Introduction:
Amyotrophic lateral sclerosis (ALS) is one of progressive neurodegenerative diseases, it belongs to group of disorders called motor neuron diseases[1,2]
Although motor dysfunction is the most prominent problem in ALS, there are growing evidence that suggests that ALS is considered a multisystem disorder where the other parts of the nervous system may also be affected.[3,4]
It is accepted that the Sensory nerve conduction study (SNCS) usually appears normal in the case of ALS. But, there are multiple literature reports documented pathogenic nature affecting the peripheral axons causing peripheral motor and sensory abnormalities. Also, A reduction in SNCS parameters had been recorded in some ALS patients. [4,5]
The aims of this study: to determine the presence of electrophysiological sensory nerve abnormalities in patients with ALS and to study if there are possible relations between these abnormal findings with the age, gender, illness duration, functional status, and receiving Edaravone treatment.
Materials and Methods:
Thirty patients, diagnosed as a definite ALS according to the El Escorial World Federation of Neurology criteria, collected from neurological consultation of teaching hospitals in Mosul city, after obtaining Institutional Ethics Committee approval. Their ages were between 45 to 65 years. 19 patients were received intravenous Edaravone injection during a period preceding the starting of this study. They were 17 males and 13 females. Sixty healthy persons were sampled randomly as a control group, they had matched ages and sex to that of the patient group. They were 32 males and 28 females and They did not complain previously from any significant sensory symptoms. After explaining the study details, informed consent was taken from all persons and patients.
Inclusion and exclusion criteria include:
- Clinical evidence of clear progression in upper motor neuron and lower motor neuron degeneration in at least three of the following body regions: bulbar, cervical, thoracic, and lumbosacral.
- Electromyographic evidence of apparent progression in lower motor neuron degeneration.
- No evidence of malignancy, diabetes mellitus, paraproteinaemia, nutritional deficiency, drug or toxic exposure or other potential causes of peripheral neuropathy.
- No evidence of multiple brain or spinal cord lesions that could explain the clinical features of patients.
- Any possibility of entrapment neuropathy electrophysiologically was excluded in wasted limbs.
- None of the patient or control groups had a positive family history of any neuromuscular disease.
- None of the control group had an abnormal neurological examination.
According to the age, the patients were divided into three groups: group 1 for those who were equal or less than 50 years, group two for those from 51 to 60 years, and group three for those who were more than 60 years old.
According to the illness duration, the patients were divided into four groups as the following: (group one for those with the duration from one month to one year, group two for those from one year to two years and group three for those from two years to three years and group four for patients who had more than three years illness duration).
To evaluate the functional status of ALS patients, The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) was used as an objective measure of pulmonary function and muscle power. The minimum score is equal to zero, the maximum score is equal to forty. The higher score the better function for the patient.
The patients were divided according to ALSFRS into four groups as the following (group one for those with a score from 31 to 40, group two for those from 21 to 30, group three for those from 11 to 20, and group four for those who had a 1 - 10 score).
To assess if there is any relation between receiving Edaravone drug and results of SNCS, I divided the patients into two groups, group (1) for those who received intravenous Edaravone injection according to the dose and schedule of administration approved by the FDA in 2017 for ALS patients, and group (2) for those who didn't receive it.
The control population and patients were examined following a standard electrophysiological examination schedule and done by using (micromed-MyoQuik) EMG machine.
The abnormalities in SNCS, which include an examination of the ulnar, median, superficial fibular, and sural nerves, are defined as a decline in SNCV, a decline in the amplitude of SNAP of at least two standard deviations from the controls mean depending on normative values that are locally used for at least 2 nerves. According to that, the population of the study was subdivided into normal and abnormal groups.
Statistical analysis: The demographic data and results of SNCS abnormalities are assisted, the variables were compared by t-test and chi-square statistics and by using (SPSS, version 25); P <0.05 was considered to describe statistical significance.
Results:
Ninety persons were included in this study, 30 of them were patients with ALS (20 males and 10 females) and the rest were the control group (32 males and 28 females).
The mean age of the patients was (56.27 ±6.24) years while in the control persons was (56.67± 5.76) year old. The mean duration of illness among patients was (18.6 ± 13.23) months. There were no significant differences between the means of age and gender distribution between both groups, Table (1).
| Table 1: Demographic data of ALS patients and control subjects |
| Data |
ALS group |
Control group |
P value* |
Mean age± SD† (years)
Maximum
Minimum |
56.27 ±6.24
67
43 |
56.67 ±5.76
65
47 |
0.38 |
Gender distribution |
Male |
20 |
32 |
0.22 |
Female |
10 |
28 |
| Duration of illness ± SD† (months) |
18.6 ± 13.23 |
|
|
| Maximum |
41 |
|
|
Minimum |
2 |
----------- |
-------- |
| Normal SNCS |
21 |
56 |
0.003 |
Abnormal SNCS |
9 |
4 |
|
| *Significant P value at < 0.05.†SD: Standard deviation. |
Four persons only (6.66%) show abnormal findings in the control group, two males had an abnormal SNAP amplitude and one female had an abnormal SNAP amplitude and one female has abnormal both SNAP amplitude and SNCV in the control group. While The percentage of abnormal SNCS was higher in the patient group (9/30=30%), where six males (6/20) and only three females (3/10) were affected and these main abnormal findings were divided equally into three subgroups (Abnormal SNAP amplitude, Abnormal SNCV or Abnormal SNAP amplitude and SNCV) as it is shown in Table (2).
| Table 2: ALS patients with an Abnormal SNCS findings: |
| Age (years) |
Gender |
Duration of illness (months) |
SNCS Abnormalities |
65 |
male |
37 |
Abnormal SNAP amplitude |
64 |
male |
40 |
Abnormal SNAP amplitude and SNCV |
61 |
male |
17 |
Abnormal SNCV |
62 |
female |
39 |
Abnormal SNAP amplitude and SNCV |
60 |
male |
32 |
Abnormal SNCV |
57 |
female |
41 |
Abnormal SNAP amplitude |
67 |
male |
38 |
Abnormal SNAP amplitude and SNCV |
64 |
female |
29 |
Abnormal SNCV |
64 |
male |
29 |
Abnormal SNAP amplitude |
The relation between gender and these abnormal SNCS findings in the patient group was not significant (p value=1.0). But, The difference in percentages of abnormal SNCS was statistically significant between the patient group and the control group (p value=0.003).
In ALS patients, the relation between the age and abnormal SNCS was assessed, it is shown in table (3). There was a significant relationship between them, as these abnormal findings increased with the increasing of the patient's age.
| Table 3: The relation between the age and abnormal SNCS in the patient group: |
| Age group |
Normal |
Abnormal SNCS |
Total |
P value* |
<=50 |
7 |
0 |
7 |
0.000 |
51-60 |
13 |
2 |
15 |
>60 |
1 |
7 |
8 |
Total |
21 |
9 |
30 |
| *Significant P value at < 0.05. |
The relationship between the duration of illness and the abnormal SNCS was addressed, it is shown in table (4). We found that the relation was significant, as these abnormal findings increased with the increasing duration of disease. Also, there was a tending for the involvement of more parameters by abnormalities with time, as all patients with abnormal both SNCV and SNAP were from those who had more than three years of illness duration.
| Table 4: The relation between the duration of illness and abnormal SNCS |
Duration |
Normal |
Abnormal SNCS |
Total |
P value* |
1m-1 y |
10 |
0 |
10 |
0.000 |
1 y-2 y |
8 |
1 |
9 |
2 y-3y |
3 |
3 |
6 |
> 3y |
0 |
5 |
5 |
Total |
21 |
9 |
30 |
| *Significant P value at < 0.05. |
The relationship between the functional status of patients with ALS and the abnormal SNCS was assessed, table (5). We found that the result was significant, as these abnormal findings increase with the increasing clinical disability of the patients.
| Table 5: the relation between the functional status of patients using (ALSFRS) and abnormal SNCS |
ALSFRS |
Normal |
Abnormal
SNCS |
Total |
P value* |
31-40 |
10 |
0 |
10 |
0.001 |
21-30 |
8 |
1 |
9 |
11-20 |
3 |
4 |
7 |
1-10 |
0 |
4 |
4 |
Total |
21 |
9 |
30 |
| *Significant P value at < 0.05. |
Finally, the relationship between receiving Edaravone injection and the SNCS finding is studied, As it is shown in table (6). it is found that there is a significant relationship between them.
| Table 6: The relation between receiving Edaravone injection and abnormal SNCS |
Edaravone injection |
Normal |
Abnormal SNCS |
Total |
P value* |
Group (1) |
16 |
3 |
19 |
0.02 |
Group (2) |
5 |
6 |
11 |
Total |
21 |
9 |
30 |
| *Significant P value at < 0.05;
Group (1): Patients who received it;
Group (2): Patients who did not receive it |
Discussion:
Thirty ALS patients included randomly in this study, from both genders, with a higher percentage of male gender (66.6%), This gender difference is seen in many studies that include sporadic and familial ALS cases[6].
Nine patients showed abnormalities in SNCS parameters, and this positive result was compatible with other ALS Electrodiagnostic studies, but with a greater proportion (30%) in comparison with abnormal findings reported in those studies as the percentages were ranged between 13% and 27% (Gregory Ret al, 1993; Mondelli M et al, 1993; Theys PA et al, 1999; Hammad M et al, 2007)[7,8,9,5]. The Pugdahl K et al reported 22.7% of patients showed abnormalities in SNCS parameters[1].
The greater percentage (70%) of patients with normal SNCS results in this study signifies that sensory nerves are not routinely affected in patients with ALS. Also, Normal SNCS had been shown in a series of studies in patients with ALS (e.g. de Carvalho M and Swash M, 2000)[10].
In the control group, we found that there are only four persons has abnormal SNCS, and there was a significant difference between the abnormal SNCS percentage among patients (30%) in comparison to that of the control group (6.66%), these findings cannot be explained by the aging process in the patient group simply as both groups have an approximate mean of ages. These abnormal results in the patient group had not been attributed to other causes of neuropathy as vasculitis, diabetes, alcohol or other toxins, a paraneoplastic syndrome or other related conditions as all of these cases were excluded from the start. Thus, the abnormal sensory findings are mostly related to ALS itself.
In addition, much evidence is supporting the peripheral nervous system (PNS) (motor and sensory) degeneration in ALS disease by the dying-back pattern. The axonal pathology precedes symptom onset and spinal motor neuron death and the burden of this pathology overcomes neuronal loss along with illness progression[4].
In this study, there is a significant relationship between the abnormal findings and the age, in which the age of 77% of affected patients was above 60 years. Although the percentage of male patients was greater than females and this is seen in multiple studies, e.g. McCombe PA and Henderson RD, 2010; who reported greater prevalence and incidence of ALS in males than in females [6]. But, The gender varieties did not have a considerable effect on the results of abnormal sensory parameters.
The abnormalities in SNCS have a significant relationship to the duration of the illness in our study, as all affected patients were with > 1 year of illness duration, and this is not agreed with Pugdahl K et al[1] and Theys PA et al[9], who found that ALS sensory abnormalities are not progressive. But, this is compatible with several pathological and clinical studies that established the occurrence of degeneration in both peripheral and central sensory pathways in MND, and this degeneration may increase with a disease progression[4,11].
According to the distribution of abnormal SNCS according to the ALSFRS, we found that these abnormalities are increased with decreasing functional status, as 88% of positive patients had ALSFRS = 20. This result suggests that increasing functional disability correlates with extensive degeneration of PNS including sensory part, and why not, it may increase the disability of those patients.
Edaravone (an antioxidant and a potent pyrazolone free radical scavenger ) approved by the FDA In May 2017, as a novel neuroprotective agent to slow the ALS progression. it is hypothesized to reduce the oxidative stress effects which are considered a part of the killing process of neurons in patients with ALS[12].
The abnormal SNCS results appear more significantly among patients who did not receive Edaravone injection. it means that Edaravone may protect against peripheral nerves degeneration, and this is supported by the study results of Saini AK et al, which demonstrate the protective effect of it on diabetic neuropathy, as a consequence of the improvement in the hemodynamics as well due to improvement in the system of antioxidant defense[13], where the antioxidant therapies are promising concerning treatment for the peripheral neuropathy generally[14]. in addition, the oxidative stress considerably increases in the early stages of ALS pathophysiology[15].
The results of the current study suggest the involvement of sensory neurons and their axonal projections in ALS patients, where the abnormalities included reduction of conduction velocity, action potential amplitude, and both of them. These findings are compatible with numerous studies (Guo et al., 2009; Vaughan et al., 2015; Vaughan et al., 2018)[16,17,18] that suggest there is a sensory pathological degeneration in ALS.
In addition, the increase of these abnormalities in this study is proportional to the degree of degeneration, which is related directly to the age, duration of illness, and functional disabilities, and it may be decreased by using Edaravone injection.
Limitation:
There are some limitations in this study include the small size of patient group, difficulties in persuading of patients with advanced stages for participation and the little number of studies that discuss the relations between SNCS and clinical characteristics of ALS patients.
Conclusion:
Numerous clinical, electrophysiological, and pathological studies indicate the involvement of the PNS in the ALS disease where the sensory neurons and their axons are affected also. This information is supported by the results of this study in which the extension of sensory involvement is corresponding to the increasing of age, illness duration, functional disabilities, and non-receiving Edaravone drug.
Acknowledgement
I extend my thanks to the colleagues in the Nineveh medical college and I would like to thank all friends for their support for us in completing this study.
References:
- Pugdahl K, Fuglsang-Frederiksen A, de Carvalho M, Johnsen B, Fawcett PR, Labarre-Vila A, Liguori R, Nix WA, Schofield IS. Generalised sensory system abnormalities in amyotrophic lateral sclerosis: a European multicentre study. J Neurol Neurosurg Psychiatry. 2007 Jul;78(7):746-9. doi: 10.1136/jnnp.2006.098533.
- Joyce NC, Carter GT. Electrodiagnosis in persons with amyotrophic lateral sclerosis. PM R. 2013 May;5(5 Suppl):S89-95. doi: 10.1016/j.pmrj.2013.03.020.
- Isaacs JD, Dean AF, Shaw CE, Al-Chalabi A, Mills KR, Leigh PN. Amyotrophic lateral sclerosis with sensory neuropathy: part of a multisystem disorder? J Neurol Neurosurg Psychiatry. 2007 Jul;78(7):750-3. doi: 10.1136/jnnp.2006.098798.
- Gentile F, Scarlino S, Falzone YM, Lunetta C, Tremolizzo L, Quattrini A, et al. The peripheral nervous system in amyotrophic lateral sclerosis: Opportunities for translational research. Front Neurosci [Internet]. 2019;13. Available from: http://dx.doi.org/10.3389/fnins.2019.00601.
- Hammad M, Silva A, Glass J, Sladky JT, Benatar M. Clinical, electrophysiologic, and pathologic evidence for sensory abnormalities in ALS. Neurology. 2007 Dec 11;69(24):2236-42. doi: 10.1212/01.wnl.0000286948.99150.16.
- McCombe PA, Henderson RD. Effects of gender in amyotrophic lateral sclerosis. Gend Med. 2010 Dec;7(6):557-70. doi: 10.1016/j.genm.2010.11.010.
- Gregory R, Mills K, Donaghy M. Progressive sensory nerve dysfunction in amyotrophic lateral sclerosis: a prospective clinical and neurophysiological study. J Neurol. 1993 May;240(5):309-14. doi: 10.1007/BF00838169.
- Mondelli M, Rossi A, Passero S, Guazzi GC. Involvement of peripheral sensory fibers in amyotrophic lateral sclerosis: Electro-physiological study of 64 cases. Muscle Nerve. 1993;16(2):166–72. https://doi.org/10.1002/mus.880160208.
- Theys PA, Peeters E, Robberecht W. Evolution of motor and sensory deficits in amyotrophic lateral sclerosis estimated by neurophysiological techniques. J Neurol. 1999 Jun;246(6):438-42. doi: 10.1007/s004150050379.
- de Carvalho M, Swash M. Nerve conduction studies in amyotrophic lateral sclerosis. Muscle Nerve. 2000 Mar;23(3):344-52.
- Jamal GA, Weir AI, Hansen S, Ballantyne JP. Sensory involvement in motor neuron disease: further evidence from automated thermal threshold determination. J Neurol Neurosurg Psychiatry. 1985;48(9):906–10. https://doi.org/10.1136/jnnp.48.9.906.
- Cruz MP. Edaravone (Radicava): A Novel Neuroprotective Agent for the Treatment of Amyotrophic Lateral Sclerosis. P T. 2018 Jan;43(1):25-28. PMID: 29290672.
- Saini AK, Kumar H.S. A, Sharma SS. Preventive and curative effect of edaravone on nerve functions and oxidative stress in experimental diabetic neuropathy. Eur J Pharmacol. 2007;568(1–3):164–72. https://doi.org/10.1016/j.ejphar.2007.04.016.
- Mallet ML, Hadjivassiliou M, Sarrigiannis PG, Zis P. The Role of Oxidative Stress in Peripheral Neuropathy. J Mol Neurosci. 2020 Jul;70(7):1009-1017. doi: 10.1007/s12031-020-01495-x. Epub 2020 Feb 26.
- Bond L, Bernhardt K, Madria P, Sorrentino K, Scelsi H, Mitchell CS. A metadata analysis of oxidative stress etiology in preclinical amyotrophic lateral sclerosis: Benefits of antioxidant therapy. Front Neurosci [Internet]. 2018;12. Available from: http://dx.doi.org/10.3389/fnins.2018.00010.
- Guo YS, Wu DX, Wu HR et al. Sensory involvement in the SOD1-G93A mouse model of amyotrophic lateral sclerosis. Exp Mol Med. 2009;41(3):140–50. https://doi.org/10.3858/emm.2009.41.3.017.
- Vaughan SK, Kemp Z, Hatzipetros T, Vieira F, Valdez G. Degeneration of proprioceptive sensory nerve endings in mice harboring amyotrophic lateral sclerosis-causing mutations: Proprioceptive Sensory Neurons and ALS. J Comp Neurol. 2015;523(17):2477–94. https://doi.org/10.1002/cne.23848.
- Vaughan SK, Sutherland NM, Zhang S, Hatzipetros T, Vieira F, Valdez G. The ALS-inducing factors, TDP43A315T and SOD1G93A, directly affect and sensitize sensory neurons to stress. Sci Rep. 2018 Nov 8;8(1):16582. doi: 10.1038/s41598-018-34510-8.
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