Time from amyotrophic lateral sclerosis symptom onset to key disease milestones: analysis of data from a multinational cross-sectional survey

Figures & data

Table 1. Demographic and clinical characteristics of people with ALS, overall and according to disease progression category.

Characteristic	Overall^a (N = 867)	Geographical region			Rate of disease progression^c
		Europe^b (N = 527)	US (N = 340)	p-Value	Slow (N = 285)	Intermediate (N = 287)	Fast (N = 295)	p-Value
Mean (SD) age, years	61.3 (11.1)	62.2 (11.4)	59.9 (10.4)	0.0023	59.1 (11.1)	61.3 (11.5)	63.3 (10.4)	<0.0001
Gender, n (%)
Male	542 (62.5)	319 (60.5)	223 (65.6)	0.1507	180 (63.2)	174 (60.6)	188 (63.7)	0.7145
Female	325 (37.5)	208 (39.5)	117 (34.4)		105 (36.8)	113 (39.4)	107 (36.3)
Mean (SD) BMI, mg/kg^2	24.3 (4.2)	24.1 (3.2)	24.7 (5.4)	0.0492	24.6 (5.4)	24.1 (3.4)	24.2 (3.5)	0.3010
Ethnicity, n (%)	(N = 866)	(N = 526)	(N = 340)	<0.0001	(N = 284)	(N = 287)	(N = 295)	0.3313
White/Caucasian	772 (89.1)	493 (93.7)	279 (82.1)		250 (88.0)	263 (91.6)	259 (87.8)
African American	21 (2.4)	0 (0.0)	21 (6.2)		6 (2.1)	7 (2.4)	8 (2.7)
Native American	3 (0.3)	0 (0.0)	3 (0.9)		1 (0.4)	0 (0.0)	2 (0.7)
Asian (Indian subcontinent)	5 (0.6)	3 (0.6)	2 (0.6)		4 (1.4)	1 (0.3)	0 (0.0)
Asian (other)	3 (0.3)	0 (0.0)	3 (0.9)		1 (0.4)	2 (0.7)	0 (0.0)
Hispanic / Latino	43 (5.0)	21 (4.0)	22 (6.5)		17 (6.0)	11 (3.8)	15 (5.1)
Middle Eastern	4 (0.5)	2 (0.4)	2 (0.6)		1 (0.4)	0 (0.0)	3 (1.0)
Mixed race	10 (1.2)	3 (0.6)	7 (2.1)		2 (0.7)	2 (0.7)	6 (2.0)
Afro-Caribbean	4 (0.5)	4 (0.8)	0 (0.0)		2 (0.7)	1 (0.3)	1 (0.3)
South-East Asian	1 (0.1)	0 (0.0)	1 (0.3)		0 (0.0)	0 (0.0)	1 (0.3)
Mean (SD) ALSFRS-R score	33.4 (12.1)	33.3 (11.9)	33.6 (12.5)	0.6931	42.0 (6.6)	33.8 (10.2)	24.8 (11.8)	<0.0001
Mean (SD) time since symptom onset, months	27.4 (27.4)	30.6 (30.1)	22.3 (21.7)	<0.0001	37.8 (40.3)	26.6 (18.5)	18.0 (10.8)	<0.0001
Mean (SD) time since diagnosis, months	(N = 850) 19.2 (22.7)	(N = 521) 21.0 (25.0)	(N = 329) 16.4 (18.3)	0.0038	(N = 275) 26.3 (33.7)	(N = 284) 19.2 (16.1)	(N = 291) 12.7 (9.8)	<0.0001
Site of onset, n (%)	(N = 862)	(N = 523)	(N = 339)	0.2188	(N = 281)	(N = 287)	(N = 294)	0.0802
Bulbar only	169 (19.6)	110 (21.0)	59 (17.4)		48 (17.1)	51 (17.8)	70 (23.8)
Other	693 (80.4)	413 (79.0)	280 (82.6)		233 (82.9)	236 (82.2)	224 (76.2)
ALS progression rate	(N = 867)	(N = 527)	(N = 340)
Mean (SD) ALSFRS-R points/month	0.73 (0.68)	0.67 (0.63)	0.83 (0.74)	0.0005
Slow, n (%)	285 (32.9)	184 (34.9)	101 (29.7)	0.0016	N/A	N/A	N/A	N/A
Intermediate, n (%)	287 (33.1)	190 (36.1)	97 (28.5)
Fast, n (%)	295 (34.0)	153 (29.0)	142 (41.8)
Currently received treatment, n (%)	(N = 867)	(N = 624)	(N = 379)	<0.0001	(N = 285)	(N = 287)	(N = 295)	0.0003
Edaravone only	93 (10.7)	0 (0.0)	104 (27.4)		32 (11.2)	28 (9.8)	33 (11.2)
Riluzole only	541 (62.4)	515 (82.5)	123 (32.5)		197 (69.1)	189 (65.9)	155 (52.5)
Edaravone + Riluzole	61 (7.0)	0 (0.0)	69 (18.2)		12 (4.2)	23 (8.0)	26 (8.8)
No ALS-approved treatment	172 (19.8)	109 (17.5)	83 (21.9)		44 (15.4)	47 (16.4)	81 (27.5)

^aNumber of people with ALS with known date of onset; ^bFrance, Germany, Italy, Spain, and the United Kingdom;

^c‘Points of score lost per month’ was calculated using ALSFRS-R score and the time since symptom onset, and people with ALS were categorized as having a slow (≤0.36), intermediate (>0.36 – <0.77) or fast (>0.77) rate of progression. ALSFRS-R, Amyotrophic Lateral Sclerosis Functional Rating Scale (revised); ALS, amyotrophic lateral sclerosis; BMI, body mass index; N/A, not applicable; SD, standard deviation; US, United States of America.

Table 2. Time from symptom onset to milestones according to progression rate (all people with ALS).

Milestone	Slow progression^a		Intermediate progression^a		Fast progression^a		Fast versus slow^a	Intermediate versus slow^a	Fast versus intermediate^a
	n	Mean (95% CI)	n	Mean (95% CI)	n	Mean (95% CI)	Mean difference (95% CI) p-Value	Mean difference (95% CI) p-Value	Mean difference (95% CI) p-Value
First consultation	261	5.37 (4.41, 6.32)	267	3.59 (3.09, 4.08)	279	2.67 (2.33, 3.02)	−2.69 (−2.08, −3.30) <0.001	−1.78 (−1.32, −2.24) <0.001	−0.91 (−0.76, −1.06) 0.136
Diagnosis	275	11.59 (9.38, 13.81)	284	7.52 (6.81, 8.24)	291	5.20 (4.71, 5.69)	−6.39 (−4.67, −8.12) <0.001	−4.07 (−2.57, −5.57) <0.001	−2.32 (−2.10, −2.55) 0.046
Employment change	73	29.80 (21.96, 37.63)	75	13.21 (11.38, 15.05)	99	8.44 (7.15, 9.74)	−21.35 (−14.82, −27.89) <0.001	−16.58 (−10.59, −22.58) <0.001	−4.77 (−4.23, −5.31) 0.318
Walking aid	98	30.38 (25.35, 35.40)	135	16.84 (15.05, 18.63)	135	8.80 (8.03, 9.58)	−21.58 (−17.33, −25.83) <0.001	−13.54 (−10.30, −16.77) <0.001	−8.04 (−7.03, −9.06) <0.001
Caregiver support	124	33.01 (25.96, 40.07)	205	18.78 (17.17, 20.39)	246	10.85 (9.88, 11.81)	−22.17 (−16.07, −28.26) <0.001	−14.23 (−8.78, −19.68) <0.001	−7.94 (−7.29, −8.58) <0.001
Wheelchair	14	58.58 (27.59, 89.57)	60	30.75 (27.71, 33.80)	121	14.73 (13.32, 16.13)	−43.85 (−14.27, −73.44) <0.001	−27.83 (0.12, −55.77) <0.001	−16.03 (−14.39, −17.67) <0.001
Communication aid	11	67.25 (22.83, 111.67)	50	32.88 (28.17, 37.59)	97	15.52 (13.77, 17.27)	−51.73 (−9.05, −94.41) <0.001	−34.37 (5.35, −74.08) <0.001	−17.36 (−14.40, −20.33) <0.001
Respiratory aid	17	80.01 (48.82, 111.21)	91	33.67 (29.95, 37.39)	153	17.64 (16.03, 19.26)	−62.37 (−32.79, −91.95) <0.001	−46.34 (−18.87, −73.82) <0.001	−16.03 (−13.92, −18.14) <0.001
Gastrostomy	9	101.97 (44.46, 159.47)	43	39.58 (34.40, 44.77)	117	18.98 (17.16, 20.80)	−82.99 (−27.30, −138.67) <0.001	−62.38 (−10.06, −114.71) <0.001	−20.60 (−17.24, −23.96) <0.001
Eye gaze technology	7	74.39 (5.21, 143.57)	26	35.39 (28.01, 42.77)	28	13.24 (10.17, 16.31)	−61.16 (4.95, −127.27) <0.001	−39.01 (22.79, −100.81) 0.004	−22.15 (−17.84, −26.46) 0.013
Care facility	6	75.39 (-15.86, 166.63)	21	36.33 (29.20, 43.47)	33	18.23 (14.34, 22.12)	−57.16 (30.20, −144.51) <0.001	−39.05 (45.06, −123.17) 0.014	−18.11 (−14.87, −21.35) 0.081

^a‘Points of score lost per month’ was calculated using ALSFRS-R score and the time since symptom onset, and people with ALS were categorized as having a slow (≤0.36), intermediate (>0.36 – <0.77) or fast (>0.77) rate of progression. CI: confidence interval.

Table 3. Time from symptom onset to milestones according to progression rate (people with ALS in the US).

Milestone	Slow progression^a		Intermediate progression^a		Fast progression^a		Fast versus slow^a	Intermediate versus slow^a	Fast versus intermediate^a
	n	Mean (95%CI)	n	Mean (95%CI)	n	Mean (95%CI)	Mean difference (95% CI) p-Value	Mean difference (95% CI) p-Value	Mean difference (95% CI) p-Value
First consultation	90	5.47 (3.34, 7.61)	87	2.59 (1.62, 3.57)	134	2.03 (1.69, 2.36)	−3.44 (−1.65, −5.24) <0.001	−2.88 (−1.72, −4.04) 0.006	−0.56 (0.08, −1.20) 1.000
Diagnosis	96	9.21 (6.83, 11.58)	95	5.09 (4.00, 6.17)	138	3.67 (3.24, 4.09)	−5.54 (−3.59, −7.49) <0.001	−4.12 (−2.83, −5.41) <0.001	−1.42 (−0.76, −2.08) 0.411
Employment change	26	24.25 (13.07, 35.42)	19	10.80 (7.61, 13.99)	58	7.35 (6.06, 8.64)	−16.90 (−7.01, −26.78) <0.001	−13.45 (−5.47, −21.43) 0.009	−3.45 (−1.54, −5.35) 1.000
Walking aid	38	26.96 (18.72, 35.20)	52	14.94 (11.59, 18.28)	77	8.35 (7.32, −9.39)	−18.60 (−11.39, −25.82) <0.001	−12.02 (−7.13, −16.92) <0.001	−6.58 (−4.27, −8.90) 0.029
Caregiver support	45	24.70 (16.83, 32.57)	55	15.20 (12.20, 18.20)	124	9.48 (8.23,10.74)	−15.22 (−8.60, −21.83) <0.001	−9.49 (−4.62, −14.37) 0.002	−5.72 (−3.98, −7.46) 0.036
Wheelchair	6	40.19 (4.66, 75.73)	13	28.91 (20.21, 37.60)	52	13.73 (11.68, 15.79)	−26.46 (7.02, −59.94) <0.001	−11.29 (15.55, −38.12) 0.229	−15.17 (−8.53, −21.82) 0.001
Communication aid	8	45.64 (12.10, 79.18)	13	28.01 (16.28, 39.73)	54	13.75 (11.93, 15.57)	−31.89 (−0.17, −63.61) <0.001	−17.64 (4.17, −39.45) 0.047	−14.26 (−4.34, −24.17) 0.014
Respiratory aid	8	79.54 (45.25, 113.83)	22	26.87 (19.68, 34.05)	87	14.89 (13.07, 16.71)	−64.65 (−32.18, −97.12) <0.001	−52.68 (−25.58, −79.77) <0.001	−11.98 (−6.60, −17.35) 0.002
Gastrostomy	3	110.33 (40.51, 180.16)	11	31.44 (20.51, 42.38)	64	16.59 (14.45, 18.73)	−93.74 (−26.05, −161.42) <0.001	−78.89 (−20.00, −137.78) <0.001	−14.85 (−6.06, −23.65) <0.001
Eye gaze technology	4	47.49 (−18.66, 113.62)	9	19.59 (13.98, 25.19)	25	12.40 (9.18, 15.61)	−35.09 (27.84, −98.02) <0.001	−27.90 (32.63, −88.43) 0.007	−7.19 (−4.80, −9.59) 0.604
Care facility	3	67.71 (-88.31, 223.73)	4	44.45 (24.55, 64.34)	20	18.29 (14.24, 22.35)	−49.42 (102.54, −201.38) 0.002	−23.27 (112.86, −159.39) 0.433	−26.15 (−10.32, −41.99) 0.079

^aPoints of score lost per month’ was calculated using ALSFRS-R score and the time since symptom onset, and people with ALS were categorized as having a slow (≤0.36), intermediate (>0.36 – <0.77) or fast (>0.77) rate of progression. CI: confidence interval; US:United States of America.

Table 4. Time from symptom onset to milestones according to progression rate (people with ALS in Europe).

Milestone	Slow progression^a		Intermediate progression^a		Fast progression^a		Fast versus slow^a	Intermediate versus slow^a	Fast versus intermediate^a
	n	Mean (95% CI)	N	Mean (95% CI)	n	Mean (95% CI)	Mean difference (95% CI) p-Value	Mean difference (95% CI) p-Value	Mean difference (95% CI) p-Value
First consultation	171	5.31 (4.37, 6.25)	180	4.07 (3.51, 4.62)	145	3.27 (2.70, 3.84)	−2.04 (−1.67, −2.41) <0.001	−1.24 (−0.85, −1.63) 0.041	−0.80 (−0.82, −0.78) 0.389
Diagnosis	179	12.87 (9.72, 16.02)	189	8.75 (7.87, 9.63)	153	6.58 (5.79, 7.37)	−6.29 (−3.93, −8.65) <0.001	−4.13 (−1.86, −6.40) 0.009	−2.17 (−2.07, −2.26) 0.408
Employment change	47	32.87 (22.19, 43.54)	56	14.03 (11.81, 16.25)	41	9.99 (7.44, 12.54)	−22.88 (−14.76, −31.00) <0.001	−18.83 (−10.38, −27.29) <0.001	−4.05 (−4.38, −3.71) 1.000
Walking aid	60	32.55 (26.08, 39.01)	83	18.04 (16.00, 20.07)	58	9.40 (8.21, 10.58)	−23.15 (−17.87, −28.43) <0.001	−14.51 (−10.08, −18.94) <0.001	−8.64 (−7.79, −9.49) 0.003
Caregiver support	79	37.75 (27.64, 47.86)	150	20.10 (18.21, 21.98)	122	12.23 (10.79, 13.67)	−25.52 (−16.85, −34.18) <0.001	−17.65 (−9.43, −25.88) <0.001	−7.86 (−7.42, −8.31) 0.017
Wheelchair	8	72.37 (19.34, 125.40)	47	31.26 (28.01, 34.52)	69	15.47 (13.53, 17.42)	−56.90 (−5.81, −107.98) <0.001	−41.11 (8.67, −90.88) <0.001	−15.79 (−14.48, −17.10) <0.001
Communication aid	3	124.87 (-115.75, 365.49)	37	34.60 (29.46, 39.73)	43	17.74 (14.56, 20.92)	−107.13 (130.31, −344.57) <0.001	−90.28 (145.21, −325.77) <0.001	−16.86 (−14.90, −18.81) 0.001
Respiratory aid	9	80.44 (21.44, 139.43)	69	35.84 (31.53, 40.15)	66	21.28 (18.59, 23.96)	−59.16 (−2.85, −115.47) <0.001	−44.60 (10.09, −99.28) <0.001	−14.57 (−12.94, −16.19) 0.001
Gastrostomy	6	97.78 (0.60, 194.97)	32	42.38 (36.49, 48.27)	53	21.87 (18.89, 24.84)	−75.92 (18.29, −170.13) <0.001	−55.40 (35.89, −146.70) <0.001	−20.52 (−17.60, −23.43) 0.002
Eye gaze technology	3	110.27 (−148.07, 368.61)	17	43.75 (35.14, 52.36)	3	20.25 (5.20, 35.30)	−90.02 (153.27, −333.31) 0.019	−66.52 (183.21, −316.25) 0.025	−23.50 (−29.94, −17.06) 0.936
Care facility	3	83.06 (−218.94, 385.06)	17	34.43 (26.18, 42.67)	13	18.12 (9.53, 26.72)	−64.93 (228.47, −358.34) 0.020	−48.63 (245.12, −342.38) 0.098	−16.30 (−16.65, −15.95) 0.636

^a’Points of score lost per month’ was calculated using ALSFRS-R score and the time since symptom onset, and people with ALS were categorized as having a slow (≤0.36), intermediate (>0.36 – <0.77) or fast (>0.77) rate of progression. CI: confidence interval.

Figure 1. Time from symptom onset to milestones for all people with ALS.

Figure 2. Time from symptom onset to milestones according to progression rate. Y: year. Error bars show 95% confidence intervals

Figure 3. Time from symptom onset to milestones according to region (Europe versus US). US: United States of America; Y: year. Error bars show 95% confidence interval

Table 5. Time from symptom onset to milestones according to region (US or Europe).

Milestone	Overall (N = 1003)		Region				US versus Europe p-Value
			Europe		US
	n	Mean (95%CI)	n	Mean (95%CI)	n	Mean (95%CI)
First consultation	807	3.9 (3.5–4.2)	496	4.3 (3.8–4.7)	311	3.2 (2.5–3.9)	0.0059
Diagnosis	850	8.0 (7.3–8.8)	521	9.5 (8.4–10.7)	329	5.7 (4.9–6.5)	<0.0001
Employment change	247	16.2 (13.6–18.8)	144	19.0 (15.1–22.9)	103	12.3 (9.1–15.4)	0.0128
Walking aid	368	17.5 (15.8–19.2)	201	19.9 (17.5–22.3)	167	14.6 (12.3–17.0)	0.0030
Caregiver support	575	18.5 (16.7–20.3)	351	21.3 (18.7–24.0)	224	13.9 (12.0–15.9)	<0.0001
Wheelchair	195	22.8 (19.9–25.7)	124	25.1 (21.1–29.2)	71	18.8 (15.2–22.3)	0.0373
Communication aid	158	24.6 (20.8–28.5)	83	29.1 (23.0–35.2)	75	19.6 (15.4–23.9)	0.0153
Respiratory aid	261	27.3 (24.2–30.4)	144	32.0 (27.5–36.4)	117	21.6 (17.6–25.5)	0.0009
Gastrostomy	169	28.6 (24.4–32.9)	91	34.1 (27.5–40.6)	78	22.3 (17.6–27.0)	0.0062
Eye gaze technology	61	29.7 (21.4–38.0)	23	49.4 (31.9–66.9)	38	17.8 (12.2–23.4)	0.0002
Care facility	60	30.3 (21.9–38.6)	33	32.4 (19.4–45.4)	27	27.7 (17.9–37.4)	0.5826

US: United States of America.