness in his calves and feet and painless flexion of the toes followed by leg weakness triggered by exertion and starvation and alleviated by rest and eating. His father had experienced exercise-induced leg dystonia at younger age. A heterozygous missense of mutation (c.823G>A; p.A275T) of SLC2A1 gene was found in the proband and his father.The proband underwent an electromyographyc study after voluntary contraction (5 minutes) to investigate muscle membrane excitability with the evaluation of compound muscle action potential (CMAP) amplitude. Results: The test disclosed significant decrement of CMAP amplitude up to −42% (n.v.≤−20%) after 40 minutes from exercise with respect to the pre-exercise CMAP amplitude (baseline). The same test repeated after carbohydrate-rich food intake showed a significant improvement of CMAP from baseline (−26%). Conclusions: The electrophysiological study after exercise showed a reduction of CMAP amplitude in this patient with GLUT1DS (A275T mutation). Our data suggest a possible involvement of muscle membrane excitability in GLUT1DS. P851 Tracking the spatiotemporal profile of cortical and peripheral motor axon hyperexcitability in amyotrophic lateral sclerosis E. Bakola1, P. Kokotis1, R. Carr2, M. Schmelz2, M. Rentzos1, T. Zambelis1, N. Karandreas1 1University of Athens, Medical School, Department of Neurology, Athens, Greece; 2University of Heidelberg, Mannheim Medical School, Department of Anesthesiology, Mannheim, Germany Question: Recent studies using magnetic and electrical excitability tracking tools have confirmed early hyperexcitability in ALS. This study sets out to use excitability testing to examine directly the spatiotemporal profile of cortical and peripheral hyperexcitability in ALS patients simultaneously, to associate these parameters to the clinical course of the disease and to compare them with healthy controls. Methods: Nineteen patients with first-diagnosed definite ALS (group A), four patients with advanced disease (group B) and ten control healthy volunteers (group C) were included in the study. Multiple axonal excitability properties (threshold electrotonus, strength-duration time constant, recovery cycle, current-threshold relationship) and TMS investigations including measurement of resting motor threshold (RMT) and motor evoked potential (MEP) were measured. Results: In group A there were greater changes in depolarizing threshold electrotonus (TD) compared with group B (t-test p<0.03). No differences in recovery cycle, strength-duration time constant, current-threshold relationship were noted between the three groups. Regarding the cortical excitability parameters, there was a significant decrease in the slope of MEP amplitude to TMS intensity in group B with the advanced disease in comparison to controls (Mann-Whitney U test p<0.05). ANCOVA showed strong correlation between TD and slope of cortical excitability (p<0.01) after correcting for the status of the disease (groups A,B,C). Conclusions: These are preliminary results of an ongoing study trying to understand the changes in axonal and cortical excitability in first-diagnosed and advanced disease in order to provide insight into the pathophysiological basis of the disease and furthermore provide useful information for the best treatment approach in the future.

P853: Nerve excitability change by chronic administration of methylglyoxal: implication for diabetic neuropathy

Question: The methylglyoxal (MGO) pathway is an offshoot of glycolysis, which converts glucose into MGO. Frequently increased in diabetic patients, MGO is highly toxic, resulting in activation of apoptosis and mitochondrial damage. Recently, MGO was found to be a causative agent for neuropathic pain. Because abnormal nerve excitability is frequently present in peripheral neuropathy and neuropathic pain, MGO can alter overall nerve excitability. The objective of the present study was to observe the chronic effects of MGO on peripheral nerve excitability in vivo. Methods: Eight adult male mice were examined. Sensory nerve multiple excitability testing (QTRAC) was performed from a tail nerve under inhalational anesthesia. The parameters were compared between at baseline and 1 week after intraperitoneal injection of MGX (0.005 ml/10g body weight) nine times (3 times weekly for 3 weeks). Results: The tested animals were all survived. The excitability parameters were similar in strength-duration time constant and threshold changes by long depolarizing current (threshold electrotonus: TE). The threshold changes by long hyperpolarizing current (TE) became smaller by MGO; (1) TEh(peak) by -70% conditioning current: -203.8±7.5 at baseline to 162.3±9.1 post-injection, P=0.003; (2) TEh(90-100ms): -94.3±4.9 at baseline to -71.7±5.5 post-injection, P=0.006. The recovery cycle showed smaller refractoriness at 2ms by MGO: 23.5±3.0 at baseline to 7.9±4.8 post-injection, P=0.01. The overall nerve excitability assessed by strength-response curves was slightly reduced after injection. Conclusions: Chronic administration of MGO changed axonal excitability in vivo. It is likely that MGO facilitated hyperpolarization-activated cation current (Ih). The upregulation of Ih may be responsible for abnormal excitability and sensory symptoms of diabetic neuropathy.

P777: Reduction in motor nerve strength-duration time constant during the anti-voltage-gated Na+ channel therapy in epilepsy

P777: Reduction in motor nerve strength-duration time constant during the anti-voltage-gated Na+ channel therapy in epilepsy

Transient impairment of the axolemma following regional anaesthesia by lidocaine in humans

The local anaesthetic lidocaine is known to block voltage-gated Na(+) channels (VGSCs), although at high concentration it was also reported to block other ion channel currents as well as to alter lipid membranes. The aim of this study was to investigate whether the clinical regional anaesthetic action of lidocaine could be accounted for solely by the block of VGSCs or whether other mechanisms are also relevant. We tested the recovery of motor axon conduction and multiple measures of excitability by 'threshold-tracking' after ultrasound-guided distal median nerve regional anaesthesia in 13 healthy volunteers. Lidocaine caused rapid complete motor axon conduction block localized at the wrist. Within 3 h, the force of the abductor pollicis brevis muscle and median motor nerve conduction studies returned to normal. In contrast, the excitability of the motor axons at the wrist remained markedly impaired as indicated by a 7-fold shift of the stimulus-response curves to higher currents with partial recovery by 6 h and full recovery by 24 h. The strength-duration properties were abnormal with markedly increased rheobase and reduced strength-duration time constant. The changes in threshold during electrotonus, especially during depolarization, were markedly reduced. The recovery cycle showed increased refractoriness and reduced superexcitability. The excitability changes were only partly similar to those previously observed after poisoning with the VGSC blocker tetrodotoxin. Assuming an unaltered ion-channel gating, modelling indicated that, apart from up to a 4-fold reduction in the number of functioning VGSCs, lidocaine also caused a decrease of passive membrane resistance and an increase of capacitance. Our data suggest that the lidocaine effects, even at clinical 'sub-blocking' concentrations, could reflect, at least in part, a reversible structural impairment of the axolemma.

Cortical excitability differences in hand muscles follow a split‐hand pattern in healthy controls

Differences in cortical and axonal excitability may underlie preferential atrophy of abductor pollicis brevis (APB) and first dorsal interosseous (FDI) in amyotrophic lateral sclerosis, termed the split-hand. Consequently, this study aimed to determine whether differences in excitability follow a split-hand pattern across the intrinsic hand muscles. Excitability studies were undertaken using threshold tracking techniques in 26 healthy controls with responses recorded over APB, FDI, and abductor digiti minimi. Short interval intracortical inhibition was significantly greater from the APB and FDI. In addition, motor evoked potential amplitude was greater, while cortical silent period was longer from APB and FDI. At a peripheral level, the strength-duration time constant was greater when recorded over APB. This study establishes that differences in cortical excitability follow the split-hand pattern in healthy controls, a finding potentially explained by evolution of specialized activity of APB/FDI in complex hand tasks. Muscle Nerve 49: 836-844, 2014.

ALS pathophysiology: Insights from the split-hand phenomenon

ObjectiveThe aim of the present study was to assess whether peripheral mechanisms, mediated through axonal dysfunction, may contribute to development of the split-hand in amyotrophic lateral sclerosis (ALS). MethodsMedian and ulnar nerve motor axonal excitability studies were undertaken on 21 ALS patients with motor responses recorded over the abductor pollicis brevis (APB), abductor digit minimi (ADM) and first dorsal interosseous (FDI) muscles, and results compared to 24 controls. ResultsThe split-hand index (SI), an objective biomarker of preferential atrophy of APB and FDI muscles, was significantly reduced in ALS (SIALS 7.8±1.7, SICONTROLS 13.1±1.1, P<0.0001). Axonal excitability studies identified significant prolongation of strength-duration time constant in ALS patients when recording over the APB (P<0.05) and ADM axons (P<0.05) but not FDI axons (P=0.22). Greater changes in depolarising threshold electrotonus were also evident across the range of intrinsic hand muscles and were accompanied by increases of superexcitability in APB (P<0.01) and FDI (P<0.05) axons. ConclusionThe present study reinforces the significance of the split-hand phenomenon in ALS and argues against a significant peripheral contribution in the underlying development. SignificanceAxonal dysfunction may appear as a downstream process that develops secondary to the intrinsic pathophysiological origins of ALS.

O3-C-3. Electrophysiological study of familial amyotrophic lateral sclerosis with expansions in the C9ORF72

A hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (C9ORF72) gene was recently discovered as a cause underlying familial amyotrophic lateral sclerosis (ALS), and considered as the most common genetic cause of sporadic ALS in Caucasian populations. We investigated electrophysiological features of an ALS patient with expansion in the C9OFR72.The patient was a 63-year-old female and had family history of ALS. She developed bulbar palsy and subsequent limb weakness for 9 months. On admission, muscle atrophy in the tongue and four limbs, and pyramidal signs in the cranial, cervical, and lumbar segments were seen. She showed neither dementia nor Parkinsonism. On electromyogram, fasciculations were detected in the tibialis anterior. Axonal excitability testing showed greater strength-duration time constant, greater changes in depolarizing threshold electrotonus, and greater supernormality in recovery cycle, which indicate increased sodium conductance and reduced potassium conductance. The above findings suggest increased axonal excitability in this case. Motor axonal hyperexcitability is considered as one of the major prognostic factors in sporadic ALS. This might enhance neuronal death also in FALS with the C9ORF72 repeat expansion.

Why are sensory axons more vulnerable for ischemia than motor axons?

ObjectiveIn common peripheral neuropathies, sensory symptoms usually prevail over motor symptoms. This predominance of sensory symptoms may result from higher sensitivity of sensory axons to ischemia.MethodsWe measured median nerve compound sensory action potentials (CSAPs), compound muscle action potentials (CMAPs), and excitability indices in five healthy subjects during forearm ischemia lasting up to disappearance of both CSAPs and CMAPs.ResultsIschemia induced: (1) earlier disappearance of CSAPs than CMAPs (mean ± standard deviation 30±5 vs. 46±6 minutes), (2) initial changes compatible with axonal depolarization on excitability testing (decrease in threshold, increase in strength duration time constant (SDTC) and refractory period, and decrease in absolute superexcitability) which were all more prominent in sensory than in motor axons, and (3) a subsequent decrease of SDTC reflecting a decrease in persistent Na+ conductance during continuing depolarisation.InterpretationOur study shows that peripheral sensory axons are more vulnerable for ischemia than motor axons, with faster inexcitability during ischemia. Excitability studies during ischemia showed that this was associated with faster depolarization and faster persistent Na+ channel inactivation in sensory than in motor axons. These findings might be attributed to differences in ion channel composition between sensory and motor axons and may contribute to the predominance of sensory over motor symptoms in common peripheral neuropathies.

Increased variability of axonal excitability in amyotrophic lateral sclerosis

ObjectiveAmyotrophic lateral sclerosis (ALS) is characterised by the increased excitability of motoneurons and heterogeneous loss of axons. The heterogeneous nature of the disease process among fibres may show variability of excitability in ALS. MethodsMultiple nerve excitability tests were performed in 28 ALS patients and 23 control subjects, by tracking at the varying threshold levels (10%, 20%, 40% and 60% of maximum amplitudes). ResultsIn normal controls, excitability measures at low target levels have the following characteristics compared to those at high target levels: longer strength–duration time constant, greater threshold reduction during depolarising currents and smaller threshold increase to hyperpolarising currents. ALS patients had less clear amplitude dependency of the parameters than the controls, indicating variability of axonal excitability. Three ALS patients demonstrated greater target-amplitude-dependent threshold changes in threshold electrotonus than controls, suggesting selective axonal hyperexcitability. ConclusionsSome of the ALS patients had variable axonal excitability at different target amplitudes, suggesting preferential hyperexcitability in the axons with low target amplitude levels. SignificanceVariable membrane potentials of motor axons in ALS may be assessed by recording excitability testing at different target amplitude levels.

Effects of Axonal Ion Channel Dysfunction on Quality of Life in Type 2 Diabetes

OBJECTIVEPharmacological agents for diabetic peripheral neuropathy (DN) target a number of mechanisms, including sodium channel function and γ-aminobutyric acid–minergic processes. At present, prescription is undertaken on a trial-and-error basis, leading to prolonged medication trials and greater healthcare costs. Nerve-excitability techniques are a novel method of assessing axonal ion channel function in the clinical setting. The aim of this study was to determine the effects of axonal ion channel dysfunction on neuropathy-specific quality-of-life (QoL) measures in DN.RESEARCH DESIGN AND METHODSFifty-four patients with type 2 diabetes mellitus underwent comprehensive neurologic assessment, nerve-conduction studies, and nerve-excitability assessment. Neuropathy severity was assessed using the Total Neuropathy Score. Neuropathy-specific QoL was assessed using a DN-specific QoL questionnaire (Neuropathy-Specific Quality of Life Questionnaire [NeuroQoL]). Glycosylated hemoglobin and BMI were recorded in all patients.RESULTSNeuroQoL scores indicated significant QoL impairment (mean 9.08 ± 5.93). Strength-duration time constant (SDTC), an excitability parameter reflecting sodium channel function, was strongly correlated with QoL scores (r = 0.545; P < 0.005). SDTC was prolonged in 48.6% of patients who experienced neuropathic symptoms. A significant correlation was also noted between SDTC and neuropathy severity (r = 0.29; P < 0.05). This relationship was strengthened when looking specifically at patients with clinically graded neuropathy (r = 0.366; P < 0.05).CONCLUSIONSThe current study has demonstrated an association between markers of sodium channel function and QoL in DN. The study demonstrates that excitability techniques may identify patients in whom altered sodium channel function may be the dominant abnormality. The findings suggest that excitability techniques may have a role in clinical decision making regarding neuropathic treatment prescription.

Functional Recovery of Regenerating Motor Axons is Delayed in Mice Heterozygously Deficient for the Myelin Protein P0 Gene

Mice with a heterozygous knock-out of the myelin protein P0 gene (P0+/-) develop a neuropathy similar to human Charcot-Marie-Tooth disease. They are indistinguishable from wild-types (WT) at birth and develop a slowly progressing demyelinating neuropathy. The aim of this study was to investigate whether the regeneration capacity of early symptomatic P0+/- is impaired as compared to age matched WT. Right sciatic nerves were lesioned at the thigh in 7-8months old mice. Tibial motor axons at ankle were investigated by conventional motor conduction studies and axon excitability studies using threshold tracking. To evaluate regeneration we monitored the recovery of motor function after crush, and then compared the fiber distribution by histology. The overall motor performance was investigated using Rotor-Rod. P0+/- had reduced compound motor action potential amplitudes and thinner myelinated axons with only a borderline impairment in conduction and Rotor-Rod. Plantar muscle reinnervation occurred within 21days in all mice. Shortly after reinnervation the conduction of P0+/- regenerated axons was markedly slower than WT, however, this difference decayed with time. Nevertheless, after 1month, regenerated P0+/- axons had longer strength-duration time constant, larger threshold changes during hyperpolarizing electrotonus and longer relative refractory period. Their performance at Rotor-Rod remained also markedly impaired. In contrast, the number and diameter distribution of regenerating myelinated fibers became similar to regenerated WT. Our data suggest that in the presence of heterozygously P0 deficient Schwann cells, regenerating motor axons retain their ability to reinnervate their targets and remyelinate, though their functional recovery is delayed.

Split hand syndrome in amyotrophic lateral sclerosis: different excitability changes in the thenar and hypothenar motor axons

BackgroundIn amyotrophic lateral sclerosis (ALS), muscle wasting preferentially affects the abductor pollicis brevis (APB) and first dorsal interosseous over the abductor digit minimi (ADM), and this is termed ‘split hand’....