Clinicopathological characteristics of patients with amyotrophic lateral sclerosis resulting in a totally locked-in state (communication Stage V)

Hayashi, Kentarō; Mochizuki, Yoko; Takeuchi, Ryoko; Shimizu, Toshio; Nagao, Masahiro; Watabe, Kazuhiko; Arai, Nobutaka; Oyanagi, Kiyomitsu; Onodera, Osamu; Hayashi, Masaharu; Takahashi, Hitoshi; Kakita, Akiyoshi; Isozaki, Eiji

doi:10.1186/s40478-016-0379-3

Cited by 19 publications

(14 citation statements)

References 27 publications

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“…The ophthalmoplegia and dysuria observed in our patients might be caused by involvement of the non-motor system including the frontal eye field and autonomic nervous centers in the brain 24,39 . Neuropathological evidences also support this idea 30,48,49 . Rapid body weight decline in the early stages of ALS might be the earliest non-motor manifestation due to multisystem neurodegeneration in ALS.…”

Section: Discussionsupporting

confidence: 52%

Body weight variation predicts disease progression after invasive ventilation in amyotrophic lateral sclerosis

Nakayama

Shimizu

Matsuda

et al. 2019

Sci Rep

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Weight loss is an independent predictor of survival in the early stages of amyotrophic lateral sclerosis (ALS). However, the effects of weight variations on the functional prognosis after tracheostomy and invasive ventilation (TIV) in ALS remain unknown. This prospective cohort study aimed to investigate the relationship between weight loss before TIV and disease progression after TIV in ALS patients. Sixty ALS patients with TIV were enrolled and classified into subgroups based on the rate of decline in body mass index, from onset to TIV utilization (ΔBMI). During follow-up, we assessed the patients for presence of communication impairments, ophthalmoplegia, total quadriplegia, mouth opening disability, and dysuria. We analyzed the relationship between ΔBMI and the communication stage or motor disabilities. The log-rank test showed that patients with a ΔBMI ≥ 1.7 kg/m 2 /year showed a shorter period of preserved communication ability ( p = 0.0001), shorter time to develop ophthalmoplegia ( p = 0.0001), total quadriplegia ( p < 0.0001), mouth opening disability ( p < 0.0001), and dysuria ( p = 0.0455). Cox multivariate analyses showed that a larger ΔBMI was an independent prognostic factor for the early development of ophthalmoplegia ( p = 0.0400) and total quadriplegia ( p = 0.0445). Weight loss in the early stages of ALS predicts disease progression in patients with advanced stages of ALS using TIV.

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Section: Discussionsupporting

confidence: 52%

Body weight variation predicts disease progression after invasive ventilation in amyotrophic lateral sclerosis

Nakayama

Shimizu

Matsuda

et al. 2019

Sci Rep

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“…Increased potentiation of the descending medial longitudinal fasciculus following corticospinal tract lesions was reported 31 . Pathologically, the presence of TDP-43 pathology in these tracts have been reported in some ALS autopsies 32,33 . These anterior horn cell-modulators may be involved in this "inverse" split-leg phenomenon.…”

Section: Discussionmentioning

confidence: 90%

Dissociated leg muscle atrophy in amyotrophic lateral sclerosis/motor neuron disease: the ‘split-leg’ sign

Min

Choi

Hong

et al. 2020

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Disproportionate muscle atrophy is a distinct phenomenon in amyotrophic lateral sclerosis (ALS); however, preferentially affected leg muscles remain unknown. We aimed to identify this split-leg phenomenon in ALS and determine its pathophysiology. Patients with ALS (n = 143), progressive muscular atrophy (PMA, n = 36), and age-matched healthy controls (HC, n = 53) were retrospectively identified from our motor neuron disease registry. We analyzed their disease duration, onset region, ALS Functional Rating Scale-Revised Scores, and results of neurological examination. Compound muscle action potential (CMAP) of the extensor digitorum brevis (EDB), abductor hallucis (AH), and tibialis anterior (TA) were reviewed. Defined by CMAPEDB/CMAPAH (SIEDB) and CMAPTA/CMAPAH (SITA), respectively, the values of split-leg indices (SI) were compared between these groups. SIEDB was significantly reduced in ALS (p < 0.0001) and PMA (p < 0.0001) compared to the healthy controls (HCs). SITA reduction was more prominent in PMA (p < 0.05 vs. ALS, p < 0.01 vs. HC), but was not significant in ALS compared to the HCs. SI was found to be significantly decreased with clinical lower motor neuron signs (SIEDB), while was rather increased with clinical upper motor neuron signs (SITA). Compared to the AH, TA and EDB are more severely affected in ALS and PMA patients. Our findings help to elucidate the pathophysiology of split-leg phenomenon.

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“…In contrast, it was reported that p‐TDP‐43 pathology often spreads to the PNL system especially in Nishihira type 2 ALS cases, but usually without severe PNLD . Severely progressed cases might be associated with PNLD; in the reported p‐TDP‐43 positive ALS cases resulting in a totally locked‐in state, all of the six cases showed moderate to severe degeneration in the substantia nigra with presence of p‐TDP‐43‐positive NCIs . The pallidum and subthalamic nucleus were also degenerated with or without p‐TDP‐43‐positive NCIs.…”

Section: Discussionmentioning

confidence: 99%

Pathological and immunoblot analysis of phosphorylated TDP‐43 in sporadic amyotrophic lateral sclerosis with pallido‐nigro‐luysian degeneration

et al. 2017

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Transactivation response DNA-binding protein 43 kDa (TDP-43) is a key protein of sporadic amyotrophic lateral sclerosis (ALS), and phosphorylated form of TDP-43 (p-TDP-43) is a major pathological protein that accumulates in sporadic ALS. p-TDP-43 is found not only in primary motor neurons, but often propagates to non-motor systems as well. However, pallido-nigro-luysian (PNL) degeneration (PNLD) is rarely associated with ALS. We describe here a 68-year-old ALS patient presenting severe PNLD. He had difficulty walking due to poor movement of his right leg, and was diagnosed as having Parkinson's disease because of akinesia. About 2 years after onset, weakness of his left hand and leg led to a diagnosis of ALS. Tube feeding and non-invasive positive-pressure ventilation were initiated. He died of respiratory failure at the age of 71. There was no family history of either neurological disorders or dementia. Neuropathological examination revealed severe loss of neurons and gliosis in the PNL system in addition to the upper and lower motor neuron system. p-TDP-43 pathology was widespread in the PNL and motor neuron systems and also in the amygdala and hippocampus where no significant gliosis or neuronal loss was detected. Synuclein pathology was not observed in the investigated areas. Immunoblot analysis of p-TDP-43 C-terminal fragments showed a type B band pattern consistent with sporadic ALS. This is the first case of ALS with PNLD, in which p-TDP-43 distribution was widespread in the hippocampal formation (Nishihira type 2 and Brettschneider stage 4), and the type B immunoblot pattern was confirmed. Our case indicated that the PNL system can be involved in the disease process in sporadic ALS cases, although rarely. We also reviewed previous autopsy cases of ALS with PNLD to clarify the clinicopathological features.

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Clinicopathological characteristics of patients with amyotrophic lateral sclerosis resulting in a totally locked-in state (communication Stage V)

Cited by 19 publications

References 27 publications

Body weight variation predicts disease progression after invasive ventilation in amyotrophic lateral sclerosis

Body weight variation predicts disease progression after invasive ventilation in amyotrophic lateral sclerosis

Dissociated leg muscle atrophy in amyotrophic lateral sclerosis/motor neuron disease: the ‘split-leg’ sign

Pathological and immunoblot analysis of phosphorylated TDP‐43 in sporadic amyotrophic lateral sclerosis with pallido‐nigro‐luysian degeneration

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