Table 1 ALS motor phenotypes – guidance for assessment

Onset region

head region onset

O1

bulbar/pseudobulbar onset

Dysarthria or/and dysphagia are first motor symptoms which reflect weakness or/and slowed, poorly coordinated voluntary movement of the tongue and palatal muscles.

A common phenotype referred to as “bulbar ALS” in previous phenotype classifications [7–13]. However, the term of “bulbar” does not describe a body region as such and has been replaced by “head region”. This term is linguistically consistent with arm, trunk and leg onset.

distal arm onset

O2d

–

Weakness or/and slowed, poorly coordinated voluntary movement in the hand muscles are first symptoms.

A common phenotype referred to as “limb ALS” in prior phenotype classifications [7–13]. However, previous classifications have not differentiated between distal vs. proximal arm onset. It addresses research on the patterns of propagation following distal vs. proximal arm onset.

proximal arm onset

O2p

–

Weakness in the shoulder muscles are first symptoms.

This phenotype is associated with an increased probability of developing the O2p, PL phenotype (syn.: flail-arm syndrome) [31, 43].

trunk respiratory onset

O3r

diaphragmatic ALS, thoracic onset ALS

Weakness of respiratory muscles and hypoventilation presenting with orthopnea or dyspnea are first symptoms.

A rare phenotype which is difficult to classify clinically, as hypoventilation may be the only symptom. Previous classifications of trunk onset have rarely distinguished between respiratory and axial onset [32].

trunk axial onset

O3a

dropped head syndrome; camptocormia

Weakness of axial l muscles of the neck and/or dorsal muscles are first symptoms.

A rare phenotype that is observed in clinical practice but rarely differentiated in previous phenotype classifications [32].

distal leg onset

O4d

–

Weakness or/and slowed, poorly coordinated voluntary movement in the foot muscles are first symptoms.

A common phenotype referred to as “limb ALS” in prior phenotype classifications [7–13]. However, previous classifications did not distinguish between distal vs. proximal leg onset. It addresses research on the patterns of propagation following distal vs. proximal leg onset.

proximal leg onset

O4p

–

Weakness or/and slowed, poorly coordinated voluntary movement onset in the hip muscles are first symptoms.

See above.

Propagation pattern

earlier propagation

PE

classic ALS

Propagation of slowed, poorly coordinated voluntary movements or weakness from the region of onset to another vertically distant body region within 12 months of symptom onset.

A common phenotype that was subsumed under “bulbar ALS” or “spinal ALS” in prior phenotype classifications [7–13].

later propagation

PL

It includes “progressive bulbar paralysis (PBP)”, “flail arm-syndrome”, and “flail leg-syndrome” (see below).

Propagation of slowed, poorly coordinated voluntary movements or weakness from the region of onset to another, vertically distant body region later than 12 months of symptom onset.

Rare phenotypes previously referred to as “progressive bulbar paralysis (PBP)”, “flail arm-syndrome”, and “flail leg-syndrome” [4, 9, 25, 43] (see below).

progressive bulbar or pseudobulbar paralysis

Refers to O1, PL

A rare phenotype previously referred to as “progressive bulbar paralysis (PBP)”. Previous classifications have not consistently defined the time criterion to differentiate between “bulbar ALS” (O1, PE) and “PBP” (O1, PL). Several authors suggested the absence of limb involvement in the first 6 months as a criterion for P1l [9]. However, a median time of 12 months was found to distinguish “bulbar ALS” (O1, PE) from “PBP (O1, PL)” [25].

flail arm syndrome, brachial amyotrophic diplegia; Vulpian-Bernhardt syndrome, hanging-arm syndrome, person-in-a-barrel syndrome, brachial amyotrophic diplegia [43]

Refers to O2d, PL and O2dp, PL

A rare phenotype previously referred to as “flail arm-syndrome”. Most authors have suggested that this phenotype begins with proximal muscle weakness and atrophy [4]. However, distal onset and asymmetric presentations have been observed and can be classified as part of this phenotype. The main criterion to distinguish O2d/p, PE from O2d/p, PL is motor neuron dysfunction in the arms without relevant propagation to other regions within 12 months of symptom onset [4, 9, 43].

flail leg syndrome, wasted leg syndrome, pseudopolyneuritic variant [30, 31].

Refers to O4d, PL and O4dp, PL

A rare phenotype previously referred to as “flail leg-syndrome”. Most authors have suggested that this phenotype begins with distal muscle weakness and atrophy. However, proximal onset has been observed and can be classified as part of this phenotype. The main criterion to distinguish O4d/p, PE from O4d/p, PL is motor neuron dysfunction in the legs without relevant propagation to other regions within 12 months of symptom onset [4, 9, 43].

propagation not classifiable

PN

–

Propagation of slowed, poorly coordinated voluntary movements or weakness from the region of onset to another, vertically distant body region not yet classifiable as time since symptom onset is less than 12 months.

An operational classification for a phenotype that is suggestive of PL with a disease duration of less than 12 months since symptom onset and therefore does not yet meet the time criterion to make the formal phenotype classification of PL [4, 9, 25, 43].

Motor neuron dysfunction

balanced motor neuron dysfunction

M0

classic ALS [6–16]

A balanced combined MN dysfunction of the upper motor neuron (UMN) and the lower motor neuron (LMN) in any of the affected body regions is found.

A common phenotype referred to as “classic ALS” in previous phenotype classifications [6–16].

dominant upper motor neuron (UMN) dysfunction

M1d

pyramidal ALS [4]

Dominant UMN dysfunction is found, presenting mainly with slowed, poorly coordinated voluntary movements, whereas discrete LMN dysfunction is also present. Each weakness is MRC grade 4 or greater [49].

A rare phenotype previously referred to as “pyramidal ALS” [4]. This phenotype can be distinguished from M0 (classic ALS) by the extent of LMN signs. M0 shows weakness (MRC 4 or lower), whereas M1d is limited to discrete LMN dysfunction with low-grade atrophy and/or weakness (MRC 4 or -5) [4, 49].

pure UMN dysfunction

M1p

primary lateral sclerosis, (PLS) [24, 25]

Pure UMN dysfunction is found, presenting mainly with slowed, poorly coordinated voluntary movements without apparent LMN dysfunction. The historic phenotype of PLS can diagnosed with certainty only after monitoring for LMN dysfunction for 48 months (M1p for 48 months) [6, 49].

A rare phenotype previously referred to as primary lateral sclerosis, (PLS) [24, 25]. Bulbar symptoms, pseudobulbar affect, atrophy, weight loss, and any weakness are more predictive of M1d or M0 than M1p. Symmetry at presentation is possible in M1p and would be uncommon in M1d. The development of marked asymmetry over the course of the disease is expected [49].

dominant lower motor neuron (LMN) dysfunction

M2d

–

Dominant LMN dysfunction is found, presenting mainly with weakness and associated atrophy, whereas discrete UMN dysfunction is also present.

A rare phenotype that can be distinguished from M1 by the extent of UMN signs. M3d is limited to preserved reflexes in atrophic and/or weak muscles. In contrast, hyperreflexia, and spread of reflexes to adjacent muscles are suggestive for M1.

pure LMN dysfunction

M2p

progressive muscle atrophy (PMA) [19–21]

Pure LMN dysfunction is found, presenting mainly with weakness and associated atrophy, without apparent UMN dysfunction. The historic phenotype of PMA can diagnosed with certainty only after monitoring for UMN dysfunction for 48 months (M2p for 48 months) [4, 6].

A rare phenotype previously referred to as progressive muscle atrophy (PMA) [19–21]. UMN dysfunction may develop in the later stages of the disease. Difficulties remain in correctly identifying the signs of UMN, especially in cases of mild involvement [16, 22, 23].

dissociated motor neuron dysfunction

M3

brachial amyotrophic spastic paraparesis variant of ALS [46, 47]

Dissociated MN dysfunction is found, presenting mainly with dominant LMN dysfunction of the arms and dominant UMN dysfunction of the legs.

A rare phenotype that is observed in clinical practice but not distinguished in previous phenotype classifications.