Pharmacological Reports Copyright © 2012 2012, 64, 2430 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences
Review
What’s the role of topiramate in the management of patients with hyperkinetic movement disorders?
Antonio Siniscalchi1*, Luca Gallelli2*, Chiara Giofrè2, Giovambattista De Sarro2
1Department of Neuroscience, Neurology Division, Annunziata Hospital, Cosenza, Italy
2Chair of Pharmacology, Department of Experimental and Clinical Medicine, School of Medicine, University of Catanzaro, Clinical Pharmacology Unit, Mater Domini University Hospital, Viale Europa Germaneto 88100 Catanzaro, Italy
Correspondence: Luca Gallelli, e-mail: [email protected]
Abstract: Topiramate (TPM) is an O-alkyl sulfamate derivative of the naturally occurring monosaccharide D-fructose with an epileptic activ- ity. However, it has been suggested that, in addition to its use in epilepsy, TPM could also be used in the treatment of neurological dis- orders, psychiatric conditions and hyperkinetic movement disorders. The clinical applications of TPM in hyperkinetic movement disorders is consistent with the multiple pharmacodynamic mechanisms e.g., the modulation of both g-aminobutyric acidergic or glutamatergic neurotransmission and the modulation of voltage-gated ion channels or intracellular signalling pathways. The purpose of the present review is to describe the mechanisms of action of TPM and its clinical efficacy in patients with hyperkinetic movement disorders.
Key words: topiramate, essential tremor, chorea, myoclonus-dystonia, restless legs syndrome
Introduction primary generalized tonic/clonic seizures [5] and tonic/atonic seizures associated with the Lennox- Gastaut syndrome [46]. In elderly patients with epi- Topiramate (TPM; 2,3,4,5-bis-O-(1-methylethylidene)- lepsy, TPM is not usually recommended as a first b-D-fructopyranose sulfamate) is an O-alkyl sulfa- treatment. However, in cognitively healthy old pa- mate derivative of the naturally occurring monosac- tients, TPM may be considered, for both very low side charide D-fructose that showed efficacy in epilepsy effects, and few drug-drug interactions than other an- [50]. Recently, TPM has been reported to be effective tiepileptic drugs [57]. Preliminary data have sug- also in drug resistance partial epilepsy [51], refractory gested that, in addition to its use in epilepsy, TPM partial and secondary generalized seizures [18, 40], may have therapeutic effects also in other neurologi-
* Siniscalchi and Gallelli share the authorship
24 Pharmacological Reports, 2012, 64, 2430 Topiramate and hyperkinetic movement disorders Antonio Siniscalchi et al.
Tab. 1. Topiramate indication in patients with hyperkinetic movement disorders Mechanisms of action of topiramate
Hyperkinetic movements disorders References Effects of TPM on GABAergic or glutamatergic Essential tremor 3, 28, 30, 54 neurotransmission Chorea 4, 15, 19, 53, 63 In experimental studies performed on cerebellar and Myoclonus 6, 41 cortical neurons cultures it have been reported that Restless Legs Syndrome 38, 57 TPM is able to bind the GABAA receptors increasing the GABA levels with a concentration-dependent ef- fect [7, 61, 62]. These effects are not dependent on cal disorders and in psychiatric conditions, however, binding with benzodiazepines on GABAA receptor, more investigations are needed to confirm these pre- because they are not antagonized by flumazenil; liminary findings. In added, the efficacy of TPM in therefore, the TPM effects could be related to uniden- bipolar and schizoaffective disorders, bulimia, neuro- tified binding sites of GABAA receptors [37, 63]. pathic pain syndromes, migraine and cluster headache However, it has been documented that TPM (10– prophylaxis has been reported [13, 27, 37, 56]. Fi- 100 µM) can inhibit neuronal excitatory pathways nally, TPM has been reported to be efficacious in through a selective antagonistic effect at a-amino-3- nicotine, alcohol and/or cocaine dependence [26, 47]. hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) Clinical evidences supported that TPM may be ef- and kainite subtypes of glutamate receptors [11, 37], ficacious in the treatment of some of the hyperkinetic without effects on N-methyl-D-aspartate (NMDA) re- movement disorders, even if it is still inadequate for ceptors also at higher concentrations (up to 200 µM) many of these disorders (Tab. 1). [11]. The block of the kainate-evoked currents repre- Dysfunctions of g-aminobutyric acidergic (GABAer- sents a known mechanism able to decrease the neu- gic) neurons in the basal ganglia may be responsible ronal excitability and to induce anticonvulsant effects of several involuntary movements representing the [49]. TPM seems to exerts a biphasic effect on hallmarks of the hyperkinetic disorders. The hyperki- kainate-evoked currents with their initial inhibition, netic movement disorders include tremor, paroxysmal followed by a delayed additional inhibitory effect that dyskinesias (e.g., dystonia and chorea), myoclonus could be related with an alteration of the phosphoryla- and restless legs syndrome. Pathophysiologically, tion state of kainate-activated channels [21]. these disorders are characterized by a reduced basal ganglia output that results in a thalamo-cortical sys- Modulation of voltage-gated ion channels tem disinhibition and in a release of the cortical motor areas that generate movements normally suppressed. TPM reduces the frequency of activation of voltage- However, changes in the patterning or the level of sensitive sodium channels in a state- or use-dependent synchronization of basal ganglia output [19], and do- manner. In cultured hippocampal neurons, TPM paminergic system dysfunction in the basal ganglia reduced the timing of spontaneous epileptiform bursts may also be involved in the pathophysiology of hy- of neuronal firing and the frequency of action poten- perkinetic disorders [35]. The variety of the proposed tials elicited by a depolarizing of electrical currents clinical applications of TPM in hyperkinetic move- [10, 11, 14]. In agreement has been documented a volt- ment disorders is consistent with the multiple pharma- age-sensitive, use-dependent, and time-dependent codynamic mechanisms including the modulation of suppression of sustained repetitive firing (SRF) in both GABAergic or glutamatergic neurotransmission cultured mouse spinal cord and neocortical cells after and the modulation of voltage-gated ion channels or TPM treatment [34]. However, the activity of TPM on intracellular signalling pathways. However, it has sodium channels differs from that of other antiepilep- been also reported a dose dependent protective effect tic drugs (AEDs), where a rapid limitation or com- of TPM on dopaminergic neurons [22]. plete block of SRF occurs. Therefore, even if TPM The purpose of the present paper is to describe both exerts anticonvulsant effects through the blocks of the mechanisms of action of TPM and its clinical effi- voltage-sensitive sodium channels, its mechanism is cacy in patients with hyperkinetic movement disor- different in respect to phenytoin, carbamazepine, or ders. lamotrigine, showing that the block of the sodium
Pharmacological Reports, 2012, 64, 2430 25 channel don’t represent the primary mechanism of antagonistic muscles [45] and it is defined as a rhyth- TPM-induced antiepileptic effects [34]. mical, involuntary oscillatory movement induced by TPM reduces the amplitude of high voltage-activated alternative contraction of agonist and antagonist mus- (HVA) calcium currents by reducing the neurotrans- cles [24]. ET may be caused by a deficiency in the mitter release and inhibiting the system of calcium- a-1-subunit of GABAA receptor, as documented in channel transduction [67]. This activity has been ex- a knockout model of mice [53]. This mechanism elu- perimentally documented in rat dentate gyrus granule cidates that a dysfunction in GABAergic system in cells, with a decrease in L-type calcium currents at the major motor pathway represents a potential target 10 µmol/l more than at 50 µmol/l, suggesting a differ- for pharmacotherapy, and that the benzodiazepines, ent mechanism of action in respect to other calcium which are GABAA receptor agonists, may be effica- channel blockers [66]. Moreover, TPM has been able cious in ET patients [28, 32]. This animal model over- to inhibit N-, P- and L-type channels in both periaque- laps with ET in humans and shows a loss of inhibitory ductal and cortical grey neurons [33]. In this light, it is neurotransmission by cerebellar Purkînje cells, with- possible to speculate that TPM can modulate neuronal out the presence of Purkînje cells degeneration [24]. excitability through an inhibitory effect on HVA cal- Based on their mechanisms of action, AEDs, that en- cium channels representing a potential anticonvulsant hance GABAergic neurotransmission, could be effec- mechanism. tive in the treatment of ET. Drugs with this potential include conventional (primidone, clonazepam) and Inhibition of carbonic anhydrase isoenzymes newer AEDs (tiagabine, gabapentin, pregabalin, levetiracetam and zonisamide). The effect of topira- TPM contains a sulfamate moiety responsible for its mate in essential tremor has been reported in open- type II and type IV carbonic anhydrase (CA)-inhib- label trials and in a small, double-blind, controlled itory properties [30], even if it is less potent (10–100 study [9]. This effect could be explained with the times) in comparison to acetazolamide [15, 37]. The modulation of GABAA receptor [29]. These findings CA inhibition is not relevant for the anticonvulsant prompted the current multicenter, double-blind trial activity, but it could be related with the development by Ondo et al., which aimed to evaluate the efficacy of the adverse effects, e.g., increased risk of nephro- and safety of topiramate for ET [38]. The remarkably lithiasis and metabolic acidosis [52, 60]. large study included 208 ET-patients treated with ei- ther topiramate or placebo. The primary efficacy vari- Effects on the phosphorylation state able was improvement on the Fahn-Tolosa-Marin of membrane proteins TRS, which evaluates the tremor severity with respect to amplitude and also – more importantly – the ability Several studies documented that TPM may bind to to perform daily motor tasks such as writing, drawing phosphorylation sites within AMPA, kainate, GABAA, and pouring. It also assesses patient-reported func- and voltage-activated sodium channels only in the tional ability in such tasks. Generally, topiramate was dephosphorylated state, exerting a bi-fold effect. There- found to have a moderate clinical effect (10.8-point fore, TPM can modulate ion conductance through the decrease from baseline TRS score, SD 9.5 points) and channel, by an immediate allosteric action and it could to be superior to placebo (5.8-point decrease from exert a delayed effect by shifting the channels toward baseline TRS score, SD 7.5 points). Notably, the stan- the dephosphorylated state [59]. dard deviations were quite high in both groups. The drug did not significantly change the tremor severity, compared with placebo, but a significant effect was seen on the motor-task and functional-disability subscales. Clinical use of topiramate in hyperkinetic The mean overall TRS score revealed a marked re- movement disorders sponse in favor of topiramate at the very first study visit (day 28, target dose 100 mg), with only a mild Essential tremor further improvement at the end of the study (day 84, target dose 400 mg). Of concern is the fact that ap- Essential tremor (ET) is a progressive neurological proximately 30% of the topiramate-treated patients disorder characterized by a synchronous activation of withdrew from the trial due to adverse effects (pares-
26 Pharmacological Reports, 2012, 64, 2430 Topiramate and hyperkinetic movement disorders Antonio Siniscalchi et al.
thesia, nausea, concentration difficulty). In a recent kinesigenic choreoathetosis may be caused by an ion clinical study, Louis et al. [31] assessed the number of channel defect [23]. TPM, by means of the enhance- the current treated-patients and the patients who gave ment of GABA activity and the modulation of volt- up with the therapy, and they documented that a half age-gated ion channels, can be efficacious in chorei- or more ET patients treated with one of the four most form movements. TPM can also improve both vascu- commonly-used medications (propranolol, primidone, lar hemichorea/hemiballism [16, 20] and vascular diazepam, topiramate), interrupted the treatment. The generalized chorea [54]. Huang et al. [23] showed that proportion of cases which were prescribed a treatment topiramate is effective in 8 patients affected by parox- and did not interrupt was higher in patients under ysmal kinesigenic choreoathetosis. A PET study TPM treatment, while the number of patients who showed that the efficacy of TMP treatment was due to stopped the treatment was lower in patients prescribed an improvement of glucose cerebral cortical metabo- with TPM. Bathia and Schneider suggested that for lism in an elderly choreatic patient [64]. these patients TPM can be considered a second-line alternative or an adjuvant therapy, even if in elderly Myoclonus-dystonia patients with dementia the prescription should be con- sidered very carefully [3]. In an old man with ET un- Myoclonus-dystonia (MD) is a movement disorder responsive to primidone treatment, the combined characterized by a combination of rapid, brief muscle therapy of topiramate and declorazepam induced contractions (myoclonus) and/or sustained twisting a rapid improvement of symptoms supporting a syner- and repetitive movements that result in abnormal pos- gic effect of both drugs [55]. tures (dystonia). The myoclonic jerks typical of MD most often affect the neck, trunk, and upper limbs Chorea with less common involvement of the legs. Approxi- mately 50% of affected individuals have additional Chorea consists of irregular, purposeless, abrupt, focal or segmental dystonia, presenting as cervical rapid, brief, jerky, unsustained movements that flow dystonia and/or writer’s cramp. Mutations in the SGCE randomly from one part of the body to another [4, 24]. gene are associated with familial MD. Although mu- The term “choreoathetosis” describes the combination tations in two other genes, DRD2 and DYT1, have of chorea and athetosis, a slow form of chorea mani- been associated with MD, the significance of the mu- fested by writhing movements predominantly involv- tations is unknown [6]. Anti-epileptic drugs topira- ing distal extremities [4, 24]. Ballism, a severe form mate, may improve myoclonic movements [6, 41]. of chorea, comprises wide amplitude, flinging move- Although, in previous studies, a disorder of spinal ments, usually involves the proximal limbs and most inhibitory interneurons is the favored pathology in often affects only one side of the body (hemiballism) most cases of spinal myoclonus, histological evidence [4, 24]. Typically, a lesion in the contralateral subtha- exists in which motoneurons are a prime candidate lamic nucleus is the cause of ballism, however, a dam- The hyperexcitability of the motoneuron could be due age in other subcortical areas may be also present. to hyperactivity of postsynaptic excitatory neurotrans- Rarely, ballism can occur bilaterally (biballism or pa- mission or to changes in the distribution of voltage- raballism) [4, 24]. Many patients with ballism have gated channels in the membrane [42, 44]. also distal choreic movements and, as recovery oc- curs, hemiballism often transforms into hemichorea Restless legs syndrome and hemidystonia [4, 24]. Chorea is defined as pri- mary when it is idiopathic or genetic in origin or sec- Restless legs syndrome (RLS) is a sensorimotor disor- ondary when it is related to other causes (i.e., such as der common in people over 65 years old and charac- vascular, metabolic and immunologic diseases, infec- terized by an irresistible urge to move the legs, ac- tions and drugs) [4, 12]. The pathophysiological pro- companied by uncomfortable and unpleasant sensa- cesses for primary neurodegenerative chorea, such as tions that diminish with motor activity and are worsen Huntington’s disease, clearly involve both excitotox- at rest [1]. These symptoms increase during the even- icity and the inhibition of histone acetylation, accom- ing and night, leading to difficulty in sleeping and panied by the loss of GABAergic medium-sized spiny therefore inducing insomnia and depression. This syn- neurons in the striatum [25, 65]. The paroxysmal drome can be a primary disorder or a secondary one,
Pharmacological Reports, 2012, 64, 2430 27 associated, for instance, with iron-deficiency, uremia targets for the action of TPM include enhancement of or polyneuropathies [17, 48]. GABAergic inhibition, decreased glutamatergic exci- The specific pathophysiology of idiopathic RLS is tation, modulation of voltage-gated sodium and cal- not well known but recent studies have raised the hy- cium channels, and effects on intracellular signalling pothesis of diencephalospinal pathway dysfunction. pathways. These mechanisms are of importance in This pathway includes spinal, subcortical and cortical controlling neuronal excitability in different ways. structures [17, 36, 58]. Research supporting the efficacy of TPM in the man- In a prospective study, the efficacy of topiramate in agement of hyperkinetic movement disorders is still RLS has been considered [39]. Nineteen patients (4 inadequate and there are only few clinical studies and women; mean age, 62 years; 12 idiopathic RLS – ICSD case reports regarding the role of TPM in patients af- criteria – seven unspecified secondary RLS) under- fected by hyperkinetic movement disorders. Thus, went a 1-week pre-entry washout period before TPM more prospective clinical trials are necessary to con- treatment (42.1 mg/day 618.7 mg, flexible dose). firm the efficacy of TMP in hyperkinetic movement Clinical efficacy was assessed with the CGI (Clinical disorders and to well define the proportion of re- Global Impressions) and PGI (Patient’s Global Im- sponders in a larger group of patients. In the future, pression) values, as well as by reporting of symptoms TPM could represent an useful therapeutic option in and sleep hours. Symptom severity, as measured on the management of hyperkinetic movement disorders the CGI scale, decreased from 79% to 37%. PGI val- where the available treatments are ineffective. ues also decreased from 73% to 37%. Eleven out of 17 patients had an improvement in sensory and motor symptoms. Sleep improved, but this was not shown to be statistically significant. Two patients dropped out References: from the study due to sleepiness, and another one due to paraesthesia. The efficacy of TPM in RLS may be 1. Allen R, Picchietti D, Hening W, Trenkwalder C, Walters due to the reduction of voltage-gated sodium channels A, Montplaisir J: Restless legs syndrome: diagnostic cri- and also to the enhances of postsynaptic GABA- teria, special considerations, and epidemiology. A report receptor currents and to the limited activation of the from the restless legs syndrome diagnosis and epidemiol- AMPA-kainate types of glutamate receptors. ogy workshop at the National Institutes of Health. Sleep Med, 2003, 4, 101–119. In contrast, other authors reported that topiramate 2. bid Bermejo PE, Restless legs syndrome induced by topira- (50 mg, ) is able to induce RLS, probably through mate: Two more cases. J Neurol, 2009, 256, 662–663. a dopaminergic antagonism [2, 43]. Therefore, the ef- 3. Bhatia KP, Schneider SA: Is the anticonvulsant topira- ficacy of TPM in RLS is considered to be still under mate beneficial in essential tremor? Nat Clin Pract Neu- investigation. rol, 2006, 2, 478–479. 4. Bhidayasiri R, Truong DD: Chorea and related disorders. Postgrad Med J, 2004, 80, 527–534. 5. Biton V, Montouris GD, Ritter F. A study of topiramate in primary generalized tonic-clonic seizures. Neurology, 1999, 52, 1330–1337. Conclusion and directions for future 6. Bressman SB, Greene PE: Treatment of hyperkinetic research movement disorders. Neurol Clin, 1990, 8, 51–75. 7. Brown SD, Wolf HH, Swinyard EA: The novel anticon- vulsant topiramate enhances GABA-mediated chloride The primary indication for TPM remains certainly flux. Epilepsia, 1993, 34, 122–123. 8. epilepsy, but the efficacy of TMP in some hyperki- Chroœciñska-Krawczyk M, Jargie³³o-Baszak M, Wa³ek M, Tylus B, Czuczwar SJ: Caffeine and the anticonvul- netic movement disorders could represent a useful sant potency of antiepileptic drugs: experimental and therapeutic option in the management of these disor- clinical data. Pharmacol Rep, 2011, 63, 12–18. ders where the available treatments are ineffective. 9. Connor GS: A double-blind, placebo-controlled trial of Several pathophysiological mechanisms inducing topiramate treatment for essential tremor. Neurology, a neuronal excitability seem to be involved in an im- 2002, 59, 132–134. 10. Coulter DA, Sombati S, DeLorenzo RJ: Selective effects balance of both GABAergic and glutamatergic neuro- of topiramate on sustained repetitive firing and spontane- transmissions and therefore could be similar in epi- ous bursting in cultured hippocampal neurons. Epilepsia, lepsy and hyperkinetic movement disorders. The main 1993, 34, 123–126.
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