Neil Simon - Academia.edu (original) (raw)

Papers by Neil Simon

Research paper thumbnail of Advances in the neurological and neurosurgical management of peripheral nerve trauma

Journal of neurology, neurosurgery, and psychiatry, Jan 28, 2015

Peripheral nerve trauma frequently affects younger people and may result in significant and long-... more Peripheral nerve trauma frequently affects younger people and may result in significant and long-lasting functional disability. Currently, diagnosis and monitoring of peripheral nerve injury relies on clinical and electrodiagnostic information, supplemented by intraoperative electrophysiological studies. However, in a significant proportion of nerve injuries, the likelihood of spontaneous regeneration resulting in good functional outcome remains uncertain and unnecessary delays to treatment may be faced while monitoring for recovery. Advances in non-invasive imaging techniques to diagnose and monitor nerve injury and regeneration are being developed, and have the potential to streamline the decision-making process. In addition, advances in operative and non-operative treatment strategies may provide more effective ways to maximise functional outcomes following severe peripheral nerve trauma. This review discusses these advances in light of the current state of the art of management ...

Research paper thumbnail of Diffusion weighted MRI and tractography for evaluating peripheral nerve degeneration and regeneration

Neural regeneration research, Jan 15, 2014

Research paper thumbnail of Visualizing axon regeneration after peripheral nerve injury with magnetic resonance tractography

Neurology, Jan 7, 2014

ABSTRACT Diffusion tensor imaging (DTI) with tractography is an MRI technique that can visualize ... more ABSTRACT Diffusion tensor imaging (DTI) with tractography is an MRI technique that can visualize nerve pathways by taking advantage of anisotropy of water diffusion in tracts with longitudinally oriented fibers. To date, no study in humans has shown that DTI and tractography can follow regeneration of axons during recovery from traumatic peripheral nerve injury. We show that tractography is able to identify regenerating axons advancing through a graft repair of an injured nerve, and demonstrate correlation with evidence of recovery on serial clinical, electrodiagnostic, and muscle MRI assessments.

Research paper thumbnail of P315 IS IVIG TREATMENT WARRANTED IN PATIENTS WITH PROGRESSIVE ASYMMETRIC LOWER MOTOR NEURON LIMB WEAKNESS WITHOUT CONDUCTION BLOCK? A PROSPECTIVE, COHORT STUDY

Research paper thumbnail of 弥散加权成像及示踪技术评价周围神经损伤及再生

Research paper thumbnail of P72 A NOVEL TOOL FOR DETECTION OF NEUROPSYCHIATRIC SYMPTOMS IN ALS–THE MIND-BEHAVIOURAL (MIND-B)

Research paper thumbnail of The Split Leg in Amyotrophic Lateral Sclerosis (P07. 083)

Research paper thumbnail of e161 What do you mean, save a soldier from war? Life’s big small decisions

Research paper thumbnail of Sustained relief with onabotulinumtoxinA from motor and sensory symptoms associated with progressive facial hemiatrophy (Parry-Romberg syndrome)

Research paper thumbnail of Quantifying disease progression in amyotrophic lateral sclerosis

Annals of neurology, 2014

Amyotrophic lateral sclerosis (ALS) exhibits characteristic variability of onset and rate of dise... more Amyotrophic lateral sclerosis (ALS) exhibits characteristic variability of onset and rate of disease progression, with inherent clinical heterogeneity making disease quantitation difficult. Recent advances in understanding pathogenic mechanisms linked to the development of ALS impose an increasing need to develop strategies to predict and more objectively measure disease progression. This review explores phenotypic and genetic determinants of disease progression in ALS, and examines established and evolving biomarkers that may contribute to robust measurement in longitudinal clinical studies. With targeted neuroprotective strategies on the horizon, developing efficiencies in clinical trial design may facilitate timely entry of novel treatments into the clinic.

Research paper thumbnail of Quantitative ultrasound of denervated hand muscles

Muscle & nerve, Jan 11, 2014

Introduction: Presentations to the neuromuscular clinic commonly involve hand muscle denervation,... more Introduction: Presentations to the neuromuscular clinic commonly involve hand muscle denervation, but few studies have evaluated hand muscle ultrasound. Methods: Ultrasound studies of abductor pollicis brevis, first dorsal interosseous, and abductor digit minimi were performed in a prospective cohort of 34 patients (77 muscles) with electromyography (EMG)-confirmed denervation, compared with 58 healthy control subjects. Results: In control subjects, muscle thickness was highly reproducible [intraclass correlation coefficient (ICC) = 0.88-0.98], and echogenicity was moderately reproducible (ICC = 0.542-0.686). Age, gender, and body mass index influenced muscle thickness and echogenicity. Ultrasound changes in denervated muscles correlated with the severity of EMG abnormalities. A z-score cut-off of 0 identified denervated muscles with a sensitivity of 100% and 89% for echogenicity and muscle thickness, respectively. © 2014 Wiley Periodicals, Inc.

Research paper thumbnail of A novel tool to detect behavioural symptoms in ALS

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2014

Research paper thumbnail of Segmental motoneuronal dysfunction is a feature of amyotrophic lateral sclerosis

Clinical Neurophysiology, 2014

There is accumulating evidence of dysfunction of spinal circuits in the pathogenesis of amyotroph... more There is accumulating evidence of dysfunction of spinal circuits in the pathogenesis of amyotrophic lateral sclerosis (ALS). The present study was undertaken to characterise the pathophysiological changes in segmental motoneuronal excitability in 28 ALS patients, using recruitment curves of the soleus H-reflex and M-wave, compared with clinical assessments of upper motor neuron (UMN) and lower motor neuron dysfunction. H-reflex recruitment curves established that Hmax/Mmax and slope (Hθ/Mθ) ratios predicted clinical UMN dysfunction (p<0.001). Changes in Hθ/Mθ were driven by reduced Mθ. Assessment of Hmax/Mmax was similar in the ALS and control groups, and was affected by overlap of the H and M recruitment curves in ALS patients. Changes in the slope ratio (Hθ/Mθ) in ALS suggested that alterations in peripheral motor nerve excitability following UMN damage may affect the recorded H-reflex. Increased collision of reflex discharges with antidromically-conducted motor impulses may be exacerbated in ALS due to preferential loss of large-caliber α-motoneurones, which may explain the similarities in Hmax/Mmax between groups. Findings from the present study provide further insight into the pathophysiology of ALS, specifically the relative contributions of premotoneuronal and segmental motoneuronal dysfunction.

Research paper thumbnail of Muscle-specific kinase antibodies: A novel cause of peripheral nerve hyperexcitability?

Antibodies that target the postsynaptic neuromuscular junction (NMJ) protein, muscle-specific kin... more Antibodies that target the postsynaptic neuromuscular junction (NMJ) protein, muscle-specific kinase (MuSK), have been associated with myasthenia gravis (MG), often with cramps and fasciculations, after administration of acetylcholinesterase inhibitors (AChE-I). In this report, 2 patients are described with elevated MuSK antibodies and evidence of peripheral nerve hyperexcitability (PNH) unrelated to AChE-I medication. Patient 1 presented with facial neuromyotonia and fasciculations, without overt weakness. EMG studies demonstrated myokymic discharges in facial muscles, with bursts of discharges after voluntary activation, and widespread fasciculation potentials in limb muscles. Patient 2 presented with bulbar weakness and fasciculations in the tongue and limbs, initially diagnosed as bulbar-onset amyotrophic lateral sclerosis. Subsequent investigation identified the presence of MuSK antibodies. We hypothesize that MuSK antibodies may induce these phenotypes through disruptive actions at the NMJ, in particular the binding of acetylcholinesterase (AChE) to MuSK via its collagen Q (ColQ) tail, producing a reduction in synaptic AChE activity.

Research paper thumbnail of The puzzling case of hyperexcitability in amyotrophic lateral sclerosis

Journal of Clinical Neurology (Korea), 2013

Research paper thumbnail of A comparison of ultrasonographic and electrophysiologic ‘inching’ in ulnar neuropathy at the elbow

Clinical Neurophysiology, 2015

The present study aimed to clarify the relationship between structural ulnar nerve changes and el... more The present study aimed to clarify the relationship between structural ulnar nerve changes and electrophysiological nerve dysfunction in patients with ulnar neuropathy at the elbow (UNE). High-resolution ultrasonography of the ulnar nerve was performed on 17 limbs with clinically and electrophysiologically confirmed UNE, and 52 control subjects at four standardised sites proximal and distal to the medial epicondyle (P2, P1, D1, D2), corresponding to segments of ulnar short-segment nerve conduction studies ("inching studies"). Ulnar nerve cross-sectional area (CSA) and hypoechoic fraction were significantly increased in patients with UNE immediately distal (D1) and proximal (P1) to the medial epicondyle (p<0.01). In patients with UNE, hypoechoic fraction was similar in asymptomatic and symptomatic limbs. Motor nerve conduction velocity across the elbow correlated with CSAmax and the maximum hypoechoic fraction (R=0.6, p<0.05). CSA and hypoechoic fraction of individual segments did not correlate with corresponding latencies on inching studies, but latencies across the D1 segment correlated with CSA at P1 (R=0.80, p<0.0001) and D2 (R=0.65, p<0.01). Sonographic abnormalities in UNE may not be maximal at the site of electrophysiological nerve dysfunction. Sonographic abnormalities may reflect secondary pathophysiological changes in segments adjacent to regions of nerve compression.

Research paper thumbnail of Axonal dysfunction with voltage gated potassium channel complex antibodies

Experimental neurology, 2014

Although autoantibodies targeted against voltage-gated potassium channel (VGKC)-associated protei... more Although autoantibodies targeted against voltage-gated potassium channel (VGKC)-associated proteins have been identified in limbic encephalitis (LE) and acquired neuromyotonia (aNMT), the role of these antibodies in disease pathophysiology has not been elucidated. The present study investigated axonal function across the spectrum of VGKC-complex antibody associated disorders. Peripheral axonal excitability studies were undertaken in a cohort of patients with LE (N=6) and aNMT (N=11), compared to healthy controls (HC; N=20). Patients with LE demonstrated prominent abnormalities in peripheral axonal excitability during the acute phase, with reduced threshold change in threshold electrotonus (depolarizing 10-20 LE: 58.5±3.1%; HC: 67.4±0.9%; P<.005; S2 accommodation LE: 17.2±1.4%; HC: 22.2±0.6%; P≤.005) and in recovery cycle parameters (superexcitability LE: -16.0±0.9%; HC: -23.4±1.1%; P<.01; subexcitability LE: 8.5±1.2%; HC: 13.8±0.7%; P≤.005). The pattern of change in LE patient...

Research paper thumbnail of Sonographic diagnosis of true neurogenic thoracic outlet syndrome

Neurology, 2013

A 32-year-old woman presented with a 5-year history of left shoulder pain, medial hand and forear... more A 32-year-old woman presented with a 5-year history of left shoulder pain, medial hand and forearm numbness, and progressive hand weakness and atrophy. Electrodiagnostic studies were characteristic of true neurogenic thoracic outlet syndrome, 1 and a chest x-ray showed bilateral elongated C7 transverse processes. High-resolution ultrasound studies revealed compression of the left lower trunk (LT) between a fibrous band and artery (figure, A). Magnetic resonance neurography (figure, B) and operative exploration (figure, C) confirmed the ultrasound findings. Clinical improvement was noted following surgical neurolysis of the LT. High-resolution ultrasound may be a useful and quick bedside tool to identify causative structural pathology in this classic neuromuscular disorder.

Research paper thumbnail of Is IVIg therapy warranted in progressive lower motor neuron syndromes without conduction block?

Neurology, 2013

To evaluate the likelihood of response to IV immunoglobulin (IVIg) by studying consecutive patien... more To evaluate the likelihood of response to IV immunoglobulin (IVIg) by studying consecutive patients presenting with progressive, asymmetric, pure lower motor neuron (LMN) limb weakness, and to determine the clinical phenotype of those who respond. Thirty-one consecutive patients with progressive, focal-onset LMN limb weakness, without evidence of clinical upper motor neuron signs; sensory, respiratory, or bulbar involvement; or evidence of motor nerve conduction block on electrodiagnostic studies, were prospectively included in this study. Each patient underwent treatment with IVIg (2 g/kg) for a minimum of 3 months. Electrodiagnostic studies, a neuromuscular symptom score, and expanded Medical Research Council sum score were documented before and after IVIg treatment. The final diagnosis was determined after prolonged clinical follow-up. Only 3 of 31 patients (10%) responded to IVIg. All responders demonstrated distal upper limb-onset weakness, EMG abnormalities confined to the clinically weak muscles, and a normal creatine kinase. This set of features was also identified in 31% of nonresponders presenting with distal upper limb weakness. Sex, age at onset, number of involved limb regions, and the duration of symptoms before treatment were not significantly different between groups. The findings of the present study do not support uniform use of IVIg in patients presenting with progressive asymmetric LMN limb weakness. It is suggested that IVIg treatment be limited to patients who demonstrate clinical and laboratory features suggestive of multifocal motor neuropathy. This study provides Class IV evidence that IVIg will not improve muscle function in 90% of patients with progressive, asymmetric, pure LMN weakness.

Research paper thumbnail of Patterns of clinical and electrodiagnostic abnormalities in early amyotrophic lateral sclerosis

Muscle & Nerve, 2014

Introduction: The distribution of clinical and neurophysiological abnormalities in patients with ... more Introduction: The distribution of clinical and neurophysiological abnormalities in patients with early amyotrophic lateral sclerosis (ALS) was investigated in an attempt to delineate patterns of disease spread. Methods: Clinical and electrodiagnostic data were prospectively collected from 150 ALS patients and analyzed based on the clinical region of onset. Results: Asymmetry of clinical and neurophysiological abnormalities was more marked in upper limb-onset than lower limb-onset disease. Significant rostral-caudal gradients of clinical weakness were identified in bulbar and lower limb-onset disease. Neurophysiological evidence of the ALS 'split hand' pattern was evident irrespective of the region of disease onset. Limbs with and without evidence of clinical weakness demonstrated similar rates of abnormalities on electromyography. Discussion: Findings from the present series suggest a pattern of disease spread in ALS. As such, the present study may serve to guide ongoing development of disease quantitation biomarkers and the targeting of future neuroprotective strategies. LIST OF ABBREVIATIONS ALS -amyotrophic lateral sclerosis; UMN -upper motor neuron; LMN -lower motor neuron; NCS -nerve conduction studies; APB -abductor pollicis brevis; ADM -abductor digiti minimi; AH -abductor hallucis; CMAP -compound muscle action potential; LLN -lower limit of normal; TA -tibialis anterior; MG -medial gastrocnemius; MU -motor unit; PSW -positive sharp wave; DML -distal motor latency; CV -conduction velocity; SEM -standard error of the mean.

Research paper thumbnail of Advances in the neurological and neurosurgical management of peripheral nerve trauma

Journal of neurology, neurosurgery, and psychiatry, Jan 28, 2015

Peripheral nerve trauma frequently affects younger people and may result in significant and long-... more Peripheral nerve trauma frequently affects younger people and may result in significant and long-lasting functional disability. Currently, diagnosis and monitoring of peripheral nerve injury relies on clinical and electrodiagnostic information, supplemented by intraoperative electrophysiological studies. However, in a significant proportion of nerve injuries, the likelihood of spontaneous regeneration resulting in good functional outcome remains uncertain and unnecessary delays to treatment may be faced while monitoring for recovery. Advances in non-invasive imaging techniques to diagnose and monitor nerve injury and regeneration are being developed, and have the potential to streamline the decision-making process. In addition, advances in operative and non-operative treatment strategies may provide more effective ways to maximise functional outcomes following severe peripheral nerve trauma. This review discusses these advances in light of the current state of the art of management ...

Research paper thumbnail of Diffusion weighted MRI and tractography for evaluating peripheral nerve degeneration and regeneration

Neural regeneration research, Jan 15, 2014

Research paper thumbnail of Visualizing axon regeneration after peripheral nerve injury with magnetic resonance tractography

Neurology, Jan 7, 2014

ABSTRACT Diffusion tensor imaging (DTI) with tractography is an MRI technique that can visualize ... more ABSTRACT Diffusion tensor imaging (DTI) with tractography is an MRI technique that can visualize nerve pathways by taking advantage of anisotropy of water diffusion in tracts with longitudinally oriented fibers. To date, no study in humans has shown that DTI and tractography can follow regeneration of axons during recovery from traumatic peripheral nerve injury. We show that tractography is able to identify regenerating axons advancing through a graft repair of an injured nerve, and demonstrate correlation with evidence of recovery on serial clinical, electrodiagnostic, and muscle MRI assessments.

Research paper thumbnail of P315 IS IVIG TREATMENT WARRANTED IN PATIENTS WITH PROGRESSIVE ASYMMETRIC LOWER MOTOR NEURON LIMB WEAKNESS WITHOUT CONDUCTION BLOCK? A PROSPECTIVE, COHORT STUDY

Research paper thumbnail of 弥散加权成像及示踪技术评价周围神经损伤及再生

Research paper thumbnail of P72 A NOVEL TOOL FOR DETECTION OF NEUROPSYCHIATRIC SYMPTOMS IN ALS–THE MIND-BEHAVIOURAL (MIND-B)

Research paper thumbnail of The Split Leg in Amyotrophic Lateral Sclerosis (P07. 083)

Research paper thumbnail of e161 What do you mean, save a soldier from war? Life’s big small decisions

Research paper thumbnail of Sustained relief with onabotulinumtoxinA from motor and sensory symptoms associated with progressive facial hemiatrophy (Parry-Romberg syndrome)

Research paper thumbnail of Quantifying disease progression in amyotrophic lateral sclerosis

Annals of neurology, 2014

Amyotrophic lateral sclerosis (ALS) exhibits characteristic variability of onset and rate of dise... more Amyotrophic lateral sclerosis (ALS) exhibits characteristic variability of onset and rate of disease progression, with inherent clinical heterogeneity making disease quantitation difficult. Recent advances in understanding pathogenic mechanisms linked to the development of ALS impose an increasing need to develop strategies to predict and more objectively measure disease progression. This review explores phenotypic and genetic determinants of disease progression in ALS, and examines established and evolving biomarkers that may contribute to robust measurement in longitudinal clinical studies. With targeted neuroprotective strategies on the horizon, developing efficiencies in clinical trial design may facilitate timely entry of novel treatments into the clinic.

Research paper thumbnail of Quantitative ultrasound of denervated hand muscles

Muscle & nerve, Jan 11, 2014

Introduction: Presentations to the neuromuscular clinic commonly involve hand muscle denervation,... more Introduction: Presentations to the neuromuscular clinic commonly involve hand muscle denervation, but few studies have evaluated hand muscle ultrasound. Methods: Ultrasound studies of abductor pollicis brevis, first dorsal interosseous, and abductor digit minimi were performed in a prospective cohort of 34 patients (77 muscles) with electromyography (EMG)-confirmed denervation, compared with 58 healthy control subjects. Results: In control subjects, muscle thickness was highly reproducible [intraclass correlation coefficient (ICC) = 0.88-0.98], and echogenicity was moderately reproducible (ICC = 0.542-0.686). Age, gender, and body mass index influenced muscle thickness and echogenicity. Ultrasound changes in denervated muscles correlated with the severity of EMG abnormalities. A z-score cut-off of 0 identified denervated muscles with a sensitivity of 100% and 89% for echogenicity and muscle thickness, respectively. © 2014 Wiley Periodicals, Inc.

Research paper thumbnail of A novel tool to detect behavioural symptoms in ALS

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2014

Research paper thumbnail of Segmental motoneuronal dysfunction is a feature of amyotrophic lateral sclerosis

Clinical Neurophysiology, 2014

There is accumulating evidence of dysfunction of spinal circuits in the pathogenesis of amyotroph... more There is accumulating evidence of dysfunction of spinal circuits in the pathogenesis of amyotrophic lateral sclerosis (ALS). The present study was undertaken to characterise the pathophysiological changes in segmental motoneuronal excitability in 28 ALS patients, using recruitment curves of the soleus H-reflex and M-wave, compared with clinical assessments of upper motor neuron (UMN) and lower motor neuron dysfunction. H-reflex recruitment curves established that Hmax/Mmax and slope (Hθ/Mθ) ratios predicted clinical UMN dysfunction (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). Changes in Hθ/Mθ were driven by reduced Mθ. Assessment of Hmax/Mmax was similar in the ALS and control groups, and was affected by overlap of the H and M recruitment curves in ALS patients. Changes in the slope ratio (Hθ/Mθ) in ALS suggested that alterations in peripheral motor nerve excitability following UMN damage may affect the recorded H-reflex. Increased collision of reflex discharges with antidromically-conducted motor impulses may be exacerbated in ALS due to preferential loss of large-caliber α-motoneurones, which may explain the similarities in Hmax/Mmax between groups. Findings from the present study provide further insight into the pathophysiology of ALS, specifically the relative contributions of premotoneuronal and segmental motoneuronal dysfunction.

Research paper thumbnail of Muscle-specific kinase antibodies: A novel cause of peripheral nerve hyperexcitability?

Antibodies that target the postsynaptic neuromuscular junction (NMJ) protein, muscle-specific kin... more Antibodies that target the postsynaptic neuromuscular junction (NMJ) protein, muscle-specific kinase (MuSK), have been associated with myasthenia gravis (MG), often with cramps and fasciculations, after administration of acetylcholinesterase inhibitors (AChE-I). In this report, 2 patients are described with elevated MuSK antibodies and evidence of peripheral nerve hyperexcitability (PNH) unrelated to AChE-I medication. Patient 1 presented with facial neuromyotonia and fasciculations, without overt weakness. EMG studies demonstrated myokymic discharges in facial muscles, with bursts of discharges after voluntary activation, and widespread fasciculation potentials in limb muscles. Patient 2 presented with bulbar weakness and fasciculations in the tongue and limbs, initially diagnosed as bulbar-onset amyotrophic lateral sclerosis. Subsequent investigation identified the presence of MuSK antibodies. We hypothesize that MuSK antibodies may induce these phenotypes through disruptive actions at the NMJ, in particular the binding of acetylcholinesterase (AChE) to MuSK via its collagen Q (ColQ) tail, producing a reduction in synaptic AChE activity.

Research paper thumbnail of The puzzling case of hyperexcitability in amyotrophic lateral sclerosis

Journal of Clinical Neurology (Korea), 2013

Research paper thumbnail of A comparison of ultrasonographic and electrophysiologic ‘inching’ in ulnar neuropathy at the elbow

Clinical Neurophysiology, 2015

The present study aimed to clarify the relationship between structural ulnar nerve changes and el... more The present study aimed to clarify the relationship between structural ulnar nerve changes and electrophysiological nerve dysfunction in patients with ulnar neuropathy at the elbow (UNE). High-resolution ultrasonography of the ulnar nerve was performed on 17 limbs with clinically and electrophysiologically confirmed UNE, and 52 control subjects at four standardised sites proximal and distal to the medial epicondyle (P2, P1, D1, D2), corresponding to segments of ulnar short-segment nerve conduction studies (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;inching studies&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;). Ulnar nerve cross-sectional area (CSA) and hypoechoic fraction were significantly increased in patients with UNE immediately distal (D1) and proximal (P1) to the medial epicondyle (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01). In patients with UNE, hypoechoic fraction was similar in asymptomatic and symptomatic limbs. Motor nerve conduction velocity across the elbow correlated with CSAmax and the maximum hypoechoic fraction (R=0.6, p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). CSA and hypoechoic fraction of individual segments did not correlate with corresponding latencies on inching studies, but latencies across the D1 segment correlated with CSA at P1 (R=0.80, p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001) and D2 (R=0.65, p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01). Sonographic abnormalities in UNE may not be maximal at the site of electrophysiological nerve dysfunction. Sonographic abnormalities may reflect secondary pathophysiological changes in segments adjacent to regions of nerve compression.

Research paper thumbnail of Axonal dysfunction with voltage gated potassium channel complex antibodies

Experimental neurology, 2014

Although autoantibodies targeted against voltage-gated potassium channel (VGKC)-associated protei... more Although autoantibodies targeted against voltage-gated potassium channel (VGKC)-associated proteins have been identified in limbic encephalitis (LE) and acquired neuromyotonia (aNMT), the role of these antibodies in disease pathophysiology has not been elucidated. The present study investigated axonal function across the spectrum of VGKC-complex antibody associated disorders. Peripheral axonal excitability studies were undertaken in a cohort of patients with LE (N=6) and aNMT (N=11), compared to healthy controls (HC; N=20). Patients with LE demonstrated prominent abnormalities in peripheral axonal excitability during the acute phase, with reduced threshold change in threshold electrotonus (depolarizing 10-20 LE: 58.5±3.1%; HC: 67.4±0.9%; P<.005; S2 accommodation LE: 17.2±1.4%; HC: 22.2±0.6%; P≤.005) and in recovery cycle parameters (superexcitability LE: -16.0±0.9%; HC: -23.4±1.1%; P<.01; subexcitability LE: 8.5±1.2%; HC: 13.8±0.7%; P≤.005). The pattern of change in LE patient...

Research paper thumbnail of Sonographic diagnosis of true neurogenic thoracic outlet syndrome

Neurology, 2013

A 32-year-old woman presented with a 5-year history of left shoulder pain, medial hand and forear... more A 32-year-old woman presented with a 5-year history of left shoulder pain, medial hand and forearm numbness, and progressive hand weakness and atrophy. Electrodiagnostic studies were characteristic of true neurogenic thoracic outlet syndrome, 1 and a chest x-ray showed bilateral elongated C7 transverse processes. High-resolution ultrasound studies revealed compression of the left lower trunk (LT) between a fibrous band and artery (figure, A). Magnetic resonance neurography (figure, B) and operative exploration (figure, C) confirmed the ultrasound findings. Clinical improvement was noted following surgical neurolysis of the LT. High-resolution ultrasound may be a useful and quick bedside tool to identify causative structural pathology in this classic neuromuscular disorder.

Research paper thumbnail of Is IVIg therapy warranted in progressive lower motor neuron syndromes without conduction block?

Neurology, 2013

To evaluate the likelihood of response to IV immunoglobulin (IVIg) by studying consecutive patien... more To evaluate the likelihood of response to IV immunoglobulin (IVIg) by studying consecutive patients presenting with progressive, asymmetric, pure lower motor neuron (LMN) limb weakness, and to determine the clinical phenotype of those who respond. Thirty-one consecutive patients with progressive, focal-onset LMN limb weakness, without evidence of clinical upper motor neuron signs; sensory, respiratory, or bulbar involvement; or evidence of motor nerve conduction block on electrodiagnostic studies, were prospectively included in this study. Each patient underwent treatment with IVIg (2 g/kg) for a minimum of 3 months. Electrodiagnostic studies, a neuromuscular symptom score, and expanded Medical Research Council sum score were documented before and after IVIg treatment. The final diagnosis was determined after prolonged clinical follow-up. Only 3 of 31 patients (10%) responded to IVIg. All responders demonstrated distal upper limb-onset weakness, EMG abnormalities confined to the clinically weak muscles, and a normal creatine kinase. This set of features was also identified in 31% of nonresponders presenting with distal upper limb weakness. Sex, age at onset, number of involved limb regions, and the duration of symptoms before treatment were not significantly different between groups. The findings of the present study do not support uniform use of IVIg in patients presenting with progressive asymmetric LMN limb weakness. It is suggested that IVIg treatment be limited to patients who demonstrate clinical and laboratory features suggestive of multifocal motor neuropathy. This study provides Class IV evidence that IVIg will not improve muscle function in 90% of patients with progressive, asymmetric, pure LMN weakness.

Research paper thumbnail of Patterns of clinical and electrodiagnostic abnormalities in early amyotrophic lateral sclerosis

Muscle & Nerve, 2014

Introduction: The distribution of clinical and neurophysiological abnormalities in patients with ... more Introduction: The distribution of clinical and neurophysiological abnormalities in patients with early amyotrophic lateral sclerosis (ALS) was investigated in an attempt to delineate patterns of disease spread. Methods: Clinical and electrodiagnostic data were prospectively collected from 150 ALS patients and analyzed based on the clinical region of onset. Results: Asymmetry of clinical and neurophysiological abnormalities was more marked in upper limb-onset than lower limb-onset disease. Significant rostral-caudal gradients of clinical weakness were identified in bulbar and lower limb-onset disease. Neurophysiological evidence of the ALS 'split hand' pattern was evident irrespective of the region of disease onset. Limbs with and without evidence of clinical weakness demonstrated similar rates of abnormalities on electromyography. Discussion: Findings from the present series suggest a pattern of disease spread in ALS. As such, the present study may serve to guide ongoing development of disease quantitation biomarkers and the targeting of future neuroprotective strategies. LIST OF ABBREVIATIONS ALS -amyotrophic lateral sclerosis; UMN -upper motor neuron; LMN -lower motor neuron; NCS -nerve conduction studies; APB -abductor pollicis brevis; ADM -abductor digiti minimi; AH -abductor hallucis; CMAP -compound muscle action potential; LLN -lower limit of normal; TA -tibialis anterior; MG -medial gastrocnemius; MU -motor unit; PSW -positive sharp wave; DML -distal motor latency; CV -conduction velocity; SEM -standard error of the mean.