|Year : 2020 | Volume
| Issue : 1 | Page : 17
Efficacy of levetiracetam in treatment of childhood stuttering
Mohammadreza Ghazavi1, Fateme Rastgu2, Jafar Nasiri2, Omid Yaghini2
1 Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease; Department of Pediatric Neurology, Imam Hossein Childrenfs Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
2 Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease; Department of Pediatric Neurology, Imam Hossein Children's Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
|Date of Submission||02-Sep-2018|
|Date of Acceptance||12-Dec-2018|
|Date of Web Publication||17-Feb-2020|
Department of Pediatric Neurology, Imam Hossein Children's Hospital, Isfahan University of Medical Sciences, Isfahan
Source of Support: None, Conflict of Interest: None
Background: Stuttering is a kind of speech disorder that affects about 1% of total population. As the origin of this disorder is not obviously diagnosed yet, various remedies have been practiced and among them different medicines have been studied, but unfortunately no significant effective drugs have been recognized yet. As stuttering imposes a great social and mental costs to the patients and their families, finding an effective medicine will help significantly. In this study we have focused on the effects of levetiracetam (LEV) treatment on children suffering from stuttering. Methods: In this clinical trial study, 30 children aged > 3 years (median 3.8 years) with stuttering and abnormal sleep electroencephalogram (EEG) were treated by LEV and followed-up for a minimum period of 6 weeks. The starting dose of 20 mg/kg/day was increased at an interval of 1 week by 20 mg/kg/day, if necessary, up to maximum dose of 60 mg/kg/day. Results: Overall LEV was effective in 70% of patients, decreasing stuttering to at least 50%. Three children (10%) became stuttering-free and only in one (3.3%) child an increase in stuttering was observed. There were statistically significant differences for efficacy in the presence of variables such as age groups, seizure, stuttering family history, and EEG data. Conclusions: LEV is an effective drug for treatment of childhood stuttering in those that have abnormal sleep EEG.
Keywords: Child, disease management,etiracetam, stuttering, speech disorders
|How to cite this article:|
Ghazavi M, Rastgu F, Nasiri J, Yaghini O. Efficacy of levetiracetam in treatment of childhood stuttering. Int J Prev Med 2020;11:17
| Introduction|| |
Speech production is a simple and easy activity for most children but it is so hard for other children who stutter. Stuttering is a disorder of speech motor production and is identified as an interruption in normal speech fluency and temporal patterning of words. Stuttering is characterized by frequent occurrences of repetitions in sound and syllable, such as monosyllabic word repetitions, sound prolongations, interjections, and broken words. Some authors refere stuttering as “emotional pain and social stigma.”, This disorder may involve complex social and emotional elements. Two kinds of stuttering are well known in the literature. These include developmental and acquired (or neurogenic) stuttering, which are distinguished clinically. Developmental stuttering, the more frequent type, begins in childhood or during early adolescence.,, Acquired stuttering, on the contrary, is uncommon and may begin in adults. Acquired stuttering is usually associated with brain lesion (e.g., head trauma, stroke, centrally acting drugs) inducing gross cerebral functional impairment., About 1% of the world population and 3–5% of preschoolers suffer from stuttering and the rate of stuttering among boys is about 3–4 times higher compared with girls. Because the cause of the disorder has not been well-established until now, a wide variety of behavioral, cognitive, interpersonal, and related treatments have been attempted with different rates of success. Several attempts are cited in the literature to identify the effective pharmacological therapies for this disorder, such as anticonvulsant agents, antidepressant agent, antipsychotic agents, alpha-receptor agonists, beta-receptor blockers, calcium channel blockers, dopamine antagonist, and so on.,,, But among those, it seems only a few anticonvulsant drugs such as levetiracetam (LEV) and divalproex sodium are effective in treating developmental and acquired stuttering., LEV is an antiepileptic drug that has been approved in adults since 2000 and in children over the age of 4 since 2005. LEV has a highly favorable pharmacokinetic profile, including 100% bioavailability, <48 h needed for steady state, linear kinetics, twice daily dosing, <10% protein binding, no hepatic metabolism, and minimal blood metabolism. In addition, LEV is well-tolerated and is having a broad spectrum of efficacy. The drug is an anticonvulsant with the potential mechanism relating to the blockade of zinc and beta-carbolines from interrupting chloride influx in the GABA and glycine receptors.,,
Recent studies have shown that although there is no significant evidence in children, LEV seems to be an effective remedy for dysfluent speech in patients with partial epilepsy and developmental stuttering. In this regard, a case study has found that 12 weeks of therapy with LEV in a patient with deficits in verbal memory, oral comprehension, and verbal fluency, a complete disappearance of stuttering was observed as well as a decrease in seizure frequency. Moreover, studies have shown that LEV provides betterments of Landau–Kleffner syndrome (LKS), that is the inability to understand or express language,,, although the symptoms of this syndrome are different to those of stuttering.
On the contrary, childhood stuttering imposes a great social and mental costs to the patients and their families, hence finding an effective medicine will help significantly. In this regard, although the efficacy of LEV on the LKS patients and stuttering disorder has been limitedly examined, in the present study we have focused on the effects of LEV treatment on children suffering from stuttering.
| Methods|| |
In this clinical trial study, 4-year-old 30 children suffered from stuttering and abnormal sleep electroencephalogram (EEG) has been subjected to this study. They have been referred to Al-Zahra Hospital, in the city of Isfahan, Iran, between June 2015 and May 2016. All research units volunteered to participate in this study. At first, the stuttering and its severity were diagnosed according to the percentage of stuttered syllabuses (%SS) by a speech-language pathologist and then LEV was prescribed. In this study, percent stuttered syllables as a measure of stuttering severity was considered, and it is calculated as the number of stuttered syllables divided by the total number of syllables spoken, multiplied by 100. Each child was treated with LEV and followed up for at least 6 weeks. The initial dose was determined as 20 mg/kg/day divided into two doses. If the dose was well-tolerated but stuttering was not insufficiently controlled, the dose could be increased to 20 mg/kg/day per week, and to a maximum dose of 60 mg/kg/day (two formulations were available, 250 and 500 mg tablets). If the treatment was not tolerated or the maximum dosage of 60 mg/kg/day was reached with no substantial benefits, the drug was gradually reduced to 20 mg/kg/day weekly. The trial consisted of a preselection visit, an initiation visit, and a follow-up visit after 6 weeks. In the preselection visit, the eligibility of children for the trial was checked and then they were referred to the speech-language pathologist. After the stuttering severity was diagnosed by speech-language pathologist by comparison of the percentage of stuttered syllabus with total ones, the LEV was started with advised dosage. Some data such as age, sex, previous history of seizure on the individual and his family, family history of stuttering, stuttering duration, sleep disorders were recorded through questionnaire. At the end of the sixth week, the stuttering severity of patient was studied again by the same speech-language pathologist and the same method to compare the severity before and after LEV remedy. The primary study endpoint was change in stuttering frequency and stuttering responder rates (>50% stuttering reduction) at six final-week assessments. The study was approved by the Medical Ethical Committees of our research center. All legal representative of participants received a full explanation of the nature of the study and were required to sign an agreement form. Statistical analyses were performed using SPSS-20, LEV (Levebel, Cobel Drou, Iran). Paired t-test and one-way analysis of variance were used to compare the decrease in means of stuttering frequencies between age group, males and females, duration of stuttering, history and family history of stuttering, types of EEG changes, and sleep disorders. P values <0.05 were considered significant.
| Results|| |
In this study, 30 children (18 males, 12 females) ranging in age from 4 to 6 years, with stuttering and abnormal sleep EEG were included between June 2015 and May 2016. The duration of stuttering before LEV treatment program ranged from 6 months to 3.1 years (mean 1.4 years). Of children, 9 (30%) had family history of stuttering, 7 (23.3%) had family history of seizure, 4 (13.3%) had both of them; 7 (23.3%) patients had history of partial or/and generalized seizures and 5 (16.6%) patients had sleep disorder. The rate of improvement was shown in [Table 1] and [Table 2]. An improvement over 50% was reported in a population of 21 children (70%), among them 3 children (10%) came out 100% recovered without any stuttering. In 6 (20%) and 2 (6.6%) patients, stuttering decreased to 25–50% and 10–25%, respectively. In one (3.3%) child, an increase in stuttering was observed, and showed no advantages within 6 weeks.
In this study, furthermore, 81 and 95.2% of children without family history of stuttering and seizure improved, respectively, while none of the patient with positive family history in both were improved. The results showed statistically inverse correlations between positive family history and rate of improvement. In other words, only 28.6% of children with past history of seizure have been improved. According to EEG data, 84% of patients improved for moderately abnormal group, while this result for mildly abnormal group is only 45.4%. According to statistical results, in 13 patients with moderately abnormal EEG and without any history of seizure or family history of stuttering and seizure, 12 patients demonstrated more than 50% reduction in stuttering after LEV treatment. So, the probability of improvement was more than 92% in these fractions.
| Discussion|| |
Although the main causes of stuttering are actually unknown, in the present study we decided to try LEV in the treatment of stuttering because we assume stuttering is output of block or re-entry in speech neuronal pathway and LEV is able to influence the stuttering with its multipotential activity in that process. Our hypothesis in facilitation or blocking model of LEV effect in neuronal pathway can explain the decrease or increase in stuttering severity after LEV therapy. This prospective study of children with stuttering suggests LEV may be a useful treatment in this condition, although in one of the cases exacerbation of stuttering occurred. Also, during the explanation of stuttering mechanism, it has been observed that changes in the perisylvian area of stuttering affected brains which might cause abnormalities in motor speech expression. Indeed, stutterers seem to initiate the motor speech program before the preparation of articulatory code.,,,,,,
It must be emphasized that our study population was heterogeneous in terms of age, suturing severity, presence of sleep disorder, past and family history, and disease duration, although there were statistically significant differences for efficacy in the presence of above variables. But sample sizes in different subgroups are so small to be appreciated. It should be considered that most of the patients had practiced different remedies before LEV without any improvement, while three of our patients became stuttering-free and another 18 patients (60% of all patients) demonstrated >50% reduction in stuttering severity after LEV therapy. Furthermore, no adverse side effects of the drug were observed and the drug was well-tolerated by children. In fact, this is the first structured study in which stuttering children were treated with LEV.
These findings were similar to those of previous studies of Sechi et al. and Canevini et al. Their results indicate that LEV may improve language abilities in patients with focal epilepsy, as well as disfluent speech irrespective of etiology, seizure frequency, EEG alterations, and localization of brain lesions. Canevini reported a 34-year-old patient suffering from intractable epilepsy and developmental stuttering who achieved a complete remission of stuttering under treatment with LEV. In the study of Sechi et al., LEV therapy for a few months cause seizure frequency to return to the rate before LEV in two patients, as well as the beneficial effect on verbal disfluency persisted unchanged in the same patients.
In our study the probability of LEV effect on the reduction of stuttering among children showed an improvement of 60–80% based on binominal distribution.
One limitation in our study is the short follow-up duration because of time and financial restrictions of our research. Hence the same study with more sample size and longer duration of follow-up and control group will strengthen the results.
| Conclusion|| |
LEV is an effective drug for treatment of childhood stuttering in those that have abnormal sleep EEG.
This research was supported by the Child Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. No funding was received from commercial interests.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Naderi S, Shahbodaghi M, Khatonabadi SA, Dadgar H, Jalaie S. Translation of the test of childhood stuttering into Persian and investigation of validity and reliability of the test. J Modern Rehab 2011;5:29-34.
Canevini MP, Chifari R, Piazzini A. Improvement of a patient with stuttering on levetiracetam. Neurology 2002;59:1288.
Rosenfield DB. Do stutterers have different brains? Neurology 2001;57:171-2.
Sechi G, Cocco GA, D'Onofrio M, Deriu MG, Rosati G. Disfluent speech in patients with partial epilepsy: Beneficial effect of levetiracetam. Epilepsy Behav 2006;9:521-3.
Grosso S, Franzoni E, Coppola G, Iannetti P, Verrotti A, Cordelli DM, et al.
Efficacy and safety of levetiracetam: An add-on trial in children with refractory epilepsy. Seizure 2005;14:248-53.
Market KE, Montague JC Jr, Buffalo MD, Drummond SS. Acquired stuttering: Descriptive data and treatment outcome. J Fluency Disord 1990;15:21-33.
Bothe AK, Davidow JH, Bramlett RE, Franic DM, Ingham RJ. Stuttering treatment research 1970–2005: II. Systematic review incorporating trial quality assessment of pharmacological approaches. Am J Speech Lang Pathol 2006;15:342-52.
Kossoff EH, Boatman D, Freeman JM. Landau–Kleffner syndrome responsive to levetiracetam. Epilepsy Behav 2003;4:571-5.
Mulder LJ, Spierings EL. Stuttering relieved by divalproex sodium. Neurology 2003;61:714.
Kessler J, Thiel A, Karbe H, Heiss WD. Piracetam improves activated blood flow and facilitates rehabilitation of poststroke aphasic patients. Stroke 2000;31:2112-6.
Piazzini A, Chifari R, Canevini MP, Turner K, Fontana SP, Canger R. Levetiracetam: An improvement of attention and of oral fluency in patients with partial epilepsy. Epilepsy Res 2006;68:181-8.
Genton P, Van BV. Piracetam and levetiracetam: Close structural similarities but different pharmacological and clinical profiles. Epileptic Disord 2000;2:99-105.
Tallal P, Chase C, Russell G, Schmitt RL. Evaluation of the efficacy of piracetam in treating information processing, reading and writing disorders in dyslexic children. Int J Psychophysiol 1986;4:41-52.
Tonekaboni SH, Ghazavi M, Karimzadeh P, Mahvelati F, Ghofrani M. Efficacy of levetiracetam in children with refractory epilepsy as an add-on trial. Epilepsy Res 2010;90:273-7.
Neyens LG, Alpherts WC, Aldenkamp AP. Cognitive effects of a new pyrrolidine derivative (levetiracetam) in patients with epilepsy. Prog Neuropsychopharmacol Biol Psychiatry 1995;19:411-9.
Landau WM, Kleffner FR. Syndrome of acquired aphasia with convulsive disorder in children. Neurology 1998;51:1241-1241-a.
Deonna TW. Acquired epileptiform aphasia in children (Landau–Kleffner syndrome). J Clin Neurophysiol 1991;8:288-98.
Pearl PL, Carrazana EJ, Holmes GL. The Landau–Kleffner syndrome. Epilepsy Curr 2001;1:39-45.
Jain LC, Patnaik S, Ichalkaranje N. Intelligent computing, communication and devices. In Proceedings of ICCD. 2014. Springer.
Hoffman L, Wilson L, Copley A, Hewat S, Lim V. The reliability of a severity rating scale to measure stuttering in an unfamiliar language. Int J Speech Lang Pathol 2014;16:317-26.
Neef NE, Anwander A, Friederici AD. The neurobiological grounding of persistent stuttering: From structure to function. Curr Neurol Neurosci Rep 2015;15:63.
Gold M, VanDam D, Silliman ER. An open-label trial of bromocriptine in nonfluent aphasia: A qualitative analysis of word storage and retrieval. Brain Lang 2000;74:141-56.
Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, et al.
The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A 2004;101:9861-6.
Buckley K, Kelly RB. Identification of a transmembrane glycoprotein specific for secretory vesicles of neural and endocrine cells. J Cell Biol 1985;100:1284-94.
Bajjalieh SM, Frantz GD, Weimann JM, McConnell SK, Scheller RH. Differential expression of synaptic vesicle protein 2 (SV2) isoforms. J Neurosci 1994;14:5223-35.
Foundas AL, Bollich AM, Corey DM, Hurley M, Heilman KM. Anomalous anatomy of speech–language areas in adults with persistent developmental stuttering. Neurology 2001;57:207-15.
[Table 1], [Table 2]