Neurol Sci DOI 10.1007/s10072-015-2181-6

BRIEF COMMUNICATION

Auditory startle response is normal in juvenile myoclonic epilepsy Melek Kandemir1 • Ays¸ egu¨l Gu¨ndu¨z2 • Nurten Uzun2 Naz Yeni2 • Meral Kızıltan2



Received: 20 January 2015 / Accepted: 17 March 2015 Ó Springer-Verlag Italia 2015

Abstract Juvenile myoclonic epilepsy (JME) is hypothesized to originate from the dysfunction of thalamocortical circuit. We aimed to analyze any changes in auditory startle response in JME patients to determine the role of brainstem in JME. The responses of 18 JME patients to auditory simulation were recorded over the unilateral orbicularis oculi, masseter, sternocleidomastoid, and extremity muscles. Results were compared with those of 18 age and gender matched healthy volunteers. Total auditory startle response frequencies were similar between the two groups (31.1 ± 11.1 % vs. 33.7 ± 8.7 %, p = 0.400).

Other parameters over each muscle were also similar. There were no impacts of antiepileptic drug use or disease duration. We may conclude that our findings may provide sufficient evidence for the lack of functional changes of the auditory startle response circuit even in longstanding cases of JME. Keywords Juvenile myoclonic epilepsy  Auditory startle response  Brainstem excitability

Introduction

& Melek Kandemir [email protected] Ays¸ egu¨l Gu¨ndu¨z [email protected] Nurten Uzun [email protected] Naz Yeni [email protected] Meral Kızıltan [email protected] 1

Department of Neurology, Bayindir Hospital Icerenkoy, Ali Nihat Tarlan Cad. Ertas Sok. No: 17, 34752 Atasehir, Istanbul, Turkey

2

Department of Neurology, Istanbul University, Cerrahpasa School of Medicine, 34098 Fatih, Istanbul, Turkey

Juvenile myoclonic epilepsy (JME) is attributed to the dysfunction of thalamo-cortical circuit, reticular thalamic neurons being the trigger point with premotor and motor cortex constituting the generator of seizures [1, 2]. In recent years, subtle structural and functional dopaminergic alterations in JME have been proposed [3– 5], which may be either the underlying cause of seizure episodes or more possibly the consequence of thalamocortical involvement. A study investigating cerebral blood flow demonstrated that reduced blood flow in thalamus, midbrain, red nucleus, and pons probably indicated the dysfunction of neural networks in the thalamus, hippocampus, brainstem, and cerebellum in JME [6]. Sudden stimuli by various modalities create startle responses in humans. Although many stimuli may be used to evoke startle responses, auditory stimuli have been mainly used for this purpose (auditory startle response-ASR). Intact ASR reflects the integrity of brainstem, specifically nucleus reticularis pontis caudalis and reticulospinal system [7, 8]. We aimed to analyze the status of ASR to determine the functional status of brainstem in JME.

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Patients and methods Participants Eighteen patients who were diagnosed as JME between October 2009 and May 2011 were included in the study. Exclusion criteria were coexistence of any other neurological or systemic diseases and age younger than 10 years or older than 60 years. The control group consisted of age and gender matched 18 healthy volunteers who did not have any neurological or systemic diseases. The study was approved by the local ethical committee. All participants or their parents gave informed consent. Clinical evaluation Antiepileptic drug (AED) usage at the time of investigation and disease duration was noted. Acoustic startle response Eight bursts of monophasic, 100 ms auditory tone burst stimuli (Neuropack-Sigma MEB-5504k, Nihon-Kohden Medical, Tokyo-Japan) were applied bilaterally. Intensity was 105 dB(HL) with random intervals of 2–5 min. The duration was increased by 50 ms at every two stimuli. Nonrectified responses were recorded over unilateral orbicularis oculi (O.oc), masseter, sternocleidomastoid (SCM), biceps brachii (BB), abductor pollicis brevis (APB), and tibialis anterior (TA) muscles. Ground electrode was placed over the sternum. Reflex response is defined as response with amplitude of at least 50 lV. Statistical analysis Latency, duration, and amplitude of the responses were measured using cursors. ASR frequencies were calculated as follows: Number of responses over each muscle ðO:oc; masseter, etc:Þ= ðnumber of total recordingsÞ ð8Þ  100:

Total ASR frequency is the sum of response frequencies over all muscles. Total ASR frequencies as well as the frequencies over each muscle were compared between the two groups. As there were insufficient responses over distal muscles like APB and TA, measurements of O.oc, masseter, SCM and BB responses were compared between two groups. Data analyses were performed using the SPSS 17.5 software statistical package (SPSS Inc., Chicago, IL, USA). Comparisons were made by Mann–Whitney U test for quantitative data and by Chi square test for qualitative

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data. Data were presented as mean values and standard deviations. p value B0.05 was considered as significant. Relation between electrophysiological parameters and AED usage were also tested using Pearson correlation test. JME group was dichotomized according to the use of valproic acid (VPA group and non-VPA group) and ASR frequency was compared between these two groups using Mann–Whitney U test.

Results Clinical findings Mean ages of JME and control groups were 24.8 ± 7.1 years and 23.1 ± 5.9 years, respectively (p = 0.400). Male gender constituted 33.3 % of JME group and 44.4 % of control group (p = 0.500). Mean duration from the diagnosis was 9.7 ± 6.6 years (range 1–22 years). Three patients did not use any medications at the time of electrophysiological examinations. AEDs were VPA (n = 11, 61.1 %), VPA and lamotrigine (n = 3, 16.7 %), and levetiracetam (n = 1, 5.5 %). The mean dosage of VPA was 715 mg/day (range 300–2000 mg/day). Acoustic startle response Total ASR frequency was similar between the two groups (31.1 ± 11.1 % in JME vs. 33.7 ± 8.7 % in controls, p = 0.400). In healthy subjects and JME patients, the frequency over O.oc was the highest (100 %), and it decreased caudally. Response frequencies of BB were similar, while masseter and SCM were lower in JME group compared to healthy volunteers, but this was statistically insignificant. Latencies, amplitudes and durations over each muscle were very similar. There was no significant difference of total ASR frequency between patients who used and did not use VPA (31.2 ± 11.4 vs. 31.5 ± 11.1, p = 0.730). JME duration did not have an effect on total ASR frequency.

Discussion To the best of our knowledge, this is the first report studying ASR in a group of epilepsy patients, and we have observed that ASR in JME was similar to healthy subjects with no effect of disease duration or VPA. A possible ASR pathway would include ventral cochlear nucleus, superior olivary complex, lateral lemniscus nuclei, and caudal colliculus [11]. Nucleus reticularis pontis caudalis is the integration center [12].

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Suppressed ASR in progressive supranuclear palsy [13] supports the importance of these cholinergic nuclei. ASR frequency decreases with increasing distance of the muscle to the startle generator. The muscle responding most frequently and with the shortest latency is the O.oc, followed by SCM, masseter, and the muscles of upper and lower limbs [9]. Recruitment pattern in JME was similar to healthy subjects. Considering normal latencies and ASR frequencies, we may suggest that there are no functional changes of ASR pathways in JME. No effect of disease duration on ASR may also suggest no degeneration of these pathways with longstanding disease. Most of the patients were using AEDs, mostly VPA. Effects of VPA, carbamazepine, and lamotrigine on prepulse inhibition of ASR were shown in mice [10]. We did not observe any effect. However, the main limitation of the study is the limited number of drug-naive patients. It is not possible to claim complete normal status of brainstem circuits only based upon ASR measurements. However, bearing also in mind the possible effects of AEDs, we may conclude that our findings provide sufficient evidence for the lack of functional changes of the ASR circuit even in longstanding cases of JME. More extensive research, especially including more drug-naive patients, is the subject of further studies. Acknowledgments The authors thank Prof. Dr. Ahmet Dirican for performing statistical analysis. Conflict of interest of interest.

The authors declare that they have no conflict

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Auditory startle response is normal in juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is hypothesized to originate from the dysfunction of thalamo-cortical circuit. We aimed to analyze any changes in au...
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