Clinical And Prognostic Features Of 153 MND-Follow-up Study From A Hospital-based Registry

Background and objectiveAmyotrophic lateral sclerosis(ALS)is the most common type of motor neuron disease(MND).It mainly affects the upper and lower motor neurons in a progressive,lethal disease course,with an average survival time of 3-5 years.Different combinations of upper and lower motor neuron in.juries in different spinal cord segments present multiple clinical subtypes with different clinical characteristics and prognosis,collectively referred to as ALS/MND.Common phenotypes include limb onset ALS,Progressive bulbar palsy(PBP),Flail arm syndrome(FAS),Isolated bulbar ALS(IBALS),Progressive muscular atrophy(PMA),Primary lateral sclerosis(PLS)and Flail leg syndrome(FLS).Despite its well-known natural history,pathophysiological and clinical characteristic for the most common ALS,other atypical variants of MND gained little attention and mainly came from sporadic cases and small series,such like FAS,FLSand IBALS.Clinically,diagnosis of ALS/MND is not hard to diagnose with the help of electrophysiological examinations.However,as an almost incurable rare disease,the rapid deterioration add difficulty to patients' regular follow-up.Predicting the prognosis of heterozygous MND patients has been a challenge for clinicians.Research purpose of the study wasto analyze survial condition of MND patients in this area and summarize the clinical and prognostic differences between different types of MND variants in this hospital.MethodsFrom 2017-1 to 2019-6,a total of 153 patients with ALS/MND were collected and registered in this study from the Department of Neurology,Qilu Hospital of Shandong University,after excluding those without complete clinical data or refused registration.Patients were classified into 6 different phenotypes based on criteria,including Limb onset ALS,Bulbar onset ALS(PBP and IBALS),FAS,PMA,PLS and FLS.Baseline data and clinical features was collected in detail by CRF.Clinical UMN and LMN involvement in each limb were quantified by a scoring system.Routine nerve conduction studies and EMG were performed in all participants.The compound muscle action potentials(CMAPs)of abductor pollicis brevis(APBs)and abductor digiti minimi(ADMs).The split-hand phenomenon was defined by CMAPAPB/CMAPADM<0.6;split elbow was defined by relative preservation of triceps over biceps strength in upper limb-onset ALS.Patients were followed up every 6 months by telephone to evaluate the progress,ALSFRS-R score and new symptoms."Event"was defined by death or NIV caused by ALS,whichever occurred first.Patients with NIV also continued to be followed until death or as of the last follow-up date 2019-12.Survival was analyzed using the Kaplan-Meier method and Cox regression analysis.RESULTS1.Of 153 patients,there were 90(58.8%)cases of classic limb onset ALS,28(18.3%)cases of bulbar onset ALS(PBP 22,IBALS 6),19 FAS(12.4%),12 PM A(7.8%).3 FLS(1.9%)and 1case of PLS(0.6%).Onset age ranged from 25 to 82 years(mean 56.16 years),with average diagnostic delay of 14.01 months(median 12 months)and male to female ratio of 1.39:1.2.By the end of censoring date,a total of 37(24.1%)people had died,75 had developed to event(death or NIV,whichever came first),20(13.0%)were lost to follow-up,and 96(62.7%)were alive.Onset to event and onset to death was 38.58months(median 30 months)and 51.22 months on average(median 57 months)respectively.Median onset to event for limb-onset ALS,FAS,PMA and bulbar onset ALS was 34.78 months,53.61 months,58.20 and 22 months respectively.Subtypes,diagnosis delay and ALSFRS-R score were prognostic predictors.3.For limb-onset ALS,53.3%and 40.5%showed split hands and split elbows.There was no concordance betweenside of onset with the dominant handiness.Survival analysis showed that the diagnostic delay less than 1 year(p=0.014),age>65 years(p=0.021)and higher LMN scores(p=0.030)were risk factors in poor prognosis.4.FAS showed a significant male predominance(5.3:1).Symptom confined to arms with an average of 29 months,longer than other phenotypes.FAS mainly affects the proximal part of upper limbs despite not all of them had a proximal onset.MRC score of the weakest muscle at registration was significantly lower than that of UL-ALS.Subclinical LMN load in FAS determined by EMG was actually as extensive as ALS.63.2%of FAS had at least one UMN sign,but not extensive and strong as UL-ALS.FAS presented a split phenomenon with similar proportion of UL-ALS.FAS-type ALS was a kind of ALS manifested as FAS but progressed rapidly,onset to event was shorter thanother UL-ALS(FAS-type ALS 20.00 months-ALS 40.96 months).So,confining to arms for more than 1 year was necessary to diagnose FAS.5.Bulbar-onset ALS patients had mean onset age of 60.71 years,with a female predominance(M:F=0.75:1),and were divided into PBP and IBALS.IBALS progressed slowly(onset to event IBALS 33.16 months,PBP 20.75 months,p=0.015)with a longer time confined to bulbar(IBALS 24.5months,PBP 6 months,p<0.001).Clinically,IBALS had a preservation of limb function,but there was no significant difference in pyramidal sign.IBALS patients have mixed bulbar palsy and 31.8%PBP only have pure LMN bulbar signs.Conclusion1.ALS/MND had heterogeneous clinical manifestations and different phenotype had variable proportion,demographic and prognostic features.Bulbar onset ALS had the worst prognosis,followed by limb onset ALS,FAS and PMA.Bulbar onset ALS,short diagnostic delay(<1 year)and lower ALSFRS-R were predictors to limited survival.2.For limb-onset ALS,there was no concordance between side of onset and the dominant handness.Shorter diagnostic delay(<1 year),older onset(>65 years)and strong LMN signsare obviously risk factors for poor prognosis.3.FAS was a subtype confined to the upper limbs with a better prognosis.It usually had a proximal onset and lower muscle strength.But the split-hand phenomenon was not different from UL-ALS.To distinguished from FAS-type ALS,it was necessary to restrict symptom confined to upper limbs more than 12 months to diagnose FAS4.1BALS had a good prognosis with a long time confined to bulbar.Limb weakness was more frequent in PBP.