ALS patients with concurrent neuroinflammatory disorders; a nationwide clinical records study

Figures & data

Table 1 International Classification of Diseases (ICD) codes used to identify amyotrophic lateral sclerosis, multiple sclerosis, myasthenia gravis, inflammatory polyneuropathies, and dermatopolymyositis in the Swedish Patient Register.

	ICD-9	1991–1996	ICD-10	1997–2014
Amyotrophic lateral sclerosis
	335.C	Amyotrophic lateral sclerosis	G12.2	Motor neuron disease
Multiple sclerosis
	340	Multiple sclerosis	G35	Multiple sclerosis
Myasthenia gravis
	358.A	Myasthenia gravis	G70.0	Myasthenia gravis
	358.B	Myasthenic syndrome in diseases classified elsewhere
	358.W	Other specified myoneural diseases; Congenital myasthenic syndrome; Acquired myasthenic syndrome (Lambert-Eaton) without malignancy
Inflammatory polyneuropathies
	357.A	Acute inflammatory polyneuropathy Guillain-Barré syndrome	G61.0	Guillain-Barré syndrome
	357.B	Polyneuropathy in collagen vascular disease	G61.8	Other specified inflammatory polyneuropathies
	357.W	Other specified inflammatory and toxic neuropathy Chronic progressive and chronic recurrent polyneuropathy of Guillain-Barré type	G61.9	Inflammatory polyneuropathy, unspecified
	357.X	Inflammatory and toxic neuropathy, unspecified
Dermatopolymyositis
	710.D	Dermatomyositis	M33.0	Juvenile dermatomyositis
	710.E	Polymyositis	M33.1	Other dermatomyositis
			M33.2	Polymyositis
			M33.9	Dermatopolymyositis, unspecified
			G72.4	Inflammatory myopathies not elsewhere classified
			G73.7	Myopathy in diseases classified elsewhere

Figure 1 Flow-chart of data collection and diagnostic accuracy decisions.

Table 2 Clinical characteristics of the patients diagnosed with concurrent amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), myasthenia gravis (MG), inflammatory polyneuropathies (IP), or dermatopolymyositis (DMPM).

Concurrent ALS +	ID	Sex	Site of ALS onset	Age at ALS onset (years)	ALS diagnostic delay (months)	Age at ALS diagnosis (years)	Cognitive impairment prior ALS diagnosis	Time between ALS diagnosis and Riluzole prescription (months)	Ever-use of enteral nutrition	Ever-use of noninvasive ventilation	Ever-use of invasive ventilation	Time from ALS diagnosis to death (months)	Age at other diagnosis (years)	Time between ALS and other diagnosis (years)	Subtype other diagnosis
MS
MS prior ALS	1	Male	Bulbar			68	No	Not on Riluzole	No	No	No	12	15	53
	2	Female	Bulbar			62	No	<1	Yes	No	No	15	53	8	RRMS
	3	Female	Bulbar			24	No	<1	No	No	No	N/A	23	<1
	4	Female	Spinal	64	16	65	No	<1	No	No	No	15	58	6	SPMS
	5	Female	Spinal			74	No	<1	No	No	No	66	61	12	RRMS
	6*	Female	Bulbar			79	No	Not on Riluzole	No	No	No	48	36	43	SPMS
	7	Male	Spinal	58	92	66	No	Not on Riluzole	No	No	No	N/A	37	28	RRMS
	8	Male	Bulbar	80	12	81	No	<1	No	No	No	2	62	18
	9	Female	Spinal	48	23	50	No	20	No	No	No	46	39	11	SPMS
	10*	Male	Spinal			52	No	2	No	No	No	N/A	46	6	PPMS
MS after ALS	11	Male	Spinal			54	No	Not on Riluzole	No	No	No	N/A	55	<1	PPMS
	12*	Female	Spinal			47	No	Not on Riluzole	No	No	No	N/A	56	8	PPMS
MG
MG prior ALS	13	Female	Bulbar	59	7	60	No	<1	No	Yes	No	19	60	<1	Generalized
	14*	Female	Bulbar			60	No	6	No	No	No	N/A	54	6	Generalized
	15	Female	Bulbar	76	7	76	No	Not on Riluzole	Yes	Yes	Yes	1	76	<1	Bulbar
	16	Female	Bulbar	82	2	82	No	<1	Yes	No	No	4	82	<1	Generalized
	17	Female	Bulbar	68	11	68	No	1	Yes	No	No	11	50	18	Generalized
MG after ALS	18	Male	Bulbar	85	6	86	No	<1	Yes	No	No	64	86	<1	Generalized
	19	Male				75	No	Not on Riluzole	Yes	Yes	No	2	75	<1	Generalized
	20*	Female	Bulbar	67	11	68	Yes	Not on Riluzole	Yes	No	Yes	10	68	<1	Bulbar
	21	Female	Spinal	73	92	81	No	<1	No	No	No	9	81	<1	Generalized
IP
IP prior ALS	22	Male	Spinal	75	5	75	No	2	No	No	No	N/A	55	20	GBS AMAN
	23	Male	Spinal			54	No	Not on Riluzole	No	No	No	22	48	5
	24	Male	Spinal			60	No	5	No	Yes	No	N/A	60	<1	CIDP
	25	Female	Spinal			48	No	Not on Riluzole	No	No	No	24	47	<1	GBS AMAN
DMPM
DMPM prior ALS	26	Female	Bulbar	73	24	75	No	1	Yes	No	No	5	75	<1	Polymyositis
	27	Female	Spinal	65	23	67	No	3	Yes	Yes	No	16	66	1	Polymyositis
	28	Male	Spinal			55	No	1	No	No	No	N/A	54	<1	Myositis

* Primary lateral sclerosis patient (included in our definition of ALS). Abbreviations: Acute Motor Axonal Neuropathy (AMAN); Chronic Inflammatory Demyelinating Polyneuropathy (CIDP); Guillain-Barré syndrome (GBS); N/A: Data not applicable because alive at the end of follow-up; Primary-Progressive MS (PPMS); Relapsing-Remitting MS (RRMS); Secondary-Progressive MS (SPMS).

Table 3 Patients diagnosed with concurrent amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), myasthenia gravis (MG), inflammatory polyneuropathies (IP), or dermatopolymyositis (DMPM) significantly differ in terms of age at ALS symptoms onset, site of ALS onset, use of Riluzole, time from ALS diagnosis to first Riluzole prescription, and use of noninvasive ventilation as compared to patients diagnosed with only ALS.

	ALS patients (N = 271)	ALS + MS/MG/ IP/DMPM patients (N = 28) (N = 28)	p Value*	ALS + MS patients (N = 12)	p Value*	ALS + MG patients (N = 9)	p Value*	ALS + IP patients (N = 4)	p Value*	ALS + DMPM patients (N = 3)	p Value*
		N (%)		N (%)		N (%)		N (%)		N (%)
Sex			0.174		0.559		0.094		0.625		0.605
Male	143 (52.8)	11 (39.3)		5 (41.7)		2 (22.2)		3 (75.0)		1 (33.3)
Female	128 (47.2)	17 (60.7)		7 (58.3)		7 (77.8)		1 (25.0)		2 (66.7)
Age at ALS onset (years)			0.298		0.955		0.235		0.459		0.858
≤ 40	22 (8.1)	0 (0.0)		0 (0.0)		0 (0.0)		0 (0.0)		0 (0.0)
41–50	41 (15.1)	1 (3.6)		1 (8.3)		0 (0.0)		0 (0.0)		0 (0.0)
51–60	59 (21.8)	2 (7.1)		1 (8.3)		1 (11.1)		0 (0.0)		0 (0.0)
61–70	87 (32.1)	4 (14.3)		1 (8.3)		2 (22.2)		0 (0.0)		1 (33.3)
71–80	43 (15.9)	5 (17.9)		1 (8.3)		2 (22.2)		1 (25.0)		1 (33.3)
≥81	17 (6.3)	2 (7.1)		0 (0.0)		2 (22.2)		0 (0.0)		0 (0.0)
Median (range)	62 (21–93)	70.5 (48–85)	0.014	61 (48–80)	0.916	73 (59–85)	0.015	75 (75–75)	0.215	69 (65–73)	0.317
ALS diagnostic delay (months)
Median (range)	13 (0–361)	11.5 (2–92)	0.571	19.5 (12–92)	0.303	7 (2–92)	0.130	5 (5–5)	0.171	23.5 (23–24)	0.404
Age at ALS diagnosis (years)			0.836		0.967		0.250		0.420		1.000
≤ 40	15 (15.5)	1 (3.6)		1 (8.3)		0 (0.0)		0 (0.0)		0 (0.0)
41–50	35 (12.9)	3 (10.7)		2 (16.7)		0 (0.0)		1 (25.0)		0 (0.0)
51–60	57 (21.0)	7 (25.0)		2 (16.7)		2 (22.2)		2 (50.0)		1 (33.3)
61–70	90 (33.2)	7 (25.0)		4 (33.3)		2 (22.2)		0 (0.0)		1 (33.3)
71–80	51 (18.8)	6 (21.4)		2 (16.7)		2 (22.2)		1 (25.0)		1 (33.3)
≥81	23 (8.5)	4 (14.3)		1 (8.3)		3 (33.3)		0 (0.0)		0 (0.0)
Median (range)	64 (22–94)	66.5 (24–86)	0.429	63.5 (24–81)	0.629	75 (60–86)	0.024	57 (48–75)	0.488	67 (55–75)	0.714
Site of ALS onset			0.037		0.343		.001		0.580		1.000
Bulbar	78 (28.8)	13 (46.4)		5 (41.7)		7 (77.8)		0 (0.0)		1 (33.3)
Spinal	193 (71.2)	14 (50.0)		7 (58.3)		1 (11.1)		4 (100.0)		2 (66.7)
Cognitive impairment prior ALS diagnosis			0.450		1.000		0.474		1.000		1.000
Yes	18 (6.6)	1 (3.6)		0 (0.0)		1 (11.1)		0 (0.0)		0 (0.0)
No	253 (93.4)	27 (96.4)		12 (100.0)		8 (88.9)		4 (100.0)		3 (100.0)
Ever-use of Riluzole			0.001		0.013		0.095		0.080		1.000
Yes	238 (87.8)	18 (64.3)		7 (58.3)		6 (66.7)		2 (50.0)		3 (100.0)
No	33 (12.2)	10 (35.7)		5 (41.7)		3 (33.3)		2 (50.0)		0 (0.0)
Time between ALS diagnosis and Riluzole prescription (months)
Median	19 (0–152)	1 (0–20)	<0.0001	<1 (0–20)	0.005	<1 (0–6)	0.0002	3.5 (2–5)	0.054	1 (1–3)	0.009
Ever-use of enteral nutrition			0.136		0.014		0.316		0.127		0.603
Yes	127 (46.9)	9 (32.1)		1 (8.3)		6 (66.7)		0 (0.0)		2 (66.7)
No	144 (53.1)	19 (67.9)		11 (91.7)		3 (33.3)		4 (100.0)		1 (33.3)
Ever-use of noninvasive ventilation			0.002		0.001		0.506		0.624		1.000
Yes	130 (48.0)	5 (17.9)		0 (0.0)		3 (33.3)		1 (25.0)		1 (33.3)
No	141 (52.0)	23 (82.1)		12 (100.0)		6 (66.7)		3 (75.0)		2 (66.7)
Ever-use of invasive ventilation			1.000		0.608		0.175		1.000		1.000
Yes	22 (8.1)	2 (7.1)		0 (0.0)		2 (22.2)		0 (0.0)		0 (0.0)
No	249 (91.9)	26 (92.9)		12 (100.0)		7 (77.8)		4 (100.0)		3 (100.0)
Time from ALS diagnosis to death (months)
Median (range)	16 (0–141)	15 (1–66)	0.579	15 (2–66)	0.451	9.5 (1–64)	0.111	23 (22–24)	0.401	10.5 (5–16)	0.409

*From Chi-square test (for categorical variables), Fisher exact test (for categorical variables with expected frequencies ≤5), or Wilcoxon test (for non-normally distributed continuous variables).

Table 4 Patients diagnosed with concurrent amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), myasthenia gravis (MG), inflammatory polyneuropathies (IP), or dermatopolymyositis (DMPM) significantly differ in terms of age at ALS symptoms onset, site of ALS onset, use of Riluzole, time from ALS diagnosis to first Riluzole prescription, and use of noninvasive ventilation as compared to patients diagnosed with only ALS. Primary lateral sclerosis was not included in our definition of ALS in this analysis.

	ALS patients (N = 254)	ALS + MS/MG/IP/DMPM patients (N = 23) (N = 28)	p Value*	ALS + MS patients (N = 9)	p Value*	ALS + MG patients (N = 7)	p Value*	ALS + IP patients (N = 4)	p Value*	ALS + DMPM patients (N = 3)	p Value*
		N (%)		N (%)		N (%)		N (%)		N (%)
Sex			0.435		0.743		0.271		0.624		0.611
Male	132 (52.0)	10 (43.5)		4 (44.4)		2 (28.6)		3 (75.0)		1 (33.3)
Female	122 (48.0)	13 (56.5)		5 (55.6)		5 (71.4)		1 (25.0)		2 (66.7)
Age at ALS onset (years)			0.290		0.953		0.166		0.458		0.857
≤ 40	22 (7.9)	0 (0.0)		0 (0.0)		0 (0.0)		0 (0.0)		0 (0.0)
41–50	36 (14.2)	1 (4.3)		1 (11.1)		0 (0.0)		0 (0.0)		0 (0.0)
51–60	56 (22.0)	2 (8.7)		1 (11.1)		1 (14.3)		0 (0.0)		0 (0.0)
61–70	81 (31.9)	3 (13.0)		1 (11.1)		1 (14.3)		0 (0.0)		1 (33.3)
71–80	42 (16.5)	5 (21.7)		1 (11.1)		2 (28.6)		1 (25.0)		1 (33.3)
≥81	17 (6.7)	2 (8.7)		0 (0.0)		2 (28.6)		0 (0.0)		0 (0.0)
Median (range)	63 (21–93)	73 (48–85)	0.021	61 (48–80)	0.962	74.5 (59–85)	0.018	75 (75–75)	0.223	69 (65–73)	0.341
ALS diagnostic delay (months)
Median (range)	13 (0–361)	12 (2–92)	0.601	19.5 (12–92)	0.313	7 (2–92)	0.130	5 (5–5)	0.170	23.5 (23–24)	0.414
Age at ALS diagnosis (years)			0.836		0.788		0.141		0.449		1.000
≤ 40	14 (5.5)	1 (4.3)		1 (11.1)		0 (0.0)		0 (0.0)		0 (0.0)
41–50	30 (11.8)	2 (8.7)		1 (11.1)		0 (0.0)		1 (25.0)		0 (0.0)
51–60	54 (21.3)	5 (21.7)		1 (11.1)		1 (14.3)		2 (50.0)		1 (33.3)
61–70	83 (32.7)	6 (26.1)		4 (44.4)		1 (14.3)		0 (0.0)		1 (33.3)
71–80	50 (19.7)	5 (21.7)		1 (11.1)		2 (28.6)		1 (25.0)		1 (33.3)
≥81	23 (9.1)	4 (17.4)		1 (11.1)		3 (42.9)		0 (0.0)		0 (0.0)
Median (range)	65 (23–94)	67 (24–86)	0.354	65 (24–81)	0.738	76 (60–86)	0.013	57 (48–75)	0.443	67 (55–75)	0.757
Site of ALS onset			0.131		0.461		0.012		0.323		1.000
Bulbar	76 (29.9)	10 (43.5)		4 (44.4)		5 (71.4)		0 (0.0)		1 (33.3)
Spinal	178 (70.1)	12 (52.2)		5 (55.6)		1 (14.3)		4 (100.0)		2 (66.7)
Cognitive impairment prior ALS diagnosis			0.378		1.000		1.000		1.000		1.000
Yes	18 (7.1)	0 (0.0)		0 (0.0)		0 (0.0)		0 (0.0)		0 (0.0)
No	236 (92.9)	23 (100.0)		9 (100.0)		7 (100.0)		4 (100.0)		3 (100.0)
Ever-use of Riluzole			0.009		0.083		0.196		0.072		1.000
Yes	225 (88.6)	16 (69.6)		6 (66.7)		5 (71.4)		2 (50.0)		3 (100.0)
No	29 (11.4)	7 (30.4)		3 (33.3)		2 (28.6)		2 (50.0)		0 (0.0)
Time between ALS diagnosis and Riluzole prescription (months)
Median	18.5 (0–152)	0.5 (0–20)	<.0001	<1 (0–20)	0.015	<1 (0–1)	0.0003	3.5 (2–5)	0.052	1 (1–3)	0.008
Ever-use of enteral nutrition			0.251		0.041		0.265		0.126		0.605
Yes	120 (47.2)	8 (34.8)		1 (11.1)		5 (71.4)		0 (0.0)		2 (66.7)
No	134 (52.8)	15 (65.2)		8 (88.9)		2 (28.6)		4 (100.0)		1 (33.3)
Ever-use of noninvasive ventilation			0.016		0.004		1.000		0.624		1.000
Yes	122 (48.0)	5 (21.7)		0 (0.0)		3 (42.9)		1 (25.0)		1 (33.3)
No	132 (52.0)	18 (78.3)		9 (100.0)		4 (57.1)		3 (75.0)		2 (66.7)
Ever-use of invasive ventilation			1.000		1.000		0.464		1.000		1.000
Yes	21 (8.3)	1 (4.3)		0 (0.0)		1 (14.3)		0 (0.0)		0 (0.0)
No	233 (91.7)	22 (95.7)		9 (100.0)		6 (85.7)		4 (100.0)		3 (100.0)
Time from ALS diagnosis to death (months)
Median (range)	16 (0–141)	15 (1–66)	0.479	15 (2–66)	0.783	9 (1–64)	0.155	23 (22–24)	0.385	10.5 (5–16)	0.417

*From Chi-square test (for categorical variables), Fisher exact test (for categorical variables with expected frequencies ≤5), or Wilcoxon test (for non-normally distributed continuous variables).