Re: primary lateral sclerosis 2024 review

[문형철]

J Clin Med

. 2024 Jan 19;13(2):578. doi: 10.3390/jcm13020578

Primary Lateral Sclerosis: An Overview

Veria Vacchiano 1, Luigi Bonan 2, Rocco Liguori 1,2, Giovanni Rizzo 1,*

Editor: Iván Castellví

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PMCID: PMC10816328  PMID: 38276084

Abstract

Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder which causes the selective deterioration of the upper motor neurons (UMNs), sparing the lower motor neuron (LMN) system. The clinical course is defined by a progressive motor disability due to muscle spasticity which typically involves lower extremities and bulbar muscles. Although classically considered a sporadic disease, some familiar cases and possible causative genes have been reported. Despite it having been recognized as a rare but distinct entity, whether it actually represents an extreme end of the motor neuron diseases continuum is still an open issue. The main knowledge gap is the lack of specific biomarkers to improve the clinical diagnostic accuracy. Indeed, the diagnostic imprecision, together with some uncertainty about overlap with UMN-predominant ALS and Hereditary Spastic Paraplegia (HSP), has become an obstacle to the development of specific therapeutic trials. In this study, we provided a comprehensive analysis of the existing literature, including neuropathological, clinical, neuroimaging, and neurophysiological features of the disease, and highlighting the controversies still unsolved in the differential diagnoses and the current diagnostic criteria. We also discussed the current knowledge gaps still present in both diagnostic and therapeutic fields when approaching this rare condition.

초록

원발성 측삭 경화증(PLS)은 

희귀한 신경 퇴행성 질환으로, 

상부 운동 신경(UMN)의 선택적 악화를 유발하고, 

하부 운동 신경(LMN) 시스템은 보호합니다. 

임상 과정은 

일반적으로 하지와 구근 근육을 포함하는 

근육 경직으로 인한 점진적인 운동 장애로 정의됩니다. 

전형적으로 산발성 질환으로 간주되지만, 

일부 친숙한 사례와 가능한 원인 유전자가 보고되었습니다. 

희귀하지만 뚜렷한 개체로 인식되고 있음에도 불구하고, 

그것이 실제로 운동신경질환의 극단적인 끝을 나타내는 것인지 여부는 여전히 미해결의 문제입니다. 

주요 지식 격차는 임상 진단 정확도를 향상시킬 수 있는 특정 바이오마커의 부족입니다. 

실제로, 

진단의 부정확성과 

UMN-우세 ALS 및 유전성 경련성 하반신마비(HSP)와의 중복에 대한 불확실성과 함께, 

특정 치료 시험의 개발에 장애물이 되고 있습니다. 

이 연구에서는 신경병리학적, 임상적, 신경영상학적, 신경생리학적 특징을 포함한 기존 문헌에 대한 포괄적인 분석을 제공하고, 감별 진단 및 현재 진단 기준에서 아직 해결되지 않은 논란을 강조했습니다. 또한 이 희귀 질환에 접근할 때 진단 및 치료 분야에서 여전히 존재하는 현재의 지식 격차에 대해서도 논의했습니다.

Keywords: primary lateral sclerosis, hereditary spastic paraplegia, ALS, motor neuron disease, review

1. Introduction

Primary lateral sclerosis (PLS) is a sporadic neurodegenerative disease characterized by the progressive degeneration of the upper motor neurons (UMNs). It is currently considered as an extreme end of the spectrum of motor neuron diseases (MNDs), of which amyotrophic lateral sclerosis (ALS) is the most represented condition. Although it may share, especially in the early phase, some clinical features overlapping with ALS, PLS is marked by the lack of clinical involvement of the lower motor neurons (LMNs), and by a more protracted clinical course with a better prognosis [1].

The disease was firstly described by Charcot in 1865, but, only ten years later, Erb reported a clinical phenotype characterized by the isolated involvement of the corticospinal tracts named “spastic spinal paralysis” [2].

The preval‎ence of PLS is estimated to be around 2–3% of total cases of MND [3]. However, this data strongly depended on the population considered, since other studies sustained a higher preval‎ence (up to 5% of the MND population [4]). The incidence is thought to be less than 0.1/100,000/year, even though the largest population-based study [5] describing the epidemiology of PLS in Catalonia in the period of 2011–2019 and in Valencia in the period of 2013–2019 pointed out an estimated incidence ranging from 0.2 to 0.6 per 100,000 people per year (higher than expected from previous data).

A male predominance has been consistently observed in PLS (range of 2–4:1) [6,7], although other studies suggested a higher preval‎ence among females [5,8,9]; no difference between races have been reported [8,9,10].

The clinical course is characterized by a progressive motor disability due to muscle spasticity which typically involves lower extremities and bulbar muscles.

Although PLS has been traditionally considered as a “pure” motor neuron disorder, some “extra-motor” features have been systematically recognized in recent years, and supported by post-mortem and imaging reports that have consistently demonstrated cortical and subcortical changes beyond the motor cortex and corticospinal tracts [11]. Extramotor involvement mainly includes some neuropsychological deficits, isolated or widespread, sometimes configuring a frank frontotemporal dementia, and extra-pyramidal features.

There is a general agreement about the fact that PLS is an extremely rare disease, and part of the scientific community still doubts its existence as a unique entity.

In the classical original study from Le Forestier et al. [12] on 20 patients with a diagnosis of PLS, the presence of mild, not-progressing, or even transient LMN signs at EMG, confirmed by muscle biopsy, together with findings from previous post-mortem studies [13,14], led to the consideration of PLS as one end of the continuous spectrum of motor neuron diseases, rather than as a discrete entity. However, the clinical imprecision in the diagnosis, together with some uncertainty about overlap with UMN-predominant ALS, has become an obstacle to the development of specific therapeutic trials. Furthermore, a further difficulty can be found in the differential diagnosis with hereditary spastic paraplegia (HSP).

In this narrative review, we provided a comprehensive analysis of the existing literature, including neuropathological, clinical, neuroimaging, and neurophysiological features of the disease, and highlighting the controversies still unsolved in the differential diagnoses and the current diagnostic criteria. We also underlined the current knowledge gaps still present in both diagnostic and therapeutic fields when approaching this rare condition.

1. 소개

원발성 측삭경화증(PLS)은

상부 운동 뉴런(UMNs)의 점진적인 퇴행을 특징으로 하는

산발성 신경 퇴행성 질환입니다.

현재 운동 뉴런 질환(MNDs)의 극단적인 끝으로 간주되고 있으며,

그중 근위축성 측삭경화증(ALS)이 가장 대표적인 질환입니다.

특히 초기 단계에서 ALS와 일부 임상적 특징이 겹치기는 하지만,

PLS는 하부 운동 신경(LMN)의 임상적 관여가 부족하고,

예후가 더 좋으며 임상 경과가 더 길다는 특징이 있습니다 [1].

이 질병은 1865년 샤르코(Charcot)에 의해 처음 기술되었지만, 10년 후 에르브(Erb)는 “경련성 척수 마비”라고 불리는 피질척수관의 고립된 침범을 특징으로 하는 임상 표현형을 보고했습니다 [2].

PLS의 유병률은 전체 MND 사례의 약 2-3%로 추정됩니다 [3]. 그러나 이 데이터는 고려된 인구에 크게 의존하는 경향이 있습니다. 다른 연구에서는 더 높은 유병률(MND 인구의 최대 5% [4])을 지지했기 때문입니다. 발병률은 0.1/100,000/년 미만으로 추정되지만, 2011-2019년 카탈로니아와 2013-2019년 발렌시아에서 PLS의 역학을 설명하는 가장 큰 인구 기반 연구[5]는 발병률이 0.2에서 0. 연간 100,000명당 6명(이전 데이터에서 예상했던 것보다 높음).

PLS에서 남성의 우세는 지속적으로 관찰되어 왔습니다(2-4:1 범위) [6,7], 다른 연구에서는 여성에서 더 높은 유병률을 제시했지만 [5,8,9]; 인종 간 차이는 보고되지 않았습니다 [8,9,10].

임상 과정은 일반적으로 하지와 구근근육을 포함하는 근육 경직으로 인한 점진적인 운동 장애가 특징입니다.

PLS는 전통적으로 “순수한” 운동 신경 장애로 간주되어 왔지만,

최근 몇 년 동안 일부 “운동 외” 특징이 체계적으로 인식되고 있으며,

사후 부검 및 영상 검사 보고서를 통해 운동 피질과 피질척수관을 넘어서는

피질 및 피질하 변화를 지속적으로 입증하고 있습니다 [11].

운동 외 영역의 침범은

주로 일부 신경심리학적 결손을 포함하며,

이는 고립적이거나 광범위하게 나타나기도 하고,

때로는 전두측두엽 치매를 구성하기도 하며, 피라미드 외 특징을 나타내기도 합니다.

PLS가

극히 드문 질병이라는 사실에 대해서는 일반적인 합의가 이루어져 있으며,

일부 과학계에서는 여전히 PLS가 고유한 실체로 존재하는지 의심하고 있습니다.

Le Forestier 등의 연구에서 PLS 진단을 받은 환자 20명을 대상으로 한 고전적인 연구 [12]에서, 근전도 검사에서 경미하거나 진행되지 않거나 일시적인 LMN 징후가 근육 생검으로 확인되었고, 이전의 사후 연구 결과 [13,14]와 함께, PLS를 개별적인 존재가 아닌 운동 신경 질환의 연속적인 스펙트럼의 한 끝으로 간주하게 되었습니다.

그러나,

임상적 진단의 부정확성과 UMN-우세성 ALS와의 중복에 대한 불확실성이

특정 치료 시험의 개발에 걸림돌이 되고 있습니다.

게다가, 유전성 경련성 하반신마비(HSP)와의 감별 진단에서 더 큰 어려움을 겪을 수 있습니다.

이 서술적 리뷰에서는 신경병리학적, 임상적, 신경영상학적, 신경생리학적 특징을 포함한 기존 문헌에 대한 포괄적인 분석을 제공하고, 감별 진단과 현재 진단 기준에서 아직 해결되지 않은 논란을 강조했습니다. 또한 이 희귀 질환에 접근할 때 진단 및 치료 분야에서 여전히 존재하는 현재의 지식 격차를 강조했습니다.

2. Neuropathology, Neurobiology, and Genetics of PLS

The main histopathological features of PLS consist of diffuse brain atrophy, the loss of pyramidal neurons in the fifth layer of the precentral gyrus, the degeneration of the white matter associated with cortico-spinal tract, and the relative sparing of lower motor neurons. The degeneration of the primary motor cortex and pyramidal tract is always present, while other findings (such as the involvement of the prefrontal and temporal cortices and ubiquitinated inclusions) are inconstant; damage of the LMNs is quite rare and tend to be slight and isolated [15].

Up to the 1980s, lots of case reports were published reporting standard descriptions of the macro- and microscopic examination of the central nervous system of patients affected by PLS. For instance, Beal et al. [16] illustrated a case with severe atrophy of the precentral gyrus of the cerebral cortex bilaterally, accompanied by a general sparing of the remaining cortices and thinning of the pyramids of the medulla. One of the first and most important reviews about PLS was published by Pringle et al. [17], who described a picture characterized by a complete loss of UMNs in the fifth layer of the motor cortex associated with a chronic degeneration of the cortico-spinal tract; LMNs were found intact and there was no involvement of other cortical areas. In general, the first pathological studies published in literature agreed on the main features of this disease, reporting a condition associated with the loss of Betz cells in the precentral gyrus. Similar data have been confirmed by a subsequent study [18], in which the authors have applied an automated analysis program and confirmed a marked total brain atrophy associated with a focal atrophy of other structures, such as the corpus callosum (especially the mid-anterior, central, and mid-posterior parts, which encompass sensory-motor fibers and projections from the dorsal–prefrontal and superior frontal cortices) and thalami (via a mechanism of Wallerian degeneration), finding a correlation between the atrophy degree and clinical severity [18].

In the late 1990 to early 2000s, several immunohistochemical studies have been published reaching different results. Some of them proved the accumulation of ubiquitin not only in the motor cortex, but also in the prefrontal and temporal cortex, depicting a condition similar to fronto-temporal lobar degeneration and excluding the presence of Bunina bodies, which were thought to be more specific of ALS than other MNDs [19]. Other authors confirmed the presence of ubiquitin-positive inclusions associated with dystrophic neuritis in layer II of the frontal and temporal cortex, accounting also for the presence of isolated Bunina bodies and neuronal inclusions in the posterior part of the putamen and in the lower motor neurons [14,15]. A single case report also described a dendritic ballooning phenomenon, which appeared to be very rare in this condition [20].

The crucial role of the transactive response DNA-binding protein of 43 kDa (TDP-43) in the major part of the MND pathology was first reported by Neumann and colleagues in 2006 [21]. They demonstrated that ubiquitinated cytoplasmic inclusion bodies—already known from the previous descriptions of PLS and FTD pathology—also contained the aggregation of TDP-43. They demonstrated a translocation of TDP-43 from the nuclei to cytoplasm (in association with ubiquitin inclusions) in the cells affected by the disease. This evidence strengthened the already existing idea that MND and fronto-temporal lobar degeneration had been part of a spectrum [22,23]. In line with this evidence, Kosaka et al. [24] reported a new case and re-examined the case originally reported by Tan et al. [15], demonstrating prominent frontotemporal atrophy, and abundant TDP-43 pathology throughout the cerebral neocortex and hippocampus, but only a few inclusions in LMNs, which were substantially preserved. Furthermore, Hirsch-Reinshagen et al. [25] described a family with a TBK1 genetic variant, in which two siblings presented with a combination of PLS and primary progressive aphasia. In both, TDP-43 pathology was present throughout the neocortex, limbic cortex, and many subcortical regions; however, the LMNs were well-preserved and only a single TDP-43 cytoplasmic inclusion was detected in the lumbar spinal cord in one of the two cases.

MacKenzie et al. recently reported the neuropathological findings in seven cases of PLS, revealing the presence of TDP-43 inclusions mainly localized in the primary motor cortex and cortico-spinal tract, but also in the LMNs, although sparse and not associated with substantial pathological changes [26]. The authors confirmed the TDP43 pathology is shared by PLS and ALS, but PLS possess some protective factors against LMN degeneration.

However, the limitations in these studies are the selection of patients mainly classified on the basis of their pathological findings, but with insufficient clinical information to determine if they actually fulfilled the clinical PLS criteria. On the other hand, a number of neuropathological reports demonstrated that PLS can be a rare clinical phenotype of other neurodegenerative diseases, such as Alzheimer’s disease and Lewy body disease [27], progressive supranuclear palsy [28], neuronal intermediate filament inclusion disease [29], globular glial tauopathy [30], and argyrophilic grain disease [31].

The precise molecular and cellular mechanisms of UMN degeneration in PLS remain mostly unknown. Numerous related cellular defects may result in UMN vulnerability, as demonstrated through several mouse models generated based on PLS-linked genetic variants. One of the recognized mechanisms underlying UMN vulnerability is based on intracellular trafficking defects. Indeed, corticospinal motor neurons are selectively vulnerable to the lack of expression‎ of Alsin, a large protein encoded by the ALS2 gene, implicated in a wide range of cellular functions ranging from endocytosis, membrane trafficking, endolysosomal protein degradation, and apoptotic signaling from mitochondria upon cellular stress [32]. In mouse models, the depletion of Alsin caused the disintegration of corticospinal motor neurons at several levels (cervical spinal cord, pyramidal decussation, and pons) and the disruption of apical dendrites with numerous vacuoles, as well as profound defects in the morphology and function of the mitochondria and the Golgi apparatus [33].

Significant ultra-structural defects in the Golgi apparatus and mitochondria suggest problems with ATP production and energy metabolism, as well as the post-translational modification of proteins and lipid homeostasis [33]. Indeed, PLS-patient-derived fibroblasts have shown elevated ATP demand and consumption, thus needing an enhanced energy metabolism through both oxidative and glycolytic ATP pathways, which, in turn, led to an overproduction of reactive oxygen species [32].

Interestingly, recessive loss-of-function mutations in the ALS2 gene have been identified in atypical forms of PLS with infantile or juvenile onset [34,35,36], infantile ascending spastic paraparesis [37], and hereditary spastic paresis [35,38], with overlapping phenotypes and no clear genotype–phenotype correlation.

Actually, although the current consensus criteria [7] state that the “screening of panels for pathogenic genetic variants associated with spastic paraparesis should be performed only in cases of progressive UMN syndromes restricted to symmetrical lower limb involvement”, our current knowledge of HSP and ALS genetics is widely incomplete. In fact, some families with multiple members affected by PLS have been reported [39,40,41,42], and, for this reason, in the current criteria, there is not mention of “lack of family history”, which was, instead, considered as a clinical criterium in the previous set of criteria (Pringle) [17].

One of the largest studies [43] which analyzed the C9orf72 gene in a PLS cohort identified the presence of the expansion in 1 patient out of 110. Another relatively large study found that 18% of patients carried a variant in either ALS (C9orf72), Parkinson’s disease (PARK2), or HSP (SPG7) genes [44]. A predicted pathogenic mutation in the SYNE2 gene was also identified [44].

Among HSP-related genes, SPG7 variants have been linked to a PLS-like presentation in several studies [45,46], while, among rarer ALS-associated genes, TBK1 genetic variants [47] have been reported in a family with PLS. Furthermore, FIG4 [48], UBQLN2 [49,50], and OPTN variants [51] have been associated with UMN-predominant MND phenotypes resembling PLS. Besides ALS2 [34,35,36], juvenile primary lateral sclerosis (JPLS) has also been linked to ERLIN2 [52] variants.

In the most recent and largest genetic study on 139 PLS patients [53], likely pathogenic or pathogenic variants in genes related to ALS-FTD (C9Orf72; TBK1), HSP (SPAST; SPG7), and the ALS-HSP-Charcot-Marie-Tooth overlap (NEFL; SPG11) were found in 7% of the cohort, remarking upon the possible significant contribution of genetics in the diagnostic work-up of PLS (Figure 1).

2. PLS의 신경병리학, 신경생물학, 유전학

PLS의 주요 조직병리학적 특징은 확산성 뇌 위축, 전두엽의 다섯 번째 층에 있는 피라미드 뉴런의 소실, 피질척수관 관련 백질의 퇴화, 그리고 상대적으로 낮은 운동 뉴런의 보존으로 구성되어 있습니다. 일차 운동 피질과 피라미드체의 퇴화는 항상 존재하는 반면, 다른 소견(전두엽과 측두엽 피질의 관여, 유비퀴틴화 내포물 등)은 일정하지 않습니다. LMN의 손상은 매우 드물고 경미하며 고립된 경향이 있습니다 [15].

1980년대까지 PLS 환자의 중추신경계에 대한 거시적, 미시적 검사에 대한 표준 설명을 보고한 사례 보고서가 많이 발표되었습니다. 예를 들어, Beal et al. [16]은 양측 대뇌 피질의 전두엽이 심하게 위축된 사례를 설명하면서, 나머지 피질은 전반적으로 보존되어 있고, 수질 피라미드가 얇아졌다고 했습니다. PLS에 대한 최초의 가장 중요한 리뷰 중 하나는 Pringle et al. [17]에 의해 발표되었습니다. 그들은 피질척수관(cortico-spinal tract)의 만성 퇴행과 관련된 운동피질 5층에서 UMN이 완전히 소실된 것을 특징으로 하는 그림을 묘사했습니다. LMN은 손상되지 않은 상태로 발견되었고, 다른 피질 영역의 침범은 없었습니다. 일반적으로, 문헌에 발표된 최초의 병리학 연구들은 이 질병의 주요 특징에 대해 동의하면서, 전두엽의 베츠 세포의 손실과 관련된 상태를 보고했습니다. 유사한 데이터는 후속 연구 [18]에서 확인되었으며, 저자들은 자동 분석 프로그램을 적용하여 뇌량(특히 전두엽 중간부)과 같은 다른 구조의 국소 위축과 관련된 현저한 전체 뇌 위축을 확인했습니다. 중추부, 중후부(감각 운동 섬유와 배측 전두엽 및 전두엽의 돌출부를 포함) 및 시상(월러 변성 메커니즘을 통해)에서 위축 정도와 임상적 심각도 사이의 상관관계를 발견했습니다 [18].

1990년대 말부터 2000년대 초까지 여러 면역조직화학 연구가 발표되었는데, 그 결과는 서로 달랐습니다. 그 중 일부는 운동피질뿐만 아니라 전두엽과 측두엽 피질에도 유비퀴틴이 축적되어 있음을 입증했는데, 이는 전두측두엽 변성과 유사한 상태를 묘사하고 다른 MND보다 ALS에 더 특이적인 것으로 여겨지는 부니나체(Bunina body)의 존재를 배제합니다 [19]. 다른 저자들은 전두엽과 측두엽 피질의 2층에서 영양 장애성 신경염과 관련된 유비퀴틴 양성 내포물이 존재한다는 것을 확인했으며, 이는 또한 후두엽과 하부 운동 뉴런의 고립된 부니나체와 신경 내포물의 존재를 설명합니다 [14,15]. 단일 사례 보고에서는 이 질환에서 매우 드물게 나타나는 수지상 팽창 현상도 설명했습니다 [20].

MND 병리의 주요 부분에서 43kDa의 트랜스액티브 반응 DNA 결합 단백질(TDP-43)의 결정적인 역할은 2006년 Neumann과 동료들에 의해 처음 보고되었습니다 [21]. 그들은 PLS와 FTD 병리에 대한 이전의 설명에서 이미 알려진 바와 같이, 유비퀴틴화된 세포질 봉입체에도 TDP-43의 응집이 포함되어 있음을 입증했습니다. 그들은 질병에 걸린 세포에서 TDP-43이 핵에서 세포질로 이동하는 것을(유비퀴틴 침전물과 함께) 증명했습니다. 이 증거는 MND와 전두측두엽변성이 스펙트럼의 일부라는 기존의 생각을 강화했습니다 [22,23]. 이 증거에 따라, Kosaka et al. [24]은 새로운 사례를 보고하고, Tan et al.이 원래 보고한 사례를 재검토했습니다. [15]에서는 전두측두엽 위축이 두드러지고, 대뇌 피질과 해마 전체에 TDP-43 병리가 풍부하게 나타나지만, 실질적으로 보존된 LMN에는 소수의 봉입체가 있는 것으로 나타났습니다. 또한, Hirsch-Reinshagen 등 [25]은 TBK1 유전 변이를 가진 가족을 설명했는데, 이 가족의 두 형제자매는 PLS와 원발성 진행성 실어증을 함께 앓고 있었습니다. 두 사례 모두에서 TDP-43 병리학은 신피질, 변연계, 그리고 많은 피질하 영역 전체에 걸쳐 존재했습니다. 그러나 LMN은 잘 보존되어 있었고, 두 사례 중 하나에서 요추 척수에서 단 하나의 TDP-43 세포질 내포만이 검출되었습니다.

MacKenzie 등은 최근 PLS 환자 7명의 신경병리학적 소견을 보고했는데, 이 보고서에 따르면 TDP-43 침윤이 주로 1차 운동피질과 피질척수관에 국한되어 존재하지만, 희박하고 실질적인 병리학적 변화와 관련이 없는 경우에도 근신경에 존재하는 것으로 밝혀졌습니다 [26]. 저자들은 TDP43 병리가 PLS와 ALS에서 공통적으로 나타나는 것으로 확인했지만, PLS는 근신경 변성에 대한 보호 요인을 가지고 있다고 주장했습니다.

그러나 이러한 연구의 한계는 주로 병리학적 소견에 근거하여 분류된 환자들을 대상으로 하고 있지만, 임상적 PLS 기준을 실제로 충족했는지 판단하기 위한 임상 정보가 충분하지 않다는 점입니다. 반면에, 여러 신경병리학 보고서에 따르면 PLS는 알츠하이머병, 루이소체병[27], 진행성 핵상마비[28], 신경교중간섬유내포체질환[29], 구상교세포타우병[30], 친수성입자병[31]과 같은 다른 신경퇴행성 질환의 드문 임상 표현형일 수 있다고 합니다.

PLS에서 UMN 퇴화의 정확한 분자 및 세포 메커니즘은 대부분 알려지지 않았습니다. PLS와 관련된 여러 가지 유전적 변이를 기반으로 생성된 여러 마우스 모델을 통해 입증된 바와 같이, 수많은 관련 세포 결함이 UMN 취약성을 초래할 수 있습니다. 알츠하이머병의 취약성을 뒷받침하는 것으로 알려진 메커니즘 중 하나는 세포 내 트래픽 결함에 기반을 두고 있습니다. 실제로, 피질척수 운동 뉴런은 ALS2 유전자에 의해 암호화된 대형 단백질인 알신(Alsin)의 발현 부족에 선택적으로 취약합니다. 알신은 세포 내 이입, 막 트래픽, 소포체 내 단백질 분해, 세포 스트레스 시 미토콘드리아에서 발생하는 세포 자멸 신호 전달 등 다양한 세포 기능에 관여합니다 [32]. 마우스 모델에서, 알신의 고갈은 여러 수준(경추 척수, 피라미드형 교차점, 그리고 뇌교)에서 피질척수 운동 뉴런의 붕괴를 야기했고, 수많은 액포를 가진 정단 수상돌기의 붕괴, 그리고 미토콘드리아와 골지체의 형태와 기능에 심각한 결함을 야기했습니다 [33].

골지체와 미토콘드리아의 심각한 초구조적 결함은 ATP 생산과 에너지 대사, 그리고 단백질 번역 후 변형과 지질 항상성에 문제가 있음을 시사합니다 [33]. 실제로, PLS 환자 유래 섬유 아세포는 ATP 수요와 소비가 증가하여 산화 및 해당 과정 ATP 경로를 통한 향상된 에너지 대사가 필요하며, 이는 결과적으로 활성 산소 종의 과잉 생산으로 이어집니다 [32].

흥미롭게도, ALS2 유전자의 열성 기능 상실 돌연변이는 유아기 또는 청소년기에 발병하는 비정형 PLS [34,35,36], 유아기 상승성 경련성 마비 [37], 유전성 경련성 마비 [35,38]에서 확인되었으며, 중복되는 표현형과 명확한 유전자형-표현형 상관관계가 없습니다.

실제로, 현재의 합의 기준[7]에 따르면, “경련성 하반신 마비와 관련된 병원성 유전자 변이에 대한 패널 검사는 대칭적인 하지의 침범이 제한적인 진행성 UMN 증후군의 경우에만 수행해야 한다”고 명시되어 있지만, 현재 HSP와 ALS 유전학에 대한 지식은 매우 불완전합니다. 실제로, PLS의 영향을 받은 여러 명의 가족이 있는 것으로 보고된 사례가 있습니다 [39,40,41,42], 그리고, 이러한 이유로, 현재의 기준에는 “가족력 부족”에 대한 언급이 없습니다. 이는 이전 기준(Pringle)에서 임상적 기준으로 간주되었던 것입니다 [17].

PLS 코호트에서 C9orf72 유전자를 분석한 가장 큰 규모의 연구 중 하나[43]는 110명 중 1명의 환자에서 확장이 존재하는 것으로 확인되었습니다. 또 다른 비교적 큰 규모의 연구에서는 환자의 18%가 ALS(C9orf72), 파킨슨병(PARK2), 또는 HSP(SPG7) 유전자 변이를 가지고 있는 것으로 나타났습니다[44]. SYNE2 유전자에서 예측된 병원성 돌연변이도 확인되었습니다 [44].

HSP 관련 유전자 중 SPG7 변이체는 여러 연구에서 PLS와 유사한 증상과 관련이 있는 것으로 밝혀졌습니다 [45,46], 희귀한 ALS 관련 유전자 중 TBK1 유전자 변이체 [47]는 PLS 가족에서 보고된 바 있습니다. 또한, FIG4 [48], UBQLN2 [49,50], OPTN 변이 [51]는 PLS와 유사한 UMN-우세한 MND 표현형과 관련이 있습니다. ALS2 [34,35,36] 외에도, 소아 원발성 측삭 경화증(JPLS)도 ERLIN2 [52] 변이와 관련이 있습니다.

139명의 PLS 환자를 대상으로 한 가장 최근의 가장 큰 규모의 유전 연구[53]에서, ALS-FTD(C9Orf72; TBK1), HSP(SPAST; SPG7), ALS-HSP-Charcot-Marie-Tooth overlap(NEFL; SPG11)은 코호트의 7%에서 발견되었으며, PLS 진단 과정에서 유전학이 상당한 기여를 할 수 있다는 점을 지적했습니다(그림 1).

Figure 1.

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Diagram showing the possible genetic work-up in PLS (only genes for which pathogenic variants have been reported are mentioned).

3. Clinical Features

The mean age of clinical onset in PLS is around 50 years, which is about a decade earlier than non-familial ALS, and a decade later than HSP. In the most part of the cases (90%), the onset of symptoms insidiously involves the lower limbs, and patients may complain of a “loss of fluidity” and/or a “loss of stability” in the gait. However, for a significant minority of the patients, a bulbar onset has been described, including dysarthria, nasal speech, and emotional lability configuring a pseudobulbar affect [54]. Dysphagia can be present but usually is not that severe so as to require gastrostomy as in ALS. Similarly, the need for ventilatory support is quite exceptional. In fact, in the prospective NEALS PLS registry [54] of 250 PLS patients, with a three-year median follow-up after enrollment, only 7% required a feeding tube and less than 1% needed permanent assisted ventilation. Usually, PLS slowly generalizes to the upper limbs, while a focal onset involving an upper limb is extremely rare [55]. The rate of progression is much slower than typically encountered in ALS, with an average disease duration ranging from 7.2 to 14.5 years [6].

Depending on the patient’s age and comorbidities, the prognosis of PLS is at least a decade from the onset of symptoms and often significantly longer [54].

Typically, the neurological examination shows only upper motor neuron signs, including spasticity and the spread of reflexes, with the absence of lower motor neuron findings (fasciculations and muscle wasting). Stiffness as a presenting symptom is observed more commonly in PLS than ALS (47% vs. 4%), and limb wasting is rare in PLS (~2%) [56].

An upper motor neuron pattern of weakness may be observed (extensors in upper extremity; flexors in lower extremity), but symptoms referred by the patients are often a combination of increased tone, decreased co-ordination, and mild weakness.

Although the involvement of the lower limbs in PLS is commonly symmetrical, a progressive hemiplegia is a very rare phenotype originally described eponymously by Mills [57]. This latter condition, also known as the “hemiplegic variant”, is characterized by slow progressive ascending weakness, usually starting in a distal lower limb, and then progressing to a proximal ipsilateral lower limb and upper limb, associated with pyramidal signs on the affected side, and sometimes also on the contralateral one [58]. Facial and bulbar weakness may be present, as well as slight sensory disturbances [59]. In most patients, the syndrome remained strictly unilateral after 15 years, although the involvement of the contralateral side has been reported in about 30% [59]. The scarcity of reports on this condition, as well as the paucity of complementary resources necessary to better define its pathophysiological mechanisms, led to doubt about the authenticity of this entity [58]. Sensory disturbances or deficits should not be observed in PLS. Among additional clinical features, the most consistently reported are bladder instability with urinary frequency and retention [60], extrapyramidal features [61,62], and cognitive disorders [62,63,64,65,66,67].

The most common neuropsychological deficits in PLS include problems in social cognition, apathy, executive dysfunction, language, and verbal fluency [62,63,64,65,66,67]. Furthermore, the co-presence of full-blown frontotemporal dementia, which was thought to be relatively rare (2%) [67], was recently found to be more common than expected in PLS patients [62].

Abnormalities in ocular movements, especially the loss of smooth pursuit, and even supranuclear palsy [17], may be present, and saccadometry has shown the loss of fixation and, particularly, prominent antisaccade errors compared to ALS patients [68].

Clinical disability in PLS is eval‎uated by clinical examination, but combined UMN scores and scales developed for other MNDs are also commonly used. These scales include the revised ALS Functional Rating Scale (ALSFRS-r) [69], the Penn Upper Motor Neuron Score (PUMNS) [70], the Modified Ashworth Scale [71], the emotional lability questionnaire [72], and the more recently validated PLS functional rating scale (PLSFRS) [73].

4. Diagnostic Criteria

Over the years, different sets of criteria were proposed to diagnose PLS.

In 1945, the PLS diagnostic criteria [74] suggested a minimum of a five-year symptom duration for diagnosing PLS, while, in 1992, the Pringle criteria [17] proposed that a minimum symptom duration of three years would have permitted a reliable diagnosis, still describing as core features an adult onset of insidious spastic paresis in the lower limbs (but also in the bulbar or upper extremities), usually symmetric and in the absence of a family history. In 2006, the Gordon criteria [75] recommended a symptom duration of four years to label the diagnosis. Finally, the recent 2020 consensus diagnostic criteria (Figure 2) [7], recognizing the implications of diagnostic delay, introduced a category of “probable PLS” for patients with isolated UMN symptoms in at least two of three regions (lower extremity, upper extremity, and bulbar) for 2–4 years. The recognition of a pragmatic category of “probable PLS” reflects the desire to facilitate the earlier inclusion of patients with PLS in future trials of potentially disease-modifying therapy before the disability becomes advanced.

Figure 2.

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Current diagnostic criteria for PLS [7]. UMN: upper motor neuron; LMN: lower motor neuron. * Minimally increased insertional activity and positive sharp waves or fibrillation potentials in extremity muscles are allowed.

5. Neurophysiological Features

The main diagnostic challenge remains the discrimination of PLS from UMN-predominant ALS patients, especially in the early phase of the disease, when the borderline between these two entities is difficult to delineate. This issue is complicated by the evidence of minimal and not-progressive electromyographic (EMG) denervation signs in some PLS patients [10,17,76,77].

In a study on 29 patients with pure UMN involvement at the initial visit, 13 were later classified as UMN-predominant ALS on average between three and four years from the onset of symptoms, due to the development of denervation, chronic motor unit changes, and fasciculation potentials in one to two muscles at EMG, as well as limited clinical LMN signs. Four of these patients eventually met the WFN El Escorial clinical trial criteria for ALS [75].

In another study on 25 PLS patients, the authors observed a more aggressive and faster disease in patients with evidence of active denervation potentials (increased insertional activity, fibrillations, and/or positive sharp waves) in one or more muscles, even though they did not meet the neurophysiological criteria for ALS [10].

In a large multicentric cohort of 217 patients with pure UMN disease, subjects were categorized into two groups according to the presence or absence of minor denervation signs. The authors found no differences between the two groups in terms of the site of onset, frequency of clinical symptoms, ALSFRS-R scale, vital capacity, or use of non-invasive positive pressure ventilation [77], suggesting that subtle EMG abnormalities can not necessarily be used as a prognostic tool in patients with clinical UMN disease.

A more recent study [78] confirmed these findings of minimal denervation activity in single muscles of PLS patients without a clear progression, even though the authors observed a faster disease progression in patients with a greater amount of EMG abnormalities.

These findings were subsequently corroborated by another cohort study [79] where 21 patients with PLS syndrome associated with definite but limited EMG denervation changes were followed up with for a median of seven years, and around 90% of this cohort maintained the PLS phenotype and diagnosis.

To conclude, although PLS patients lack evident clinical lower motor neuron signs on the neurological examination, several studies report minor and stable changes with needle EMG, including sparse fibrillations, fasciculations, and enlarged motor unit potentials, generally limited to one or two muscles [10,17,76,77]. After four years, the probability of developing new lower motor neuron findings on the EMG becomes low (~20%) [75].

For this reason, EMG findings consistent with mild and not-progressing involvement of lower motor neurons are tolerated in the category of “probable PLS”, coined in the last set of diagnostic criteria [7].

Conversely, if a patient has EMG denervation and, subsequently, developed focal LMN signs and symptoms over the course of four years, but still does not meet the criteria for ALS [80], a diagnosis of UMN-predominant ALS would be more appropriate than PLS [7]. However, the reason for this resistance to LMN degeneration in PLS, at variance from ALS, is widely unknown. The most obvious explanation is that PLS and ALS syndromes present different underlying pathogenic processes.

Besides the LMN assessment, neurophysiological tools can be used to quantify UMN involvement. The most conventional tool is transcranial magnetic stimulation, which have proven abnormalities in the motor-evoked potentials, showing the absence of reproducible cortical responses or longer central motor conduction times in PLS compared to ALS [76]. Furthermore, high threshold measures for cortical stimulation, which suggest cortical inexcitability, are a specific signature of PLS, probably reflecting a greater degree of neurodegeneration within the motor cortex and the corticospinal tracts, as the resting motor threshold reflects the density of corticomotoneuronal projections into spinal motor neurons, as well as the excitability of large motor cortical neurons. These findings also reliably distinguish PLS from HSP [81], where cortical excitability is preserved.

6. Neuroimaging

Conventional imaging studies in PLS are primarily used to rule out alternative causes of isolated UMN dysfunction at the brain or spinal cord levels.

However, with the advancement of both structural and functional imaging technologies over the years, several studies attempted to examine deeper aspects of the pathogenesis and to define specific signatures of PLS [82].

Obviously, the main brain structure altered and investigated in PLS is the pyramidal pathway. Case reports and case series reported some qualitative abnormalities in conventional magnetic resonance imaging (MRI) (Figure 3), such as the focal atrophy of the precentral gyrus, sometimes with a “knife edge” appearance of the gyri [83]. Furthermore, corticospinal tract (CST) hyperintensities in the brain and spinal cord [84,85] have been reported on T2- and FLAIR-weighted images, occasionally with a “wine glass” appearance in the coronal view at the diencephalic level [86], and the hypointensity of primary motor cortex (motor band sign) on susceptibility-weighted imaging (SWI) [87]. However, these changes are not specific to PLS, and have been systematically reported in ALS [4,88], and also in HSP, although with an apparently lower frequency [88].

Figure 3.

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MRI in a PLS patient. (A) Sagittal T1 sequence showing atrophy of primary motor cortex with enlargement of central sulcus (white arrow). (B) Coronal flair sequence showing bilateral corticospinal tract hyperintensities (black arrows).

Cross-sectional quantitative imaging studies invariably confirmed the atrophy of the precentral gyrus [18,89], the reduction of the premotor cortex surface area [76], as well as its focal thinning [90,91,92], while the CST pathology was highlighted by the increase in diffusivity and reduction of fractional anisotropy by means of diffusion tensor imaging (DTI) studies [93,94,95]. The motor pathway in PLS was also eval‎uated by metabolic and functional techniques. Proton MRI spectroscopy studies of the premotor cortex in PLS patients showed reduced N-acetyl aspartate (NAA)/creatine (Cr) ratios [55,96,97] and increased myo-inositol/Cr ratios [98], consistent with neuronal dysfunction or loss, and gliosis, respectively. Functional MRI studies reported increased functional connectivity in PLS [99,100], which were interpreted as an adaptive, compensatory process, similarly to ALS [101]. A few [18F]-FDG PET studies in PLS have been published, but failed to find a “signature” of PLS as compared to ALS, mainly showing a prominent hypometabolism of the prefrontal and premotor cortices [102]. However, recent advances in metabolic imaging suggest that a combined cord and brain [18F]-FDG PET may differentiate ALS from PLS [103]. Several ligand PET studies have been conducted with exploratory purposes, but they are beside the scopes of this review.

Extra-motor cortical and subcortical involvement in PLS has been variably reported by volumetric, vertex, and morphometric analyses, ranging from pathology in specific brain regions, including the thalamus, caudate, and hippocampus [104,105,106], to widespread parietal, prefrontal, cerebellar, and brainstem degeneration [107,108,109]. Certain structures such as the thalamic motor and sensory nuclei seem to be selectively affected in PLS [105,106]. Over 20 diffusion tensor imaging studies, other than confirm‎ing the CST pathology [93,94,95], revealed corpus callosum [98,110] and cerebellar [107,111] abnormalities. Interestingly, a recent study [107] on 42 patients diagnosed with PLS assessed by volumetric and voxelwise analyses revealed several focal cerebellar alterations along with significant diffusivity alterations within the superior cerebellar peduncle, indicating the disruption of the main cerebellar outflow tracts. These findings supported a cerebro-cerebellar connectivity disruption which probably contributes to the motor disability in PLS. Other DTI studies have specifically highlighted extra-corpus callosum diffusivity alterations involving the superior and inferior longitudinal fasciculi, fornix, thalamic radiations, and parietal lobes [112,113]. At variance from ALS, there is a relative lack of longitudinal imaging studies in PLS. Existing longitudinal studies in PLS are limited due to cohort size limitations, typically presenting only two timepoints, and varying considerably in follow-up intervals [97,114,115,116]. Interestingly, a study of eight suspected PLS patients who initially did not fulfill the diagnostic criteria exhibited progressive precentral gyrus thinning and increasing functional connectivity [117]. Other studies of suspected PLS patients showed connectivity and gray/white matter abnormalities even before meeting the diagnostic criteria [117,118]. A more recent study on 41 PLS patients, through a 3D T1-weighted structural, diffusion tensor imaging, and resting-state functional MRI protocol, confirmed the progressive primary motor cortex degeneration, the significant supplementary motor and pre-motor area involvement, the progressive brainstem atrophy, the cortico-medullary and inter-hemispheric disconnection, and the close associations between clinical upper motor neuron scores and somatotopic connectivity indices in PLS, highlighting that PLS should not be considered as a “benign” motor neuron disease [119].

7. Differential Diagnoses

As previously stated, the differential diagnosis for PLS might be challenging because there are many different conditions which can mimic its clinical features.

The most represented disease which clinically overlaps with PLS is hereditary spastic paraparesis (HSP), a genetic syndrome characterized by progressive weakness and spasticity in the lower limbs, caused by around 70 genetic variants recognized so far, with all possible patterns of inheritance reported [120]. The age of onset can be variable, but, usually, the more common autosomal-dominant forms occur between the second and third decades. HSP is historically classified in “pure”, if the spastic paraplegia together with the subtle involvement of the dorsal column are the primary manifestations, and “complicated” if other additional features are present, encompassing dementia, cognitive delay, epilepsy, neuropathy, and others [120]. In the most common form of autosomal-dominant disease, the SPG4 (caused by genetic variants in the gene encoding for spastin) is associated with a “pure” phenotype, while, among the autosomal-recessive forms, SPG11 is the most frequent, and associated with a “complicated” phenotype.

Some clinical elements may help in distinguishing HSP from PLS, such as the presence of a family history (PLS is mainly considered a sporadic disease), the earlier and symmetric onset of the disease, the presence of a diminished vibratory sensation on clinical examination, the absence of bulbar involvement, and the slower disease progression in patients with HSP compared to PLS [121]. Nonetheless, the clinical distinction between these two entities could be practically impossible in some circumstances, and genetic testing remains essential for ruling out HSP as the etiology for an apparently sporadic adult-onset UMN syndrome with leg onset.

This is especially true when PLS started with lower extremity involvement [122], or in some specific forms of HSP (i.e., spastic paraplegia types 4 and 7) where the clinical onset could be in later adulthood [123]. Furthermore, asymptomatic UMN signs or a frank clinical involvement of the upper limbs may be observed in HSP cases [124], as well as asymmetry [125]. Moreover, a negative family history can occur in 40% of cases due to recessive or X-linked inheritance, or even de novo genetic variants [125].

To further complicate this issue, a study on 90 patients with apparently sporadic UMN syndrome, categorized in phenotypes of HSP (involvement of legs only), HSP-PLS overlap (involvement of arms and legs), and PLS (bulbar involvement) showed significant overlap in the age of symptom onset and no differences between the groups in features classically used to distinguish the two diseases, such as mild dorsal column dysfunction (decreased vibratory sense or abnormal leg somatosensory evoked potentials), symptoms of urinary urgency, or mild electromyographic abnormalities [126].

Among neurodegenerative diseases, as previously reported, the UMN-predominant ALS is the most difficult differential diagnosis. This entity is defined by the presence of motor disability mainly secondary to UMN signs with known EMG and/or clinical LMN signs that do not meet the criteria for clinically definite, clinically probable, or probable-laboratory-supported ALS as defined by the revised El Escorial criteria [80,127]. Interestingly, the progression of patients with UMN-predominant ALS is slower than typical ALS patients [128], probably suggesting that this phenotype lies in the area between PLS and ALS along the complex spectrum of the disease. However, an interesting study [127] showed that patients with isolated UMN signs at the first visit, but destined to develop LMNs in the next four years, presented, more frequently, a bulbar onset and a shorter time to the first eval‎uation (an indirect sign of the disease progression rate) than the PLS group. Additional findings of muscular atrophy on initial examination, weight loss, and any MRC grade less than 4 at the initial visit were predictive of UMN-predominant or classic ALS as compared to patients remaining with a PLS phenotype. Interestingly, patients with PLS may develop weakness, but it was usually mild and often generalized in a UMN distribution.

Finally, reduced FVC was related to UMN-predominant or classic ALS groups, suggesting that FVC was a measure of LMN function in the phrenic nerve more than of UMN involvement.

Other mimics of PLS can be subdivided into: metabolic disorders (adrenomyeloneuropathy); neuroinflammatory diseases (e.g., primary progressive multiple sclerosis, and anti-amphiphysin paraneoplastic syndrome); and infections such as human T-cell leukemia virus type 1 and 2 (HTLV1 and HTLV2 myelopathy) and neurosyphilis. Other brain and spine structural abnormalities are relatively easily “ruled out” by brain and spine imaging, such as multiple infarcts, cervical spondylosis, syringomyelia, Chiari malformation, compressive foramen magnum lesions, and spinal cord tumors.

Among inflammatory diseases, progressive solitary sclerosis [129] deserves a special mention. This is a rare entity which may present with both symmetrical and unilateral UMN features of progressive motor impairment, but it is considered a localized variant of multiple sclerosis, due to the presence of a single demyelinating lesion in the central nervous system and of cerebrospinal fluid (CSF) oligoclonal bands.

The differential diagnoses of PLS are summarized in Table 1.

Table 1.

Differential diagnoses of primary lateral sclerosis.

DiseaseEtiologyClinical Hallmarks

Hereditary spastic paraparesis (most commonly type 4 or 7 for late-onset)	Genetic disorders	Symmetric paresis usually limited to lower limbs Slower progression Presence of family history or genetic variant
UMN-predominant ALS	Degenerative disorders	Faster progression Progressive development of clinical LMN involvement
Adrenomyeloneuropathy	Metabolic disorders	Impaired sensory vibration Elevated blood levels of adrenocorticotropic hormone Elevated serum levels of very long chain fatty acids Cerebral MRI white matter abnormalities Pathogenic variants in ABCD1 gene
Primary progressive multiple sclerosis	Neuroinflammatory disorders	Presence of other neurological deficits (cerebellar dysfunction, brainstem syndromes, and visual loss) Demyelinating lesions of brain and cord Possible CSF oligoclonal bands
Progressive solitary sclerosis		Single demyelinating lesion in CNS Possible CSF oligoclonal bands
Anti-amphiphysin syndrome		Limbic encephalitis Dysautonomia Cerebellar dysfunction Positive anti-amphiphysin antibodies Presence of tumour
Tropical spastic paraparesis (HTLV-1 and -2 myelopathy)	Infectious diseases	Sphincter dysfunction Sensitive dysfunctions Positive serology
Neurosyphilis		Positive VDRL and TPHA Multisystemic involvement
Vascular and ischemic lesions	Brain and spine structural abnormalities	Imaging findings
Cervical spondylosis
Syringomyelia
Chiari malformation
Compressive foramen magnum lesions
Spinal cord tumours

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Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; LMN, lower motor neuron; UMN, upper motor neuron; VDRL, venereal disease research laboratory; TPHA, treponema pallidum hemagglutination test.

8. Biofluid Biomarkers

Biomarkers are an area of active interest to exploit CSF or blood components which may add a diagnostic and/or prognostic value in the assessment of neurodegenerative diseases.

Among biofluid biomarkers, neurofilaments have emerged as promising diagnostic and prognostic biomarkers in motor neuron diseases [130]. Several studies have shown that both the neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) are highly elevated in ALS and correlate with measures of disease progression [131,132,133].

Some studies have shown lower levels of NfL in PLS compared to ALS [134,135], reflecting its much slower progression, although other studies have not shown significant changes between the two groups [136,137], probably due to the small number of PLS patients included. Interestingly, in some cohorts, NfL was found to be lower in PLS than in UMN-predominant ALS patients, with practical diagnostic relevance, given the relatively better prognosis of PLS [138,139].

Additionally, cerebrospinal fluid chitinases, thought to be macrophage-derived, were found to be lower in PLS compared to ALS [140,141], and showed the best performance in distinguishing these two categories [141], reflecting a lesser extent of microglial neuroinflammation in PLS, which, in turn, may be linked to axonal loss. However, these observations deserve to be confirmed in multicentric larger cohorts, and further studies are needed to explore the key distinction of PLS from UMN-predominant ALS.

9. Management and Treatment

Currently, there are no disease-modifying treatments approved or tested in experimental trials for PLS, probably due to the rarity of the disease and lack of significant understanding of its underlying pathophysiology. Therefore, the approach to treatment remains essentially targeted to alleviate the symptoms and improve the quality of life of patients. Since clinical trials of symptomatic treatments are limited, clinical experience based on other neurological disorders with similar symptoms has been used to guide treatments. A multidisciplinary approach should be preferred in order to manage several disturbances that can be present along the disease course, such as spasticity, fatigue, pseudobulbar palsy, pain, depression, and sphincteric and sexual dysfunctions. Non-medication approaches including physical and occupational treatment are essential for gait and balance training, the reduction of the discomfort from muscle stiffness, and eval‎uation for assistive devices, along with speech therapy, pneumological assessment, and psychosocial support. Experimental data on physiotherapy in patients with PLS are lacking, but a strictly monitored exercise program has been proposed to potentially reduce motor deterioration in patients with ALS [142]. Preliminary observations suggest that combining robot-aided and conventional rehabilitation could be a promising approach to mitigate the PLS disability burden [143].

For spasticity, which is the most disabling symptom, the first-line oral agents include baclofen, tizanidine, benzodiazepines (e.g., clonazepam and diazepam), gabapentin, pregabalin, and dantrolene. These drugs can cause some side-effects, most commonly somnolence and the worsening of hyposthenia. For patients who achieve some benefit with anti-spasticity drugs, but are limited by these side-effects, a trial of intrathecal baclofen—and subsequent baclofen pump placement—may be useful. In recent years, cannabinoids have been increasingly used to treat spasticity with significant improvement and without serious adverse events [144], and delta-9-tetrahydrocannabinol and cannabidiol (THC/CBD: 50:50) spray (nabixomols) had a positive effect on spasticity symptoms in a placebo-controlled randomized phase 2 trial in patients with motor neuron disease [145]. Treatment with botulinum toxin type A associated with physiotherapy has also proven beneficial in the short term and long term in patients with moderate-to-severe spasticity [146,147]. Dalfampridine (4-aminopyridine) has also been shown to be effective in spasticity [148]. Furthermore, there are data to support the effectiveness of some non-pharmacological therapies such as transcutaneous electrical nerve stimulation [149] and acupuncture [150] on spasticity, although more controlled studies are needed.

The management of excess oral secretions or drooling is similar to that used in ALS [151]. Most patients have beneficial effects with oral anticholinergic medications—amitriptyline, scopolamine, glycopyrrolate, or atropine drops. For drooling unresponsive to oral therapies, botulism toxin injections into submandibular glands may be beneficial.

For pseudobulbar affect, selective serotonin reuptake inhibitors can help patients with emotionality even in the absence of depression [152,153,154]. Furthermore, the combination of dextromethorphan and quinidine (Neudexta) [155] may prove beneficial. Tricyclic antidepressants may be useful in patients without significant beneficial effects from Neudexta. Urinary urgency can be relieved by drugs such as oxybutynin.

10. Conclusions

PLS appears to be a rare but distinct disease, which, first and foremost, represents a diagnostic challenge, due to the clinical overlap with HSP and UMN-predominant ALS, especially in the early phases. The main knowledge gap in the field of clinical diagnosis is characterized by the lack of specific biomarkers that may contribute to improving our diagnostic accuracy. This is further complicated by evidence suggesting that the PLS phenotype may be the clinical expression‎ of different neuropathological entities.

As stated before, PLS has been reported to be the predominant clinical phenotype in cases with a confirmed neuropathological diagnosis of dementia and atypical parkinsonism (including progressive supranuclear palsy, neuronal intermediate filament inclusion disease, globular glial tauopathy, or argyrophilic grain disease) [27,28,29,30,31]. PLS has also been described as a rare clinical phenotype of a variety of systemic diseases, including several conditions consisting of autoimmune [156] or metabolic error disorders [157]. However, these publications illustrated heterogeneous cases and might contain a bias towards unusual cases.

Despite the efforts of clinicians in implementing several sets of diagnostic criteria, currently, there is no gold standard for the diagnosis, which is necessarily based on recognizing characteristic clinical features and ruling out other potential causes.

As a result, the efforts in researching specific biofluid or imaging biomarkers are marred by diagnostic imprecision, which obviously creates bias in the selection of clinical cohorts. The addition of a histopathological gold standard to the diagnostic criteria for PLS would constitute a substantial step forward and should be focused on in future efforts.

Another promising field is the advancement of genetic testing, which might help to clarify the contribution of genetics to PLS susceptibility, as already shown by the association of rare genetic variants, classically responsible for other diseases, with the PLS phenotype. Thus, understanding the underlying pathophysiology of PLS would potentially guide therapy development, such as antisense-based approaches, as has already happened for other neurodegenerative diseases.

However, as is already the case for ALS, DNA testing may yield results that are difficult to interpret, thereby further complicating the clinical counseling of those patients who are already dealing with unsolved clinical questions.

From a clinical perspective, patients are worried about their prognosis and future; therefore, clinical research should focus on better defining the natural history of the disease, which cannot arise without an diagnostic advancement.

The most accurate diagnosis possible will, in turn, allow us to study more homogeneous patient samples with a view to obtaining a better pathophysiological interpretation of the disease and, last but not least, to identify possible disease-modifying treatments.

10. 결론

PLS는 드물지만 뚜렷한 질병으로, 특히 초기 단계에서 HSP 및 UMN-우세 ALS와 임상적으로 겹치는 부분이 있어 진단상의 어려움을 야기합니다. 임상 진단 분야에서 가장 큰 지식 격차는 진단 정확도를 높이는 데 기여할 수 있는 특정 바이오마커의 부족으로 특징지어집니다. 또한, PLS 표현형이 다른 신경병리학적 실체의 임상적 표현일 수 있다는 증거로 인해 상황은 더욱 복잡해집니다.

앞서 언급한 바와 같이,

PLS는

치매와 비정형 파킨슨증

(진행성 핵상마비, 신경원 중간 필라멘트 내포 질환, 구상성 아교세포 타우병 또는 아르기필성 입자 질환 포함)의

신경병리학적 진단이 확정된 사례에서

가장 흔한 임상적 표현형으로 보고되었습니다 [27,28,29,30,31].

PLS는

또한 자가면역성 질환[156] 또는 대사 이상 장애[157]를 비롯한

다양한 전신 질환의 드문 임상 표현형으로 묘사되어 왔습니다.

그러나 이러한 출판물들은 이질적인 사례를 보여주고 있으며, 특이한 사례에 대한 편견을 포함하고 있을 수 있습니다.

임상의들이 여러 진단 기준을 시행하려는 노력에도 불구하고, 현재로서는 특징적인 임상 특징을 인식하고 다른 잠재적 원인을 배제하는 데 반드시 기반을 두어야 하는 진단에 대한 황금 기준이 없습니다.

결과적으로, 특정 생체액 또는 영상 바이오마커를 연구하려는 노력은 진단의 부정확성으로 인해 손상되고, 이는 임상 코호트 선택에 편견을 야기합니다. PLS 진단 기준에 조직병리학적 표준 기준을 추가하는 것은 실질적인 발전이며, 향후 연구의 초점이 되어야 합니다.

또 다른 유망한 분야는 유전적 검사의 발전입니다. 이 검사는 다른 질병의 원인으로 여겨지는 희귀 유전적 변이체와 PLS 표현형과의 연관성이 이미 입증된 바와 같이, 유전적 요인이 PLS에 얼마나 영향을 미치는지를 명확히 하는 데 도움이 될 수 있습니다. 따라서 PLS의 근본적인 병태생리학을 이해하면, 다른 신경퇴행성 질환에 이미 적용된 것처럼, 안티센스 기반 접근법과 같은 치료법 개발에 잠재적으로 도움이 될 수 있습니다.

그러나 ALS의 경우와 마찬가지로 DNA 검사 결과도 해석하기 어려울 수 있기 때문에, 이미 해결되지 않은 임상적 문제에 직면한 환자의 임상 상담이 더욱 복잡해질 수 있습니다.

임상적 관점에서 환자들은 예후와 미래에 대해 걱정하고 있습니다. 따라서 임상 연구는 진단의 발전 없이는 불가능한 질병의 자연사를 더 잘 정의하는 데 초점을 맞춰야 합니다.

가장 정확한 진단을 통해 더 나은 병리 생리학적 해석을 얻기 위해 더 균질한 환자 표본을 연구할 수 있으며, 마지막으로 중요한 것은 가능한 질병 조절 치료를 식별할 수 있다는 것입니다.

Acknowledgments

V.V. and R.L. are members of the European Reference Network for Neuromuscular Diseases. G.R. is a member of the European Reference Network for Rare Neurological Diseases.

Author Contributions

Conceptualization, G.R. and R.L.; resources, V.V. and L.B.; data curation,. V.V., L.B. and G.R.; writing—original draft preparation, V.V., L.B. and G.R.; writing—review and editing, G.R. and R.L.; and supervision, G.R. and R.L. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no competing interests in relation to this work. R.L. reports consultation fees (Alfasigma, Amicus Therapeutics s.r.l.), lecture fees (SIMG Service, Adnkronos Salute unipersonale s.r.l., Fondazione Società Italiana di Neurologia, LT3 s.r.l., First Class s.r.l.), advisory board fees (Argon Healthcare s.r.l., Editree Eventi s.r.l., PREX s.r.l., LT3 s.r.l.), congress chair fees (DOC Congress s.r.l.), and scientific meeting organization chair fees (First Class s.r.l., I & C s.r.l.). Other authors: No disclosures.

Funding Statement

This research received no external funding.

Footnotes

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