CHAPTER TWELVE
Antiepileptic Drugs and Tourette Syndrome Andrea E. Cavanna*,†,{,1, Andrea Nani*
*Michael Trimble Neuropsychiatry Research Group, BSMHFT and University of Birmingham,Birmingham, United Kingdom † School of Life and Health Sciences, Aston University, Birmingham, United Kingdom { Sobell Department of Motor Neuroscience and Movement Disorders, UCL and Institute of Neurology, London, United Kingdom 1 Corresponding author: e-mail address: [email protected]
Contents 1. 2. 3. 4.
Introduction TS: From Motion to Emotion Pharmacological Treatments for Tics Treatment with AEDs 4.1 Topiramate 4.2 Levetiracetam 4.3 Clonazepam 5. Discussion Acknowledgments References
374 375 377 378 378 379 383 383 385 385
Abstract Tourette syndrome is a neurodevelopmental disorder characterized by the chronic presence of multiple motor tics and at least one vocal/phonic tic for the duration of 1 year. The clinical picture of patients with Tourette syndrome is often complicated by ticrelated behavioral problems and associated psychopathology. The pathophysiology of Tourette syndrome is not thoroughly understood, however converging evidence from neuroimaging studies suggests abnormalities within the frontostriatal pathways which are mediated by several neurotransmitters. The pharmacological management of the tic symptoms focuses on the dopaminergic and noradrenergic pathways and aims to improve the health-related quality of life of patients. The most common medications are neuroleptics and atypical antipsychotics, which have a strong D2 blocking action. Also, preliminary studies have documented the efficacy of antiepileptic drugs in controlling tics. Thus far, two anticonvulsants (topiramate and levetiracetam) have been tested with a randomized, double-blind, placebo-controlled procedure in the treatment of tics. A study has reported an improvement in the control of tics with topiramate. This pharmacological agent was also reported to be well tolerated by the patients. However, the most frequent observed topiramate side effects (such as somnolence, cognitive
International Review of Neurobiology, Volume 112 ISSN 0074-7742 http://dx.doi.org/10.1016/B978-0-12-411546-0.00012-3
#
2013 Elsevier Inc. All rights reserved.
373
374
Andrea E. Cavanna and Andrea Nani
problems, and weight loss) could not have manifested because of the short trial duration. Levetiracetam has shown conflicting results. A study found significant improvements in the control of tics, also associated with improvement in school performance. These results, however, were not replicated in other studies. Further investigations are therefore needed to assess the real efficacy of antiepileptic drugs in the treatment of tics.
1. INTRODUCTION Gilles de la Tourette’s syndrome or Tourette syndrome (TS) is a chronic neurodevelopmental disorder characterized by the presence of multiple motor tics and at least one vocal/phonic tic. Current diagnostic criteria stipulate the duration of more than 1 year, without tic-free intervals longer than 3 consecutive months and with onset before 18 years of age (typically 3–8 years for motor tics and 11 years for vocal tics; DSM-IV-TR; American Psychiatric Association, 2000; Robertson & Cavanna, 2008). The etiology of TS is complex; in addition to heterogeneous genetic influences, both repeated streptococcal infections and pre/perinatal complications have been shown to affect the phenotype (Robertson, 2005). Several genetic variants have been identified in patients with TS, suggesting the possibility that TS might include different clinical phenotypes (Abelson et al., 2005; Keen-Kim & Freimer, 2006). From the neurophysiological point of view, TS seems to involve primarily alterations in dopamine neurotransmission. In particular, increased expression of dopamine receptors has been documented both in the striatum and cortex, with abnormalities in dopamine binding being localized at the level of the basal ganglia (Roessner et al., 2011). Converging findings from neuroimaging investigations have revealed abnormal patterns of activity within the basal ganglia in patients with TS compared to healthy subjects. These results have also been confirmed by studies on brain metabolism, with particular involvement of the caudate nucleus and ventral striatum, which are essential regions for the expression of motor behavior (Frey & Albin, 2006). The central implication of the striatum in the pathophysiology of TS has been supported by multiple lines of evidence (Bronfeld & Bar-Gad, 2013; Draganski et al., 2010). This brain area subserves a variety of activities in cooperation with the frontal cortex, ranging from cognitive to behavioral and motor functions (Alexander, DeLong, & Strick, 1986; DeLong et al., 1984). Over the last few decades, it has become apparent that these functions, rather than being
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parallel separate domains, are in fact strictly interweaved (Haber, Kim, Mailly, & Calzavara, 2006; Haber, Lynd, Klein, & Groenewegen, 1990). It has been suggested, therefore, that the striatum may operate as a relay station for the expression thoughts and actions along the compulsive–impulsive spectrum (Frank, Piedad, Rickards, & Cavanna, 2011; Wright, Rickards, & Cavanna, 2012). This concept has the merit to account for the multifaceted symptomatology of TS, characterized by motor, psychiatric, and cognitive features (Cavanna & Rickards, 2013).
2. TS: FROM MOTION TO EMOTION A large multicenter study showed that only 12% of 3500 patients with TS do not present a concomitant psychopathology (Freeman et al., 2000). The most commonly reported comorbidities were obsessive–compulsive disorder (OCD) and attention deficit/hyperactivity disorder (ADHD), followed by affective and personality disorders (Cavanna & Rickards, 2013). These findings have been replicated in both clinic and community settings. In particular, studies using quantitative methods, such as principal component factor analysis, hierarchical cluster analysis, and latent class analysis, have indicated that TS should be considered a complex heterogeneous condition rather than a unitary disorder, with a spectrum of symptoms ranging from tics to comorbid behavioral problems. A recent study looking at the behavioral spectrum of TS in a sample of 639 patients from a single specialist clinic showed that only 10.6% of the patients did not fulfill diagnostic criteria for associated psychiatric disorders (66.6% of the patients had comorbid ADHD, 36.4% OCD, and 36.1% affective disorders). The authors identified three different factors accounting for 48.5% of the total symptomatic variance: complex motor tics and echo-paliphenomena, attention deficit and hyperactivity symptoms plus aggressive behaviors, and complex vocal tics and coprophenomena (Cavanna et al., 2011). Another study (Khalifa & von Knorring, 2005), conducted within a community setting, examined a total population of 4479 children and found a similar prevalence of comorbid psychiatric disorders in the children diagnosed with TS (n ¼ 25). In this study, 68% of patients have comorbid ADHD, 20% depression, and 16% OCD. Moreover, parents and siblings of children with TS had an increased prevalence of tic disorders, OCD, ADHD, and depression (80% had a firstdegree relative with a psychiatric disorder). Converging data indicate that 60–80% of patients with TS fulfill diagnostic criteria for ADHD (Cavanna & Rickards, 2013). Of note, comorbid
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psychiatric problems are persistently correlated with the severity of tic symptoms (Zhu, Leung, Liu, Zhou, & Su, 2006). ADHD symptoms usually precede the onset of tics and may therefore contribute more to behavioral problems, difficulties in school performance, and deficits in executive functions (Singer et al., 1995). Moreover, the ability to concentrate of patients with TS may be significantly affected by the constant effort that they need to exert in order to suppress their tics (Jankovic, 2001; Leckman, 2002; Simpson, Jung, & Murphy, 2011). In consideration of this, it has been suggested that the clinical assessment of patients with TS and ADHD should focus on the identification of the most problematic symptoms in order to select a treatment strategy (Robertson, 2006). Similar to TS, OCD generally begins at a young age (Shafran, 2001). In the abovementioned multicenter study, obsessive–compulsive symptoms were found in 32% of cases, whereas 27% of patients fulfilled formal diagnostic criteria for OCD (Freeman et al., 2000). The two conditions seem to be intrinsically associated, albeit the percentage of patients with TS that also manifest OCD symptoms can vary from 11% to 80%, according to the different methodologies adopted in cross-sectional studies (Cavanna, Servo, Monaco, & Robertson, 2009; Robertson, 2000). In favor of the association between TS and OCD, there is also the clinical observation that relatives of patients with TS frequently present obsessive–compulsive symptoms or even OCD (Eapen, Pauls, & Robertson, 1993; Pauls, Towbin, Leckman, Zahner, & Cohen, 1986; Robertson & Gourdie, 1990). Significantly, it has been highlighted that TS and OCD share certain neurochemical and neuroanatomical features (Como, LaMarsh, & O’Brien, 2005). In fact, specific abnormalities at the level of the frontal cortex and basal ganglia have been found in both these pathologies, and specific functional alterations in the striatum and limbic system appear to be involved in the generation of motor and vocal/phonic tics when primarily affecting the dopaminergic and noradrenergic circuits or obsessions and compulsions when primarily affecting the serotonergic circuit (Cavanna & Rickards, 2013). In the multicenter study by Freeman et al. (2000), 20% of patients with TS also presented with clinically significant depressive symptoms. Depressive symptomatology seems to depend on the degree of severity and duration of tics, as well as on the presence of premonitory urges, OCD, ADHD, sleep disorders, and self-injurious behaviors (Robertson, 2006). However, given the multifactorial etiology of depression, this psychiatric condition does not appear to be associated with TS per se, as it is the case with other
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comorbidities such as ADHD and OCD (Shafran, 2001). For example, in a number of patients depressive symptoms are likely to develop as a side effect of antidopaminergic medications (Robertson, 2000). Finally, personality disorders are relatively common in patients with TS. In a study with a sample of 102 cases, 15% of patients received a diagnosis of personality disorder according to the DSM-IV criteria (Cavanna, Robertson, & Critchley, 2007). The presence of multiple psychiatric comorbidities positively correlated with schizotypal manifestations. The strongest predictors of schizotypy appear to be the presence of obsessive–compulsive symptoms and trait anxiety (Cavanna, Martino, et al., 2009).
3. PHARMACOLOGICAL TREATMENTS FOR TICS The treatment choice for TS is complicated by the vast range of symptoms and the variability of TS phenotypes across patients. A further complicating factor is the intrinsic waxing and waning nature of tics. With regard to efficacy, no pharmacological agent has yet been found to be capable of reliably improving tics in all patients. A trial-and-error approach is therefore often necessary in order to identify the most suitable treatment for a patient, especially in case of comorbidities such as ADHD and OCD (Eddy, Rickards, & Cavanna, 2011a). The most common treatment for tics is pharmacotherapy. Since the pathophysiology of TS appears to involve abnormalities in dopaminergic circuits, dopamine antagonists are the mainstay for pharmacological treatment, sometimes in addition to behavioral interventions such as habit reversal therapy (Robertson, 2011). In particular, robust evidence supports the administration of typical antipsychotic or neuroleptics (especially haloperidol and pimozide), which have a strong D2 blocking action. Generally, the higher the efficacy of dopamine-blocking action, the stronger the tic-suppressing effects (Scahill et al., 2006). However, neuroleptics can have significant side effect as they also interfere with cholinergic, serotonergic, histaminergic, and a-adrenergic pathways. Newer drugs characterized by affinity for D2 receptors are the atypical antipsychotics (e.g., risperidone, aripiprazole, olanzapine, etc.). Atypical antipsychotics are characterized by a more selective blocking dopamine receptor D2, but they can also have an effect on serotonin. Compared to typical antipsychotics, atypical antipsychotics may be considered safer drugs for the treatment of tics, due to a lesser risk of acute or subacute motor side effects (Cavanna et al., 2007).
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Other pharmacological agents, which can be used as alternative to neuroleptics and atypical antipsychotics are benzamides (such as sulpiride and tiapride), tetrabenazine, a-adrenergic agonist (such as clonidine and guanfacine), dopamine agonists (such as pergolide, apomorphine, etc.), anticholinergics (such as nicotine), and cannabinoids (Cavanna et al., 2007; Thomas & Cavanna, 2013). However, some of these medications show a tolerability profile partially overlapping with that of antidopaminergic agents, especially with regard to behavioral (depression) and metabolic (weight gain, sedation, hyperprolactinemia) side effects. Over the last few years, preliminary studies have explored the potential efficacy of antiepileptic drugs (AEDs) in controlling tics (Goetz, 1992; Steingard, Goldberg, Lee, & De Maso, 1994; Troung, Bressman, Shale, & Fahn, 1988). AEDs are characterized by multiple mechanisms of action, which can account for their multifaceted spectrum of therapeutic actions. The next section is dedicated to review the recent scientific literature on this topic.
4. TREATMENT WITH AEDs As we have seen, TS pathophysiology is likely to involve abnormalities in the regulation of dopaminergic activity, especially within the basal ganglia and frontal cortex. In fact, there is converging evidence that cortico-striatothalamo-cortical pathways are a key site for the origin of tics and related neuropsychiatric problems. This physiological abnormality can be caused by an excess of thalamic excitation accompanied by an impaired intracortical inhibition. Specifically, it has been hypothesized that an increase in glutaminergic cortical excitability could lead to the appearance of tics, due to an alteration of cortical inhibition of the thalamocortical afferences (Singer & Minzer, 2003). As g-aminobutyric acid (GABA) is one of the several neurotransmitters involved in these circuits, different studies have been carried out in recent years in order to investigate the effectiveness of GABAmodulating agents in the treatment of tics.
4.1. Topiramate Topiramate is a broad-spectrum AED that can be used as monotherapy or add-on to other pharmacological agents to optimize seizure control. It has also been reported that topiramate can be efficacious in the treatment of headache, bipolar affective disorder, pain, and essential tremor (Ondo et al., 2006). The exact mechanisms of action of topiramate is unclear,
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but the agent is likely to enhance GABA subtype A (GABAA)receptor-mediated chloride flux, thereby potentiating GABA-mediated inhibition. It is also known that topiramate blocks the AMPA/kainite subtype of glutamate receptors, without having effects on the N-methyl-Daspartate subtype. In humans, topiramate increases GABA, homocarnosine, and pyrrolidinone concentrations while it inhibits carbonic anhydrase activity (Lyseng-Williamson & Yang, 2007). Topiramate has a peak serum concentration 1–4 h after ingestion and carries no risk of tardive dyskinesia or weight gain compared to neuroleptics. In 2010, a randomized double-blind placebo-controlled study was conducted to test the efficacy of topiramate in patients with a DSM-IV-validated diagnosis of TS (Jankovic, Jimenez-Shahed, & Brown, 2010). Subjects included in the research were between 7 and 65 years of age and presented with moderate to severe symptoms (Yale Global Tic Severity Scale (YGTSS) 19). All participants were considered markedly impaired according to the Clinical Global Impression (CGI) scale, with a severity score 4. Subjects taking more than one drug for tics or more than one agent for comorbid behavioral symptoms were excluded. Of the 29 patients (26 males) that met the inclusion criteria, 20 (69%) completed the doubleblind phase of the research. Fifteen were allocated to the topiramate group, whereas 14 were the placebo group. Attention deficit disorder (with or without hyperactivity), OCD, and migraine headaches were the most common comorbidities diagnosed in both the topiramate group and the placebo group. The study reported significant improvements in the ratings of the Total Tic Score (TTS) with a dose of about 100 mg/day, as well as statistically improvements in the other components of the YGTSS and CGI. These results confirmed a previous study in which two adult patients with TS reported a significant improvement in their symptoms with topiramate (50–200 mg/day) (Abuzzahab & Brown, 2001). In the study by Jankovic et al., topiramate was well tolerated, but it is possible that the commonly observed side effects of topiramate (such as somnolence, cognitive problems, and weight loss) did not emerge because of the brief trial duration. Therefore, a larger trial with a longer follow-up period is needed before recommending topiramate as a routine treatment for tics.
4.2. Levetiracetam Levetiracetam is an AED with atypical GABAergic effects (Poulain & Margineanu, 2002). It enhances chloride ion influx at the GABAA–receptor
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complex by reducing the effect of zinc and beta carbolines, which can interrupt the chloride flux (Awaad, Michon, & Minarik, 2005). An open-label study reported the effect of levetiracetam on motor and vocal/phonic tics in a population of 60 patients with TS (Awaad et al., 2005). All the patients were newly diagnosed and therefore never previously treated (drug naive) for TS. They were 18 years of age and met DSM-IV criteria for tic disorders and TS. The study reports that the initial dose of levetiracetam was 250 mg/day, subsequently titrated over a 3-week period up to 1000–2000 mg/day, according to individual response and tolerability. Every 5–7 days, the dosage was increased by 250 mg. Patients were treated with levetiracetam for 1 year without add-on medications. The effect of the drug was recorded with regard to measures of behavior and school performance. Results demonstrated that levetiracetam improved the clinical condition in all the patients. Forty-three patients improved in both their behavior and school performance according to the rating scores determined by the Revised Conners’ Parent Rating Scale and the Conners–Wells’ Adolescent Self-Report Scale-Short version. Moreover, all 60 patients exhibited significant improvements in their motor and vocal/phonic tics according to the rating scores determined by YGTSS, TTS, CGI, and Tic Impairment Score (TIS). The authors highlighted that levetiracetam has a very low potential for interacting with other drugs, an important factor for patients who need the concurrent use of other medications to treat comorbidities, such as ADHD. In a 4-year follow-up of this study, levetiracetam was still 100% effective for tic regulation and 70% of the patients kept showing improvement in behavior and school performance (Awaad & Minarik, 2005). Another study, however, found no significant improvement in using levetiracetam for treating tics (Smith-Hicks, Bridges, Paynter, & Singer, 2007). The research was a double-blind randomized placebo-controlled trial in which each child was administered 10 mg/day for 1 week. The dose was then increased by 10 mg/day on a weekly basis to a maximum dosage of 30 mg/day. After 4 weeks patients were assessed with standardized outcome scales (YGTSS, CGI, TIS, and TTS). Then medications were reduced over a 10-day period at a rate of 5–10 mg/day every third day. Subjects were reassessed after a 5-day drug-free interval. The participants were 22 children (21 males; age range 8–16) with TS, fulfilling diagnostic criteria provided by Tourette Syndrome Classification Study Group (1993). All patients had moderate to severe tics as indicated by TTS. With regard to comorbidities, 11 patients presented with ADHD symptoms, 10 with
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obsessive–compulsive behaviors, 2 with full-blown OCD, 4 with rage, and 7 with anxiety. Eleven patients were administered other tic-suppressing medications, including clonidine (six patients), guanfacine (four patients), risperidone (one patient). Other medications included citalopram (one patient) and methylphenidate (one patient). Side effects were also assessed according to the expanded Pittsburgh Side Effect Scale (Pelham et al., 1993), modified by the authors in order to include levetiracetam side effects. ADHD was assessed according to the scale developed by Barkley, DuPaul, and McMurray (1991); obsessive–compulsive behaviors were assessed using the Child Yale–Brown Obsessive–Compulsive Scale (Scahill et al., 1997); anxiety symptoms were rated according to the Multidimensional Anxiety Scale for Children (March, Parker, Sullivan, Stallings, & Conners, 1997); depression was evaluated with the Child Depression Inventory (Kovacs, 1985). In contrast to the study described earlier, this study did not identify benefit in using levetiracetam for controlling tics. Tic suppression scores showed similar improvements in both the drug and placebo phases. Also secondary outcome measures, related to inattentiveness, hyperactivity, obsessive–compulsive behaviors, rage, depression, and anxiety did not improve. Thus, authors concluded that levetiracetam is not more effective for the treatment of tics than placebo. The effectiveness of levetiracetam has further been investigated in another research which involved a 12-week, prospective, open-label study on 29 patients with TS (25 males), diagnosed according to DSM-IV criteria (Ferna´ndez-Jae´n, Ferna´ndez-Mayoralas, Mun˜oz-Jaren˜o, & Calleja-Pe´rez, 2009). Authors considered the following exclusion factors: heart or kidney failure, decompensated associated diseases, pregnancy, mental retardation, generalized developmental disorder, psychosis, or inability to adhere to a stable treatment regimen. Levetiracetam dosage started with 20 mg/day and was gradually titrated up to 30–40 mg/day over 1 week. The reached maximum dose was 2000 mg/day, which was received by one boy, while the minimum dose was 800 mg/day, which was received by one girl; all the other patients were administered up to 1000 mg/day. The following data were recorded: age at which treatment started, gender, age at diagnosis, prior and concomitant treatments, health status at the beginning of the study using the YGTSS and the modified Clinical Global Impression Scale (MCGI) (Leckman et al., 1989), and clinical assessment after 3 months using the same scales. Comorbidities were ADHD in 22 patients, OCD in 11 patients, and oppositional defiant disorder in 9 patients. Twenty-two children have previously been treated with neuroleptics, 14 with methylphenidate, 5 with
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clonidine, and 4 with tricyclic antidepressants. During the trial, 10 children received concomitant treatment with neuroleptics, 14 with methylphenidate, and 3 with clonidine. Twenty-one out of the 29 patients improved according to YGTSS and MCGI scores, while tics worsened in 5 patients. Significantly, patients with ADHD showed a marked improvement with respect to those without this comorbidity. No significant improvement was noticed with other comorbid disorders. With regard to side effects, the most common were irritability (affecting six patients) and drowsiness (affecting two patients). Only three patients discontinued their medication because of poor tolerability. Authors concluded that levetiracetam may be a useful treatment to control tics in selected patients with TS, who can be particularly sensitive to this drug, especially with a comorbidity with ADHD. Finally, levetiracetam has been studied in comparison with clonidine in a randomized, double-blind, crossover study (Hedderick, Morris, & Singer, 2009). Clonidine is an a-2 adrenergic receptor agonist mainly targeting presynaptic autoreceptors in the locus coeruleus, thereby reducing norepinephrine release and turnover. Based on limited evidence for its efficacy (Goetz et al., 1987; Leckman et al., 1991), clonidine has been used in the treatment of tics for more than three decades (Cohen, Young, Nathanson, & Shaywitz, 1979). Of the 12 patients with TS (aged 8–30 years) who were enrolled for the study, 10 completed the 15-week randomized, double-blind, flexibledose crossover protocol. Patients fulfilled the diagnostic criteria for TS defined by the Tourette Syndrome Classification Study Group (1993). All patients had moderate to moderately severe tics according to the TTS and YGTSS. Patients with comorbid conditions, such as ADHD, OCD, and conduct disorder, were not excluded. By contrast, patients were excluded if they presented with secondary tics, current major depression, untreated generalized anxiety disorder, separation anxiety disorder, psychotic signs (clinically evaluated), pervasive developmental disorder, autism, mental retardation (intelligent quotient
Antiepileptic Drugs and Tourette Syndrome Andrea E. Cavanna*,†,{,1, Andrea Nani*
*Michael Trimble Neuropsychiatry Research Group, BSMHFT and University of Birmingham,Birmingham, United Kingdom † School of Life and Health Sciences, Aston University, Birmingham, United Kingdom { Sobell Department of Motor Neuroscience and Movement Disorders, UCL and Institute of Neurology, London, United Kingdom 1 Corresponding author: e-mail address: [email protected]
Contents 1. 2. 3. 4.
Introduction TS: From Motion to Emotion Pharmacological Treatments for Tics Treatment with AEDs 4.1 Topiramate 4.2 Levetiracetam 4.3 Clonazepam 5. Discussion Acknowledgments References
374 375 377 378 378 379 383 383 385 385
Abstract Tourette syndrome is a neurodevelopmental disorder characterized by the chronic presence of multiple motor tics and at least one vocal/phonic tic for the duration of 1 year. The clinical picture of patients with Tourette syndrome is often complicated by ticrelated behavioral problems and associated psychopathology. The pathophysiology of Tourette syndrome is not thoroughly understood, however converging evidence from neuroimaging studies suggests abnormalities within the frontostriatal pathways which are mediated by several neurotransmitters. The pharmacological management of the tic symptoms focuses on the dopaminergic and noradrenergic pathways and aims to improve the health-related quality of life of patients. The most common medications are neuroleptics and atypical antipsychotics, which have a strong D2 blocking action. Also, preliminary studies have documented the efficacy of antiepileptic drugs in controlling tics. Thus far, two anticonvulsants (topiramate and levetiracetam) have been tested with a randomized, double-blind, placebo-controlled procedure in the treatment of tics. A study has reported an improvement in the control of tics with topiramate. This pharmacological agent was also reported to be well tolerated by the patients. However, the most frequent observed topiramate side effects (such as somnolence, cognitive
International Review of Neurobiology, Volume 112 ISSN 0074-7742 http://dx.doi.org/10.1016/B978-0-12-411546-0.00012-3
#
2013 Elsevier Inc. All rights reserved.
373
374
Andrea E. Cavanna and Andrea Nani
problems, and weight loss) could not have manifested because of the short trial duration. Levetiracetam has shown conflicting results. A study found significant improvements in the control of tics, also associated with improvement in school performance. These results, however, were not replicated in other studies. Further investigations are therefore needed to assess the real efficacy of antiepileptic drugs in the treatment of tics.
1. INTRODUCTION Gilles de la Tourette’s syndrome or Tourette syndrome (TS) is a chronic neurodevelopmental disorder characterized by the presence of multiple motor tics and at least one vocal/phonic tic. Current diagnostic criteria stipulate the duration of more than 1 year, without tic-free intervals longer than 3 consecutive months and with onset before 18 years of age (typically 3–8 years for motor tics and 11 years for vocal tics; DSM-IV-TR; American Psychiatric Association, 2000; Robertson & Cavanna, 2008). The etiology of TS is complex; in addition to heterogeneous genetic influences, both repeated streptococcal infections and pre/perinatal complications have been shown to affect the phenotype (Robertson, 2005). Several genetic variants have been identified in patients with TS, suggesting the possibility that TS might include different clinical phenotypes (Abelson et al., 2005; Keen-Kim & Freimer, 2006). From the neurophysiological point of view, TS seems to involve primarily alterations in dopamine neurotransmission. In particular, increased expression of dopamine receptors has been documented both in the striatum and cortex, with abnormalities in dopamine binding being localized at the level of the basal ganglia (Roessner et al., 2011). Converging findings from neuroimaging investigations have revealed abnormal patterns of activity within the basal ganglia in patients with TS compared to healthy subjects. These results have also been confirmed by studies on brain metabolism, with particular involvement of the caudate nucleus and ventral striatum, which are essential regions for the expression of motor behavior (Frey & Albin, 2006). The central implication of the striatum in the pathophysiology of TS has been supported by multiple lines of evidence (Bronfeld & Bar-Gad, 2013; Draganski et al., 2010). This brain area subserves a variety of activities in cooperation with the frontal cortex, ranging from cognitive to behavioral and motor functions (Alexander, DeLong, & Strick, 1986; DeLong et al., 1984). Over the last few decades, it has become apparent that these functions, rather than being
Antiepileptic Drugs and Tourette Syndrome
375
parallel separate domains, are in fact strictly interweaved (Haber, Kim, Mailly, & Calzavara, 2006; Haber, Lynd, Klein, & Groenewegen, 1990). It has been suggested, therefore, that the striatum may operate as a relay station for the expression thoughts and actions along the compulsive–impulsive spectrum (Frank, Piedad, Rickards, & Cavanna, 2011; Wright, Rickards, & Cavanna, 2012). This concept has the merit to account for the multifaceted symptomatology of TS, characterized by motor, psychiatric, and cognitive features (Cavanna & Rickards, 2013).
2. TS: FROM MOTION TO EMOTION A large multicenter study showed that only 12% of 3500 patients with TS do not present a concomitant psychopathology (Freeman et al., 2000). The most commonly reported comorbidities were obsessive–compulsive disorder (OCD) and attention deficit/hyperactivity disorder (ADHD), followed by affective and personality disorders (Cavanna & Rickards, 2013). These findings have been replicated in both clinic and community settings. In particular, studies using quantitative methods, such as principal component factor analysis, hierarchical cluster analysis, and latent class analysis, have indicated that TS should be considered a complex heterogeneous condition rather than a unitary disorder, with a spectrum of symptoms ranging from tics to comorbid behavioral problems. A recent study looking at the behavioral spectrum of TS in a sample of 639 patients from a single specialist clinic showed that only 10.6% of the patients did not fulfill diagnostic criteria for associated psychiatric disorders (66.6% of the patients had comorbid ADHD, 36.4% OCD, and 36.1% affective disorders). The authors identified three different factors accounting for 48.5% of the total symptomatic variance: complex motor tics and echo-paliphenomena, attention deficit and hyperactivity symptoms plus aggressive behaviors, and complex vocal tics and coprophenomena (Cavanna et al., 2011). Another study (Khalifa & von Knorring, 2005), conducted within a community setting, examined a total population of 4479 children and found a similar prevalence of comorbid psychiatric disorders in the children diagnosed with TS (n ¼ 25). In this study, 68% of patients have comorbid ADHD, 20% depression, and 16% OCD. Moreover, parents and siblings of children with TS had an increased prevalence of tic disorders, OCD, ADHD, and depression (80% had a firstdegree relative with a psychiatric disorder). Converging data indicate that 60–80% of patients with TS fulfill diagnostic criteria for ADHD (Cavanna & Rickards, 2013). Of note, comorbid
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psychiatric problems are persistently correlated with the severity of tic symptoms (Zhu, Leung, Liu, Zhou, & Su, 2006). ADHD symptoms usually precede the onset of tics and may therefore contribute more to behavioral problems, difficulties in school performance, and deficits in executive functions (Singer et al., 1995). Moreover, the ability to concentrate of patients with TS may be significantly affected by the constant effort that they need to exert in order to suppress their tics (Jankovic, 2001; Leckman, 2002; Simpson, Jung, & Murphy, 2011). In consideration of this, it has been suggested that the clinical assessment of patients with TS and ADHD should focus on the identification of the most problematic symptoms in order to select a treatment strategy (Robertson, 2006). Similar to TS, OCD generally begins at a young age (Shafran, 2001). In the abovementioned multicenter study, obsessive–compulsive symptoms were found in 32% of cases, whereas 27% of patients fulfilled formal diagnostic criteria for OCD (Freeman et al., 2000). The two conditions seem to be intrinsically associated, albeit the percentage of patients with TS that also manifest OCD symptoms can vary from 11% to 80%, according to the different methodologies adopted in cross-sectional studies (Cavanna, Servo, Monaco, & Robertson, 2009; Robertson, 2000). In favor of the association between TS and OCD, there is also the clinical observation that relatives of patients with TS frequently present obsessive–compulsive symptoms or even OCD (Eapen, Pauls, & Robertson, 1993; Pauls, Towbin, Leckman, Zahner, & Cohen, 1986; Robertson & Gourdie, 1990). Significantly, it has been highlighted that TS and OCD share certain neurochemical and neuroanatomical features (Como, LaMarsh, & O’Brien, 2005). In fact, specific abnormalities at the level of the frontal cortex and basal ganglia have been found in both these pathologies, and specific functional alterations in the striatum and limbic system appear to be involved in the generation of motor and vocal/phonic tics when primarily affecting the dopaminergic and noradrenergic circuits or obsessions and compulsions when primarily affecting the serotonergic circuit (Cavanna & Rickards, 2013). In the multicenter study by Freeman et al. (2000), 20% of patients with TS also presented with clinically significant depressive symptoms. Depressive symptomatology seems to depend on the degree of severity and duration of tics, as well as on the presence of premonitory urges, OCD, ADHD, sleep disorders, and self-injurious behaviors (Robertson, 2006). However, given the multifactorial etiology of depression, this psychiatric condition does not appear to be associated with TS per se, as it is the case with other
Antiepileptic Drugs and Tourette Syndrome
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comorbidities such as ADHD and OCD (Shafran, 2001). For example, in a number of patients depressive symptoms are likely to develop as a side effect of antidopaminergic medications (Robertson, 2000). Finally, personality disorders are relatively common in patients with TS. In a study with a sample of 102 cases, 15% of patients received a diagnosis of personality disorder according to the DSM-IV criteria (Cavanna, Robertson, & Critchley, 2007). The presence of multiple psychiatric comorbidities positively correlated with schizotypal manifestations. The strongest predictors of schizotypy appear to be the presence of obsessive–compulsive symptoms and trait anxiety (Cavanna, Martino, et al., 2009).
3. PHARMACOLOGICAL TREATMENTS FOR TICS The treatment choice for TS is complicated by the vast range of symptoms and the variability of TS phenotypes across patients. A further complicating factor is the intrinsic waxing and waning nature of tics. With regard to efficacy, no pharmacological agent has yet been found to be capable of reliably improving tics in all patients. A trial-and-error approach is therefore often necessary in order to identify the most suitable treatment for a patient, especially in case of comorbidities such as ADHD and OCD (Eddy, Rickards, & Cavanna, 2011a). The most common treatment for tics is pharmacotherapy. Since the pathophysiology of TS appears to involve abnormalities in dopaminergic circuits, dopamine antagonists are the mainstay for pharmacological treatment, sometimes in addition to behavioral interventions such as habit reversal therapy (Robertson, 2011). In particular, robust evidence supports the administration of typical antipsychotic or neuroleptics (especially haloperidol and pimozide), which have a strong D2 blocking action. Generally, the higher the efficacy of dopamine-blocking action, the stronger the tic-suppressing effects (Scahill et al., 2006). However, neuroleptics can have significant side effect as they also interfere with cholinergic, serotonergic, histaminergic, and a-adrenergic pathways. Newer drugs characterized by affinity for D2 receptors are the atypical antipsychotics (e.g., risperidone, aripiprazole, olanzapine, etc.). Atypical antipsychotics are characterized by a more selective blocking dopamine receptor D2, but they can also have an effect on serotonin. Compared to typical antipsychotics, atypical antipsychotics may be considered safer drugs for the treatment of tics, due to a lesser risk of acute or subacute motor side effects (Cavanna et al., 2007).
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Other pharmacological agents, which can be used as alternative to neuroleptics and atypical antipsychotics are benzamides (such as sulpiride and tiapride), tetrabenazine, a-adrenergic agonist (such as clonidine and guanfacine), dopamine agonists (such as pergolide, apomorphine, etc.), anticholinergics (such as nicotine), and cannabinoids (Cavanna et al., 2007; Thomas & Cavanna, 2013). However, some of these medications show a tolerability profile partially overlapping with that of antidopaminergic agents, especially with regard to behavioral (depression) and metabolic (weight gain, sedation, hyperprolactinemia) side effects. Over the last few years, preliminary studies have explored the potential efficacy of antiepileptic drugs (AEDs) in controlling tics (Goetz, 1992; Steingard, Goldberg, Lee, & De Maso, 1994; Troung, Bressman, Shale, & Fahn, 1988). AEDs are characterized by multiple mechanisms of action, which can account for their multifaceted spectrum of therapeutic actions. The next section is dedicated to review the recent scientific literature on this topic.
4. TREATMENT WITH AEDs As we have seen, TS pathophysiology is likely to involve abnormalities in the regulation of dopaminergic activity, especially within the basal ganglia and frontal cortex. In fact, there is converging evidence that cortico-striatothalamo-cortical pathways are a key site for the origin of tics and related neuropsychiatric problems. This physiological abnormality can be caused by an excess of thalamic excitation accompanied by an impaired intracortical inhibition. Specifically, it has been hypothesized that an increase in glutaminergic cortical excitability could lead to the appearance of tics, due to an alteration of cortical inhibition of the thalamocortical afferences (Singer & Minzer, 2003). As g-aminobutyric acid (GABA) is one of the several neurotransmitters involved in these circuits, different studies have been carried out in recent years in order to investigate the effectiveness of GABAmodulating agents in the treatment of tics.
4.1. Topiramate Topiramate is a broad-spectrum AED that can be used as monotherapy or add-on to other pharmacological agents to optimize seizure control. It has also been reported that topiramate can be efficacious in the treatment of headache, bipolar affective disorder, pain, and essential tremor (Ondo et al., 2006). The exact mechanisms of action of topiramate is unclear,
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but the agent is likely to enhance GABA subtype A (GABAA)receptor-mediated chloride flux, thereby potentiating GABA-mediated inhibition. It is also known that topiramate blocks the AMPA/kainite subtype of glutamate receptors, without having effects on the N-methyl-Daspartate subtype. In humans, topiramate increases GABA, homocarnosine, and pyrrolidinone concentrations while it inhibits carbonic anhydrase activity (Lyseng-Williamson & Yang, 2007). Topiramate has a peak serum concentration 1–4 h after ingestion and carries no risk of tardive dyskinesia or weight gain compared to neuroleptics. In 2010, a randomized double-blind placebo-controlled study was conducted to test the efficacy of topiramate in patients with a DSM-IV-validated diagnosis of TS (Jankovic, Jimenez-Shahed, & Brown, 2010). Subjects included in the research were between 7 and 65 years of age and presented with moderate to severe symptoms (Yale Global Tic Severity Scale (YGTSS) 19). All participants were considered markedly impaired according to the Clinical Global Impression (CGI) scale, with a severity score 4. Subjects taking more than one drug for tics or more than one agent for comorbid behavioral symptoms were excluded. Of the 29 patients (26 males) that met the inclusion criteria, 20 (69%) completed the doubleblind phase of the research. Fifteen were allocated to the topiramate group, whereas 14 were the placebo group. Attention deficit disorder (with or without hyperactivity), OCD, and migraine headaches were the most common comorbidities diagnosed in both the topiramate group and the placebo group. The study reported significant improvements in the ratings of the Total Tic Score (TTS) with a dose of about 100 mg/day, as well as statistically improvements in the other components of the YGTSS and CGI. These results confirmed a previous study in which two adult patients with TS reported a significant improvement in their symptoms with topiramate (50–200 mg/day) (Abuzzahab & Brown, 2001). In the study by Jankovic et al., topiramate was well tolerated, but it is possible that the commonly observed side effects of topiramate (such as somnolence, cognitive problems, and weight loss) did not emerge because of the brief trial duration. Therefore, a larger trial with a longer follow-up period is needed before recommending topiramate as a routine treatment for tics.
4.2. Levetiracetam Levetiracetam is an AED with atypical GABAergic effects (Poulain & Margineanu, 2002). It enhances chloride ion influx at the GABAA–receptor
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complex by reducing the effect of zinc and beta carbolines, which can interrupt the chloride flux (Awaad, Michon, & Minarik, 2005). An open-label study reported the effect of levetiracetam on motor and vocal/phonic tics in a population of 60 patients with TS (Awaad et al., 2005). All the patients were newly diagnosed and therefore never previously treated (drug naive) for TS. They were 18 years of age and met DSM-IV criteria for tic disorders and TS. The study reports that the initial dose of levetiracetam was 250 mg/day, subsequently titrated over a 3-week period up to 1000–2000 mg/day, according to individual response and tolerability. Every 5–7 days, the dosage was increased by 250 mg. Patients were treated with levetiracetam for 1 year without add-on medications. The effect of the drug was recorded with regard to measures of behavior and school performance. Results demonstrated that levetiracetam improved the clinical condition in all the patients. Forty-three patients improved in both their behavior and school performance according to the rating scores determined by the Revised Conners’ Parent Rating Scale and the Conners–Wells’ Adolescent Self-Report Scale-Short version. Moreover, all 60 patients exhibited significant improvements in their motor and vocal/phonic tics according to the rating scores determined by YGTSS, TTS, CGI, and Tic Impairment Score (TIS). The authors highlighted that levetiracetam has a very low potential for interacting with other drugs, an important factor for patients who need the concurrent use of other medications to treat comorbidities, such as ADHD. In a 4-year follow-up of this study, levetiracetam was still 100% effective for tic regulation and 70% of the patients kept showing improvement in behavior and school performance (Awaad & Minarik, 2005). Another study, however, found no significant improvement in using levetiracetam for treating tics (Smith-Hicks, Bridges, Paynter, & Singer, 2007). The research was a double-blind randomized placebo-controlled trial in which each child was administered 10 mg/day for 1 week. The dose was then increased by 10 mg/day on a weekly basis to a maximum dosage of 30 mg/day. After 4 weeks patients were assessed with standardized outcome scales (YGTSS, CGI, TIS, and TTS). Then medications were reduced over a 10-day period at a rate of 5–10 mg/day every third day. Subjects were reassessed after a 5-day drug-free interval. The participants were 22 children (21 males; age range 8–16) with TS, fulfilling diagnostic criteria provided by Tourette Syndrome Classification Study Group (1993). All patients had moderate to severe tics as indicated by TTS. With regard to comorbidities, 11 patients presented with ADHD symptoms, 10 with
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obsessive–compulsive behaviors, 2 with full-blown OCD, 4 with rage, and 7 with anxiety. Eleven patients were administered other tic-suppressing medications, including clonidine (six patients), guanfacine (four patients), risperidone (one patient). Other medications included citalopram (one patient) and methylphenidate (one patient). Side effects were also assessed according to the expanded Pittsburgh Side Effect Scale (Pelham et al., 1993), modified by the authors in order to include levetiracetam side effects. ADHD was assessed according to the scale developed by Barkley, DuPaul, and McMurray (1991); obsessive–compulsive behaviors were assessed using the Child Yale–Brown Obsessive–Compulsive Scale (Scahill et al., 1997); anxiety symptoms were rated according to the Multidimensional Anxiety Scale for Children (March, Parker, Sullivan, Stallings, & Conners, 1997); depression was evaluated with the Child Depression Inventory (Kovacs, 1985). In contrast to the study described earlier, this study did not identify benefit in using levetiracetam for controlling tics. Tic suppression scores showed similar improvements in both the drug and placebo phases. Also secondary outcome measures, related to inattentiveness, hyperactivity, obsessive–compulsive behaviors, rage, depression, and anxiety did not improve. Thus, authors concluded that levetiracetam is not more effective for the treatment of tics than placebo. The effectiveness of levetiracetam has further been investigated in another research which involved a 12-week, prospective, open-label study on 29 patients with TS (25 males), diagnosed according to DSM-IV criteria (Ferna´ndez-Jae´n, Ferna´ndez-Mayoralas, Mun˜oz-Jaren˜o, & Calleja-Pe´rez, 2009). Authors considered the following exclusion factors: heart or kidney failure, decompensated associated diseases, pregnancy, mental retardation, generalized developmental disorder, psychosis, or inability to adhere to a stable treatment regimen. Levetiracetam dosage started with 20 mg/day and was gradually titrated up to 30–40 mg/day over 1 week. The reached maximum dose was 2000 mg/day, which was received by one boy, while the minimum dose was 800 mg/day, which was received by one girl; all the other patients were administered up to 1000 mg/day. The following data were recorded: age at which treatment started, gender, age at diagnosis, prior and concomitant treatments, health status at the beginning of the study using the YGTSS and the modified Clinical Global Impression Scale (MCGI) (Leckman et al., 1989), and clinical assessment after 3 months using the same scales. Comorbidities were ADHD in 22 patients, OCD in 11 patients, and oppositional defiant disorder in 9 patients. Twenty-two children have previously been treated with neuroleptics, 14 with methylphenidate, 5 with
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clonidine, and 4 with tricyclic antidepressants. During the trial, 10 children received concomitant treatment with neuroleptics, 14 with methylphenidate, and 3 with clonidine. Twenty-one out of the 29 patients improved according to YGTSS and MCGI scores, while tics worsened in 5 patients. Significantly, patients with ADHD showed a marked improvement with respect to those without this comorbidity. No significant improvement was noticed with other comorbid disorders. With regard to side effects, the most common were irritability (affecting six patients) and drowsiness (affecting two patients). Only three patients discontinued their medication because of poor tolerability. Authors concluded that levetiracetam may be a useful treatment to control tics in selected patients with TS, who can be particularly sensitive to this drug, especially with a comorbidity with ADHD. Finally, levetiracetam has been studied in comparison with clonidine in a randomized, double-blind, crossover study (Hedderick, Morris, & Singer, 2009). Clonidine is an a-2 adrenergic receptor agonist mainly targeting presynaptic autoreceptors in the locus coeruleus, thereby reducing norepinephrine release and turnover. Based on limited evidence for its efficacy (Goetz et al., 1987; Leckman et al., 1991), clonidine has been used in the treatment of tics for more than three decades (Cohen, Young, Nathanson, & Shaywitz, 1979). Of the 12 patients with TS (aged 8–30 years) who were enrolled for the study, 10 completed the 15-week randomized, double-blind, flexibledose crossover protocol. Patients fulfilled the diagnostic criteria for TS defined by the Tourette Syndrome Classification Study Group (1993). All patients had moderate to moderately severe tics according to the TTS and YGTSS. Patients with comorbid conditions, such as ADHD, OCD, and conduct disorder, were not excluded. By contrast, patients were excluded if they presented with secondary tics, current major depression, untreated generalized anxiety disorder, separation anxiety disorder, psychotic signs (clinically evaluated), pervasive developmental disorder, autism, mental retardation (intelligent quotient
