Effect of cryotherapy in controlling spasticity of calf muscles in patients with multiple sclerosis

Abstract

BACKGROUND:

Spasticity is a common symptom of multiple sclerosis (MS), affecting 80% of patients. Many studies have aimed to detect methods to reduce spasticity under these conditions and found that spasticity can be efficiently reduced using cryotherapy.

OBJECTIVE:

To examine the impact of cryotherapy on spasticity among patients with MS.

METHODS:

Thirty-two participants were randomized into two groups. The study group was given airflow cryotherapy and a selected physical therapy program, whereas the control group was only given a selected physical therapy program. The treatment was administered three times each week for a total of twelve consecutive sessions. The outcome measures were the modified Ashworth scale and the H/M ratio.

RESULTS:

The study group showed significant decrease in calf muscle spasticity, indicated by a reduction in spasticity grade (p = 0.001) and a decrease in the H/M ratio of 33.81% (p = 0.001). The control group also showed significant reduction in calf muscle spasticity, as indicated by a reduction in spasticity grade (p = 0.001) and a reduction in the H/M ratio of 19.58% (p = 0.001). There was a significant decrease in the spasticity grade and H/M ratio of the study group posttreatment compared with those of the control group (p = 0.02 and p = 0.001).

CONCLUSION:

The combined effect of cryotherapy and a selected physical therapy program are more effective in controlling the spasticity of calf muscles in patients with MS than a selected physical therapy program alone.

Keywords

Cryotherapy selected physical therapy program spasticity multiple sclerosis

1 Introduction

Multiple sclerosis (MS) refers to an immunologically induced central nervous system disease marked by chronic inflammation as well as progressive demyelinating lesions without a known cause (Sîrbu et al., 2022). The major pathogenic mechanisms causing clinical symptoms include demyelination, inflammation and axonal degeneration (Ptaszek et al., 2022). Excluding trauma, MS is the predominant cause of long-lasting disability among young individuals across central nervous system problems (Ramagopalan & Sadovnick, 2011). The human body’s reaction to whole-body cryotherapy includes changes in the hormonal, circulatory, neurological, muscular, and immunological systems (Janský & Janský, 2002; Leppäluoto et al., 2009). Research has shown a correlation between cold temperatures and alterations in the levels of certain hormones or enzymes including adrenocorticotropic hormone (ACTH), beta-endorphin, cortisol, catecholamines, cytokines, uric acid, tumor necrosis factor, adrenaline, noradrenaline, and testosterone, in individuals with MS (Lombardi et al., 2017; Brenke et al., 2010; Cholewka et al., 2012).

Eighty percent of patients with MS develop spasticity, which is characterized by a shortening of the muscular tissues or involuntary contraction caused by a disruption in the transmission of inhibitory impulses across nerve fibers in the central nervous system (Hugos & Cameron, 2019; Henze et al., 2006). This condition results from a nonsynchronous as well as intermittent activation of the muscles due to a change in sensory-motor control caused by an upper motor neuron lesion (Caravaca et al., 2022).

Spasticity is clinically defined by high muscular tone that causes stiffness, pain, and movement limitations. It can be chronic or intermittent, with painful spasms in addition to involuntary muscle contractions (Flachenecker et al., 2014).

Spasticity is commonly associated with muscle weakness, and it is of changing intensity, with a frequent increase at night. The legs are more commonly affected than the arms or trunk. Spasticity may be accompanied by bladder dysfunction, sleep difficulties, exhaustion, and other symptoms and consequently significantly influence daily activities (ADL) and quality of life (Zwibel, 2009).

Many pharmacological and nonpharmacological treatments have been used to control spasticity, both of which can be used at the same time to prevent complications, improve functional capabilities and improve quality of life rather than decrease spasticity (Elkeblawy et al., 2023; Kuo & Hu, 2018). The lower extremity antigravity muscles exhibit the greatest progression of velocity-dependent increases in muscle tone (Bhattacharya et al., 2017).

Spasticity was defined as a contraction of the hypertonic muscle or muscular group by (Moga, 2019). Spastic muscles exhibit structural changes as a result of their ability to adapt to abnormal utilization or inactivity. Spastic muscles are initially anatomically normal and as a result, they are not normally elastic (Paul et al., 2018).

One of the ideal definitions of cryotherapy is the use of cold to decrease the tissue temperature for therapeutic patients. (Garcia et al., 2019). Local cryotherapy methods, including ice massage therapy, ice packs, cold gel packs, and cold air flow therapy at –32°C for a longer period of time, can effectively lower the temperature of both the skin and joints. This leads to analgesia, a decrease in inflammation, and a reduction in muscle spasms. As a result, physical function improves, and disease activity decreases (Paul et al., 2018).

2 Subjects and methods

2.1 Study design

A randomized controlled study was carried out from July 2023 to December 2023 at Faculty of Physical Therapy, Deraya University, Minya, Egypt. The study received approval from the Ethical Committee of the Faculty of Physical Therapy at Cairo University (P.T. REC/012/004854).

Inclusion criteria for patients were relapsing-remitting (RR) or secondary progressive (SP) MS subtypes, aged 30 to 45 years, male or female, remission, duration of illness ranging from 5 to 12 years, and spasticity in calf muscles either unilaterally or bilaterally. (At least one of the evaluated muscles received a modified Ashworth scale score≥one). Exclusion criteria for patients were primary progressive MS, relapse, botulinum toxin injection within the last year, or the use of an orthosis. Musculoskeletal abnormalities included shortness and contracture of the calf muscle. Individuals suffer from cryoglobulinemia, peripheral artery occlusive disease, paroxysmal cold hemoglobinuria, Reynaud’s symptoms, or diabetes mellitus.

2.2 Sample size calculation

The sample size was calculated using G*POWER statistical software (version 3.1.9.2; Universität Kiel, Germany). Based on the data obtained from a pilot study involving 5 participants in each group, the H/M ratio analysis indicated that a sample size of 15 subjects per group is necessary. The calculations were performed with a significance level (α) of 0.05, a statistical power of 80%, and an effect size of 1.1.

2.3 Randomization

The patients who were enlisted were allocated randomly, after completing the consent form, into two distinct groups. A randomized controlled trial was conducted by allocating even numbers to the study group and odd numbers to the control group. After randomization, there was attrition of patients from the study, as presented in Fig. 1.

Fig. 1

Flowchart of patient recruitment.

2.4 Subjects

A total of 40 people with MS and 32 patients were selected according to the sample size calculation by G. Power; these patients were referred by neurologists and selected from the outpatient clinic of the Faculty of Physical Therapy, Deraya University, Minya, Egypt. The participants fulfilled the inclusion criteria and agreed to participate in the study by signing an informed consent form. The patients were randomized into two groups, the study group and the control group, using the closed envelope method. Before their involvement, all patients underwent a clinical examination to rule out the presence of any cardiac or vascular conditions. In the control group, a physical therapy program involving the application of moist heat for 5 minutes followed by passive stretching and myofascial release of the calf muscle was used while the patient was in a prone-lying position for 35 minutes, with 120 seconds held for each session (Kumar et al., 2014; Elnassag et al., 2019). The total duration of the selected physical therapy program was 40 minutes. In the experimental group, a similar physical therapy program was used for 20 minutes, along with cryotherapy air flow application for 20 minutes. The total duration of cryotherapy and the selected physical therapy program was 40 minutes. The treatment consisted of 12 sessions, with 3 sessions per week, conducted consecutively for 4 weeks.

2.5 Assessment procedure

Electrophysiological testing:

A computerized electromyographic apparatus (Section 8 Ronald S. Bienstock EMG, Inc., UK; Serial Number 77736183) was utilized to evaluate the Hoffman reflexmyogenic (H/M) ratio. Two silver surface electrodes were used to record the electromyographic signals from the soleus muscle. The patients were placed in a prone position, after which the tibial nerve at the popliteal fossa was stimulated. Just below where the gastrocnemius muscle attaches to the Achilles tendon, on the distal one-third of the soleus muscle, was where the active electrode was positioned. Approximately six cm above the calcaneus, the reference electrode was positioned over the Achilles tendon. Over the fibular head, an electrode was inserted to serve as a reference ground. The level of spasticity (Querry et al., 2008), which indicates the excitability of the CNS, is measured by the ratio between the maximum Hoffman reflex and maximum myogenic responses utilizing the EMG machine. This ratio reflects the excitability of the motor neuron pool (Dimitrijeric et al., 1992).

Modified Ashworth scale:

The modified Ashworth scale entails passively stretching the calf muscle during dorsiflexion by moving the ankle joint throughout its full range of motion (Bohanon & Smith, 1987).

2.6 Treatment procedure

Cryoteherapy

A cryo-flow 700/1000 machine (GymnaUniphy NV – Version 01/2003, Bilzen, Belgium) was used, a portable therapeutic device that produces regulated amounts of cold air by drawing air from nearby surroundings and cooling it. The patient assumed a prone posture while the spastic calf muscle was subjected to continuous application of cold air for 20 minutes. The calf muscle was cooled to 15°C using a 25 mm nozzle positioned 5 cm away from the skin (Farhat et al., 2022). The treatment consisted of 12 sessions, with 3 sessions per week, conducted consecutively over 4 weeks. No adverse effects or problems were observed in the patients treated with the cryotherapy employed in the present study (Figs. 2 and 3).

Fig. 2

Components of airflow cryotherapy.

Fig. 3

Airflow cryotherapy during application.

2.7 Statistical analysis

The unpaired sample t-test was employed to compare the subject characteristics across different groups. The chi-squared test was employed to assess the disparity in gender distribution across various groups. The Wilcoxon signed ranks test was employed to examine the levels of spasticity, while the paired sample t-test was utilized to compare the H/M ratio before and following treatment. The Mann— Whitney U test was employed to examine the levels of spasticity, whereas the unpaired sample t-test was utilized to compare the H/M ratio across different groups. For all the statistical tests, a p-value less than 0.05 was considered to indicate statistical significance. All the statistical analyses were conducted using the Windows version of the Statistical Program for Social Studies (SPSS), version 25.

3 Results

3.1 Baseline demographic and clinical characteristics of patients in the control and study groups

Table 1 presents the subject characteristics of the study and control groups. There was no substantial difference among the groups regarding age, BMI, or sex distribution (p > 0.05)

Table 1
Characteristics of the groups

Study group Control group

Mean±SD Mean±SD t-value p-value

Age (years) 37.56±5.02 38.44±3.52 –0.57 0.57

BMI (kg/m²) 31.44±3.61 31.31±3.66 0.09 0.92

Sex, n (%)

FemalesMales 11 (68.8%)5 (31.3%) 10 (62.5%)6 (37.5%) (χ² = 0.14) 0.71

	Study group	Control group
Age (years)	37.56±5.02	38.44±3.52	–0.57	0.57
BMI (kg/m²)	31.44±3.61	31.31±3.66	0.09	0.92
Sex, n (%)
FemalesMales	11 (68.8%)5 (31.3%)	10 (62.5%)6 (37.5%)	(χ² = 0.14)	0.71

SD, standard deviation; χ², chi-squared value; p-value, probability value.

3.2 Effect of treatment on spasticity and the H/M ratio

Within-group comparison When comparing the study and control groups before and after therapy, there was a substantial reduction in spasticity grades in addition to the H/M ratio (p = 0.001). The H/M ratio changed by 33.81% in the study group and 19.58% in the control group (p = 0.001) (Tables 2 and 3).

Comparison between study and control groups: In comparison to the control group, the study group showed a substantial decrease in spasticity grade after treatment (p = 0.02). After therapy, the H/M ratio in the study group was substantially lower than that in the control group (p = 0.001) (Tables 2 and 3).

Table 2
Mean values of spasticity grades:

Study group Control group

Median (IQR) Median (IQR) U-value p-value

Spasticity grades

Pre-treatment 3 (3, 2) 3 (3, 2) 121.5 0.79

Post-treatment 1 (2, 1) 2 (3, 1.25) 73 0.02

Z-value –3.66 –3.46

p = 0.001 p = 0.001

	Study group	Control group
Spasticity grades
Pre-treatment	3 (3, 2)	3 (3, 2)	121.5	0.79
Post-treatment	1 (2, 1)	2 (3, 1.25)	73	0.02
Z-value	–3.66	–3.46
	p = 0.001	p = 0.001

IQR, interquartile range; U value, Mann— Whitney test; Z value, Wilcoxon signed rank test; p-value, level of significance.

Table 3

The mean H/M ratios

H /M ratio	Study group	Control group
	mean±SD	mean±SD	MD	t-value	p-value
Pre-treatment	122±7.87	118.13±9.04	3.87	1.29	0.21
Post-treatment	80.75±7.75	95±5.67	–14.25	–5.93	0.001
MD	41.25	23.13
% of change	33.81	19.58
t-value	17.86	8.70
	p = 0.001	p = 0.001

SD, standard deviation, MD, mean difference; p-value, level of significance.

4 Discussion

This study was designed to examine the impact of cryotherapy and selected physical therapy program on spasticity in MS patients. According to our statistical findings, there was no substantial distinction in age and BMI between the two groups at the beginning, suggesting that both groups were similar in terms of these characteristics. The study group showed a significant decrease in calf muscle spasticity as there was a decrease in spasticity grades (p = 0.001) and a decrease in H/M ratio by 33.81% (p = 0.001). Also, the control group showed a significant decrease in calf muscle spasticity as there was a decrease in spasticity grades (p = 0.001) and a decrease in H/M ratio by 19.58% (p = 0.001). There was a substantial decline in spasticity grade and H/M ratio of the study group after treatment when contrasted with that of the control group (p = 0.02 and p = 0.001), demonstrating the efficacy of cold air therapy in managing spasticity in patients diagnosed with MS.

The findings align with a study that indicated that the application of cold can suppress the activity of the muscle’s gamma motor neurons while enhancing the activity of the alpha motor neurons. When the overall effect of gamma suppression surpasses the excitement of alpha motor neurons, it leads to a reduction in muscle spasticity (Allison & Abraham, 2001). Lowering the temperature of the sensory nerves extends the length of their action potential, resulting in a longer refractory period. Consequently, this reduces the number of fibers that will undergo depolarization within the same timeframe. As a result, the frequency at which pulses are sent decreases when the threshold for exciting nerve cells increases (Felice & Santana, 2009). Cooling was found to suppress ankle clonus by decelerating neuronal conduction and diminishing receptor activation in both peripheral axons and muscle receptors. This highlights the importance of peripheral input concerning central processes in regulating spasticity. Consequently, employing both central and peripheral effective mechanisms simultaneously may yield superior outcomes in the treatment of clonus and spasticity. Furthermore, the persistence of cold impacts provides evidence for the presence of spinal adaptability and neuroplasticity in individuals with neurological impairments (Boyraz et al., 2009).

The outcomes of this study are in line with those of (Alcantara et al., 2019; Garcia et al., 2018), who reported a reduction in spasticity after applying ice packs to the plantar flexor muscle for 20 minutes, which reduced muscle tone (Farhat et al., 2022). Their study revealed that the cooling time required to decrease spasticity is controversial. In most of the studies, cryotherapy was applied for 20 minutes using ice packs, immersion, or cold air therapy.

The results of (Cavalcanti et al., 2019) also supported our results, as cryotherapy has a moderate impact on lowering plantar flexor spasticity following 20 minutes of application, suggesting short-term advantages in clinical practice, which is consistent with our findings. When administered before exercise therapy, cryotherapy has the potential to reduce spasticity and facilitate motor training.

Additionally, another study by Anju et al. (2013) reported that the impacts of ice cooling on the viscoelastic response of calf muscle in able-bodied persons indicate that a small increase in viscous and elastic responses occurs with cryotherapy. The study by Lee et al. (2002) is also in line with our results, as they reported that muscle temperature should be reduced to achieve an effective decrease in excitatory impulses, thus decreasing spasticity. Hence, he recommended applying cryotherapy for at least 25-30 minutes, which is the ideal time to reduce muscle temperature.

Many studies supported the results of the control group (Bovend, 2008), who discovered that stretching exercises were most effective when used in conjunction with other forms of exercise or as part of a general intervention without a set program. This study regarded stretching exercises as a unique treatment for MS patients. In addition, patients with MS can reduce stretch reflex overactivity and spasticity by performing stretching exercises that target the muscle spindle, Golgi tendon organ, autogenic inhibition, and reciprocal inhibition. Additionally, Motl et al. (2012) and Halabchi et al. (2017) reported that stretching exercise also reduced limb and muscle stiffness and increased range of motion (ROM) in MS patients. As a result, MS patients may have less pain and greater functional mobility as a result of these changes in their muscles, joints, and limbs.

The findings of this study align with those of a prior study (Salvi, 2012) that investigated the immediate impact of myofascial release on spasticity among individuals who suffered from spastic cerebral palsy. The results indicated that a combination of myofascial release and stretching of the calf muscle produced better results than stretching alone in treating spasticity.

On the other hand, our findings disagree with Nilsaga et al. (2006), who reported no effect of wearing a cooling garment for 45 minutes in a single session on spasticity in MS patients. It may be argued that the cooling garment was not in direct contact with the subject’s skin, while the present technique was intended to maintain continuous and direct contact with the cool air flow on the skin, which may explain the discrepancy in the outcomes.

5 Conclusion

The outcomes of this study suggest that the combined effect of cryo-airflow therapy and a selected physical therapy program are more effective in decreasing the spasticity of calf muscles in patients with MS than a selected physical therapy program alone.

Footnotes

Acknowledgments

The authors thank all participants in this project.

Funding

None to report.

Conflict of interest

The authors declare no conflicts of interest.

Ethics statement

This study was approved by the Medical Ethics Committee of Cairo University (P.T. REC/012/004854). Written informed consent was obtained from all study participants.

Author Contribution

Concept – NMA, MME, HMA; Design – MME, NMA, HMS; Materials – HMS, NAM; SS; Data Collection and/or Processing – MME, NMA, HMS; Analysis and/or Interpretation – HMA, NMA, THM; Writing Manuscript – NMA, THM, HMS; Critical Review – THM, NMA, HMA and SS.

References

Alcantara,

C. C.

, Blanco,

, De Oliveira,

L. M.

, Ribeiro,

, Herrera,

, Nakagawa,

T. H.

, Reisman,

D. S.

, Michaelsen,

S. M.

, Garcia,

L. C.

, Russo,

T. L.

(2019). Cryotherapy reduces muscle hypertonia but does not affect lower limb strength or gait kinematics post-stroke: a randomized controlled crossover study. Topics in Stroke Rehabilitation, 26((4)), 267–280; DOI: https://doi.org/10.1080/10749357.2019.1593613.

Allison,

S.C.

, Abraham,

L.D.

(2001). Sensitivity of qualitative and quantitative spasticity measures to clinical treatment with cryotherapy. Int J Rehabil Res, 24((1)), 15–24.

Anju,

, Nidhi,

, Sarla,

, Tushar,

(2013). Spasticity – Pathogenesis, prevention and treatment strategies: Saudi J Anesthesia, 7((4)), 453–460; DOI: https://dOI: 10.4103/1658-354X.121087.

Bhattacharya,

, Bhattacharyya,

N.C.

, Bhattacharya,

(2017). Efficacy of Myofascial Release Technique in Comparison with Passive Stretching in Reducing Spasticity in Children with Cerebral Palsy. Journal of Medical Science and Clinical Research, 5((11)), 30515–30520; DOI: https://doi.org/10.18535/jmscr/v5i11.120.

Bohanon,

R. W.

, Smith,

M. B.

(1987). Interrater reliability of a modified Ashworth scale of muscle spasticity. J Physical Therapy, 67((2)), 206–208.

Bovend Eerdt,

T. J.

, Newman,

, Barker,

, Dawes,

, Minelli,

, Wade,

D. T.

(2008). The effects of stretching in spasticity: a systematic review. Arch Phys Med Rehabil, 89((7)), 1395–1406; DOI: https://doi.org/10.1016/j.apmr.2008.02.015.

Boyraz,

, Oktay,

, Celik,

, Akyuz,

, Uysal,

(2009). Effect of cold application and Tizanidine on clonus: Clinical and electrophysiological assessment. J Spinal Cord Med, 32((2)), 132–139; DOI: https://doi.org/10.1080/10790268.2009.11760764.

Brenke,

(2010). Effekte und Wirkmechanismen der so genannten Abhärtung. Schweizerische Zeitschrift für Ganzheitsmedizin/Swiss. Journal of Integrative Medicine, 22((1)), 37–44; DOI: https://doi.org/10.1159/000265572.

Caravaca,

A. L.

, Ramos-Campo,

D. J.

, Chung,

L. H.

, Rubio-Arias,

J.Á.

(2022). Can strength training modify voluntary activation, contractile properties and spasticity in Multiple Sclerosis: A randomized controlled trial. Physiology & Behavior, 255, 113932; DOI: https://doi.org/10.1016/j.physbeh.2022.113932.

10.

Cavalcanti,

G. L.

, Carmona,

A. C.

, Lopes,

S. G.

, Lucilene,

M. D.

, Paula,

F. S.

, Esperanza,

, Theresa,

H. N.

, Darcy,

S. R. L. S.

, Almeida,

M. J.

, Luiz,

R. T.

(2019). Cryotherapy Reduces Muscle Spasticity but Does Not Affect Proprioception in Ischemic Stroke. American Journal of Physical Medicine & Rehabilitation, 98((1)), 51–57; DOI: https://doi.org/10.1097/PHM.0000000000001024.

11.

Cholewka,

, Stanek,

, Sieroń,

, Drzazga,

(2012). Thermography study of skin response due to whole-body cryotherapy. Skin Research and Technology, 18((2)), 180–187; DOI: https://doi.org/10.1111/j.1600-0846.2011.00550.

12.

Dimitrijeric,

M. R.

, McKay,

W. B.

, Sarjanovic,

, Sherwood,

A. M.

, Svirtlit,

, Vrbovà,

(1992). Co-activation of ipsi- and contra-lateral muscle groups during contraction of ankle dorsiflexors. J Neuro Sci, 109((1)), 49–55; DOI: https://doi.org/10.1016/0022-510X(92)90092-Y.

13.

Elkeblawy,

M. A.

, Mahmoud,

M. S.

, Ibrahim,

H. H.

, Lahseen,

Y. R.

(2023). Influence of Continuous Airflow Cryotherapy on Serum Creatine Kinase Level in Induced Muscle Soreness in Healthy Subjects: A Randomized Control Trial. Journal of Pharmaceutical Negative Results, 1, 306–314; DOI: https://doi.org/10.47750/pnr.2023.14.S01.33.

14.

Elnassag,

B. A.

, Rashad,

U. M.

, Belal,

E. S.

, Sarhan,

E.E.

(2009). Efficacy of cryo-airflow therapy on calf muscle spasticity in stroke patients: a randomized controlled trial. J Clin Anal Med, 10((3)), 320–324; DOI: https://doi.org//10.4328/JCAM.5773.

15.

Farhat,

, Khalaf

, Fakih,

, Ashour

, Haidar,

H. K.

, Kheir,

E. H.

(2022). PJM and Cryotherapy in a New Approach for Spasticity Management: An Experimental Trial. International Journal of Pharmaceutical and Bio-Medical Science, 2((8)), 302–313; DOI: https://doi.org/10.47191/ijpbms/v2-i8-07.

16.

Felice,

T. D.

, Santana,

L. R.

(2009). Physiotherapeutic resources (Cryotherapy and Thermotherapy) in spasticity: a review of literature. Rev Neuroscience, 17((1)), 57–62; DOI: https://doi.org/10.34024/rnc.2009.v17.8605.

17.

Flachenecker,

, Henze,

, Zettl,

U. K.

(2014). Spasticity in patients with multiple sclerosis– clinical characteristics, treatment and quality of life. Acta Neurologica Scandinavica, 129((3)), 154–162; DOI: https://doi.org//10.1111/ane.12202.

18.

Garcia,

L. C.

, Alcântara,

C. C.

, Santos,

G. L.

, Monção,

J. V. A.

, Russo,

T. L.

(2019). Cryotherapy reduces muscle spasticity but does not affect proprioception in ischemic stroke. American Journal of Physical Medicine & Rehabilitation, 98((1)), 51–57; DOI: https://doi.org//10.1097/PHM.0000000000001024.

19.

Halabchi,

, Alizadeh,

, Sahraian,

M. A

, Abolhasani,

(2017). Exercise prescription for patients with multiple sclerosis; potential benefits and practical recommendations. BMC Neurol, 17, 185; DOI: https://doi.org//10.1186/s12883-017-0960-9.

20.

Henze,

, Rieckmann,

, Toyka,

K. V.

(2006). Multiple Sclerosis Therapy Consensus Group of the German Multiple Sclerosis Society. Symptomatic treatment of multiple sclerosis. Multiple Sclerosis Therapy Consensus Group (MSTCG) of the German Multiple Sclerosis Society. Eur Neurol, 56((2)), 78–105; DOI: https://doi.org/10.1159/000095699.

21.

Hugos,

C. L

, Cameron,

M. H.

(2019). Assessment and measurement of spasticity in MS: State of the evidence. Curr Neurol Neurosci Rep, 19((10)), 79; DOI: https://doi.org/10.1007/s11910-019-0991-2.

22.

Janský,

, Janský,

(2002). Sites and cellular mechanisms of human adrenergic thermogenesis– a review. J. Therm. Biol, 27((4)), 269–277; DOI: https://doi.org/10.1016/S0306-4565(01)00089-4.

23.

Kumar,

, Vaidya,

S.N.

(2014). Effectiveness of myofascial release on spasticity and lower extremity function in diplegic cerebral palsy: Randomized controlled trial. Int J Phys Med Rehabil, 3((1)), 253; DOI: https://doi.org/10.4172/2329-9096.1000253.

24.

Kuo,

C. L.

, Hu,

G. C.

(2018). Post-stroke Spasticity: A Review of Epidemiology, Pathophysiology, and Treatments. International Journal of Gerontology, 12((4)), 280–284; DOI: https://doi.org/10.1016/j.ijge.2018.05.005.

25.

Lee,

S. U.

, Bang,

M. S.

, Han,

T. R.

(2002). Effect of cold air therapy in relieving spasticity: applied to spinalized rabbits. Spinal Cord, 40((4)), 167–173; DOI: https://doi.org/10.1038/sj/sc/3101279.

26.

Leppäluoto,

, Westerlund,

, Huttunen,

, Oksa,

, Smolander,

, Dugué,

, Mikkelsson,

(2009). Effects of long-term whole-body cold exposures on plasma concentrations of ACTH, beta-endorphin, cortisol, catecholamines and cytokines in healthy females. Scand. J. Clin. Lab. Invest, 68, 145–153; DOI: https://doi.org/10.1080/00365510701516350.

27.

Lombardi,

, Ziemann,

, Banfi,

(2017). Whole-body cryotherapy in athletes: from therapy to stimulation. An updated review of the literature. Frontiers in Physiology, 8((8)), 258–263; DOI: https://doi.org/10.3389/fphys.2017.00258.

28.

Moga,

(2019). Muscle spasticity and its interaction with myofascial system of children with central paresis. EUREKA: Health Sciences, 31((4)), 35–41; DOI: https://doi.org/10.21303/2504-5679.2019.00954.

29.

Motl,

R. W.

, Pilutti,

L. A.

(2012). The benefits of exercise training in multiple sclerosis. Nat Rev Neurol, 8((9)), 487–497.

30.

Nilsagård,

, Denison,

, Gunnarsson,

L. G.

(2006). Evaluation of a single session with cooling garment for persons with multiple sclerosis— a randomized trial. Disability and rehabilitation. Assistive Technology, 1((4)), 225–233, DOI: https://doi.org/10.1080/09638280500493696.

31.

Paul,

, Nathan,

S. C.

, Kumar,

P. R.

, Remya,

R. K.

(2018). Effectiveness of myofascial release in reduction of hamstrings spasticity among diplegic cerebral palsy children. IJMAES, 4((1)), 453–458. DOI: 10.36678/ijmaes.2018.v04i01.003.

32.

Ptaszek,

, Podsiadło,

, Ledwig

O.C.

, Maciejczyk,

, Teległów

(2022). Effect of Whole-Body Cryotherapy on Iron Status and Biomarkers of Neuroplasticity in Multiple Sclerosis Women. In Health Care, 10((9)), 1681; DOI: https://doi.org/10.3390/healthcare10091681.

33.

Querry,

R. G.

, Pacheco,

, Annaswamy,

, Goetz,

, Winchester,

P. K.

, Tansey,

K.E.

(2008). Synchronous stimulation and monitoring of soleus H reflex during robotic body weight-supported ambulation in subjects with spinal cord injury. JRRD, 45((1)), 175–186; DOI: https://doi.org/10.1682/JRRD.2007.02.0028.

34.

Ramagopalan,

S. V.

, Sadovnick,

A. D.

(2011). Epidemiology of multiple sclerosis. Neurologic Clinics, 29((2)), 207–217; DOI: https://doi.org/10.1016/j.ncl.2010.12.010.

35.

Saha,

, Bahlara,

(2012). Myofascial Release. International Journal of Health Sciences & Researcher, 2((2)), 69–77.

36.

Sîrbu,

C. A.

, Thompson,

D. C.

, Plesa,

F. C.

, Vasile,

T. M.

, Jianu,