Temperature-induced symptoms in adolescents and adults with spinal muscular atrophy

Abstract

Introduction:

Temperature-induced aggravation of weakness is a well-known characteristic of demyelinating and motor neuron disorders. We investigated prevalence, frequency, and severity of symptoms during heat and cold exposure in patients with 5q-spinal muscular atrophy (SMA).

Methods:

We conducted a longitudinal cohort study systematically assessing temperature-induced symptoms by means of a standardized questionnaire at baseline and after one year in adolescents and adults with SMA types 1–4 and age-matched healthy and disease controls. All patients were treatment-naïve for SMN-augmenting therapies at baseline.

Results:

We included 103 patients with SMA types 1–4 (median age 39 years, range 13–67 years), 25 healthy controls and 46 disease controls. Eighty-four (82%) patients with SMA and 24 (52%) disease controls were non-ambulatory. Ninety patients with SMA (87%) reported cold-induced symptoms, primarily as aggravation of weakness (85%, n = 88), i.e., cold paresis. Cold paresis was more prevalent in non-ambulatory patients with SMA (94% vs. 47%) and associated with lower Revised Upper Limb Module (RULM) scores in these patients. Healthy controls did not report cold-induced symptoms, in contrast to the 30 (65%) disease controls who did experience cold paresis. Cold paresis was more prevalent in non-ambulatory patients with SMA compared to disease controls. The prevalence of cold paresis was unchanged after one year of disease-modifying treatment.

Conclusions:

Cold paresis is commonly experienced by patients with SMA, particularly those with more severe weakness based on SMA type, ambulatory status, and RULM score. Better understanding of the underlying mechanisms of cold paresis might lead to new symptomatic treatment to preserve motor functionality.

Trial registration information: NL72562.041.20 (registered at www.toetsingonline.nl; 26-03-2020).

Keywords

cold paresis temperature-induced symptoms cold-induced symptoms spinal muscular atrophy SMN-targeting therapy neuromuscular disorders

Introduction

Spinal muscular atrophy (SMA), also referred to as 5q-SMA, is caused by loss-of-function mutations of the Survival Motor Neuron 1 (SMN1) gene on chromosome 5q, which results in reduced concentrations of intracellular SMN protein levels. SMA is characterized pathologically by changes in the motor unit, including degeneration of alpha motor neurons and changes of axons, neuromuscular junctions, and muscle fibers^1–5 and clinically by muscle weakness, most pronounced in proximal and axial muscle groups.^6,7 SMA manifests a wide range of severity, reflected by the clinical classification system of SMA that distinguishes five types, i.e., types 0 to 4, based on the age at symptom onset and achieved motor milestones.⁸

Muscle weakness is progressive in patients with SMA but also shows functionally relevant day-to-day variation.^9,10 The best-known example is fatigability, defined as transient exacerbations of weakness following repetitive movements, such as chewing, using the arms or hands or walking.^5,11 In our experience, patients also spontaneously report that muscle weakness worsens during cold exposure. This symptom, also known as cold paresis, has been reported in various neuromuscular disorders (NMDs)^12,13 and systematically assessed in patients with peripheral nerve disorders, such as multifocal motor neuropathy (MMN), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), chronic idiopathic axonal polyneuropathy (CIAP) and progressive spinal muscular atrophy (PSMA), but not in SMA.¹⁴

Understanding the impact of cold paresis might help to further improve supportive care. We, therefore, aimed to assess the prevalence, frequency and severity of temperature-induced symptoms in patients with SMA and to explore the association of these symptoms with clinical characteristics.

Methods

Literature research

To investigate the prevalence of cold paresis in NMDs we searched MEDLINE (through PubMed) for articles on cold-induced weakness and neurological disorders (final search date 29th of April 2024), using a combination of the following terms: “cold”, “cold temperature”, “cold-induced” and “muscle weakness”, “paresis” or “cold (induced) paralysis”. We screened title and abstract for full inclusion, and cross-checked references of all included articles to ensure no articles were missed. Full article screening was conducted by two of the authors (LV and RW).

Study design

We conducted a single-center, longitudinal cohort study to assess temperature-induced symptoms using a questionnaire. Participants were adolescents and adults with SMA, healthy controls and disease controls. Patients with SMA responded to the questionnaire twice: once at baseline (at the time of screening for nusinersen) and a second time at follow-up after approximately one year of treatment with DMT. Due to the variation in time of screening for nusinersen treatment among the patients with SMA, the season in which these assessments were conducted differed per patient. Healthy and disease controls completed the questionnaire at baseline only.

The local medical ethics committee of the University Medical Center Utrecht approved this study (No. 20-143; registered in the Dutch registry for clinical studies and trials (www.toetsingonline.nl – NL72562.041.20)). We included all participants between May 2020 and May 2024. This study is reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria.¹⁵

Participants

All patients with SMA participated in a national longitudinal cohort study on SMA, of which the protocol has been previously published.¹⁶

We used the SMA classification system with some additions to determine SMA type.^8,10 In case of discrepancies between age at onset and achieved motor milestones, we used motor milestones for the final classification: patients with SMA type 1c never learned to sit, patients with type 2a learned to sit unsupported at some moment in life, patients with type 2b learned to stand supported, and patients with types 3 and 4 learned to walk independently but experienced onset of weakness before and after the age of 18 years, respectively. In patients with type 3a, onset of symptoms was before the age of 3 years, and in those with type 3b, between 3 and 18 years.¹⁷

The deletion of the SMN1 gene and SMN2 copy numbers were determined with Multiplex Ligand-dependent Probe Amplification (SALSA MLPA-kit PO21-B1, MRC Holland).

All patients with SMA were treatment-naïve for any of the SMN-targeting disease-modifying therapies (DMT, i.e., nusinersen or risdiplam) at baseline. At follow-up they had been using nusinersen or risdiplam for approximately 12 months. Treatment allocation was based on Dutch reimbursement criteria, which at the time of this study generally precluded a choice by the patient or treating physician. Nusinersen treatment was available for patients with SMA types 1–4 without contra-indications or anatomical constraints for repeated intrathecal injections. Treatment with risdiplam was only available through a compassionate use program in patients with SMA type 1c and 2 without intrathecal access (mostly after spinal fusion surgery).

We recruited 25 age-matched healthy controls through our website (www.smacentrum.nl), the newsletter for patients with SMA, and the newsletter of the patient organization Spierziekten Nederland (www.spierziektennederland.nl). We randomly selected 46 disease controls at the Neuromuscular clinic of the University Medical Center Utrecht, aiming at a 1: 1 ratio for ambulant and non-ambulant patients. Disease controls had to be >18 years and had to have some degree of muscle weakness.

We obtained written and oral informed consent from all participants and/or their parents or legal representative in case of minors (participants aged 12 through 16 years as defined by the regulation of the Dutch Central Committee on research Involving Human Subjects).

Questionnaire

We systematically assessed temperature-induced symptoms in all participants by means of a previously designed and validated questionnaire.¹⁴ The questionnaire contains questions that aim to examine the effect of temperature on the following symptoms: muscle weakness, numbness, tingling, pain, and overall fatigue in the past year. Cold paresis was defined as cold-induced worsening of muscle weakness experienced and reported by the participant. Similarly, heat paresis was defined as heat-induced worsening of muscle weakness. Questions were restricted to events occurring during the past year to minimize recall bias. A detailed description of the questions included in the questionnaire is provided in Appendix 1. One of the authors (LR) performed all the questionnaire-based interviews to limit inter-rater bias.

Clinical assessments

We assessed motor function in patients with SMA using the Revised Upper Limb Module (RULM), ranging from score 0 to 37 and the expanded Hammersmith Functional Motor Scale (HFMSE), ranging from score 0 to 66.^18,19 Trained and experienced physical therapists conducted all motor function scoring. Motor function assessments were standardized, but dependent on the DMT and their reimbursement criteria (e.g., conditional reimbursement). Patients treated with nusinersen were evaluated by means of the HFMSE and RULM, while patients treated with risdiplam were evaluated by means of the RULM. Reimbursement of risdiplam was only available for patients with SMA type 1 and 2 for whom intrathecal nusinersen was not eligible (e.g., more severely affected patients) and therefore RULM was used instead of HFMSE to detect changes over time.

We further stratified participants as ‘ambulatory’ or ‘non-ambulatory’ according to their motor ability at baseline: the ability to walk four or more steps without support, as scored in item 20 of the HFMSE. We used the most recent clinical notes (<6 months), to determine the ambulatory status of disease controls.

Statistical analysis

We used descriptive analyses for participant characteristics. We assessed the normality of data distribution with the Shapiro-Wilk test. For normally distributed data, we used the independent-samples t-test, and for non-normally distributed data, the Mann-Whitney U (MWU) or Kruskal-Wallis (KW) test. Differences in baseline characteristics or occurrence of temperature-induced symptoms were analyzed using the Chi-square test (χ²) or Fisher's exact test between SMA types, patients with SMA and (disease or healthy) controls, and between the seasons. We combined SMA types 1c and 2a and types 3b and 4 because of the similarity in their symptoms.

We assessed the influence of disease progression by stratifying for ambulatory status. For linear association between SMA type and dichotomous variables, we used the Mantel-Haenszel chi-square test for linear trend, and for continuous variables, the Kruskal-Wallis test. To evaluate the difference between the paired samples of baseline and follow-up assessments, we applied the McNemar test for binary data, Wilcoxon signed-rank test for non-normally distributed data, and the paired-samples t-test for normally distributed data. To assess whether the association between the participant group (patients with SMA versus disease controls) and the presence of cold paresis differed by ambulatory status, we performed a multivariable binary logistic regression including participant group, ambulatory status, and their interaction term. Age (continuous, in years) and sex were included as covariates to adjust for potential confounding. The reference category for the participant group were the disease controls, and ambulatory participants for ambulatory status.

Statistical analysis was performed using SPSS (version 29.0, IBM Corp., Armonk, NY, USA). Significance was set at P < .05 for all tests. We conducted multivariable analysis and data visualization using R (version 4.4.0 for macOS with RStudio version 2024.04.2 + 764 and 2025.05.0 + 496, ^© 2024 by Posit Software, PBC).

Results

Results of the literature search are presented in Table S1.

Baseline characteristics of the participants are shown in Table 1. Disease controls included neurogenic, myopathic, dystrophic and neuromuscular junction–related disorders (subscript Table 1).

Table 1.

Clinical characteristics of patients with SMA, disease-, and healthy controls.

	SMA	Disease controls	Healthy controls
Count	103	46	25
Sex, female	57 (55)	24 (52)	14 (56)
Age at time of assessment in years	39 (13-67)^a	52 (18-81)^a	35 (14-70)
Disease duration at time of assessment in years	35 (5-63)	ND	NA
SMA type
1	7 (7)	NA	NA
2	45 (46)	NA	NA
3	44 (45)	NA	NA
4	3 (3)	NA	NA
SMN2 copy number
2	2 (1)	NA	NA
3	65 (36)	NA	NA
4	34 (19)	NA	NA
5	2 (1)	NA	NA
NMD group^b
Myopathies	NA	7 (15)	NA
Myasthenic syndromes	NA	4 (9)	NA
Muscular dystrophies	NA	25 (54)	NA
Motor-neuron diseases	103 (100)	10 (22)	NA
Ambulatory status
Non-ambulatory	84 (82)^a	24 (52)^a	0
Ambulatory	19 (18)^a	22 (48)^a	25 (100)
Pyridostigmine use	38 (37)	2 (4)	0
Motor function scores^c
RULM score (max. 37), n = 97	14 (0–37)	ND	ND
HFMSE score (max. 66), n = 52	8 (0–66)	ND	ND
Follow-up time in months	14 (9–24)	NA	NA
DMT^d
Nusinersen	52 (50)	0	0
Risdiplam	45 (44)	0	0

Data is presented in count (%) or median (range).

Significant difference between groups (χ² or MWU: P < 0.05).

Included diagnoses of post-polio syndrome, hereditary spastic paraparesis, primary lateral sclerosis, amyotrophic lateral sclerosis, myasthenia gravis, immune-mediated necrotizing myopathy, systemic sclerosis overlap myositis, morbus Sjogren myositis, antisynthetase syndrome myositis, inclusion body myositis, myotonic dystrophy type 1, Duchenne muscular dystrophy, facioscapulohumeral dystrophy, limb-girdle muscular dystrophies (sarcoglycan or fukutin-related protein gene-related, or unspecified), Becker muscular dystrophy, ECEL1-associated distal arthrogryposis and arthrogryposis multiplex congenita.

RULM is performed in patients prior to starting any DMT, HFMSE is performed in patients prior to starting nusinersen specifically.

DMT is started during follow-up.

DMT: Disease-modifying treatment; HFMSE: Hammersmith Functional Motor Scale – Expanded; F: Female; M: Male; NA: Not applicable; ND: Not determined; NMD: Neuromuscular disorder; RULM: Revised Upper Limb Module.

Sex distribution is similar in both patient and control groups. Patients with SMA and healthy controls are similar in age, but younger than the disease controls (median of 39 years vs. 52 years; MWU: P = 0.001). Six patients (32%) with SMA type 3a, 10 (53%) with type 3b and all 3 patients with type 4 were ambulant at time of assessment. Reimbursement criteria dictated that all ambulatory patients were treated with nusinersen (n = 19) and non-ambulatory patients with either Nusinersen (n = 33, 39%), Risdiplam (n = 45, 54%) or no DMT (n = 6, 7%) during follow-up. Patients who did not start treatment were not able to receive nusinersen due to contra-indications (e.g., no possibility for intrathecal injection) and were not eligible for risdiplam treatment due to reimbursement criteria (e.g., SMA type 3). Thirty-eight (37%) patients with SMA used pyridostigmine as add-on to improve endurance.²⁰ Pyridostigmine use was higher in non-ambulatory than in ambulatory patients (χ²: P = 0.008): 36 (43%) versus 2 (11%), respectively.

Temperature exposure

All patients with SMA, disease- and healthy controls recalled episodes of cold and heat exposure in the past year, mainly consisting of seasonal weather changes. Seventy-two (70%) patients with SMA and 36 (72%) disease controls referred to the use of hot packs or electric blankets. When asked about other experiences with heat exposure, an additional four (4%) patients with SMA reported the use of different heating elements to keep their hands and/or legs warm. Three (3%) patients with SMA mentioned maintaining a consistent high temperature (up to 23 degrees Celsius) in their home.

Cold paresis in SMA

Of the ninety (87%) patients with SMA who reported cold-induced symptoms when asked about transient worsening of symptoms during cold-exposure, 88 (85%) reported cold paresis. Women (n = 53, 93%) reported cold paresis more often than men (n = 35, 76%; χ²: P = 0.016).

The prevalence and frequency of cold paresis during cold exposure, and the severity in arms and legs are presented in Figure 1. Seventy-six of the 88 (86%) patients with SMA who reported cold paresis experienced it consistently during cold exposure. Cold primarily affected the arm muscles (n = 84, 95%) and was reported as severe by 58 (66%) and mild by 26 (30%) patients. Cold paresis of the leg muscles was reported by 31 patients (35%; 9 ambulatory), less frequently as severe (n = 14, 16%). However, reports of severity of cold paresis of the arm muscles by non-ambulatory patients were similar to reports of severity of cold paresis of the leg muscles by ambulatory patients (Figure 1C).

Figure 1.

Prevalence, frequency and severity of cold paresis in patients with SMA. (A) Prevalence of cold paresis is higher in non-ambulatory patients. (B) Frequency of cold paresis is higher in non-ambulatory patients. (C) Severity of cold paresis of the arm and leg muscles combined is similar in ambulatory and non-ambulatory patients. NA Not applicable.

The prevalence of cold paresis was higher among non-ambulatory (n = 79; 94%) than ambulatory patients (n = 9; 47%) (Fisher's exact test: P < 0.001) (Figure 2A) and was inversely associated with SMA type (χ² for trend: P < 0.001) (Figure 2B). In addition, non-ambulatory patients reported a higher frequency (i.e., ‘always’ or ‘often’ compared to ‘now and then’) (MWU: P = 0.006; Figure 1B).

Figure 2.

Cold-induced symptoms at baseline and follow-up in patients with SMA by ambulatory status and SMA type. (A) Cold paresis is reported by more non-ambulatory (n = 79; 94%) than ambulatory (n = 9; 47%) patients at baseline and follow-up (n = 65, 92% and n = 9; 47%, respectively). (B) Cold paresis is reported by all patients with types 1c, 2a and 2b, 23 (77%) with type 3a, 10 (63%) with type 3b and 1 (33%) with type 4 (3b/4 combined: 58%) at baseline. At follow-up, cold paresis is reported by all 5 patients with type 1c, 28 (97%) with type 2a (1c/2a combined: 97%), 16 (94%) with type 2b, 18 (82%) with type 3a, 8 (57%) with type 3b and none with type 4 (3b/4 combined: 47%). SMA Spinal muscular atrophy.

Cold paresis was reported more often by patients with lower motor function scores (RULM median 12 vs. 37; HFMSE 4 vs. 38, MWU: P ≤ 0.001). However, when stratified by ambulatory status, motor function score difference was only seen in the RULM score in non-ambulatory patients (MWU: P = 0.021; Figure 3). The reporting of cold paresis was not influenced by the season during which we conducted the assessment (Fishers exact test: P > 0.05). For example, patients did not report to have experienced cold paresis more frequently over the past year when assessed during winter than during summer. Heat exposure improved muscle strength in 51 (58%) patients with SMA who reported cold paresis.

Figure 3.

Motor function scores in patients with SMA with and without cold paresis based on ambulatory status. (A) Scores are expressed as median(range). Non-ambulatory patients with cold paresis had lower RULM scores than non-ambulatory patients without cold paresis: 10(0-30) versus 17(11-32). (B) HFMSE scores are of patients treated with nusinersen, i.e., all ambulatory and 33 non-ambulatory (n = 52). HFMSE scores of patients with or without cold paresis did not differ. HFMSE Hammersmith functional motor scale – expanded; ns Non-significant; RULM Revised upper limb module; SMA Spinal muscular atrophy.

Other temperature-induced symptoms in SMA

Forty-six (45%) patients with SMA reported multiple cold-induced symptoms, all in addition to cold paresis, with the exception of isolated pain and fatigue in 2 patients (Figure 2).

Heat paresis was reported by 13 (13%) patients with SMA, 12 of whom also reported cold paresis. These patients reported heat paresis less frequently than cold paresis (reported by most as ‘now and then’ (n = 10, 77%) as opposed to ‘always’ for cold paresis). Patients with SMA reporting heat paresis did so mostly during periods of extreme heat (n = 8, 62%), specified by 2 patients as exceeding 30 degrees Celsius. In addition, 2 patients explicitly reported a positive effect of moderate warming and a negative effect of extreme heat on their symptoms.

Effect of DMT on cold paresis and other symptoms in SMA

We reassessed temperature-induced symptoms in patients with SMA after approximately one year of treatment with nusinersen (n = 47) or risdiplam (n = 43). Six patients did not start DMT, 4 patients stopped treatment, and 1 patient died before the follow-up assessment. Two patients were included prior to the amendment to the study protocol that allowed the inclusion of follow-up data.

At follow-up, cold and heat exposure was comparable to baseline (McNemar: P > 0.05). The prevalence of cold paresis was comparable to baseline (n = 74, 82%), as well as other cold-induced symptoms (McNemar: P > 0.05) (Figure 2).

We did not observe significant motor function changes after one year of DMT in patients with and without cold paresis at baseline (Table S2). Patients treated with risdiplam reported a reduced frequency of their cold paresis (Wilcoxon signed-rank test: P = 0.041): 8 (19%) patients reported a reduction in the frequency of cold paresis, and only 1 (2%) an increase. When stratified by SMA type, RULM scores did not improve during risdiplam treatment. Patients treated with nusinersen reported a similar frequency of their cold paresis (Wilcoxon signed-rank test: P > 0.05): 7 (13%) reported a reduction and 8 (15%) an increase. When stratified by SMA type, RULM and HFMSE scores did not improve during nusinersen treatment. We found no significant association between the season of assessment and reduced reporting of cold paresis frequency. On the other hand, in 6 out of 9 patients with increased cold paresis frequency at follow up, the questionnaire was conducted during a colder season. Reported severity of cold paresis in the arms and legs was similar to baseline (Wilcoxon signed-rank test: P > 0.05).

Cold paresis was more prevalent in more severe SMA types (e.g., types 1 and 2) (χ² for trend: P < 0.001; Figure 2B). There was no association between motor function scores and cold paresis (χ²: P > 0.05) at follow-up.

Temperature-induced symptoms in healthy and disease controls compared to SMA

Healthy controls did not report any cold-induced symptoms. The prevalence of cold paresis varied among different NMDs (Figure 4): it was higher in non-ambulatory disease controls (n = 19, 79%) than ambulatory disease controls (n = 11, 50%) (χ²: P = 0.038).

Figure 4.

Prevalence of cold paresis in disease controls by diagnosis and ambulatory status. The prevalence of cold paresis is higher in non-ambulatory disease controls than ambulatory disease controls (79% versus 50%). Cold paresis was reported by 19 (76%) disease controls with muscular dystrophy, 7 (70%) with MND, 3 (43%) with myopathy and 1 (25%) with a myasthenic syndrome. MND Motor neuron disease; SMA Spinal muscular atrophy.

The prevalence was higher in non-ambulatory patients with SMA (n = 79; 94%) compared to non-ambulatory disease controls (n = 19, 79%; Fisher's exact test: P = 0.042; OR 5.03, 95% CI [1.38–18.34], P = 0.014), 16 (84%) of whom were patients diagnosed with muscular dystrophy (10 patients with Duchenne muscular dystrophy) (Figure 5A). The prevalence was comparable in ambulatory patients with SMA and disease controls (Figure 5A). The reported frequency and severity of cold paresis was comparable for patients with SMA and disease controls with matching ambulatory status (Figure 5B and 5C).

Figure 5.

Prevalence, frequency and severity of cold paresis in patients and disease controls by ambulatory status. (A) The prevalence of cold paresis is higher in non-ambulatory patients with SMA than in disease controls. (B) The frequency of cold paresis is similar in patients with SMA and disease controls. (C) When stratified by ambulatory status, the severity of cold paresis in the arms and legs combined is similar in patients with SMA and disease controls. NA Not applicable; SMA Spinal muscular atrophy.

Patients with SMA and disease controls gave similar reports of other cold-induced symptoms (χ²: P > 0.05). Fifty-one (58%) patients with SMA reported improvement of strength during heat exposure compared to only 12 (24%) disease controls (χ²: P = 0.003).

Discussion

Our prospective, longitudinal questionnaire-based study on patient-reported, temperature-induced symptoms shows that the large majority (85%) of patients with SMA recognize cold as a (consistent) cause of transient worsening of their muscle weakness. Cold paresis was most often reported by patients with severe SMA phenotypes. It is more prevalent in non-ambulatory patients with SMA than in other NMDs with similar functional status, however, the frequency and severity of cold paresis is reported similarly. Temperature-related symptoms due to cold were supported by the fact that heat improved symptoms, while only a minority of patients with SMA recognized (severe) heat as a cause of diminished muscle strength. Weakness was by far the most common cold-induced complaint, even though patients with SMA also reported numbness, tingling, pain, and fatigue as a result of cold-exposure.

The arm muscles were more affected by cold than the leg muscles, likely due to the overrepresentation of non-ambulatory patients with SMA in our study. No difference in severity was observed when both muscle groups were analyzed together or when severity of cold paresis in the leg muscles in ambulatory patients was compared to the arm muscles in non-ambulatory patients, suggesting that cold paresis predominantly affects the muscle groups most frequently used. Although cold paresis was associated with more severe weakness, the range of muscle weakness (e.g., motor function scores) was wide in patients with SMA expressing cold paresis. Cold paresis was also present in ambulatory patients, even those with relatively preserved muscle strength.

That cold paresis is common implies that it has an impact on functioning in daily life in countries with a moderate climate. The average temperature in the Netherlands is ≤10 degrees Celsius for at least six months per year, although winters are seldom very cold.²¹ Winter episodes in temperate climates may, therefore, restrict patients with SMA from engaging in outdoor activities. Some patients reported that their cold paresis was so severe that it completely precluded any kind of activity. The awareness of the impact of cold is important for disease management and anticipation.

The reported prevalence of cold paresis did not change during one year of treatment with DMTs, even though muscle score did change positively or negatively in some of these patients over time. The lack of effects of DMTs on cold-induced symptoms might be the result of these symptoms being resistant to DMT effects, the fact that the observed treatment period was relatively short, or motor function scores not capturing the subtle changes in muscle strength induced by temperature changes. The latter two suggestions are supported by the fact that the reported frequency of cold paresis events diminished in patients treated with risdiplam (e.g., 19% reported a reduction of cold paresis) which suggests a potential effect of SMN-targeting therapy on this particular temperature-induced symptom.

Cold paresis has been described in various other NMDs, with a prevalence apparently similar to that reported by our patients with SMA, and with frequencies as high as 81–92% in Hirayama disease,^12,22–24 MMN,¹⁴ spinal and bulbar muscular atrophy¹³ and metabolic myopathies.^25,26 Lower prevalence of 44–50% is described in other peripheral nerve disorders: CIDP, CIAP, PSMA.¹⁴ Cold paresis is even reported to be present in 100% of patients with skeletal muscle channelopathies.^27–31 These percentages predominantly rely on case reports and (older) literature (Table S1).

Cold paresis in NMDs appears to arise from a combination of mechanisms affecting both axonal and muscle function. Cold exposure also enhances persistent nodal sodium conductance, which leads to hyperexcitability in both motor neurons and muscle fibers.^13,27 Axons that are already in a state of depolarization or hyperexcitability are particularly vulnerable to the effects of cooling.¹⁴ Reduced sodium–potassium pump activity at lower temperatures,^13,14,24,32 as well as prolonged open states of persistent nodal sodium channels³² can exacerbate depolarization and lead to conduction block and impaired signal transmission.^33,34 Reinnervated muscle fibers, resulting from axonal loss and collateral sprouting, are also more susceptible to conduction block due to their altered structural and functional properties, possibly related to the increased presence of sodium channels on the axons following sprouting.^14,24

At the muscle level, cooling similarly affects sodium dynamics, with increasing sodium influx during cold exposure contributing to muscle weakness.³¹ Other mechanisms for muscle dysfunction include changes in contraction, afferent information conduction, and increased viscosity or stiffness of the muscles.^35–39 This may account for the high prevalence of cold paresis among patients with Duchenne Muscular Dystrophy in the cohort of disease controls.

In SMA, both neurogenic and muscle fiber features are implicated,^2–4^,33,34,40 and the involvement of both these levels in cold paresis likely contributes to its higher prevalence in non-ambulatory patients with SMA compared to other disease controls.

Thus far, the use of heating elements or thermal clothing is probably the only available approach to attenuate the impact of cold paresis, but therapies for ion channel functionality, axonal excitability, and muscle contractability could prove to be of added value. Insight into the pathophysiology underlying cold paresis in SMA might lead to new therapeutic strategies.¹³

Our study has important strengths. The incentive to conduct this work stemmed directly from patient reports of cold paresis, underscoring the perceived significance and relevance of this study for clinical practice. We included a large cohort of patients, representative of the entire SMA spectrum. This allowed us to assess temperature-induced symptoms in both non-ambulatory and ambulatory patients with SMA. We systematically assessed temperature-induced symptoms via a standardized questionnaire conducted by one assessor. Furthermore, we included healthy and disease controls to assess whether cold paresis was SMA-specific. We also systematically reviewed the literature on cold paresis. Limitations of this study include possible recall bias when using self-reported data and the subjective nature of these measures. Nevertheless, when patients were asked at follow-up to report their symptoms during the past year, data were similar: there was no increase in reports of paresis during winter, a time when cold exposure might be more vividly remembered. Management of cold-induced symptoms is not yet standardized in the Netherlands; therefore, we could not systematically evaluate all potential therapeutic effects (e.g., other medications or physical therapy) on cold paresis. A potential confounder is change in motor function over time due to disease progression or treatment effects (including physical therapy). However, other factors – often introduced by seasonal changes – such as activity levels, mental state, or clothing, may also affect symptom perception and reporting. For example, heavy or restrictive clothing may limit mobility and contribute to motor function impairment or perception of muscle weakness, particularly in patients with severely restricted motor function. Disease controls were not perfectly matched for ambulatory status to our study population: there were more ambulatory than non-ambulatory disease controls, because of the lack of available non-ambulatory patients with other NMDs in our outpatient clinic.

The presence of temperature induced symptoms in patients with SMA and other NMDs implies a potential effect of temperature on motor function assessment. These assessments and their protocols require standardized performance in order to interpret motor status correctly, but most protocols do not include standardization of temperature surroundings or seasonal influences. Therefore, we recommend conducting motor function testing under standardized conditions, including (room) temperature and seasonal timing when investigating change in motor function over time. If this is not feasible, correction of these potential biases should be considered.

In summary, to the best of our knowledge, this is the first study to describe temperature-induced symptoms in patients with SMA. Cold paresis is commonly reported by patients with SMA as well as other NMDs, especially in those with more severe weakness. Raising awareness about the effects of cold is crucial for managing and anticipating disease symptoms in both patients and healthcare providers. Additionally, better understanding of the underlying mechanisms of cold paresis might lead to new forms of symptomatic treatment to preserve motor functionality.

Supplemental Material

sj-docx-1-jnd-10.1177_22143602251406497 - Supplemental material for Temperature-induced symptoms in adolescents and adults with spinal muscular atrophy

Supplemental material, sj-docx-1-jnd-10.1177_22143602251406497 for Temperature-induced symptoms in adolescents and adults with spinal muscular atrophy by Leandra AA Ros, Lina M Vermeer, Boudewijn THM Sleutjes, Fay-Lynn Asselman, Esther T Kruitwagen-van Reenen, Danny R van der Woude, Bart Bartels, W Ludo van der Pol and Renske I Wadman in Journal of Neuromuscular Diseases

Footnotes

Acknowledgements

We express our sincerest gratitude to all patients with SMA, patients with other NMDs, and healthy volunteers who contributed to this study. We are highly appreciative of the continued support provided by the patient organization Spierziekten Nederland. We would like to acknowledge Saskia Hogervorst, Bea Visser-de Heus, and Thijs Ruyten for their dedication and expertise as physical therapists in the collection of the motor function score data, which was essential to this research.

Ethical considerations

The local medical ethics committee of the University Medical Center Utrecht approved this study (No. 20-143).

Consent to participate

Author contributions

LR, LV, FA, BS, WLP, RW contributed to study conception and design. LR, LV, FA, DW, BB, EKR contributed to acquisition and data collection. LV, LR, RW conducted analyses, and LV, LR, WLP, RW contributed to interpretations of data. LV, LR, WLP, RW drafted the manuscripts, and all authors revised the final manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is supported by a grant from the non-profit organizations Stichting Spieren voor Spieren and Prinses Beatrix Spierfonds (combined grant W.OS18-01). The funding bodies played no part in study conception, data collection, analyses, and/or interpretations. The researchers have full access to the data and have the right to publish independently of any sponsor.

Declarations of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: BS receives research support from the Netherlands ALS foundation. BB is a member of the physical therapy scientific advisory board of Scholar Rock and provides consultancy for Biogen, Novartis, Scholar Rock and Roche for which his employer receives fees. BB receives research support from Prinses Beatrix Spierfonds, Stichting Spieren voor Spieren, Piet Poortman Fonds and SIA-RAAK, all non-profit foundations. WLP is a member of the scientific advisory board of SMA Europe, provides ad hoc consultancy for Biogen and Novartis gene therapy, and receives research support from Prinses Beatrix Spierfonds, Vriendenloterij, and Stichting Spieren voor Spieren. RW receives research support from Prinses Beatrix Spierfonds and Stichting Spieren voor Spieren. All other authors (LR, LV, FA, EKR, DW) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability

The anonymized data supporting the findings of this study are available from the corresponding author upon reasonable request.

Supplemental material

Supplemental material for this article is available online.

ORCID iDs

Leandra AA Ros

Lina M Vermeer

Boudewijn THM Sleutjes

Fay-Lynn Asselman

Esther T Kruitwagen-van Reenen

Danny R van der Woude

Bart Bartels

W Ludo van der Pol

Renske I Wadman

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