The future of ALS diagnosis and staging: where do we go from here?

Figures & data

Figure 1 Proposed mechanisms underlying amyotrophic lateral sclerosis. (1) Nucleocytoplasmic transport defects including altered transport of RNA molecules and RNA-binding proteins. (2) Altered RNA metabolism. RNA-binding proteins including TDP-43 or FUS may become mislocalized in the cytoplasm leading to altered transcription and splicing. Stress granule dynamics are also affected. (3) Proteostasis is impaired with aggregating proteins including TDP-43 accumulating in the cytoplasm. There is evidence that the two main protein clearance pathways, autophagy and the UPS may be involved. (4) Impaired DNA repair: several ALS-linked genes including FUS, TARDBP, TAF15, SETX, and EWSR1 are involved in DNA repair. (5) Mitochondrial dysfunction resulting in the increased formation of reactive oxygen species (ROS) has been proposed as an initiating factor in ALS. Several ALS-linked proteins including SOD1, TDP-43, and FUS interact with mitochondria. (6) Axonal transport defects have been implicated in ALS pathogenesis. Neuropathological evidence has shown evidence of this including neurofilament accumulation and cytoskeletal disorganization. (7) Several ALS-linked genes including OPTN, VAPB, CHMP2B, and UNC13A are involved in vesicular transport. Impaired vesicular trafficking can lead to protein accumulation and golgi fragmentation which has been observed in ALS patients. (8) Neuroinflammation: the secretion of inflammatory proteins by activated microglia leads to the potentially neurotoxic activation of astrocytes, which may contribute to the death of neurons and oligodendrocytes. (9) Excitotoxicity: glutamate receptor overstimulation has been proposed to occur via several mechanisms including increased synaptic glutamate release, alterations to AMPA receptors and reduced clearance of glutamate by astrocytes. (10) Oligodendrocyte dysfunction may lead to reduced support for neurons. Changes in lactate production and transport via MCT1 have been implicated. Taken from Mejzini et al. (37). Copyright © Mejzini, Flynn, Pitout, Fletcher, Wilton and Akkari. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).

Figure 2 Timeline of amyotrophic lateral sclerosis diagnostic criteria and prognosis staging. Top timeline shows diagnostic criteria; bottom timeline shows prognostic staging. ALSFRS: ALS Functional Rating Scale; ALSFRS-R: ALS Functional Rating Scale-Revised; MiToS: Milano-Torino functional staging.

Table 1 Amyotrophic lateral sclerosis diagnostic criteria overview.

	El Escorial criteria (25)	El Escorial criteria revised, Airlie House (26)	El Escorial criteria revised, Awaji Criteria (27)	Gold coast criteria (33)
Presence of ALS	√	√	√	√
Definite ALS	√	√	√	x
Probable ALS	√	√	√	x
Clinical probable ALS: Laboratory-supported	x	√	x	x
Possible ALS	√	√	√	x
Suspected ALS	√	x	x	x
Benefits	Widely accepted first criteria developed for diagnosis Includes UMN and LMN signs	Increased sensitivity vs 1994 criteria EMG data supplements clinical findings	Increased sensitivity vs 1994 and 2000 criteria Enhanced integration of EMG data Increased reliance on neurophysiology for diagnostic utility in early disease stages	Increased sensitivity vs 1994, 2000 and 2008 criteria Reduced categories for diagnosis High specificity Sensitivity across motor neuron disease phenotypes EMG data retained Cognitive and behavioral data included Simple criteria for ease of clinical and research use
Limitations	Lacks diagnostic sensitivity Low test-retest reliability Complex to apply Disease may not evolve through all identified categories No electrophysiology, neuro-imaging or immune-chemistry analysis	Concerns on sensitivity during early disease stages Complex to apply due to multiple categories Disease may not evolve through all identified categories Low inter-rater variability Cognitive and behavioral data not included	Concerns on sensitivity due to elimination of clinical probable ALS: Laboratory-supported Complex to apply due to multiple categories Disease may not evolve through all identified categories Low inter-rater variability Cognitive and behavioral data not included No genome analysis	Should be used in conjunction with a staging system to preserve prognostic information Limited research on the accuracy of criteria in clinical practice and trials No genetic testing or biomarkers included so will require revision once tests/tools are validated for ALS

ALS: Amyotrophic lateral sclerosis; EMG: electromyography; LMN: lower motor neuron; UMN: upper motor neuron.

Table 2 Amyotrophic lateral sclerosis prognostic scoring and staging systems overview.

	ALSFRS (36)	ALSFRS-R (35)	Kings clinical staging system (38)	Milano-Torin, MiToS (39)	Fine till 9 (40)
Overview	Scoring system Monitors rate of disease progression	Scoring system Monitors rate of disease progression Based on symptom management and medical decisions	Staging system 5 stages assess disease progression (clinical and anatomical) 1 (symptom onset) − 5 (death)	Staging system 6 stages assess functional burden of disease 0 (normal function) −5 (death)	Staging system 5 stages assigned by number of ALSFRS-R sub scores ≤9 points 0 (0 ALSFRS-R sub scores ≤9) − 4 (4 ALSFRS-R sub scores ≤9)
Benefits	Useful to measure functional decline	Useful to measure functional decline Can be administered virtually	Discrete stages of disease progression Superior staging in earlier disease vs MiToS Simple to apply Stages occur in order with forward progression only Less vulnerable to misclassification vs ALSFRS-R	Discrete stages of disease progression Superior staging in later disease vs Kings Based on ALSFRS/ALSFRS-R so familiar to clinicians and based on patient function Less vulnerable to misclassification vs ALSFRS-R	Superior staging in earlier disease vs MiToS More sensitive to disease progression vs MiToS Easily applicable to retrospective data Permits estimation of multidimensional effects of variables on treatment outcome
Limitations	May not fully capture functional characteristics of later stage ALS No agreed upon thresholds for transitions in functional status No respiratory data	May not fully capture functional characteristics of later stage ALS No agreed upon thresholds for transitions in functional status Multidimensions limit clinical utility Low responsiveness during plateaus Does not provide information of the expected speed of disease progression	Based on clinical milestones rather than functional ones	Reversion in stages has been noted	Same weaknesses as ALSFRS-R Misclassifications and reversals in staging lead to instability No validation in clinical trials or research

ALS: Amyotrophic lateral sclerosis; ALSFRS: amyotrophic lateral sclerosis functional ratings scale; ALSFRS-R: amyotrophic lateral sclerosis functional rating scale-revised; MiToS: Milano-Torino functional staging.

Figure 3 Map of worldwide registries in amyotrophic lateral sclerosis developed between 2010 and 2017. Adapted from Barbalho et al. (2).

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