|Year : 2014 | Volume
| Issue : 3 | Page : 321-324
Multimodal evoked potentials in spinocerebellar ataxia types 1, 2, and 3
Vijay Chandran1, Ketan Jhunjhunwala1, Meera Purushottam2, Sanjeev Jain2, Pramod Kumar Pal1
1 Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India
2 Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India
|Date of Submission||16-Dec-2013|
|Date of Decision||20-Jan-2014|
|Date of Acceptance||30-Jan-2013|
|Date of Web Publication||12-Aug-2014|
Pramod Kumar Pal
Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore - 560 029, Karnataka
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Aims: Spinocerebellar ataxias (SCA) are a clinically heterogeneous group of disorders that are characterized by ataxia and an autosomal dominant pattern of inheritance. The aim of our study was to describe the findings of evoked potentials (EPs) among genetically proven SCA types 1, 2, and 3 and to additionally evaluate if EPs can be used to differentiate between them. Materials and Methods: Forty-three cases of genetically proven SCA (SCA1 = 19, SCA2 = 13, and SCA3 = 11) were evaluated with median somatosensory-EP (mSSEP), visual-EP (VEP), and brainstem auditory-evoked response (BAER) by standard procedures and compared with normative laboratory data. An EP was considered abnormal if latency was prolonged (>mean + 3 standard deviation (SD) of laboratory control data) or the waveform was absent or poorly defined. The waves studied were as follows: mSSEP - N20, VEP - P100 and BAER - interpeak latency 1-3 and 3-5. Results: EPs were abnormal in at least one modality in 90.9% of patients. The most common abnormality was of BAER (86.1%) followed by VEP (34.9%) and mSSEP (30.2%). The degree of abnormality in VEP, mSSEP, and BAER among patients with SCA1 was 42.1, 41.2, and 73.3%, respectively; among patients with SCA2 was 38.5, 27.3, and 100%, respectively; and among patients with SCA3 was 18.2, 37.5, and 88.9%, respectively. The differences between the subgroups of SCAs were not statistically significant. Conclusions: BAER was the most frequent abnormality in SCA types 1, 2, and 3; abnormalities of mSSEP were comparable in the three SCAs; whereas, abnormality of VEP was less often noted in SCA3.
Keywords: Brainstem auditory evoked response, evoked potentials, median, posterior tibial, spinocerebellar ataxia, somatosensory evoked potentials, visual evoked potential
|How to cite this article:|
Chandran V, Jhunjhunwala K, Purushottam M, Jain S, Pal PK. Multimodal evoked potentials in spinocerebellar ataxia types 1, 2, and 3. Ann Indian Acad Neurol 2014;17:321-4
|How to cite this URL:|
Chandran V, Jhunjhunwala K, Purushottam M, Jain S, Pal PK. Multimodal evoked potentials in spinocerebellar ataxia types 1, 2, and 3. Ann Indian Acad Neurol [serial online] 2014 [cited 2018 Mar 24];17:321-4. Available from: http://www.annalsofian.org/text.asp?2014/17/3/321/138519
| Introduction|| |
Spinocerebellar ataxias (SCA) compromise a heterogeneous group of inherited ataxias primarily characterized by an autosomal dominant pattern of inheritance. Several genetic mutations have been described, each resulting in a particular type of ataxia. Among them SCA types 1, 2, and 3 are common and result from an expansion in a translated trinucleotide (CAG) repeat on chromosome 6p 22-23,  12q 23-24.1, ,, and 14q 24.3-32.2,  respectively. The SCA types 1, 2, and 3 have a similar clinical presentations and have been classified by Harding  as autosomal dominant cerebellar ataxia (ADCA) type 1, which includes features of cerebellar ataxia, pyramidal signs, ophthalmoparesis, and extrapyramidal involvement. Pathologically these findings result due to degeneration of the olivopontocerebellar tracts  and involvement of other neural networks. ,, The overlapping clinical features and imaging findings make it difficult to differentiate between each of these three types without resorting to genetic testing.
Data on evoked potential (EP) in genetically proven SCA types 1, 2, and 3 is inadequate. The aim of our study was to describe the findings of visual-EPs (VEPs), brainstem auditory-evoked response (BAER), and somatosensory-EPs (SSEPs) in a large cohort of genetically proven SCA types 1, 2, and 3. We also analyzed whether EP could be used to differentiate between these clinically similar SCA subtypes.
| Materials and Methods|| |
Patients with genetically proven SCA who had been evaluated at the outpatient clinic of the Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India were recruited. All patients gave written informed consent for the study and the study was approved by the Institute's Ethics Committee. Patients underwent evaluation with VEP, BAER and median SSEP (mSSEP) using standard procedures. The VEP and BAER were studied bilaterally; whereas mSSEP was studied only on the right side. At the time of SSEP recordings, the skin temperature was maintained between 33 and 34°C. The waves that were evaluated in each of the EPs were as follows: P100 for VEP, N20 for mSSEP, interpeak latency between wave 1 and wave 3 as well as between wave 3 and wave 5 for BAER, and these were compared with normative laboratory data. An EP was considered abnormal if the waveform was absent or poorly defined or if the latency was prolonged (>mean + 3 standard deviation (SD) of laboratory control data). Statistical analysis was carried out using SPSS version 16.0. Data were expressed as frequency and percentages for categorical variables and mean ± SD for continuous variables. Comparison between the groups was carried out by the chi-square test and P < 0.05 was considered significant.
| Results|| |
Forty-three patients with SCA were studied. These included 19 patients with SCA1 (five women, 14 men), 13 patients with SCA2 (two women, 11 men) and 11 patients with SCA3 (four women, seven men). The mean (±SD) age was 30.8 ± 11.3 for SCA1, 30.4 ± 17.3 for SCA2 and 42.2 ± 8.4 for SCA3. The mean (± SD) CAG repeat length for the abnormal allele was 53.5 ± 6.7 for SCA1, 46.1 ± 9.0 for SCA2, and 71.4 ± 1.9 for SCA3.
VEP data of both sides were available in all patients. The mSSEP data were missing in two (10.5%) patients with SCA1, two (10.5%) with SCA2, and three (27.3%) patients with SCA3 adding up to seven (16.3%) in the SCA group as a whole; BAER data were missing on the right side in three patients (15.8%) and on the left side in four patients (21.2%) with SCA1; whereas, it was missing on both sides in two (18.2%) patients in both SCA2 and SCA3 adding up to seven (16.3%) patients with missing data on the right side and eight (18.6%) patients with missing data on the left side in the SCA group as a whole. Data on all the three modalities of EP were available in 33 patients (76.7%).
EPs were abnormal in at least one modality in 83.7% of the SCA patients (n = 43). However, on analyzing patients who had undergone all three EP studies (n = 33), the percentage of abnormality was as high as 90.9%. In the SCA group as a whole, BAER showed the maximum abnormality with 86.1% of patients having an abnormality in one or more interpeak latencies on one side or both; this was followed by VEP that was abnormal in 34.9% of patients on one side or both and finally by mSSEP that was abnormal in 30.2% of patients (only one side was studied). The abnormalities were seen bilaterally in 23.3% of patients who underwent VEP and in 57.1% of patients who underwent BAER. In BAER, after having excluded patients with a poor waveform, the I-III interpeak latency was prolonged in 56.5% of patients; whereas, the III-V interpeak latency was prolonged in 33.3% of patients, both interpeak latencies were prolonged only in 19.0%.
Details with regard to abnormalities in mSSEP, VEP, and BAER and side of abnormality between each of the SCA types (after having excluded missing data) are given in [Table 1]. We also analyzed as to whether the abnormalities were confined to one side or involved both sides in VEP and BAER (mSSEP excluded as it was performed only on one side) among the different types of SCAs; the percentages were calculated after excluding patients with missing data and the details are given below.
|Table 1: Details of abnormalities of evoked potentials in the subtypes of SCA|
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- VEP was abnormal on one side in 10.5% and on both sides in 31.6% of the patients, that is, 42.1% had abnormality on at least one side
- BAER was abnormal on one side in 40.0% and on both sides in 33.3% of the patients, that is, 73.3% had abnormality on at least one side.
- VEP was abnormal on one side in 15.4% and on both sides in 23.1% of the patients, that is, 38.5% had abnormality on at least one side
- BAER was abnormal on one side in 9.1% and on both the sides in 90.9% of the patients, that is, 100% had abnormality on at least one side.
- VEP was abnormal on one side in 9.1% and on both the sides in 9.1% of the patients, that is, 18.2% had abnormality on at least one side
- BAER was abnormal on one side in 33.3% and on both the sides in 55.6% of patients, that is, 88.9% had abnormality on at least one side.
The differences between the subgroups of SCAs were not statistically significant.
In BAER after having excluded those patients with an abnormal or poor waveforms, the I-III interpeak latency was abnormal in 45.5% of patients with SCA1, 57.1% of patients with SCA2, and 80% of SCA3; whereas, the III-V interpeak latency was abnormal in 50% of SCA1, 57.2% of SCA2, and 25.0% of SCA3. The differences in the abnormalities of the interpeak latencies among the different types of SCA did not reach statistical significance.
| Discussion|| |
EP studies evaluate the functional activity and integrity of sensory pathways in contrast to imaging studies that are used primarily to define the anatomy and structure of neural pathways. Current literature primarily focuses on the use of advanced imaging studies in the evaluation of neurological disorders such as SCA. However, the information provided by EPs has a few advantages over imaging, including the following: (a) May provide evidence of subclinical dysfunction of sensory pathways and (b) may show objective evidence of abnormality even when imaging is normal. This information can be used to guide future research and improve our understanding of the pathophysiology of a neurological disease. Despite these advantages, the literature is limited with regards to EPs in genetically proven patients with SCAs and we were able to identify only three such studies, the summary of which is provided in [Table 2]. Abele et al.,  evaluated the clinical characteristics, nerve conduction, and EP in 41 patients with genetically proven SCAs (SCA1: 9, SCA2: 14, and SCA3: 18); Αlvarez-Paradelo et al.,  evaluated 10 patients with SCA2 and 12 with SCA3 using a battery of neurophysiological tests including EP; whereas, Peretti et al.,  evaluated five patients from two families with SCA1 and 11 patients from two families who showed linkage to SCA 2 locus according to molecular analysis.
|Table 2: Summary of evoked-potential data from prior studies on SCA types 1, 2, and 3|
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In our study, we found 42.1% had abnormal VEP, 41.2% had abnormal mSSEP; whereas, 73.3% had abnormal BAER. In comparison, Abele et al., found a much higher degree of abnormality in VEP (i.e., 78%) and much lesser degree of abnormality of BAER among patients with SCA1 (50%). The SSEP data are not comparable as Abele et al., studied tibial SSEP (tSSEP); whereas, we evaluated mSSEP; however, they did find a higher degree of abnormality (75%) in patients with SCA1 as compared with the SSEP data from our study. The high degree of abnormality of BAER among SCA1 patients in our study is comparable with the findings of Peretti et al.,  who found that 80% of patients with SCA1 had abnormal BAER; however, comparisons with the SSEP and VEP data of this study are fallacious because of small number of patients and incomplete data.
In our patients with SCA2, we found that 38.5% had abnormal VEP, 27.3% had abnormal mSSEP; whereas, 100% had abnormal BAER. Compared with earlier studies, our VEP findings were comparable with Abele et al., (36%), but much less than what was detected by Αlvarez-Paradelo et al.,  (71%); whereas, our SSEP data showed much less abnormality than what had been detected in earlier studies (Abele et al., tSSEP: 69%, Αlvarez-Paradelo - mSSEP: 77% and tSSEP: 88%). The finding that all patients with SCA2 had an abnormal BAER is in contrast to earlier studies that have found much less degree of abnormality (Abele et al., 42%, Αlvarez-Paradelo −40%).
In our SCA3 cohort, we found 18.2% had abnormal VEP, 37.5% had abnormal mSSEP; whereas, 88.9% had abnormal BAER. The degree of abnormality detected on VEP is almost similar to what has been reported by Abele et al., (25%) and Αlvarez-Paradelo et al., (16%). In SSEP, although Αlvarez-Paradelo et al., (mSSEP: 42%, tSSEP: 66%) showed similar results, the study by Abele et al., (tSSEP: 75%) showed much greater abnormality. We found a much higher degree of abnormality on BAER as compared with earlier studies (Abele et al., −63%, Αlvarez-Paradelo et al., 17%).
Two types of abnormalities have been reported in EPs among patients with SCAs: (i) A prolongation of latency of the studied waves and (ii) a poor or absent waveform. Prolongation of latency usually occurs due to slowing of conduction velocity resulting from loss of myelin; however, the reason for prolonged latencies in patients with SCA is not clear and probably results from a loss of predominantly large myelinated fibers. Another interesting point is that despite the symmetrical clinical findings in most patients with SCA, the EP may show asymmetric abnormalities as shown by our study. A higher degree of abnormality is detected on tSSEP because of several possible reasons including (a) longer segment of the posterior column being evaluated in tSSEP as compared with mSSEP and (b) dysfunction of posterior column sensations are clinically more often seen in the lower extremity in patients with SCA; however, this may be confounded by coexistent neuropathy affecting large diameter fibers of the lower limbs. Most of the earlier studies have not evaluated for the presence of coexistent neuropathy when reporting tSSEP data and hence may be overestimating the degree of SSEP abnormality; in contrast our data are likely to underestimate the degree of SSEP abnormality.
Overall, none of the studies (including ours) till date have shown a consistent pattern of abnormality in EP data among patients with SCA types 1, 2, and 3 except for decreased likelihood of abnormality in VEP among patients with SCA3. The lack of a consistent pattern of abnormality is probably multifactorial and may include such factors as age of onset of illness, duration of illness, degree of expansion of trinucleotide repeats, and interaction with other genes.
Our study does provide some interesting data on EP in patients with SCAs and suggests that BAER is abnormal in most patients with SCA type 1, 2, and 3, and it reaffirms an earlier observation that abnormality of VEP is uncommon in SCA type 3.
| References|| |
|1.||Orr H, Chung MY, Banfi S, Kwiatkowski TJ Jr, Servadio A, Beaudet AL, et al. Expansion of an unstable trinucleotide (CAG) repeat in spinocerebellar ataxia type 1. Nat Genet 1993;4:221-6. |
|2.||Imbert G, Saudou F, Yvert G, Devys D, Trottier Y, Garnier JM, et al. Cloningof the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet 1996;14:285-91. |
|3.||Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 1996;14:269-76. |
|4.||Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H, et al. Identificationof the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet 1996;14:277-84. |
|5.||Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 1994;8:221-8. |
|6.||Harding AE. The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. A study of 11 families, including descendants of the ′the Drew family of Walworth′. Brain 1982;105:1-28. |
|7.||Dürr A, Smadja D, Cancel G, Lezin A, Stevanin G, Mikol J, et al. Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies). Clinical and neuropathological analysis of 53 patients from three unrelated SCA2 families. Brain 1995;118:1573-81. |
|8.||Rüb U, Del Turco D, Del Tredici K, de Vos RA, Brunt ER, Reifenberger G, et al. Thalamic involvement in a spinocerebellar ataxia type 2 (SCA2) and a spinocerebellar ataxia type 3 (SCA3) patient, and its clinical relevance. Brain 2003;126:2257-72. |
|9.||Rüb U, Bürk K, Timmann D, den Dunnen W, Seidel K, Farrag K, et al. Spinocerebellar ataxia type 1 (SCA1): New pathoanatomical and clinico-pathological insights. Neuropathol Appl Neurobiol 2012;38:665-80. |
|10.||Ishida C, Komai K, Yonezawa K, Sakajiri K, Nitta E, Kawashima A, et al. An autopsy case of an aged patient with spinocerebellar ataxia type 2. Neuropathology 2011;31:510-8. |
|11.||Abele M, BuÈrk K, Andres F, Topka H, Laccone F, BoÈsch S, et al. Autosomal dominant cerebellar ataxia type I. Nerve conduction and evoked potential studies in families with SCA1, SCA2 and SCA3. Brain 1997;120:2141-8. |
|12.||Álvarez-Paradelo S, García A, Infante J, Berciano J. Multimodal neurophysiological study of SCA2 and SCA3 autosomal dominant hereditary spinocerebellar ataxias. Neurologia 2011;26:157-65. |
|13.||Peretti A, Santoro L, Lanzillo B, Filla A, De Michele G, Barbieri F, et al. Autosomal dominant cerebellar ataxia type I: Multimodal electrophysiological study and comparison between SCA1 andSCA2 patients. J Neurol Sci 1996;142:45-53. |
[Table 1], [Table 2]