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S Enz Farret2022 Article AntiseizureDrugsAndMovementDis
S Enz Farret2022 Article AntiseizureDrugsAndMovementDis
DOI:
10.1007/s40263-022-00937-x
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REVIEW ARTICLE
Abstract
The relationship between antiseizure drugs and movement disorders is complex and not adequately reviewed so far. Antisei-
zure drugs as a treatment for tremor and other entities such as myoclonus and restless leg syndrome is the most common
scenario, although the scientific evidence supporting their use is variable. However, antiseizure drugs also represent a
potential cause of iatrogenic movement disorders, with parkinsonism and tremor the most common disorders. Many other
antiseizure drug-induced movement disorders are possible and not always correctly identified. This review was conducted
by searching for all the possible combinations between 15 movement disorders (excluding ataxia) and 24 antiseizure drugs.
The main objective was to describe the movement disorders treated and worsened or induced by antiseizure drugs. We also
summarized the proposed mechanisms and risk factors involved in the complex interaction between antiseizure drugs and
movement disorders. Antiseizure drugs mainly used to treat movement disorders are clonazepam, gabapentin, lacosamide,
levetiracetam, oxcarbazepine, perampanel, phenobarbital, pregabalin, primidone, topiramate, and zonisamide. Antiseizure
drugs that worsen or induce movement disorders are cenobamate, ethosuximide, felbamate, lamotrigine, phenytoin, tiagabine,
and vigabatrin. Antiseizure drugs with a variable effect on movement disorders are carbamazepine and valproate while no
effect on movement disorders has been reported for brivaracetam, eslicarbazepine, lacosamide, and stiripentol. Although
little information is available on the adverse effects or benefits on movement disorders of newer antiseizure drugs (such as
brivaracetam, cenobamate, eslicarbazepine, lacosamide, and rufinamide), the evidence collected in this review should guide
the choice of antiseizure drugs in patients with concomitant epilepsy and movement disorders. Finally, these notions can
lead to a better understanding of the mechanisms involved in the pathophysiology and treatments of movement disorders.
* Alfonso Fasano
[email protected]
Key Points
1
Edmond J. Safra Program in Parkinson’s Disease, Morton The relationship between antiseizure drugs and move-
and Gloria Shulman Movement Disorders Clinic, Toronto ment disorders is complex.
Western Hospital, University Health Network, Division
of Neurology, University of Toronto, 399 Bathurst St, Antiseizure drugs are typically used for tremor, myo-
Toronto, ON M5T 2S8, Canada clonus, and restless leg syndrome.
2
Department of Neurology, University of Groningen,
Groningen, The Netherlands Antiseizure drugs also represent a potential cause of
3 iatrogenic movement disorders (parkinsonism and tremor
Expertise Center Movement Disorders Groningen, University
Medical Center Groningen, Groningen, The Netherlands mainly).
4
UCLA Seizure Disorder Center, Department of Neurology, Antiseizure drugs with a variable effect on movement
David Geffen School of Medicine, UCLA, Los Angeles, CA, disorders are carbamazepine and valproate.
USA
5 No effect on movement disorders has been reported for
Departments of Neurology and Neurological Sciences
and Neurosurgery, Stanford University, Stanford, CA, USA brivaracetam, eslicarbazepine, lacosamide, and stiripen-
6 tol.
Medical College of Georgia, Augusta University, Augusta,
GA, USA
7
Krembil Brain Institute, Toronto, ON, Canada
8
Center for Advancing Neurotechnological Innovation
to Application (CRANIA), Toronto, ON, Canada
Vol.:(0123456789)
860 M. Sáenz‑Farret et al.
Phenobarbital The anticonvulsant properties were discovered serendipitously in 1912 when a psychiatry resi- Binding of GABA-A receptor, prolonging the opening of the associated chloride channel
dent sedated patients with epilepsy with phenobarbital so that he could get a good night’s sleep
Phenytoin Discovered by Houston Merritt and Tracy Putnam in 1938 Blockage of the VGSC
Primidone The anticonvulsant properties were discovered in early 1949 by Bogue and Carrington. The ini- Converted in the liver into phenobarbital and phenylethylmalonamide
tial evidence on tremor came from an unexpected benefit when given to patients with epilepsy
and concomitant tremor
Ethosuximide Introduced in 1958 for absence seizures Blockage of T-type calcium channels
Antiseizure Drugs and Movement Disorders
Clonazepam The first clinical study as an anticonvulsant agent was published on 1963 Binding of the GABA-A receptor, increasing the frequency of GABA-mediated chloride channel
openings
Valproate Meunier et al. first reported on the anticonvulsant properties in 1963 GABA enhancement, blockage of T-type calcium and VGSC
Carbamazepine The first clinical report on the antiepileptic action was published in 1964, after prior use in treat- Blockage of the VGSC
ment of depression
Stiripentol The anticonvulsant properties of the drug have been under investigation since the 1970s Interaction with the GABA-A receptor
Zonisamide Originally synthesized in Japan in 1974. Its benefit on parkinsonian symptoms was found seren- Blockage of the T-type calcium and sodium channels, and inhibition of carbonic anhydrase activity
dipitously in a patient with PD treated for seizures
Lamotrigine The potential value of lamotrigine in the treatment of generalized tonic-clonic and partial sei- Blockage of the VGSC, inhibition of glutamate release, enhancement of GABA release and addi-
zures was reported in 1986 tional partially unknown mechanisms
Gabapentin The first study of the antiepileptic properties of gabapentin in patients with severe epilepsies Binding of the alpha-2-delta subunit of Ca+ channel
resistant to standard ASDs was published in 1987
Topiramate The anticonvulsant effects of topiramate were discovered in 1987 Antagonism of AMPA/kainate glutamate receptors, enhancement of GABA activity, blockage of
VGSC, and carbonic anhydrase inhibition
Oxcarbazepine Open clinical studies indicated equal efficacy but better tolerability than carbamazepine, its Blockage of the VGSC, inhibition of high-voltage-activated calcium channels (N type)
10-keto analog, since 1987
Vigabatrin First approved in the UK in 1989 Inhibition of GABA transaminase
Tiagabine Preclinical anticonvulsant properties were reported in 1991 Inhibition of GABA uptake
Levetiracetam The anticonvulsant properties were reported in 1992 Binding of the synaptic vesicle glycoprotein SV2A
Felbamate Released in 1993 NMDA glutamate receptor antagonism, GABA enhancement, and sodium channel blocking
Pregabalin The anticonvulsant activity in vivo was reported in 1993 Binding of the alpha-2-delta subunit of Ca+ channel
Rufinamide Preclinical studies reported antiepileptic activity since 1993 Blockage of the VGSC, prolongation of inactive state of sodium channels
Lacosamide Preclinical studies documented the anticonvulsant activity in 1995 Blockage of the VGSC, enhancing slow inactivation
Brivaracetam The antiepileptic properties were reported in 2008 Binding of the synaptic vesicle glycoprotein SV2A
Perampanel The antiepileptic properties were first reported in 2011 Selective noncompetitive AMPA glutamate receptor antagonism
Eslicarbazepine Approved in the USA for focal seizures in 2013 Reduction of VGSC activity through enhancement of slow activation
Cenobamate Approved in the USA for focal seizures in 2019 Inhibition of the persistent component of the sodium current by enhancing the fast and slow inacti-
vation of the channel, allosteric modulation of GABA channel
AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, ASDs antiseizure drugs, GABA gamma aminobutyric acid, NMDA N-methyl-d-aspartate, PD Parkinson´s disease, VGSC voltage-
gated sodium channels
861
862 M. Sáenz‑Farret et al.
respectively); accelerometer findings confirmed a positive Initial evidence for the benefit of clonazepam in the treat-
effect on tremor amplitude (p < 0.01) in the absence of any ment of drug-induced akathisia came from cases success-
effect on frequency [10]. Another study based on a quanti- fully treated with a combination of baclofen and clonazepam
tative measurement of hand tremor concluded that primi- [25]. A subsequent study of ten patients with schizophre-
done is superior to phenobarbital in treating ET, although nia and akathisia showed that clonazepam could reduce
authors also concluded that the latter may be of some benefit the akathisia subscale of the Chouinard Extrapyramidal
in patients who are intolerant to primidone and unrespon- Symptom Rating Scale from a mean of 4 (range 3–6) to 1.6
sive to beta-blockers [11]. In addition to ET, phenobarbital (range 1–3) [p < 0.005] [26], as also confirmed by another
has shown effectiveness in patients with orthostatic tremor open-label trial [27] and a randomized controlled trial (RCT)
(OT) [12]. [28]. A systematic review concluded that benzodiazepines
With respect to movement disorders other than tremor, may reduce the symptoms of antipsychotic-induced acute
a 75-year-old man with evidence of a right thalamic stroke akathisia over a short follow-up period [29]. Recent reviews
who developed negative myoclonus on his left upper limb are also in accordance with this notion [30].
completely resolved his movement disorder with pheno- A double-blind, placebo-controlled RCT of 19 patients
barbital [13]. A controlled study of clonazepam versus the with TD found an overall 35% decrease in rating scale scores
active placebo of phenobarbital in psychiatric patients with with clonazepam treatment; six patients with predominantly
tardive dyskinesia (TD) significantly reduced dyskinetic dystonic symptoms showed a greater benefit than 13 patients
movements in both groups [14]. with predominantly choreoathetoid dyskinesias [31]. A
systematic review concluded that there is only low-quality
3.2 Primidone evidence from few small and poorly reported trials on the
effect of benzodiazepines as an adjunctive treatment for
Primidone is one of the first-line agents for the treatment of antipsychotic-induced TD [32].
tremor. One double-blind placebo-controlled study found Anecdotal reports have described the efficacy of clon-
that primidone was significantly superior to placebo in azepam in treating chorea, hemichorea, and paroxysmal
reducing the magnitude of hand tremor by 55.9% (p < 0.01), non-kinesigenic dyskinesia [33]. Intravenous injections of
as also confirmed by performance tests (p < 0.01), clinical clonazepam were investigated in patients with either seg-
assessment (p < 0.02), and a patient’s self-assessment (p < mental dystonia (two patients), generalized dystonia (six), or
0.01). No consistent attenuation of head tremor was found Meige syndrome (six), in whom 1 mg significantly reduced
[15]. In addition, add-on therapy with 250 mg of primidone the subjective scores although the reduction in the global
was found to be beneficial in a patient with OT treated with score was not significant [34]. Clonazepam significantly
clonazepam [16]. In comparing primidone to phenobarbi- improved the mean bruxism index from 9.3 to 6.3/hour of
tal, it should be noted that phenobarbital is the long-lasting sleep in a single-blind non-randomized study [35]. Finally,
metabolite of primidone, but primidone itself and a short- clonazepam has also been employed as a treatment of rest-
acting metabolite, phenyl-ethyl malonic acid, also may have less legs syndrome (RLS), although the level of evidence is
anti-tremor effects [11]. poor [36].
In addition to tremor, myoclonus is another movement
disorder with benefit from primidone. Patients with chronic 3.4 Zonisamide
post-hypoxic myoclonus after cardiac arrest best responded
to co-application of primidone and other antimyoclonic A high level of evidence that zonisamide is safe and effective
drugs in a retrospective study [17]. as an adjunctive treatment for Parkinson´s disease (PD) came
from a double-blind RCT showing a significant improvement
3.3 Clonazepam in the total score of the Unified Parkinson Disease Rating
Scale Part III (motor section) in the 25-mg/day and 50-mg/
The benefit of clonazepam in cortical and subcortical day arm versus placebo [37]. Another randomized double-
myoclonus is well known [18], as well as in other forms blind study confirmed the efficacy of zonisamide 50 mg/day
of myoclonus, including post-hypoxic myoclonus [17, 19], for a reduction in “off” time in patients with PD with wear-
opsoclonus-myoclonus [20], and spinal myoclonus [21]. ing-off phenomena. The “off” time significantly reduced by
Clonazepam is one of the most used treatments for OT with 0.719 ± 0.179 hours for zonisamide 50 mg compared with
variable results [22]. In a recent systematic review, clon- placebo (0.011 ± 0.173 hours, p = 0.005) [38]. A post hoc
azepam was the most effective medication in the slow OT analysis of phase II and phase III clinical trials revealed that
variant (≤ 12 Hz) [23]. Other types of tremor might benefit zonisamide improves wearing off without exacerbating dys-
from clonazepam but evidence is weak, as in the case of kinesia in PD. Moreover, zonisamide 50 mg may improve
palatal tremor [24]. dyskinesia [39].
Antiseizure Drugs and Movement Disorders 863
Zonisamide 50 mg/day as an adjunctive treatment also 2400 mg/day. Orthostatic tremor was evaluated with sub-
improved the total Unified Parkinson Disease Rating Scale jective scales, tremor rating scales, and electromyography
Part III score in Lewy body dementia without worsening of frequency analysis. Gabapentin induced the disappearance
cognitive function or psychiatric symptoms in a 12-week of OT in three patients and a consistent reduction in another
double-blind RCT (between-group difference of 4.1, 95% patient [47].
confidence interval [CI] −6.8 to −1.4; p = 0.003) [40]. This
dosage is significantly lower than the usual 300−600 mg per 3.6 Topiramate
day used to prevent seizures in adults.
Class I evidence indicates that zonisamide improves myo- Topiramate is a sulfonamide ASD, with a structure, anti-sei-
clonus and related disability in patients with myoclonus dys- zure actions, and side effects similar to those of zonisamide.
tonia. In a double-blind crossover RCT, zonisamide signifi- It is not therefore surprising that topiramate has anti-tremor
cantly improved both action myoclonus (median improvement: actions. After some initial open-label clinical observations,
−5, 95% CI −9.25 to 21.44, p < 0.003) and related functional double-blind placebo-controlled studies concluded that
disability (-2, 95% CI −2.58 to −2.46, p = 0.007) compared topiramate improves tremor severity, motor task perfor-
with placebo. Zonisamide also significantly improved the mance, and functional disability in patients with moderate
Burke–Fahn–Marsden–Dystonia Rating Scale (median improve- to severe ET [48]. In addition, topiramate has been reported
ment: −3, 95% CI −8.46 to 0.03, p = 0.009) [41]. to be efficacious in other types of tremor such as Holmes
Zonisamide provided benefit in secondary paroxysmal dys- tremor, writing tremor, and cerebellar tremor due to multiple
tonia in a patient with pyruvate dehydrogenase deficiency and sclerosis or stroke [49]. Furthermore, topiramate has been
in two patients with neonatal hemochromatosis, the patients had deemed useful in hemichorea-hemiballismus and general-
an incomplete response to acetazolamide followed by a com- ized chorea secondary to vascular and metabolic (hypergly-
plete response to zonisamide [42]. Zonisamide therapy was also cemia) insults [50]. In eight patients with PKD, 100–200
effective in 13 of 14 (92.9%) patients with paroxysmal kinesi- mg of topiramate monotherapy resulted in the complete
genic dyskinesias (PKD): complete remission for more than 3 resolution of the attacks during a follow-up period range
months after zonisamide therapy (n = 7), decreased dyskinesia of 8–24 months [51]. Topiramate appears to be a promising
frequency by more than 90% (n = 4), dyskinesia frequency by medication with good efficacy and tolerability for children
75–90% (n = 2), and no change in dyskinesia frequency (n = with tic disorders [52]; however, evidence is still weak [53].
1) [43].
3.7 Oxcarbazepine
3.5 Gabapentin
Oxcarbazepine is structurally related to the classical ASD carba-
Gabapentin has been extensively studied in RLS since 1994, mazepine but with a different metabolic pathway. The best docu-
after a number of positive results in open-label studies were mented positive effect of oxcarbazepine in movement disorders
confirmed by a small 12-week RCT of 24 patients with RLS is available for PKD, with some patients achieving the complete
(two cases secondary to iron deficiency) [44]. In this RCT, resolution of the attacks. A retrospective study reviewed the use
the International RLS Rating Scale total score was lower of carbamazepine or oxcarbazepine in 28 patients with PKD.
with gabapentin than with placebo (9.5 ± 1.35 vs. 17.9 ± Ten patients in the oxcarbazepine group and 12 in the carba-
1.35, p < 0.0005), as also confirmed by the Clinical Global mazepine group continued the therapy for more than 12 months.
Impression (CGI) Scale: 1.8 ± 0.3 versus 2.9 ± 0.3 (p < Both groups showed a marked reduction in attack frequency
0.01). Larger trials with a similar design confirmed the effi- without differences in terms of efficacy and tolerability [54].
cacy of gabapentin on RLS [44]. A systematic review and Treatment with oxcarbazepine has also resulted in a sub-
meta-analysis recommend gabapentin as the first option for stantial reduction in the frequency and severity of episodes of
RLS mainly because it rarely causes augmentation [45]. paroxysmal non-kinesigenic dyskinesia [55]. Oxcarbazepine is
After some initial observations in open-label studies, a also useful in primary and secondary RLS [56].
multiple-dose, double-blind, RCT enrolling 20 patients with
ET showed positive effects of gabapentin in treating tremor. 3.8 Levetiracetam
Overall, patient’s global assessment (p < 0.05), tremor
scores (p < 0.005), water pouring scores (p < 0.05), and Similarly to valproate and clonazepam, levetiracetam has
Activities of Daily Living scores (p < 0.005) significantly showed a clear benefit in the chronic form of post-hypoxic
improved. Accelerometry scores, spirographs, and investiga- myoclonus (Lance–Adams syndrome) and even in post-
tor’s CGI scale score did not improve [46]. encephalitic myoclonus [57]. A pilot open-label trial enroll-
Gabapentin is effective for OT, as initially showed by a ing five patients with post-hypoxic myoclonus, myoclonus
double-blind crossover study in four patients using up to dystonia, paraneoplastic myoclonus, and spinal myoclonus
864 M. Sáenz‑Farret et al.
reported a reduction in the Unified Myoclonus Rating Scale, is related to tremor. Initial case reports [69, 70] described
although a significant difference was found only in terms of a clear improvement of OT and a case series in 20 patients
a patient’s self-assessment and a physician’s assessment of confirmed these findings [71]. Of the 12 patients who com-
disability [58]. pleted the study, 92% indicated that their OT symptoms
Levetiracetam was evaluated in a RCT involving 50 patients improved after 1 month, with 75% indicating a moderate-
with TD [59]. A mixed regression model revealed a 43.5% to-marked improvement on a self-administered subjective
reduction in the Abnormal Involuntary Movements Scale in the scale based on the disability part of the Fahn–Tolosa–Marin
active group compared with a 18.7% reduction with placebo Tremor Clinical Rating Scale (mean score of improvement:
(p = 0.022). Patients continuing levetiracetam in the open- 1.9 ± 0.9). This benefit was not sustained at the 3-month fol-
label phase continued to improve, and patients crossed over to low-up (0.9 ± 1.3). A rebound of OT symptoms that lasted
open-label levetiracetam improved to a similar degree [59]. A 2–6 weeks was observed in most patients who discontinued
1-month single-blind study of eight patients confirmed a 44% the medication [71].
reduction in the Abnormal Involuntary Movements Scale (p = Perampanel was superior to placebo in a recent 14-week
0.001) and the Goetz Dyskinesia Scale (p = 0.026), as well as a RCT in 26 patients with ET [72], as evaluated by means
26% reduction in the CGI Scale (p = 0.031) [60]. of the videotaped performance subscale of the ET Rating
Assessment Scale (TETRAS-P) [p = 0.028], Activities of
3.9 Pregabalin Daily Living questionnaire (p = 0.009), and subjective CGI
Scale (p = 0.016), but not in terms of quality of life (p =
Pregabalin is an anti-seizure and anti-neuropathic pain medi- 0.48). An open-label trial in 12 patients with moderate-to-
cine that is chemically related to gabapentin. Pregabalin is very severe ET also showed positive results with perampanel.
effective in treating RLS. A double-blind RCT in 98 patients According to the Tremor Clinical Rating Scale, there was
provided Class II evidence of its effectiveness in the treatment a significant improvement in tremor, from a mean baseline
of idiopathic RLS [61]. Patients receiving pregabalin treatment (day 1) score of 73.75 ± 7.07 to 38.75 ± 12.69 by day 56,
had a greater improvement in the International RLS Rating representing a relative reduction of 47% (p < 0.001). Sub-
Scale score than placebo (63% vs 38.2%; p < 0.05). Similarly, jective tremor improvement in percentage terms was 61%,
improvements were observed in terms of the CGI Scale, RLS-6 with four of the eight patients achieving an improvement of
scale, and the Medical Outcomes Study Sleep Scale (all p < over 70%. All eight patients who completed the study opted
0.01) [61]. Pregabalin is one of the main recommended drugs to continue with perampanel treatment [73].
for RLS because in addition to the significant efficacy and good Perampanel was found to be effective in RLS in one pro-
tolerability, it rarely causes augmentation according to a sys- spective 2-month open trial. In the 20 patients who com-
tematic review [45]. pleted the study, the International RLS Rating Scale score
After some patients with ET were successfully treated with improved from a mean (± standard deviation) of 23.7 ± 4.2
pregabalin (at least a 40% reduction in tremor amplitude as to 11.5 ± 5.3. Treatment with perampanel also resulted in
measured by accelerometry), a pilot double-blind RCT of 22 an improvement in the mean (± standard deviation) peri-
patients with ET confirmed these findings also using clinical odic leg movement index from 27.8 ± 6.9 to 4.36 ± 2.0
scales and accelerometry [62]. However, a subsequent double- [74]. Evidence from case reports suggests that perampanel
blind crossover RCT in 20 patients found no improvement and is effective in cortical myoclonus and as add-on therapy in
a statistically significant worsening of quality of life in patients Lance–Adams syndrome [75, 76].
taking pregabalin [63].
at toxic concentrations. Focal chorea restricted to one upper disorder) [98]. Reversible parkinsonism secondary to lamotrig-
limb [81], the face with or without buccolingual movements ine use has been reported in the absence of presynaptic nigros-
(especially with toxic levels) [82], and the combination of triatal involvement [99]. In patients with PD receiving dopamin-
facial buccolingual dyskinesias and generalized chorea have ergic treatment, adding lamotrigine has been associated with
been reported [83]. Acute focal and generalized dystonic the onset of dyskinesias [100]. This effect was also replicated
reactions have been reported as well [79, 84]. Although less in three patients enrolled in a double-blind, placebo-controlled,
frequently, parkinsonism, rest tremor, and gait disturbances crossover study that failed to demonstrate any symptomatically
have also been reported, especially in patients with traumatic beneficial effects of lamotrigine on PD [101].
brain injury [85, 86]. Accordingly, phenytoin has also been Lamotrigine worsen tics in Tourette syndrome but it can also
observed to interfere with the beneficial effect of levodopa induce de-novo tics [102, 103]. Tics developed within 4–10
on parkinsonism [87]. months either with lamotrigine monotherapy or in combination
with other ASDs in a report of five patients [104]. Blepharos-
4.2 Ethosuximide pasm has been reported in association with lamotrigine, also in
association with tics [105]. Toxic concentrations of lamotrigine
Generalized chorea (also including orofacial movements have been associated with oculogyric crises, which resolved
with tongue involvement) has been reported after ethosux- after reducing the dose [106].
imide administration, a drug used to treat absence and occa-
sionally myoclonic seizures. Phenomenology and complete 4.5 Felbamate
resolution with diphenhydramine have led to the hypothesis
that mechanism of action is similar to phenothiazine-related Two years after the introduction of felbamate, Kerrick et al.
dyskinesias [88]. Akathisia in combination with dyskinesia reported two patients with reversible abnormal movements,
has been reported as well [89]. one with akathisia, choreiform movements, and dystonia,
and the other with acute right gaze deviation [107]. Fel-
4.3 Vigabatrin bamate is now rarely used because of risks to the liver and
bone marrow.
Vigabatrin irreversibly inactivates the main enzyme respon-
sible for metabolizing GABA, resulting in elevated synap- 4.6 Tiagabine
tic GABA levels and increased inhibition [90]. The drug is
rarely used because of dose-dependend and time-dependent Tiagabine is an ASD that is believed to inhibit seizures by
retinal toxicity. Multifocal electroencephalogram-negative blocking the synaptic uptake of released GABA, thereby
myoclonus has been reported in two patients with epilepsy leaving GABA longer at synapses. Although tiagabine has
treated with vigabatrin while also taking carbamazepine been hypothesized to ameliorate tremor in ET, an open-label
(plus clobazam in one patient) [91]. Vigabatrin worsened trial did not confirm it at the tested mean dose of 135 mg
parkinsonism without a significant reduction in dyskine- daily [108], which is over twice the usual maximal dose used
sias in patients with PD when this drug was investigated for for seizures. Tremor is the movement disorder most com-
levodopa-induced dyskinesias [64]. monly associated with tiagabine use, occurring in 9–12%
of treated patients, and severe exacerbation of tremor in
4.4 Lamotrigine patients with ET has also been reported [109, 110].
Focal limb dystonia, oromandibular dystonia, and writ-
Lamotrigine is a broad-spectrum ASD useful for focal and er’s cramp have been observed in three patients treated with
generalized-onset seizures [90]. Cortical (epileptic) myo- carbamazepine when tiagabine was added [111]. Reversible
clonus usually responds favorably to lamotrigine, but some- athetoid movements were also reported in a patient with par-
times lamotrigine induces or exacerbates myoclonus [92]. tial complex seizures secondary to encephalitis [112].
Myoclonus of a subcortical origin is a common adverse
effect of lamotrigine in patients with and without epilepsy 4.7 Cenobamate
[93]. The combination of lamotrigine and valproate (which
increases serum lamotrigine concentrations via a pharma- Cenobamate is a novel tetrazole alkyl carbamate deriva-
cokinetic drug interaction) has been related to the occur- tive recently approved for the treatment of adults with focal
rence of action and resting tremor [94]; however, only the seizures. In a recent phase II RCT of adjunctive cenoba-
former has been related to lamotrigine monotherapy [95]. mate in patients with uncontrolled focal seizures, tremor
Chorea has been reported in patients treated with the com- was reported in seven patients (6.2%) versus three patients
bination of lamotrigine and phenytoin [96] but also with lamo- (2.8%) in the placebo group. The phenomenology and locali-
trigine alone [97], and also in patients without epilepsy (bipolar zation of the tremor were not described [113]. An interim
866 M. Sáenz‑Farret et al.
report from the largest phase III RCT of adjunctive cenoba- Valproate-associated tremor in the absence of parkinson-
mate in 1339 patients with uncontrolled focal seizures did ism is usually a symmetrical 10-Hz postural type but in a
not report tremor or any other movement disorder [114]. few patients it can also be present at rest [131]. Most studies
have concluded that resting tremor is a long-term compli-
cation, although the infusion of valproate can also cause a
5 Antiepileptic Drugs with Mixed Effects resting tremor in a short period of time [132]. Controlled-
on Movement Disorders release valproate might be less tremorigenic as compared
with standard formulations, possibly because of the greater
5.1 Carbamazepine peak–trough variation with the latter [133], while no differ-
ences are seen when comparing the severity and frequency
The dibenzazepine ASDs include carbamazepine, oxcar- of tremor in patients using divalproex sodium versus val-
bazepine, and the more recently approved eslicarbazepine. proate magnesium [134].
In a recent review of six databases, 191 individuals were A study comparing 118 patients taking valproate alone or
reported to have myoclonus, dystonia, parkinsonism, tics, combined with other ASDs versus 53 patients taking other
and akathisia, most of them caused by carbamazepine [115]. ASDs reported that tremor was more frequently observed
Carbamazepine occasionally can exacerbate myoclonic in the former group, particularly in terms of postural upper
seizures. Accordingly, the development of non-epileptic limb tremor (49% vs 15% and 48.3% vs 13.2% for the right
multifocal myoclonus in patients with epilepsy has also been and left side, respectively, p < 0.001). In addition, the total
reported [116]. The combination of non-epileptic myoclonic Fahn–Tolosa–Marin Tremor Clinical Rating Scale score was
jerks and tic-like movements has been reported in patients higher in patients also taking valproate (12.14 vs 3.06, p
with and without epilepsy [117]. Tics can develop or worsen < 0.001), who more often required a treatment for tremor
in patients with Huntington’s disease, TD, and Tourette syn- (23.7% vs 5.6%, p = 0.005) [134]. These authors also tried to
drome as the sole adverse effect in patients treated for epi- find differences between ET and valproate-induced tremor:
lepsy or mood disorders [118, 119]. although postural tongue tremor seemed more frequent in
Generalized or segmental dystonia has been related to the latter and a frank orientation axis in the Archimedes
carbamazepine use in patients with and without epilepsy, spirals was more common in the former, these features had a
within normal and toxic plasma concentrations [120, 121]. relatively low diagnostic accuracy. A study of the short-term
The combination of carbamazepine and isoniazid or lithium side effects of low-dose valproate monotherapy in 209 epi-
has been reported to induce an oculogyric crisis and severe leptic children reported that tremor, myoclonus, and bruxism
dystonic movements including opisthotonos and blepharos- were seen in 1.4%, 1.0%, and 0.5% of patients, respectively
pasm [122]. Acute generalized chorea has been noted after [135].
the increase of the carbamazepine dose in patients with epi- Despite rare reports of chorea secondary to its use, val-
lepsy [123]. proate can improve chorea, such as post-traumatic choreo-
Paroxysmal kinesigenic dyskinesias and to a lesser extent athetosis [136], ‘senile’ chorea [137], hemiballismus of
paroxysmal non-kinesigenic dyskinesia are well known to be vascular origin [138], and particularly Sydenham’s chorea
carbamazepine responsive, with an efficacy and tolerability [139], as confirmed by small series showing sustained and
similar to oxcarbazepine [54, 124]. An early, double-blind, dramatic effects within a few days from treatment initiation
cross-over RCT showed that carbamazepine decreases the [140].
severity of RLS symptoms based on a four-point scale and Dystonia is less clearly associated with valproate; how-
the number of days of unpleasant sensations [125]. Carba- ever, patients have developed this movement disorder while
mazepine has also been effective for chorea in a prospective using this drug [141], a patient with acute schizoaffective
trial of children with Sydenham’s chorea [126]. disorder developed severe anterocollis a few days after the
introduction of valproic acid while taking quetiapine [142].
5.2 Valproate The positive effects of valproate on epileptic (cortical)
and non-epileptic myoclonus, including spinal segmen-
Parkinsonism and tremor are well known side effects of val- tal myoclonus [12] and Lance–Adams syndrome [143],
proate [127]. Parkinsonism has been reported even with very is well known [144]. In addition valproate demonstrated
short periods of valproate use (1 week) and even in children efficacy in reducing the total number of motor tics, their
[128]. However, there is a greater vulnerability in elderly frequency, intensity, complexity, and impairment in a
patients [129] and most often the development of the clinical patient who had not responded to numerous other medica-
features occurs in a progressive manner: in one case series, tions [145]. The efficacy of a combination of valproate and
the mean time to onset of the movement disorder was 7.6 baclofen has been reported in Meige syndrome [146]. Single
years [130].
Antiseizure Drugs and Movement Disorders 867
Fig. 1 Schematic neuronal synapse showing the mechanism(s) of GABA transporter type 1, KCNQ voltage-gated potassium channels,
action of the antiseizure drug (ASDs) discussed in this review. AMPA NMDA N-methyl-D-aspartate, SV2A synaptic vesicle protein 2A,
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, GABA VGSC voltage-gated sodium channels
gamma aminobutyric acid, GABA-T GABA-transaminase, GAT-1
cases of secondary and ‘essential’ palatal tremor have been respect to the pathophysiology of movement disorders by
reported to improve with valproate [147]. clustering them in four groups: effects on ion channels,
inhibitory neurotransmitters, dopaminergic effects, and
multiple mechanisms.
6 Mechanisms Involved in Movement
Disorders Treated and Worsened by ASDs 6.1 Effects on Ion Channels
Anti-seizure disorders have different, often concomitant, 6.1.1 Sodium Channel Inhibition in Paroxysmal Dyskinesias
mechanisms of action, thus resulting in a pleomorphic
cascade of effects in the central nervous system (Fig. 1). Carbamazepine, phenytoin, and lamotrigine act on sodium
The following section summarizes these mechanisms with channels, which are involved in the pathophysiology of
868 M. Sáenz‑Farret et al.
epilepsy and movement disorders such as paroxysmal dys- 6.2.3 Tremor and Parkinsonism Associated with GABAergic
kinesias. Oxcarbazepine is similarly effective and tolerated Antiepileptic Drugs
as carbamazepine, but given its additional mechanisms of
action (Table 1), it has also been hypothesized that modu- The inhibition of GABA transaminase by vigabatrin and its
lation of calcium influx in the cortex and striatum could uptake by tiagabine increase the extracellular level of this inhibi-
increase the inhibitory output of globus pallidus internus and tory neurotransmitter, particularly in the globus pallidus and
the substantia nigra pars reticulata, thus reducing thalamic substantia nigra. A simple basal ganglia model suggests that
and cortical hyperexcitability [54]. blockade of the GABAergic inhibitory striato-pallidal pathways
might cause chorea, whereas stimulation causes a Parkinsonian
6.1.2 Myoclonus with ASDs Binding Voltage‑Gated Calcium syndrome. Therefore, these ASDs were explored for the treat-
and Sodium Channels ment of PD and levodopa-induced dyskinesia, although the
outcome was an aggravation of Parkinsonism without a reduc-
Anti-seizure drugs blocking sodium or calcium channels tion in dyskinesia (Table 2) [149]. A negative correlation was
(carbamazepine, lamotrigine, gabapentin, and pregabalin) found between the change in the TD score and the change in
can cause myoclonus. Evidence suggests that gabapentin and the parkinsonian score in one study using vigabatrin [150], thus
pregabalin modulate the release of excitatory neurotransmit- implying that a possible anti-dopaminergic effect (see below),
ters, particularly glutamate, noradrenaline, and substance P as well as a more generic sedative effect, may have contributed
(Table 1). Serotonin has been intimately linked to myoclonus to the anti-dyskinetic effect.
and an increase in its transmission has been proposed for
sodium channel inhibitors (Table 2) [93]. 6.3 Dopaminergic Mechanisms
Table 2 Beneficial or negative effects on movement disorders according to the ASDs mechanism of action
ASD mechanism Drug Adverse effect Benefit
Table 2 (continued)
ASD mechanism Drug Adverse effect Benefit
AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, ASDs antiseizure drug, ET essential tremor, FXTAS fragile X-associated tremor/
ataxia syndrome, GABA gamma aminobutyric acid, GLUT1D glucose transporter type 1 deficiency, HD Huntington´s disease, LBD Lewy body
dementia, LID levodopa-induced dyskinesia, OT orthostatic tremor, PD Parkinson’s disease, PKD paroxysmal kinesigenic dyskinesia, PNKD
paroxysmal non-kinesigenic dyskinesia, RLS restless leg syndrome, SCA spinocerebellar ataxia, TD tardive dyskinesia, TS Tourette syndrome
Antiseizure Drugs and Movement Disorders 871
Lamotrigine has additional possible mechanisms to produce diverse, including the interaction between neurotransmitter
tics as this drug inhibits the release of the excitatory amino systems and basal ganglia. Taken together this information
acids glutamate and aspartate (Table 2). Glutamatergic path- highlights the possible mechanisms involved in these disor-
ways provide key excitatory inputs from the motor cortex to ders and the potential implications for treatment develop-
the subthalamic nucleus; and from the subthalamic nucleus ment (Table 2). This is, for example, the case of safinamide,
to the internal segment of the globus pallidus and the sub- currently approved for PD, which is structurally related to
stantia nigra pars reticulata. zonisamide. Other studies are presently exploring the role
of new ASDs in the field of movement disorders. An open-
6.4 Multiple Mechanisms label phase IIa study is currently evaluating the safety and
tolerability of perampanel in subjects with cervical dystonia
6.4.1 GABAergic and Dopaminergic Mechanisms in RLS (NCT02131467).
The mechanisms underlying the side effects caused by
The exact mechanism of gabapentin in treatment of RLS is ASDs also depend on the presence of predisposing factors,
unknown. Modulation of dopamine and/or serotonin release, such as the type of epilepsy and other types of structural
as well as GABA increase, appear to be involved [152]. brain changes, although movement disorders have been
However, pregabalin has no direct effect on dopaminergic reported in patients without pre-existing brain diseases. An
systems, which argues against a central role for the dopa- example is the emergence of movement-related side effects
minergic hypothesis and supports an additional effect at the when ASDs are used to treat neuropathic pain. A genetic
spinal level, possibly modulated by dopamine in the dorsal predisposition has also been considered for ASD-induced
horn [61]. The mechanism by which carbamazepine and movement disorders. The ASD dose may play a role as well,
oxcarbazepine improve RLS is also poorly known. Oxcar- although movement disorders have been induced while in
bazepine enhances dopaminergic neurotransmission and pro- the therapeutic range. Finally, although many patients devel-
duces a central dopaminergic effect that may also mediate oped a movement disorder while receiving monotherapy, the
its anti-depressive effect. This observation contrasts with the contribution of poly-pharmacology should be acknowledged.
induction of parkinsonism reported with this ASD (Table 2). For example, many patients who developed myoclonus and
dystonia while taking GABAergic drugs were also receiving
6.4.2 Tremor and Parkinsonism Associated with Valproate treatment with carbamazepine and lamotrigine and pheno-
barbital in the case of athetosis.
Valproate is the ASD that most commonly causes parkinson- The benefit of ASDs on different movement disorders
ism. The following three hypotheses have been postulated often was found serendipitously, further complicating the
in this regard: (1) a disturbance in the GABAergic path- generation of hypotheses. Evidence for a positive effect of
way in the basal ganglia; (2) dopaminergic inhibition; and ASDs on movement disorders is poor in many cases and
(3) a mitochondrial respiratory chain dysfunction. In more may derive from a single case report (Table 3). Most adverse
detail, an accumulation of valproate and mainly its metabo- effects of ASDs are reported in case reports or series, and
lite delta-2-valproate has been demonstrated in the substan- occasionally in RCTs. Interpretation is further complicated
tia nigra, superior and inferior colliculi, hippocampus, and by the profound changes in the field of movement disor-
brainstem. Additionally, an increase of GABA release in the ders in the past decade. For example, many ASDs have been
lateral segment of the globus pallidus has been detected in tested for ‘essential’ palatal tremor, once termed ‘palatal
experimental parkinsonism induced by MPTP (1-methyl- myoclonus’ and now known to be functional (psychogenic)
4-phenyl-1,2,3,6-tetrahydropyridine). Finally, treatment with in most cases.
valproate has been associated with oxidative stress and mito- Little information is available on movement adverse
chondrial dysfunction, both features of PD pathophysiology effects or benefits for the new ASDs, including brivaracetam,
[153]. cenobamate, eslicarbazepine, lacosamide, and rufinamide.
While it is possible that newer agents are more selective
and better tolerated, it should be taken into account that
7 Conclusions iatrogenic movement disorders are overall uncommon and
more real-world data are needed before drawing conclusions
This review summarizes the complex interplay between [154].
movement disorders and ASDs. A single agent can have both
therapeutic and toxic effects on motor symptoms, depending Supplementary Information The online version contains supplemen-
tary material available at https://d oi.o rg/1 0.1 007/s 40263-0 22-0 0937-x.
upon dose, individual variability, concurrent medications,
and many other poorly understood conditions. The proposed
mechanisms between ASDs and movement disorders are
872 M. Sáenz‑Farret et al.
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Funding No funding was received for the preparation of this article.
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bureau of Greenwich, Eisai, Sunovion, UCB, and Livanova. Michel 10. Baruzzi A, Procaccianti G, Martinelli P, Riva R, Denoth F,
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