Differentiating Slowly Progressive Subtype of Lower Limb Onset ALS From Typical ALS Depends on the Time of Disease Progression and Phenotype

Abstract

BackgroundFlail leg syndrome (FLS) is a regional variant of amyotrophic lateral sclerosis (ALS) with the characteristics of slow progression and the symptoms confined to the lumbosacral region for extended periods. However, FLS may not be easily differentiated from typical ALS.ObjectiveThe objective of the study was to determine a cutoff time of disease progression that could differentiate FLS from the typical lower limb onset ALS.MethodsA cutoff point analysis was performed with maximally selected log–rank statistics in patients with lower limb onset ALS registered from 2009 to 2013. Based on the cutoff duration from the lower limb onset to second region significantly involved (SRSI), all patients were divided into the slowly progressive subtype of lower limb onset ALS group and the typical lower limb-onset ALS group. Patients with the slowly progressive subtype of the lower limb onset ALS, who had the flail leg phenotype, were classified as patients with FLS. Differences between groups were analyzed.ResultsAmong the 196 patients recruited, 157 patients with a duration <14 months from lower limb onset to SRSI were classified as having typical lower limb onset ALS. Twenty-nine patients with a duration more than or equal to 14 months and the flail leg phenotype were classified as having FLS. Patients with FLS exhibited a median diagnostic delay of 25 months, a median duration of 24 months from lower limb onset to SRSI, a forced vital capacity abnormity rate of 12.5% at the first visit to our department, and a median survival time of 80 months, which were significantly different from those of patients with typical lower limb onset ALS (p < 0.001, p < 0.001, p = 0.024, p < 0.001). The 5-year survival rate of the FLS group (79.3%) was much higher than that of the other group (1.9%).ConclusionsA crucial feature in differentiating FLS from typical lower limb onset ALS in Chinese patients may be symptoms confined to the lumbosacral region for at least 14 months, which may be better than 12 or 24 months used in the previous studies. The FLS was characterized by slower progression, less and later respiratory dysfunction, and a more benign prognosis than the typical lower limb onset ALS.

Case report: Flail leg syndrome in familial amyotrophic lateral sclerosis with L144S SOD1 mutation

“…According to Wijesekera et al ( 4 ) UK and Melbourne clinical studies, FLS is defined as a progressive, distal onset LMN pattern of weakness and wasting confined solely to the lower limbs for at least 12 months. Deep tendon reflexes from the lower limbs are usually diminished or absent; however, brisk lower limb DTRs or positive Babinski sign do not preclude the diagnosis of FLS, as long as hypertonia and clonus are absent ( 3 , 4 ). FLS of asymmetric onset may present with brisk DTRs from unaffected limbs ( 8 ).…”

“…Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, which in its classic form is characterized by symptoms of simultaneous upper and lower motor neuron involvement at the onset ( 1 ). It has a mean prevalence of 5.4/100.000 in Europe ( 1 ) with flail leg syndrome (FLS, also known as pseudopolyneuritic variant) accounting for up to 5% of ALS cases ( 2 ), in which lower motor neuron signs predominate at onset, affecting the lower limbs usually as a triad of distal paresis, muscle atrophy, and hyporeflexia/areflexia ( 3 ).…”

“…Flail leg syndrome was discovered by Pierre Marie and later described by his student Patrikios in 1918 as asymmetric-onset, slowly progressing, distal lower limbs muscle weakness with the absence of lower limb deep tendon reflexes (DTRs) and presence of subtle or late upper motor neuron (UMN) signs ( 4 ). FLS is a rare phenotype of ALS, characterized by lower motor neuron (LMN) signs restricted to the lumbosacral region for an extended period of time (which varies in the literature from 12 to 24 months), with a more favorable prognosis than the classic form of ALS in the means of slower progression and longer mean survival between 75.9 and 87 months with diminished and late respiratory involvement ( 3 ). The longer the disease is confined to the lumbosacral region, the longer the survival ( 4 ).…”

Gut Microbial Metabolome and Dysbiosis in Neurodegenerative Diseases: Psychobiotics and Fecal Microbiota Transplantation as a Therapeutic Approach—A Comprehensive Narrative Review

“…Another study analyzed stool samples from ALS patients, concluding that, as in previous studies, ALS patients showed a loss of diversity in their GM. Moreover, they found that majority of patients had high intestinal inflammation (measured by the presence of metabolites such as LPS) [274]. Therefore, the use of prebiotic, probiotic, or metabolite treatments (for example, Prevotella spp., or changing butyrate metabolism) could be useful in the treatment of ALS [275].…”

Flail leg syndrome misdiagnosed as inflammatory myopathy a case report

“…It affects both upper and lower motor neurons, and shows rapid progress of muscular atrophy and respiratory muscle weakness.FLS is a variant type of ALS , symptoms of which limited in lower limbs and it progresses slowly in a long time after disease's onset. [2]Here we report a case of FLS that admitted in the seventh Affiliated Hospital of Sun Yat-sen University in May 2022. We summarized its clinical characteristics in combination with published literatures.…”