Pain-Related Vertex Evoked Potentials. Comparison of Surface Electrical to Heat Stimulation.

INTRODUCTION: Demonstration of nociceptive fiber abnormality is important for diagnosing neuropathic pain and small fiber neuropathies. This is usually assessed by brief heat pulses using lasers, contact heat, or special electrodes. We hypothesized that pain-related evoked potentials to conventional surface electrical stimulation (PREPse) can index Aδ afferences despite tactile Aß fibers coactivation. PREPse may be more readily used clinically than contact heat evoked potentials (CHEPS). METHODS: Twenty-eight healthy subjects. Vertex (Cz-A1/A2) recordings. Electrical stimulation of middle finger and second toe with conventional ring, and forearm/leg skin with cup, electrodes. Contact heat stimulation to forearm and leg. Compression ischemic nerve blockade. RESULTS: PREPse peripheral velocities were within the midrange of Aδ fibers. N1-P1 amplitude increased with pain numerical rating scale graded (0-10) electrical stimulation (n = 25) and decreased with increasing stimulation frequency. Amplitudes were unchanged by different presentation orders of four stimulation intensities. PREPse N1 (∼130 milliseconds) and N2 (∼345 milliseconds) peaks were approximately 40 milliseconds earlier than that with CHEPS. PREPse and CHEPS N1-N2 interpeak latency (∼207 milliseconds) were similar. PREPse became unrecordable with nerve blockade of Aδ fibers. CONCLUSIONS: PREPse earlier N1 and N2 peaks, and similar interpeak N1-N2 latencies and central conduction velocities, or synaptic delays, to CHEPS are consistent with direct stimulation of Aδ fibers. The relation of vertex PREPse amplitude and pain, or the differential effects of frequency stimulation, is similar to pain-related evoked potential to laser, special electrodes, or contact heat stimulation. The relationship to Aδ was validated by conduction velocity and nerve block. Clinical utility of PREPse compared with CHEPS needs validation in somatosensory pathways lesions.

Review of techniques useful for the assessment of sensory small fiber neuropathies: Report from an IFCN expert group.

Nerve conduction studies (NCS) are an essential aspect of the assessment of patients with peripheral neuropathies. However, conventional NCS do not reflect activation of small afferent fibers, including Aδ and C fibers. A definitive gold standard for laboratory evaluation of these fibers is still needed and therefore, clinical evaluation remains fundamental in patients with small fiber neuropathies (SFN). Several clinical and research techniques have been developed for the assessment of small fiber function, such as (i) microneurography, (ii) laser evoked potentials, (iii) contact heat evoked potentials, (iv) pain-related electrically evoked potentials, (v) quantitative thermal sensory testing, (vi) skin biopsy-intraepidermal nerve fiber density and (vii) corneal confocal microscopy. The first five are physiological techniques, while the last two are morphological. They all have advantages and limitations, but the combined use of an appropriate selection of each of them would lead to gathering invaluable information for the diagnosis of SFN. In this review, we present an update on techniques available for the study of small afferent fibers and their clinical applicability. A summary of the anatomy and important physiological aspects of these pathways, and the clinical manifestations of their dysfunction is also included, in order to have a minimal common background.

Motor cortical excitability predicts cognitive phenotypes in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are well-recognised as an extended disease spectrum. This study hypothesised that cortical hyperexcitability, an early pathophysiological abnormality in ALS, would distinguish cognitive phenotypes, as a surrogate marker of pathological disease burden. 61 patients with ALS, matched for disease duration (pure motor ALS, n = 39; ALS with coexistent FTD, ALS-FTD, n = 12; ALS with cognitive/behavioural abnormalities not meeting FTD criteria, ALS-Cog, n = 10) and 30 age-matched healthy controls. Cognitive function on the Addenbrooke's cognitive examination (ACE) scale, behavioural function on the motor neuron disease behavior scale (MiND-B) and cortical excitability using transcranial magnetic stimulation (TMS) were documented. Cortical resting motor threshold (RMT), lower threshold indicating hyperexcitability, was lower in ALS-FTD (50.2 ± 6.9) compared to controls (64.3 ± 12.6, p < 0.005), while ALS-Cog (63.3 ± 12.7) and ALS (60.8 ± 13.9, not significant) were similar to controls. Short interval intracortical inhibition (SICI) was reduced across all ALS groups compared to controls, indicating hyperexcitability. On receiver operating characteristic curve analysis, RMT differentiated ALS-FTD from ALS (area under the curve AUC = 0.745, p = 0.011). The present study has identified a distinct pattern of cortical excitability across cognitive phenotypes in ALS. As such, assessment of cortical physiology may provide more precise clinical prognostication in ALS.

Early focality and spread of cortical dysfunction in amyotrophic lateral sclerosis: A regional study across the motor cortices.

OBJECTIVE: To characterise the regional cortical patterns underlying clinical symptomatology in amyotrophic lateral sclerosis (ALS). METHODS: 138 patients prospectively underwent transcranial magnetic stimulation studies from hand and leg cortical regions of each hemisphere, obtaining motor evoked potentials from all four limbs. Patients were categorised by clinical phenotype and underwent clinical and peripheral evaluation of disease. RESULTS: Cortical dysfunction was evident across the motor cortices, with reduction in short-interval intracortical inhibition (SICI) suggesting the presence of widespread cortical hyperexcitability, most prominently from clinically affected regions (hand p < 0.0001; leg p < 0.01). In early disease, cortical abnormalities were asymmetric between hemispheres, focally corresponding to clinical site-of-onset (p < 0.05). Degrees of cortical dysfunction varied between phenotypes, with the bulbar-onset cohort demonstrating greatest reduction in SICI (p = 0.03). CONCLUSIONS: The pattern of cortical dysfunction appears linked to clinical evolution in ALS, with early focal asymmetry preceding widespread changes in later disease. Cortical differences across phenotypes may influence clinical variability. SIGNIFICANCE: This is the first study to extensively map cortical abnormalities from multiple motor regions across hemispheres. The early cortical signature mirrors symptom laterality, supporting a discrete region of disease onset. Phenotypes appear to exist within a pathophysiological continuum, but cortical heterogeneity may mediate observed differences in clinical outcome.

The effect of coil type and limb dominance in the assessment of lower-limb motor cortex excitability using TMS.

PURPOSE: Clinical application of transcranial magnetic stimulation (TMS) has rapidly increased but the majority of studies have targeted upper limb muscles, with few exploring the lower-limb. Differences of coil choice have added to methodological difficulties of lower-limb studies and have challenged consistent interpretation of these parameters. The aims of this study were to determine the optimal coil choice for assessing lower-limb cortical excitability and assess laterality of normal cortical function. METHODS: 69 recordings were undertaken from the tibialis anterior muscle from 48 healthy participants. Three coil types currently used in lower-limb studies (90 mm circular; 70 mm figure-of-8; and 110 mm double cone) were explored using single pulse TMS and paired-pulse threshold tracking TMS (TT-TMS) paradigms, with peripheral function also assessed. Cortical symmetry was ascertained with bilateral recordings (dominant versus non-dominant muscles). RESULTS: The double-cone coil showed greatest efficacy, with significantly lower resting motor thresholds (49.0 ± 2.3%, p<0.0005) and greater intracortical facilitation compared to the alternate coil choices. Using the double-cone coil, paired-pulse TT-TMS generated an averaged short interval intracortical inhibition of 11.3 ± 1.2%, with an averaged intracortical facilitation of -6.1 ± 1.9%. There were no differences between dominant and non-dominant hemispheres. CONCLUSIONS: The present study identified key differences in cortical parameters between the currently utilised coils for lower-limb TMS. Specifically, this indicates the importance of standardizing the lower-limb TMS protocol, particularly for accurate interpretation in disease pathology.

Comparison of cross-sectional areas and distal-proximal nerve ratios in amyotrophic lateral sclerosis.

INTRODUCTION: This study explored potential diagnostic markers of nerve ultrasound in differentiating amyotrophic lateral sclerosis (ALS) from mimic disorders. METHODS: Ultrasound of the median, ulnar, and tibial nerves was conducted in 53 patients with ALS, 32 patients with ALS-mimic disorders, and 30 controls. Nerve cross-sectional area (CSA) and distal-proximal ratios were calculated. RESULTS: The median nerve CSA in the upper arm was decreased (7.9 ± 1.3 mm2 vs. 9.0 ± 1.4 mm2 , P < 0.05), and the median nerve wrist-upper arm ratio was increased in ALS patients compared with controls (1.3 ± 0.4 vs. 1.1 ± 0.2; P < 0.01). In differentiating ALS from mimic presentations, assessment of median nerve CSA in the upper arm and comparison of a median and ulnar nerve CSA distal-proximal ratio provide diagnostic potential. DISCUSSION: Assessment of nerve CSA combined with calculation of nerve CSA distal-proximal ratio provides a useful marker to aid in the diagnosis of ALS. Muscle Nerve 58:777-783, 2018.

Primary lateral sclerosis and the amyotrophic lateral sclerosis-frontotemporal dementia spectrum.

AIM: To investigate whether primary lateral sclerosis (PLS) represents part of the amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum of diseases. METHODS: Comprehensive assessment was taken on 21 patients with PLS and results were compared to patients diagnosed with pure motor ALS (n = 27) and ALS-FTD (n = 12). Clinical features, Addenbrooke's Cognitive Examination (ACE) scores, Motor Neuron Disease Behaviour (Mind-B) scores, motor disability on the ALS functional rating scale (ALSFRS) and survival times were documented. Motor cortex excitability was evaluated using transcranial magnetic stimulation (TMS). RESULTS: Global cognition was impaired in PLS (mean total ACE score 82.5 ± 13.6), similar to ALS-FTD (mean total ACE score 76.3 ± 7.7, p > 0.05) while behavioural impairments were not prominent. TMS revealed that resting motor threshold (RMT) was significantly higher in PLS (75.5 ± 6.2) compared ALS-FTD (50.1 ± 7.2, p < 0.001) and ALS (62.3 ± 12.6, p = 0.046). Average short-interval intracortical inhibition (SICI) was similar in all three patient groups. The mean survival time was longest in PLS (217.4 ± 22.4 months) and shortest in ALS-FTD (38.5 ± 4.5 months, p = 0.002). Bulbar onset disease (ß = - 0.45, p = 0.007) and RMT (ß = 0.54, p = 0.001) were independent predictors of global cognition while motor scores (ß = 0.47, p = 0.036) and SICI (ß = 0.58, p = 0.006) were significantly associated with ALSFRS. CONCLUSION: The cognitive profile in PLS resembles ALS-FTD, without prominent behavioural disturbances. A higher RMT in PLS than ALS and ALS-FTD is consistent with differential cortical motor neuronal abnormalities and more severe involvement of corticospinal axons while SICI, indicative of inhibitory interneuronal dysfunction was comparable with ALS and ALS-FTD. Overall, while these findings support the notion that PLS lies on the ALS-FTD spectrum, the mechanisms underlying slow disease progression are likely to be distinct in PLS.

A unified model of the excitability of mouse sensory and motor axons.

Non-invasive nerve excitability techniques have provided valuable insight into the understanding of neurological disorders. The widespread use of mice in translational research on peripheral nerve disorders and by pharmaceutical companies during drug development requires valid and reliable models that can be compared to humans. This study established a novel experimental protocol that enables comparative assessment of the excitability properties of motor and sensory axons at the same site in mouse caudal nerve, compared the mouse data to data for motor and sensory axons in human median nerve at the wrist, and constructed a mathematical model of the excitability of mouse axons. In a separate study, ischaemia was employed as an experimental manoeuvre to test the translational utility of this preparation. The patterns of mouse sensory and motor excitability were qualitatively similar to human studies under normal and ischaemic conditions. The most conspicuous differences between mouse and human studies were observed in the recovery cycle and the response to hyperpolarization. Modelling showed that an increase in temperature in mouse axons could account for most of the differences in the recovery cycle. The modelling also suggested a larger hyperpolarization-activated conductance in mouse axons. The kinetics of this conductance appeared to be much slower raising the possibility that an additional or different hyperpolarization-activated cyclic-nucleotide gated (HCN) channel isoform underlies the accommodation to hyperpolarization in mouse axons. Given a possible difference in HCN isoforms, caution should be exercised in extrapolating from studies of mouse motor and sensory axons to human nerve disorders.

Ectopic impulse generation in peripheral nerve hyperexcitability syndromes and amyotrophic lateral sclerosis.

OBJECTIVE: To elucidate differences in the distribution and firing frequency of fasciculations between peripheral nerve hyperexcitability syndromes and amyotrophic lateral sclerosis (ALS) and to explore the generator site of fasciculations. METHODS: Ultrasound of 14 preselected muscles was performed in patients with peripheral hyperexcitability and ALS. The distribution and firing frequency of fasciculations were calculated. Cortical excitability assessment was also done by threshold tracking transcranial magnetic stimulation. RESULTS: In total, 518 muscles from 37 peripheral hyperexcitability patients and 756 muscles from 54 ALS patients were examined. Regarding the detection rate, 74% of muscles in ALS patients demonstrated fasciculations, compared with 34% of muscles in peripheral hyperexcitability patients (P < 0.001). The number of unique repeating focal muscle fasciculation movements per muscle and firing frequency of individual fasciculations in ALS were both significantly higher than those in peripheral hyperexcitability (P < 0.001). Furthermore, cortical silent period duration negatively correlated with the number and firing frequency of fasciculations in ALS (P < 0.05). A similar relationship was not evident in peripheral hyperexcitability. CONCLUSIONS: In ALS patients, fasciculations were more widespread, greater in number and higher in firing frequency than in peripheral hyperexcitability patients. SIGNIFICANCE: A significant proportion of fasciculations in ALS may be influenced by changes in central excitability.

Dynamic muscle ultrasound identifies upper motor neuron involvement in amyotrophic lateral sclerosis.

OBJECTIVE: The aim of the present study was to elucidate the pattern of change in bulbar muscles using ultrasound in patients diagnosed with amyotrophic lateral sclerosis (ALS). METHODS: Changes in the mylohyoid and geniohyoid muscle complex (mylohyoid-geniohyoid-muscle-complex) thickness were recorded while swallowing 5 ml of water using M-mode ultrasound in 30 ALS patients compared to 20 healthy controls. The ratio of mylohyoid-geniohyoid-muscle-complex thickness as determined by the maximum thickness of mylohyoid-geniohyoid-muscle-complex during swallowing divided by thickness at rest, was compared between ALS patients and controls, with the correlation between thickness ratio, echogenicity and clinical parameters assessed. RESULTS: Overall, the thickness ratio in ALS patients was 1.39 ± 0.23 (mean ± SD) compared to 1.55 ± 0.17 in controls (p < 0.05). In sub-analysis, the thickness ratio was significantly decreased in ALS patients with bulbar-onset disease compared to those with limb-onset disease (p < 0.01) and controls (p < 0.01). Thickness ratio negatively correlated with the severity of upper motor neuron involvement in the bulbar region (p < 0.05). CONCLUSIONS: Bulbar muscle ultrasound represents a novel method to detect impaired mobility and thereby provides an objective assessment of upper motor neuron involvement in the bulbar region of ALS patients.

Detection of fasciculations in amyotrophic lateral sclerosis: The optimal ultrasound scan time.

INTRODUCTION: This study seeks to elucidate the optimal scan time to detect fasciculations by using ultrasound in the diagnosis of amyotrophic lateral sclerosis (ALS). METHODS: The intervals between fasciculations were recorded from tongue, abdominal, and limb muscles in ALS patients, incorporating assessment of the cumulative probability of 2 fasciculations occurring. RESULTS: From prospective studies of 228 muscles from 19 ALS patients, fasciculations were detectable in 68% of patients. The longest interfasciculation interval recorded was 81.4 s in the hand muscle. The cumulative probability of 2 fasciculations occurring was calculated as ≥0.9 in all muscles during a period of 60 s. DISCUSSION: A definition of 2 or more fasciculations occurring during a scan time of 60 s reliably allowed detection of fasciculations in ALS. Muscle Nerve, 2017.

Differentiating lower motor neuron syndromes.

Lower motor neuron (LMN) syndromes typically present with muscle wasting and weakness and may arise from pathology affecting the distal motor nerve up to the level of the anterior horn cell. A variety of hereditary causes are recognised, including spinal muscular atrophy, distal hereditary motor neuropathy and LMN variants of familial motor neuron disease. Recent genetic advances have resulted in the identification of a variety of disease-causing mutations. Immune-mediated disorders, including multifocal motor neuropathy and variants of chronic inflammatory demyelinating polyneuropathy, account for a proportion of LMN presentations and are important to recognise, as effective treatments are available. The present review will outline the spectrum of LMN syndromes that may develop in adulthood and provide a framework for the clinician assessing a patient presenting with predominantly LMN features.

Laterality of motor cortical function measured by transcranial magnetic stimulation threshold tracking.

INTRODUCTION: Threshold tracking paired-pulse transcranial magnetic stimulation (TTTMS) examines cortical function and is useful for diagnosis of motor neuron disorders. Differences in cortical function have been identified between dominant and non-dominant limbs using constant stimulus methods, but they remain unclear, potentially due to methodological differences. In this study we aimed to clarify differences in cortical function between dominant and non-dominant limbs using TTTMS. METHODS: Single-pulse TMS, TTTMS, and nerve conduction studies were performed in 25 healthy, right-handed participants by recording from the abductor pollicis brevis muscle. RESULTS: There were no side-to-side differences observed in resting motor threshold, motor evoked potential (MEP) amplitude, MEP latency, central motor conduction time, cortical silent period, short-interval intracortical inhibition and facilitation, compound muscle action potential (CMAP) amplitude, CMAP latency, F-wave latency, or neurophysiological index. CONCLUSIONS: These findings suggest that, when using TTTMS, there are no differences in cortical function between dominant and non-dominant hemispheres. Muscle Nerve 55: 424-427, 2017.

Treatment approaches in motor neurone disease.

PURPOSE OF REVIEW: Although there is no cure for motor neurone disease (MND), the advent of multidisciplinary care and neuroprotective agents has improved treatment interventions and enhanced quality of life for MND patients and their carers. RECENT FINDINGS: Evidence-based multidisciplinary care, respiratory management and disease-modifying therapy have improved the outcomes of patients diagnosed with MND. Supportive approaches to nutritional maintenance and optimization of symptomatic treatments, including management of communication and neuropsychiatric issues, improve the quality of life for MND patients. SUMMARY: Recent progress in the understanding of the clinical, pathophysiological and genetic heterogeneity of MND has improved the approach of clinicians to treatment. Notwithstanding improvement to care and quality of life, survival benefit has become evident with the advent of a multidisciplinary care framework, early treatment with riluzole and noninvasive ventilation. Weight maintenance remains critical, with weight loss associated with more rapid disease progression. The end-of-life phase is poorly defined and treatment is challenging, but effective symptom control through palliative care is achievable and essential. Encouragingly, current progress of clinical trials continues to close the gap towards the successful development of curative treatment in MND.

Vitamin B-12 treatment of asymptomatic, deficient, elderly Chileans improves conductivity in myelinated peripheral nerves, but high serum folate impairs vitamin B-12 status response assessed by the combined indicator of vitamin B-12 status.

BACKGROUND: It is uncertain whether vitamin B-12 supplementation can improve neurophysiologic function in asymptomatic elderly with low vitamin B-12 status or whether folate status affects responses to vitamin B-12 supplementation. OBJECTIVE: We assessed the effects of a single intramuscular injection of 10 mg vitamin B-12 (which also contained 100 mg vitamin B-6 and 100 mg vitamin B-1) on vitamin B-12 status and neurophysiologic function in elderly community-dwelling Chileans with low serum vitamin B-12 concentrations who were consuming bread fortified with folic acid. DESIGN: A pretreatment and posttreatment study was conducted in 51 participants (median ± SD age: 73 ± 3 y; women: 47%) with serum vitamin B-12 concentrations <120 pmol/L at screening. Vitamin B-12 status was defined by combining vitamin B-12, plasma total homocysteine (tHcy), methylmalonic acid (MMA), and holotranscobalamin into one variable [combined indicator of vitamin B-12 status (cB-12)]. The response to treatment was assessed by measuring cB-12 and neurophysiologic variables at baseline and 4 mo after treatment. RESULTS: Treatment increased serum vitamin B-12, holotranscobalamin, and cB-12 (P < 0.001) and reduced plasma tHcy and serum MMA (P < 0.001). Treatment produced consistent improvements in conduction in myelinated peripheral nerves; the sensory latency of both the left and right sural nerves improved on the basis of faster median conduction times of 3.1 and 3.0 ms and 3.3 and 3.4 ms, respectively (P < 0.0001). A total of 10 sensory potentials were newly observed in sural nerves after treatment. Participants with high serum folate at baseline (above the median, ≥33.9 nmol/L) had less improvement in cB-12 (P < 0.001) than did individuals whose serum folate was less than the median concentration (i.e., with a concentration <33.9 nmol/L). CONCLUSION: Asymptomatic Chilean elderly with poor vitamin B-12 status displayed improved conductivity in myelinated peripheral nerves after vitamin B-12 treatment and an interaction with folate status, which was detected only with the use of cB-12. This trial was registered at www.controlled-trials.com as ISRCTN02694183.