Introduction/Aims: In patients with amyotrophic lateral sclerosis (ALS), axonal spheroids in motor axons have been identified in post-mortem studies. In this study, axonal spheroids and swellings on C-fibers of ALS patients were investigated using corneal confocal microscopy (CCM) and skin biopsy, respectively.Methods: Thirty-one ALS patients and 20 healthy subjects were evaluated with CCM to assess corneal nerve-fiber length (CNFL), -fiber density (CNFD), -branch density (CNBD), dendritic cell (DC) density, and axonal spheroids originating from C-fibers (>100 mu m(2)). In addition, intraepidermal nerve fiber density (IENFD) and axonal swellings (>1.5 mu m) were assessed in skin biopsies obtained from the arms and legs of 22 patients and 17 controls.Results: In ALS patients, IENFD, CNFD, CNFL, and CNBD were not different from controls. The density of DCs and the number of patients with increased DC density were higher in ALS patients than controls (p = .0005 and p = .008). The number of patients with axonal spheroids was higher than controls (p = .03).Discussion: Evaluation of DCs and axonal bulbs in C-fibers of ALS patients could provide insights into pathophysiology or potentially serve as biomarkers in ALS.

OBJECTIVE:Recent evidence indicated that amyotrophic lateral sclerosis (ALS) also impairs spinal circuits, including those mediating cutaneous silent period (CSP). However, most studies utilised surface electromyography (sEMG), which needs more resolution to pinpoint changes at the single motoneuron level. We aimed to investigate CSP properties using single motor unit discharges in ALS. METHODS:In mild and severe ALS patients and controls, CSP was recorded in the first dorsal interosseus and analysed using the discharge rate method, which accurately shows the inhibitory postsynaptic potentials (IPSPs) profile. RESULTS:Our findings confirmed that the CSP latency was prolonged only in severe ALS patients. Moreover, the CSP duration was similar in each group, but late-stage ALS patients tend to have a longer CSP duration. The discharge rate method revealed a significantly longer duration (up to 150 ms) than the duration detected using sEMG. Strikingly, the motoneuron discharge rate - IPSP duration inverse relationship is lost in ALS patients, indicating a possible impairment in the motoneuron integrative properties. CONCLUSIONS:Our data support previous findings of prolonged latency, presented input-output modifications of motoneurons, and revealed the entire course of the CSP, representing a much stronger inhibitory event than previously thought. SIGNIFICANCE:Motoneuron integrative property modification assessed by CSP could be a new biomarker for ALS.

Objective: Previous studies have identified autonomic dysfunction in amyotrophic lateral sclerosis (ALS) using mostly neurophysiological techniques. In this study, stereological evaluation of autonomic fibers and sweat glands has been performed to identify structural evidence of autonomic denervation in patients with ALS. Methods: In this study, 29 ALS patients were compared to 29 controls using COMPASS-31 questionnaire, sympathetic skin response (SSR), and heart rate variability (HRV) at rest. From the same cohorts, 20 ALS patients and 15 controls were further evaluated using staining of autonomic nerve fibers and sweat glands in skin biopsies. SSR and resting HRV were repeated in the ALS patient cohort one year later. Results: COMPASS-31 total score, gastrointestinal- and urinary-sub scores were higher in ALS patients than controls (P = 0.004, P = 0.005, and P = 0.049, respectively). In the ALS patient cohort, SSR amplitudes in hands and feet were lower than in controls (P<0.0001 and P = 0.0009, respectively), but there was no difference in resting HRV (P>0.05). While there was no change in nerve fibers innervating sweat glands, their density was lower in ALS patients than controls, and semi-quantitative analysis also showed structural damage (P = 0.02 and P = 0.001, respectively). SSR and resting HRV of ALS patients remained stable during the one-year follow-up period (P>0.05). Discussion: Supporting abnormal neurophysiological tests, stereological analysis revealed direct evidence of autonomic denervation in ALS patients. However, the degenerative process in autonomic nerve fibers is relatively slow, compared to the rate of motor neuron degeneration in this condition. (c) 2022 Elsevier Masson SAS. All rights reserved.

BACKGROUND:The pattern of lower motor neuron (LMN) degeneration in amyotrophic lateral sclerosis (ALS), i.e., dying-back (from the nerve ending to cell body) or dying-forward (from the cell body to nerve ending), has been widely discussed. In this study, we aimed to evaluate LMN loss using compound muscle action potential (CMAP), motor unit number index (MUNIX), and MScan-fit-based motor unit number estimation (MUNE) to understand the pattern of neurodegeneration in ALS.METHODS:Twenty-five patients were compared with 25 controls using CMAP amplitude and area, MUNIX, and MScan-fit MUNE in three proximal and distal muscles innervated by the ulnar nerve.RESULTS:Unlike the controls, the CMAP area, MScan-fit MUNE, and MUNIX recorded in ALS patients showed more neurodegeneration in distal muscles than proximal muscles. In ALS patients with unaffected CMAP amplitudes (n = 13), the CMAP area, MScan-fit MUNE, and MUNIX showed subtle motor unit loss of 30.7 %, 53.8 %, and 38.4 %, respectively.CONCLUSION:The CMAP area, MScan-fit MUNE, and MUNIX showed neurodegeneration earlier than the reduction in CMAP amplitude. These tests confirmed dying-back neurodegeneration, while only MUSIX showed re-innervation in ALS.

PURPOSE:This study aims to determine the intrarater and interrater reliability of the Heckmatt score in the upper extremity muscles in patients with amyotrophic lateral sclerosis and to investigate its relationship with the clinical features and quantitative echo intensity measurements.METHODS:The Heckmatt scores of multiple upper extremity muscles were calculated in 28 patients with amyotrophic lateral sclerosis and examined the relationships of these values with quantitative ultrasound (QUS) measurements and the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised.RESULTS:The Heckmatt scores showed strong intrarater and interrater correlations with Cohen's Kappa scores ranging from 0.7 to 0.91. In all investigated muscles, the Heckmatt scores showed moderate correlations with quantitative echo intensity measurements and Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised dressing subscale.CONCLUSIONS:The Heckmatt score is a reliable method in evaluating muscles of the upper extremities in patients with amyotrophic lateral sclerosis. It moderately correlates with quantitative values and functional status.

OBJECTIVE:In patients with chemotherapy-induced peripheral neuropathy (CIPN), demonstration of small fibre (SF) damage is important to understand chronic late effects.METHODS:Thirty patients having complaints compatible with possible CIPN following treatment with oxaliplatin or docetaxel were compared with 27 healthy subjects. All subjects were evaluated with quantitative sensory testing (QST) assessing SF function and laser evoked potentials (LEP). In addition, SF-damage was assessed using cutaneous silent periods evoked with electrical (El-CSP) and laser (Ls-CSP) stimuli.RESULTS:For LEP, N2P2 amplitudes were significantly smaller in patients than controls in both upper (P = 0.007) and lower extremities (P = 0.002), and the N1 amplitude in upper extremities of patients were significantly smaller than in controls (P = 0.001). SF-QST, LEP, Ls-CSP, and El-CSP were abnormal in 10 (33.3%), 16 (53.3%), 19 (63.3%), and 24 (80%) of CIPN patients, respectively.CONCLUSIONS:In patients with possible CIPN, El-CSP and Ls-CSP were more often abnormal than LEP and QST. This is probably because El-CSP and Ls-CSP inform mainly about peripheral nociceptive fibres, while LEP and QST inform about peripheral and central nociceptive pathways together.SIGNIFICANCE:LEP and QST are established methods to detect SF-damage. El- and Ls-CSP might help clinicians in diagnosing SF-damage.

OBJECTIVES:Amyotrophic lateral sclerosis (ALS) disrupts motoneurons that control movement and some vital functions, however, exact details of the neuronal circuits involved in ALS have yet to be fully endorsed. To contribute to our understanding of the responsible neuronal circuits, we aimed to investigate the spinal recurrent inhibition (RI) and post-activation depression (P-AD) in ALS patients.METHODS:In two groups of ALS patients, i.e. lumbar-affected (clinical signs in leg muscles) and nonlumbar-affected (clinical signs in arms or bulbar region but not in the legs), RI and P-AD on the soleus muscle were investigated using single motor units and amplitude changes of H-reflex in surface electromyography, respectively. The data were compared with healthy subjects.RESULTS:Compared to controls, P-AD of H-reflex was reduced severely in lumbar-affected patients and reduced to a certain degree in nonlumbar-affected patients. Similarly, a significant reduction in the duration of RI on firing motoneurons was found in lumbar-affected patients (11.5 ± 2.6 ms) but not in nonlumbar-affected patients (29.7 ± 12.4 ms, P < 0.0001) compared to controls (30.8 ± 7.2 ms, P < 0.0001).CONCLUSION:The current study revealed that spinal inhibitory circuits are impaired in ALS.SIGNIFICANCE:These findings may provide insight for proposing new therapeutic approaches and following disease progression in humans.

The last decade has proven that amyotrophic lateral sclerosis (ALS) is clinically and genetically heterogeneous, and that the genetic component in sporadic cases might be stronger than expected. This study investigates 1,200 patients to revisit ALS in the ethnically heterogeneous yet inbred Turkish population. Familial ALS (fALS) accounts for 20% of our cases. The rates of consanguinity are 30% in fALS and 23% in sporadic ALS (sALS). Major ALS genes explained the disease cause in only 35% of fALS, as compared with ~70% in Europe and North America. Whole exome sequencing resulted in a discovery rate of 42% (53/127). Whole genome analyses in 623 sALS cases and 142 population controls, sequenced within Project MinE, revealed well-established fALS gene variants, solidifying the concept of incomplete penetrance in ALS. Genome-wide association studies (GWAS) with whole genome sequencing data did not indicate a new risk locus. Coupling GWAS with a coexpression network of disease-associated candidates, points to a significant enrichment for cell cycle- and division-related genes. Within this network, literature text-mining highlights DECR1, ATL1, HDAC2, GEMIN4, and HNRNPA3 as important genes. Finally, information on ALS-related gene variants in the Turkish cohort sequenced within Project MinE was compiled in the GeNDAL variant browser (www.gendal.org).

The motor unit number index (MUNIX) method is used to estimate alterations attributed to changes in number and size (MUSIX) of motor units (MUs) using the compound muscle action potential (CMAP) and surface electromyographic interference pattern (SIP). In sixteen patients with Amyotrophic Lateral Sclerosis (ALS) and 16 controls, compound muscle action potentials (CMAP), MUNIXs and MUSIXs were recorded from flexor carpi ulnaris (FCU), abductor digiti minimi (ADM), and first dorsal interosseous (FDI) muscles. In ALS patients, mean values of MUNIXs recorded form FCU (76.7 ± 24.01 vs 71.5 ± 32.4, P = 0.22), ADM (130.3 ± 1.4 vs. 66.4 ± 2.3, P = 0.008), and FDI (181.8 ± 1.3 vs. 63.6 ± 2.8, P = 0001) muscles were lower and MUSIXs of FCU (59.9 ± 11.6 vs. 54.4 ± 13.4, P = 0.6), ADM (85.6 ± 1.4 vs. 99.1 ± 1.6, P = 0.34), and FDI (72.9 ± 1.2 vs. 99.9 ± 1.6, P = 0.03) were higher than controls. CMAPs deteriorated in proximal (i.e., FCU; 6 ALS vs. 0 controls, P = 0.009) muscle more than distal (i.e., ADM; 5 ALS vs. 0 control, P = 0.02 and FDI; 3 ALS vs. 1 control, P = 0.3) while MUNIXs deteriorated in distal (i.e., FDI; 9 ALS vs. 0 control, P = 0.003) more than proximal (i.e., ADM; 7 ALS vs. 1 control, P = 0.02, and FCU; 1 ALS vs. 0 control, P = 0.5) muscles. Unlike CMAPs, MUNIX was considered to define denervation process overwhelming the impact of re-innervation using SIPs. In addition to utility in long term assessment of ALS patients, MUNIX could be used to estimate quantitative alterations in motor units for diagnostic purpose.

Compression over a peripheral nerve leads to several changes in structural and physiological properties of that nerve. Paranodal myelin abnormalities and impaired axonal transport are some pathological incidents defined after acute compression. In sixteen ALS patients and 16 controls, CMAP Scan curves were recorded from first dorsal interosseus (FDI) muscle by stimulating ulnar nerve at elbow before compression, compression in 5 consecutive CMAP scanning cycles, and after compression. Stimulus intensities needed to elicit 10% and 90% of CMAP and step number and step% were calculated for each scan. As a further comparison, areas under CMAP scan curves were examined using natural values, percentages, and differences between compression (comp) cycles. For both patients and controls, conventional CMAP scan parameters were not significantly different in consecutive cycles. During compression, a tendency of reduction in area under CMAP scan curve of ALS patients (164.8 mVms, 156.3 mVms, 146.5 mVms, 142.1 mVms, 142.7 mVms, 137 mVms, and 174.9 mVms for pre-comp, 1st comp, 2nd comp, 3rd comp, 4th comp, 5th comp, and post- comp cycles, respectively) and a tendency of increase in CMAP scan curve area of healthy subjects (283.3 mVms, 315.6 mVms, 298.5 mVms, 319.7 mVms, 336.1 mVms, 361.4 and 308.1 mVms for pre-comp, 1st comp, 2nd comp, 3rd comp, 4th comp,5th comp, and post- comp cycles, respectively) were observed. Probably due to incidental changes in nerve excitability, ALS patients mostly reacted differently to nerve compression when compared with healthy subjects.

Many neurophysiological and pathological studies showed sensory abnormalities in ALS patients as a part of multisystem disease. In this study, we assessed progression of sensory changes in ALS patients, using nerve conduction studies (sNCS) in two consecutive visits. sNCSs were evaluated based on amplitudes and velocities of bilateral dorsal sural (DS), medial plantar, superficial peroneal (SP), sural and left radial sensory nerves. In addition a global Total Sensory Score (TSens) was determined using the amplitudes of these nerves. Although, for both visits, TSens was smaller in patients (p = 0.04 and P = 0.01, for consecutive visits) then controls, there was no significant change between two visits of the patients (P = 0.19). ALS patients had significantly smaller amplitudes and slower velocities for bilateral DS, and left radial nerves for both visits. TSens was reduced in 7 (63.3%) but increased in 4 (36.6%) ALS patients. Although, ALS patients showed considerable changes in NCS, sensory denervation is probably slowly progressive. The patients with improved sNCS were attributed to possible changes in sensory nerve excitability following corrective measures, e.g. administration of parenteral gastrostomy or high caloric diet.

Objective:To determine symptoms and characteristics of chronic sensory neuropathy in patients treated with oxaliplatin and docetaxel, including patterns of somatosensory abnormalities, pain descriptors, and psychological functioning.Design:A retrospective cross-sectional study.Setting:A chronic pain research center.Subjects:Thirty-eight patients with chronic peripheral pain and/or dysesthesia following chemotherapy.Methods:Sensory profiles, psychological functioning, and quality of life were assessed using standardized questionnaires. In addition, standardized quantitative sensory testing and nerve conduction studies were carried out.Results:The sensory profiles and clinical symptoms were very similar in the two groups. Pricking, numbness, and burning were common descriptors in both groups, and the predominant finding was sensory loss to A beta-mediated sensory modalities with decreased mechanical and vibration detection thresholds. A high frequency of abnormalities in thermal sensory limen and the presence of paradoxical heat sensation seem to be sensitive markers of small fiber loss. Both groups had mainly sensory, axonal large fiber or mixed fiber polyneuropathy, which tended to be most severe in the oxaliplatin group.Conclusions:Both oxaliplatin-induced and docetaxel-induced polyneuropathies represent a significant problem that affects the daily life of the patients. Our results, defining the somatosensory phenotype, can improve the understanding of the pathophysiological mechanisms useful for future studies in the tailored treatment of prevention of chemotherapy-induced peripheral neuropathy and pain.

Konka bulloza KB , sinonazal anatominin en yaygin anatomik varyasyonlarindan biridir ve konkanin pnomatizasyonunu ifade eder. Tek tarafli surekli bas agrisi ile otonom bulgularin birarada gorulmesi klinik pratikte KB ve hemikrania kontinuayi kolayca karistirmaktadir. Rino-sinus bas agrilari genellikle anatomik olarak yakin iliskilerinden dolayi birincil bas agrilariyla karisabilir. Gunluk Noroloji pratiginde akilda tutulmalidir.

Nerve conduction studies have limited diagnostic power to assess Aδ and C fibers in patients with mixed (large and small fibre neuropathy together) neuropathy, and no power to diagnose small fiber neuropathy (SFN). An option to assess small fibers using standard electro-diagnostic equipment could be cutaneous silent period (CSP) recordings. Thirty patients with chronic pain and/or dysesthesia due to chemotherapy were compared with 27 healthy subjects. Electrical stimulation (25 mA × 1 ms) was delivered on median-sensory and sural nerves. CSPs were recorded from abductor pollicis brevis (APB) and anterior tibial (TA) muscles. In addition, a derived parameter, silent period ratio (SPR), was used to assess Aδ functions. The yields of the tests were compared with laser evoked potentials (LEPs) from upper and lower extremities. Latencies of APB-CSP and TA-CSP were not significantly different (p > 0.05) between groups. On the other hand, mean APB-CSP duration was longer (32.5 ± 12.6 vs 27.4 ± 9.2 ms, p = 0.004), mean TA-CSP duration shorter (11.8 ± 12.7 vs 39.9 ± 11.6 ms, p < 0.0001), and SPR was lower (0.3 ± 0.3 vs.1.5 ± 0.5, p < 0.0001) in patients than controls. The number of patients with abnormal APB-CSP, TA-CSP, and SPR were 5 (16.6%), 22 (73.3%), and 26 (86%), respectively. CSP and SPR revealed comparable results with LEPs (16 patients, 53.3%) to define the patients with SFN. CSP and SPR could be used to assess peripheral Aδ functions. CSPs could be an option to diagnose SFN in the laboratories having only standard electro-diagnostic equipment.

Laser evoked potentials (LEPs) have shown less sensitive results than other tests (e.g., skin biopsies, quantitative sensory testing) in diagnosing small fiber neuropathy (SFN), probably because both central and peripheral nociceptive pathways are assessed. Alternatively, laser evoked cutaneous silent period (Ls-CSP) could selectively evaluate peripheral nociceptive pathways only. Thirty patients with chemotherapy-induced chronic pain and/or dysesthesia were compared with 27 healthy subjects. LEPs were recorded from scalp and Ls-CSPs from the abductor pollicis brevis (APB) muscle following random Neodymium-doped yttrium aluminum perovskite (Nd:YAP) laser stimuli given on hairy skin of the extremities. For LEPs, mean values of N1 amplitude in upper extremities (8.6 ± 5.4 vs 12.7 ± 5.2 μV) and N2P2-amplitudes in upper ( 27.9 ± 17.0 vs 35.8 ± 9.6 μV) and lower extremities (14.5 ± 11.2 vs 24.4 ± 7.7 μV) were significantly lower in patients than controls (p<0.01). Ls-CSPs were not reproducible in lower extremities. In 18 patients, Ls-CSPs from APB muscle were not recorded. In the rest of the patients (n = 12), Ls-CSP latencies (139.9 ± 12.4 vs. 131.9 ± 13.7 ms) and durations (19.8 ± 1.4 vs 18.5 ± 1.3 ms) were not different from controls (p>0.05). Overall, LEPs and Ls-CSPs were abnormal in 16 (53.3%) and 19 (63.3%) patients, respectively. Ls-CSPs in upper extremities defined more patients than LEPs in upper and lower extremities. Ls-CSPs in hands were more sensitive than LEPs in detecting patients with SFN. Ls-CSP could be a useful supplementary test in the diagnosis of SFN, especially in cases with subtle LEP changes.

Objective: The electrodiagnosis of polyneuropathy (PNP) may benefit from examination using near-nerve needle technique (NNT) and from inclusion of distal nerves. This study compared the diagnostic utility of distal nerve conduction studies (NCS) and NNT recording.& para;& para;Methods: Bilateral NNT and surface recording of the sural nerve and surface recording of the dorsal sural and medial plantar nerves were prospectively done in 91 patients with clinically suspected PNP. Distal NCS were additionally done in 37 healthy controls. Diagnostic reference standard was the final clinical diagnosis retrieved from the patients medical records after 1-4 years.& para;& para;Results: The clinical follow-up diagnosis confirmed PNP in 68 patients. Equally high sensitivities of the dorsal sural (72%), medial plantar (75%), and sural nerve with NNT recording (77%) were seen, while the sensitivity of conventional surface recording of the sural nerve was lower (60%). Sural NCS with both NNT and surface recording and dorsal sural NCS showed high specificities (85-95%) and positive predictive values (94-98%), while a lower specificity was seen for the medial plantar nerve (68%).& para;& para;Conclusion: NCS of distal nerves, especially the dorsal sural nerve, have high diagnostic power equalling sural NNT recording.& para;& para;Significance: The electrodiagnostic evaluation of patients with suspected PNP benefits from NCS of distal nerves. (C) 2017 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Objective: Mild involvement of sensory nerves has been reported in previous studies in ALS patients. In this study, we assessed sensory pathways in ALS patients using laser evoked potentials (LEPs) and somatosensory evoked potentials (SSEPs).Methods: We recruited 18 ALS patients and 31 healthy subjects. Neodymium-doped yttrium aluminium perovskite (Nd: YAP)-laser was used to evoke LEPs in upper (UE) and lower (LE) extremities. N1 and N2P2 potentials were obtained from contralateral insular cortex (T3 or T4) and vertex (Cz), respectively. Median SSEPs were recorded from C3' or C4' and tibial SSEPs from Cz'.Results: Compared to controls, ALS patients had longer N2 and P2 latencies, and smaller N2P2 amplitudes in both UE-and LE-LEPs (p < 0.05), and longer latencies for median and tibial SSEPs (p < 0.05). LEPs and SSEPs were abnormal in 72.2% and 56.6% patients, respectively.Conclusions: Cortical potentials showed that A-beta or A-delta sensory fibres, or both, were impaired in more than half of the ALS patients.Significance: The findings support that ALS is a multi-systemic disorder involving, although to a lesser degree, other systems than the motor. (C) 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

ABSTRACTIntroductionThe diagnostic criteria for amyotrophic lateral sclerosis (ALS) require normal sensory nerve conduction studies (NCS) or abnormal NCS only in the presence of neuropathy of identified etiology. In this study, we investigated the presence and extent of involvement of Aß sensory fibers in ALS.MethodsDistal sensory NCS [antidromic dorsal sural (DS) and orthodromic medial plantar (MP)] and conventional sensory NCS (unilateral median sensory and bilateral sural nerves) were performed in 16 definite and 2 probable ALS patients (based on Awaji criteria) and 31 controls.ResultsAbnormal conventional sensory NCS were found in 8 (44.4%) ALS patients and 1 (3.2%) control subject (P = 0.002), whereas abnormal distal sensory NCS were found in 12 (66.7%) ALS patients and 3 (9.6%) controls (P < 0.0001).ConclusionDistal sensory NCS were more often abnormal than conventional sensory NCS in ALS. Muscle Nerve 54: 1086–1092, 2016