Electrophysiological Characteristics And Diagnostic Value Of Split Hand Phenomenon In Amyotrophic Lateral Sclerosis

Part 1 The significance of split-hand index based on F-waves in the diagnosis of amyotrophic lateral sclerosisObjectiveTo study the split-hand phenomenon in patients with amyotrophic lateral sclerosis(ALS)through the F-wave persistence and amplitude recorded from the abductor pollicis brevis(APB),first dorsal interosseous muscle(FDI),and abductor digiti minimi(ADM).We proposed a novel split-hand index(SI)using F-wave persistence and the F/M amplitude ratio and assessed its diagnostic utility in ALS.MethodsEighty-three patients-with ALS who visited the outpatient department of neurology in our hospital from December 2017 to December 2018 and required electrophysiological examination to support the diagnosis were enrolled in our study,and 50 age-?gender-and height-matched healthy volunteers recruited as a healthy control group(HCs).The basic information and clinical data from ALS patients and basic information from healthy volunteers were collected by a clinical registry system.Motor nerve conduction study and F-waves were performed to median and ulnar nerves from all subjects.Bilateral compound muscle action potentials(CMAP),F wave persistence,and amplitude were recorded from APB,FDI,and ADM.The SI derived from CMAP amplitude,F wave persistence,and amplitude were calculated using the following formula:SI?(APB x FDI)/ADM.The sensitivity and specificity of SIFP,SIF/M,and SICMAP in differentiating ALS from HCs were derived from receiver-operating characteristic(ROC)curve analysis.This prospective study recruited patients from the outpatient department of neurology in our hospital between June 2019 and December 2019.Patients who were 18-80 years old,had clinical neuromuscular symptoms affecting the upper limbs,and required electrophysiological examinations to aid diagnosis were eligible.CMAPs and F-waves recorded from the APB,FDI,and ADM were examined.SIFP and SICMAP were calculated.All studies were performed unilaterally on the more clinically affected limb.By comparing the amplitudes of CMAPs from individual nerves compared with the laboratory-established lower limit of normal for each nerve,the ALS patients were classified into"early-stage'(normal amplitude)and "more advanced"(reduced amplitude)groups.The sensitivity and specificity of SIFP and SICMAP in differentiating ALS from non-ALS conditions were derived by analyzing the ROC curves.ResultsBoth SIFP and SICMAP were significantly reduced,and SIF/M was significantly increased in ALS patients.The ROC curve analysis indicated that all SIFP,SIF/M and SICMAP reliably differentiated ALS from HCs[AUC 0.915(95%CI:0.88-0.95);AUC 0.814(95%CI:0.76-0.86);AUC 0.862(95%CI:0.82-0.91)],but SIFP showed better diagnostic accuracy than SIF/M and SICMAP(P=0.003;P=0.039).The cut-off value of 80.7 was potentially useful in distinguishing ALS patients from controls,with high sensitivity(81.2%)and specificity(97%).In subgroup analyses,SIFP appeared to be a better variable than SIF/M and SICMAP for differentiation of ALS patients with normal CMAP from HCs.Comparison of the ROC curves for SIFP and SICMAP in the bulbar-and limb-onset ALS patients revealed no significant.A total of 309 participants,comprising 91(29.4%)with ALS and 218(70.6%)with other neuromuscular disorders,were enrolled after 54 were excluded.Both SIFP and SICMAP were significantly reduced in the ALS group compared with the non-ALS group(P<0.001).A significant reduction in SIFP was also evident in the early-stage group(P<0.001)compared to the non-ALS group,but not the SICMAP(P?0.62).By ROC curve analysis,a SIFP cut-off of 73.3 showed a sensitivity of 85.7%sensitivity and 80.7%specificity for differentiating ALS from non-ALS.SICMAP showed lower sensitivity(75.8%,P=0.001)than SIFP for ALS diagnosis.The combination SIFP and SICMAP did not have greater sensitivity or specificity than SIFP alone.In subgroup analyses,the ROC curve for early-stage ALS patients had an AUC of 0.816,and the diagnostic efficiency of a reduction in SIFP,especially the sensitivity,was significantly greater than that of SICMAP(AUC 0.529,P<0.001).Besides,we noted SIFP had an AUC of 0.904 which was greater than that of SICMAP(AUC 0.832,P=0.009)in limb-onset ALS patients.A comparison of the ROC curves for SIFP and SICMAP in the more advanced and limb-onset ALS patients revealed no significant.ConclusionSIFP,SIF/M,and SICMAP can be used as evaluation indicators of the split-hand phenomenon in ALS.However,SIFP appears to be more sensitive.Importantly,the SIFP reliably distinguished ALS patients from HCs and non-ALS conditions,and it could be a sensitive and noninvasive neurophysiological diagnostic marker for ALS patients particularly in the early stage of the disease.In particular,a SIFP value of 73.3 might be the optimal cut-off value to diagnose ALS.Part 2 The electrophysiological features and mechanisms of split-hand syndrome in amyotrophic lateral sclerosisObjectiveWe investigated the difference of dysfunction between the spinal motoneuron innervated the first dorsal interosseous(FDI)and abductor digit minimi(ADM)muscles in patients with amyotrophic lateral sclerosis(ALS)by investigating F-waves recorded by FDI and ADM.Combined with triple-stimulation technique(TST)to assess the contribution of cortical dysfunction and spinal motor neuron excitability changes in the split-hand phenomenon of ALS.MethodsOne hundred and five sporadic ALS patients were recruited at the department of neurology in Peking Union Medical College Hospital between December 2017 and December 2019.Thirty age-,gender-and height-matched healthy controls(HCs)were enrolled.Motor nerve conduction studies and F-waves were performed bilaterally on the ulnar nerves in all subjects.Among them,22 patients with ALS were performed TMS and TST recorded from FDI and ADM.Two groups were established from the ALS patients,an affected hand group(69 patients),and an unaffected hand group(36 patients).The differences in FDI/ADM CMAP amplitude ratio,and F-wave parameters recorded from FDI and ADM were compared among different groups.Furthermore,we compared the difference of indicators which reflect spinal neuron excitability and indicators of central motor conduction time(CMCT),motor evoked potential(MEP)latency,MEP/CMAPErb amplitude ratio,resting motor threshold(RMT),cortical silent period(CSP),TST amplitude ratio,and TST area ratio recorded from FDI and ADM which reflect cortical excitability and function of the corticospinal tract.ResultsA significant reduction of FDI/ADM CMAP amplitude ratio was observed in the affected hand group compared with HCs,confirming that the split-hand phenomenon was evident in the present ALS patients.HCs revealed prominently longer F-wave latencies,lower chronodispersion,persistence,mean F-wave amplitude,and mean and maximal F/M amplitude ratio(P<0.001),and higher index repeating neuron,and index F-wave repeater(P<0.05)in the FDI compared to the ADM.This trend was similar in the unaffected hand group.Besides,the F-wave persistence significantly decreased(P<0.05),mean F-wave amplitude,mean F/M amplitude ratio,index repeating neuron,and index F-wave repeater significantly increased(P<0.001)recorded from FDI but not ADM in the unaffected hand group compared with HCs.However,no significant differences in almost all F-wave parameters between the FDI and ADM were observed in ALS patients with affected hands except the minimum and mean F-wave latency.These data suggest that excitability is greatly changed in the spinal motoneurons innervating the FDI.At the cortical level,the MEP latencies recorded from ADM was significantly increased;RMT were significantly increased,CSP,and TST amplitude ratio,and TST area ratio were significantly reduced recorded from both FDI and ADM in ALS patients compared with HCs.Importantly,in HCs and ALS groups,no difference was observed in CMCT,MEP latency,MEP/CMAPErb,amplitude ratio,RMT,CSP,TST amplitude ratio,and TST area ratio recorded between FDI and ADM.Furthermore,the F-wave persistence,mean and maximum F-wave amplitude,index repeating neuron,and index F-wave repeater of the FDI and ADM were significantly correlated with the FDI/ADM CMAP amplitude ratio in ALS patients but not of the parameters of TMS/TST.ConclusionThe physiological differences existed in the F-wave parameters recorded from FDI,and ADM in healthy subjects,the spinal motoneurons innervating the FDI have greater inhibitory modulation than the ADM.The dysfunction of spinal motoneurons between the FDI and ADM was different in ALS,and the changed excitability is more prominent in spinal motoneurons innervating the FDI that is consistent with the split-hand sign.However,the changes in cortical excitability and function of the corticospinal tract did not follow a split-hand distribution argues against cortical excitability changes associated with the development of the split-hand syndrome.Thus,spinal excitability changes may underly the development of the split-hand sign in ALS.Part 3 Evaluation of split-foot phenomenon in amyotrophic lateral sclerosis:differential involvement of the extensor digitorum brevis and abductor hallucis muscles ObjectiveWe aim to evaluate the pattern of involvement of the extensor digitorum brevis(EDB)and the abductor hallucis(AH)muscles by compound muscle action potential(CMAP)amplitudes and F-waves from peroneal nerve and tibial nerve,as well as to elucidate the split muscle phenotype of the foot in ALS.Additionally,we investigated whether CMAP or F-wave parameters recorded from EDB and AH could serve as simple neurophysiological biomarkers for ALS diagnosis.MethodsWe recruited 60 consecutive patients with ALS and 25 healthy controls(HCs)at the department of neurology in Peking Union Medical College Hospital between December 2017 and November 2018.CMAPs and F-waves were recorded over the EDB and AH muscles in all subjects.For comparison,we classified patients into two categories based on the presence or absence of lower limb symptoms.ResultsThe EDB/AH CMAP amplitude ratio was significantly reduced in patients with affected legs(0.33±0.21,P=0.007),whereas patients with unaffected legs had a ratio similar to that of the HCs.In the unaffected leg group,the F-wave latencies,mean and maximal F/M amplitude ratios,and the persistence of the total repeater F-wave shapes(index Freps)recorded from EDB were significantly increased(P<0.001),but not the AH,compared with HCs.Comparison with HCs,no significant differences in almost all F-wave parameters recorded from EDB and AH in the affected leg group were observed except the chronodispersion recorded from EDB and the mean F-wave amplitude recorded from AH;meanwhile,the EDB/AH ratios for the F-wave latencies,mean F-wave amplitude,mean F/M amplitude ratio,and index Freps of the EDB-AH,were significantly increased in the affected leg group,whereas the EDB/AH ratio for F-wave persistence was significantly reduced.These findings indicated dysfunction of spinal motoneurons innervating the EDB were happened in the early stage and seem to be more affected than the spinal motoneuron innervating the AH.ROC curve analysis suggested that the max,mean,and min F-wave latency(AUC 0.868;0.842 and 0.803),mean F/M amplitude ratio(AUC 0.827),and index Freqs(AUC 0.869)recorded from EDB more strongly differentiated patients with ALS from the HCs compared to the EDB/AH CMAP amplitude ratio(AUC=0.61).Notably,the maximal F-wave latency and index Freqs recorded from EDB reliably differentiated patients with unaffected legs from the HCs,with AUCs of 0.83 and 0.81,respectively.ConclusionWe found that the EDB and AH of patients with ALS exhibited a different degree of involvement.There is preferential involvement of EDB compared to AH,a split-foot pattern of split muscle phenotype is established.The maximal F-wave latency and index Freqs of the EDB robustly differentiated patients with ALS from HCs,which might facilitate earlier identification of ALS.