Lamotrigine-Associated Movement Disorder: A Literature Review
Keywords: BW430C, drug-induced, lamotrigine, movement disorder, review
Lamotrigine (LMT) is a phenyltriazine derivative that was originally described as an antiepileptic drug [Figure 1]. The first chemical studies with this drug started in the decade of 1980 by scientists at Wellcome Laboratories; in the same decade, in animal models, LMT was found to have considerable anticonvulsant activity. After extensive publishing data about efficacy and safety, LMT was first approved in Ireland in 1990. Only four years later, approved by the Food and Drug Administration for adjunctive use in epilepsy in the United States. It is worthy of mentioning that it was noted in epileptic patients that LMT improved mood; after these occasional results, studies have begun to assess the efficacy of LMT in bipolar disorder.
LMT is approved for adjunctive therapy into partial-onset seizures, primary generalized tonic-clonic seizures, generalized seizures of Lennox-Gastaut syndrome; conversion to monotherapy in adolescents with partial-onset seizures; maintenance treatment of bipolar type I disorder. The off-label uses include acute bipolar depression, fibromyalgia, migraines, peripheral neuropathy, neuropathic pain, restless legs syndrome, schizophrenia, and unipolar depression.,
The mechanism of action of LMT is not entirely understood, but the main actions are in the presynaptic antagonism of type 2 voltage-gated sodium channels (preferentially to the inactivated state) and high-voltage-activated calcium channels. The blockade of these channels modulates the release of glutamate/aspartate and γ-aminobutyric acid (GABA). The decrease of glutamate/aspartate leads to an increase of serotonin neuronal firing, which is one of the explanations for the use of LMT associated with antidepressants as an augmentation agent. The GABA modulation is more complex and is dependent on the site of action; for example, LMT decreased the release of GABA in the amygdala, but increases in the entorhinal cortex [Figure 2].,,,,
The side effects of this anticonvulsant that occur in more than ten percent of the individuals are ataxia, blurred vision, diplopia, dizziness, headache, nausea, pharyngitis, rash, rhinitis, and somnolence. There is a boxed warning by the FDA about cases of life-threatening serious rashes, which are more frequently due to exceeding recommended doses of LMT or coadministration of valproic acid without dose adjustment. In this context, the most common movement disorders secondary to LMT are ataxia (22%), tremor (4%), and speech disorder (3%);, other abnormal movements are infrequently and in the majority of the times challenging in the clinical practice. This literature reviews to evaluate the clinical epidemiological profile, pathological mechanisms, and management of lamotrigine-associated movement disorders.
We searched six databases in an attempt to locate any and all existing reports on movement disorders secondary to lamotrigine published between 1993 and 2019 in electronic form. Excerpta Medica (Embase), Google Scholar, Latin American and Caribbean Health Sciences Literature (Lilacs), Medline, Scientific Electronic Library Online (Scielo), and Science Direct were searched. Search terms were “parkinsonism, tic, dyskinesia, dystonia, stuttering, myoclonus, restless legs syndrome, akathisia, tremor, chorea, restlessness, ataxia, ballism, hyperkinetic, hypokinetic, bradykinesia, movement disorder”. These terms were combined with “Lamotrigine, BW430C” [Supplementary Material].
Inclusion and exclusion criteria
Case reports, case series, original articles, letters to the editor, bulletins, and poster presentations published from 1993 to 2019 were included in this review with no language restriction. The two authors independently screened the titles and abstracts of all papers found from the initial search. Disagreements between the authors were resolved through discussion.
We excluded cases that the cause of the movement disorder was better explained by another diagnosis than an adverse event of lamotrigine. Cases that the individual motor symptoms not worsened by or were not related to lamotrigine were not included in the analysis. Reports that had more than one contributing factor to the movement disorder were evaluated based on the Naranjo algorithm to estimate the probability of the event occurring. Studies that were not accessible by electronic methods including after a formal request to the authors of the study by email were excluded. Also, reports that the individuals only developed tremor or ataxia after lamotrigine use were not included.
A total of 7441 papers were found; 6853 were irrelevant [Figure 3]. When provided, we extracted author, department, year of publication, country of occurrence, number of patients affected, lamotrigine indication including off-label uses, time from first lamotrigine-dose till movement disorder onset, time from lamotrigine withdrawal to symptoms improvement, patient's status at follow-up, and important findings of clinical history and management. The majority of the reports did not clearly describe the time of occurrence of symptoms after lamotrigine starting and the time from drug withdrawal to the improvement of the symptoms. The data were extracted by two independent authors, double-checked to ensure matching, and organized by whether the movement disorder was a side effect of the lamotrigine use.
The clinical characteristics and definitions of the movement disorders such as parkinsonism, tic, dyskinesia, dystonia, stuttering, myoclonus, restless legs syndrome, akathisia, tremor, chorea, restlessness, ataxia, ballism, hyperkinetic, hypokinetic, bradykinesia were obtained from the reference Jankovic and Tolosa. The clinical diagnosis for the psychiatric conditions was obtained from the diagnostic and statistical manual of mental disorders (DSM-5). The Naranjo algorithm was used for determining the likelihood of whether an adverse drug reaction was actually due to the drug rather than the result of other factors. In the cases where the non-English literature was beyond the authors' proficiency (English, Portuguese, Spanish, Italian, French, and German), and the English abstract did not provide enough data, such as Japanese, Korean, Chinese, Russian, and Dutch, Google Translate service was used.
For the years 1993 and 2019, a total of 48 reports containing 108 cases who developed movement disorders secondary to LMT from 19 countries were reported [Table 1].,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, [Figure 4] shows the number of reports associated with movement disorders and LMT shows throughout time. The origin was North American 57 cases, European 35, Asian 10, South American 4, and Australian in 2. The movement disorders associated with LMT found were 29 tics, 21 dyskinesias, 14 myoclonus, 13 parkinsonism, 10 dystonia, and 1 stuttering. The not clearly defined cases included 10 akathisia, 4 myoclonus, 4 cerebellar syndromes, 1 hypertonia, 1 dyskinesia, and an unknown number of dystonia cases.
The mean reported age was 33.34 years (age range: 1.574 years) and the median was 28 years. The male was the predominant sex in 53.84% of the cases (35/65). The most common LMT indication was epilepsy in 63.88% (46/72), followed by bipolar disorder (17). and Parkinson's disease (9). The mean LMT-dose at the movement disorder onset was 228 mg (dose range: 50800 mg).
The time from LMT start to the onset of movement disorder was defined in 53 cases; the time was less than 1 month in 13 cases, between 1 and 6 months in 30 cases, and 10 in more than 6 months (onset range: 2 days—2.91 years). The time from LMT withdrawal to complete recovery was reported in 31 cases; the time was within one month in 26 cases (recovery range: 1.5 days—4 months).
The most common management was the LMT withdrawal in 61% (44/72). The other options were the LMT maintenance, LMT-dose decrease, LMT-dose decrease followed by a progressive slow LMT-dose increase, or the starting of another medication such as Levodopa, risperidone, and benzodiazepines. A full recovery was observed in 93% of the individuals (54/58), the other 30 cases did not report the patient's follow-up.
LMT is among the one hundred most commonly prescribed medications in the United States. It is on the World Health Organization's list of essential medicines, the most effective and safest medicines needed in a health system. Also, medicaid recently published the national average drug acquisition cost, and the amount has a wholesale cost of about less than five dollars a month per person. Consequently, LMT is one of the best-selling and safety profile anticonvulsants that we have on the market today.
We can suppose a general presentation based on the 108 cases of LMT-associated movement disorder reported. In the majority of the cases, a young adult North American male with epilepsy presented to a neurology clinic. LMT was started as add-on therapy with small increases every week until 200-250mg. After about 1-6 months, the individual reported motor and vocal tics with some of them complaining of blepharospasms. The physician advised the LMT withdrawal. In the follow-up within 1 month, the patient had a full recovery.
Cases only reporting tremors and ataxia were excluded from the analysis due to unclear descriptions in clinical trials and be more suggestive than a complaining. In the not clearly defined subgroup, the case reported by Buckley and coworkers probably was parkinsonism with ataxia, but due to insufficient data, we cannot conclude a diagnosis. Some of the cases also reported cerebellar syndromes presenting with slurred speech, nystagmus, and ataxia., Also, although akathisia is a frequent central nervous system found in the clinical trials for FDA approval, we only find a study reporting, so probably this abnormal movement disorder is not as common as previously thought.
Herein, we would like to discuss some of the movement disorders in subtopics to give a better comprehension of the data. [Figure 5] shows a resume of the hypothesized pathophysiological mechanisms that we proposed for the development of movement disorders following the use of LMT. Also, the figure shows that there is a relationship between the movement disorder and the LMT-dose; for example, tics may be associated with a glutamatergic mechanism, and in our study was observed that the tic reports have higher LMT doses when compared to the general data. Therefore, we can indirectly assume that the selective inhibition of the neurotransmitter is related to LMT-dose; this can be supported by hamster and rat models that this relation was already presupposed.,,
In the tic subgroup, the mean LMT-dose and the time from LMT start to movement disorder onset were higher than the general data. The distribution between the sexes was the same. The patients presented with motor, vocal, or motor and vocal tics. Some had vocal tic related to obsessive-compulsive disorder. The majority of the motor tics involved the facial muscles, eye blinking, coughing, or sniffing. The tics were also described in the literature as drug-induced Tourettism.
The most common management was drug withdrawal. But, the LMT-dose decrease was also effective to improve the symptoms. Moreover, the rechallenge in a lower LMT-dose showed no reoccurrence of tics. Therefore, we believe that before withdrawal LMT, a dose adjustment based on the benefits and adverse events with careful evaluation case-by-case can be done.
The pathophysiological mechanisms of tics are unclear, but probably dopamine plays an important role. This hypothesis can be supported by the presence of tics after central nervous system stimulants that release dopamine and the effectiveness in the treatment of tics by dopamine receptor antagonists., LMT is chemically structural different from most anticonvulsants and does not have any significant activity on dopamine transmission. However, LMT influences the release of the glutamate/aspartate, which is the key excitatory input to the basal ganglia pathways [Figure 6]., Moreover, this neurotransmitter can inhibit the dopamine release in the substantia nigra and striatum as was already shown in animal studies. Also, it is worthy of mentioning that in brain autopsy studies in Tourette syndrome, low glutamate levels in the medial globus pallidus were observed. So, the LMT decreases the glutamate release, which can lead to a facilitation of the movement, in a state of prokinetic effect, like tics.
It is interesting that only some patients develop tic so may have a predisposition for this association. Menezes et al. hypothesized that individuals with previous brain injury are more susceptible to developing tics secondary to LMT due to possible excitotoxin-mediated neuronal damage, which in their case series the majority of the individuals had some preexisting brain abnormality.
The Dyskinesias (DKN) cases were poorly described with lacking information about the neurological examination and the times of movement disorder onset and recovery. The presentation was choreoathetotic or choreiform in almost all cases, except for only one that reported bilateral ballism. Zesiewicz et al. reported DKN-symptoms after a rapid dosage increase (start with 100 mg/day). The LMT rechallenge was not tried in any of the cases probably because the DKN-symptoms severely compromised the quality of life in the individuals reported. The most frequent management was drug withdrawal; benzodiazepines were tried in one individual after LMT overdose, but the outcomes were not described. It is noteworthy that LMT in patients with Huntington's disease showed significant improvement of choreiform hyperkinesias.
An assumption for the mechanism of drug-induced DKN is an abnormal adaptation of the striatal organization leading to overactivation of the direct pathway. This hypothesis is feasible for the development of LMT-induced DKN in some of the reported cases but does not explain those cases that the abnormal movement occurred in a short period of time. In this way, we hypothesized that the decrease of GABA by LMT in the striatum, which can lead to an excess of dopamine and activation of the direct pathway, is probably the main neurotransmitter associated with DKN in the reported cases. This is supported by reports with schizophrenic patients showing reduced expression of glutamic acid decarboxylase, the key enzyme in GABA synthesis. However, GABA can also be increased by LMT.In this context, the excess of GABA can supersensitive the dopaminergic neurotransmission leading to the DKN-symptoms, which was already shown in rat models. Thereby, both the increase and the decrease of GABA may explain the mechanism of the DKN secondary to LMT.
The sex most prevalent in the myoclonus (MCL) subgroup was the female, which differs from the general records and the literature about drug-induced MCL that the sex ratio 1:1. The individuals were using for a long time LMT before the occurrence of the abnormal movement. In the majority of the cases, the MCL was multifocal with a cortical source showed by epileptic electrodiagnostic studies; but in two cases with higher doses, the source was subcortical with a normal electroencephalogram.,
The management was the LMT withdrawal in an important percentage of the subjects. LMT-dose reduction showed a decrease in the MCL frequency or even the complete recovery. Piracetam was attempted in one case without any improvement. In another case after the occurrence of MCL, LMT-dose was reduced; after LMT-dose was slowly and progressively increased again without the development of new symptoms. None of the reports used outpatient benzodiazepines, we believe that maybe a trial with clonazepam should be done to alleviate the symptoms and reduce the recovery time. A large part of the cases did not report the recovery time, but those who described it was days-weeks, which is a long time for a disabling symptom like MCL.
The different sources of MCL can be explained by the variety of sodium channels with distinct localization, sensitivity, and binding properties to LMT. It is possible that cortical neurons are more affected and sensitive to LMT, whereas inhibitory interneurons in the spinal cord and brainstem are vulnerable to cause MCL., Therefore, the glutamate and GABA balance could explain the origin of the abnormal movement; for example, when there is a greater inhibition to release GABA than glutamate, a relative excess of glutamate will occur and facilitate the occurrence of the jerks and even a status epilepticus. This hypothesis can be supported by animal studies that low to moderate LMT-dose was correlated with the lower release of GABA. Furthermore, in the cases reported the LMT-dose was moderate in more than half of the cases.
The population affected by Parkinsonism (PKN)-induced LMT was more than 20 years older than the general data, which can be explained by the age as an important component in this association. But, Santens et al. described normal dopamine striatal uptake with ioflupane single-photon emission computed tomography. The doses when PKN occurred were moderate and the time from LMT start till PKN onset was longer. LMT withdrawal was effective to improve the symptoms.
It is believed that there is an interaction between glutamatergic and dopaminergic neurotransmission. Soon after the discovery that LMT can reduce the release of glutamate, it was thought that LMT could have antiparkinsonian effects, but this was not confirmed in animals or even humans studies. In addition, the administration of high doses in the normal mice decreases spontaneous locomotor activity and causes posture and gait impairments. In this way, the stabilization of presynaptic cell membranes and subsequent inhibition of glutamate/aspartate release may contribute to a decrease/increase of dopamine turnover and locoregional differences of the glutamate balance, in the same way as for tic-induced LMT.
The patients presented in decreased order of frequency with blepharospasms, oromandibular, cervical, and axial DTN. The LMT-doses related to DTN were lower when compared to the general data, but DTN is also more commonly found in LMT overdose in toxicologic studies. The drug was withdrawn in almost all cases, except one that LMT-dose was reduced with symptoms improvement. In two pediatric patients, the drug withdrawal only slightly alleviated DTN, as a result, levodopa was started, and showed rapid recovery of symptoms.
The first reports of DTN secondary to LMT were observed in hamster models. The DTN was observed in lower doses of LMT and appears to be the movement disorder more sensible to LMT. This data can be supported by the present review that revealed lower LMT-dose causing DTN. It was interesting that in the hamster there was no difference in prodystonic effect after parenteral or oral administration, which can be explained by the well-absorption oral via; probably this adverse event will be associated with the coming LMT intravenous formulations. The decrease of glutamatergic transmission probably does not explain the DTN following LMT use because many experiments had already demonstrated antidystonic activity of glutamate receptor antagonists. Therefore, we believe that the DTN is probably involved with the decrease of GABA leading to an interruption in the direct and indirect pathways; which probably predominant affects the indirect pathway, and as a result, this disruption can increase the thalamocortical drive and eventually cause dystonia.
LMT is associated with tics, DKN, MCL, PKN, DTN, stuttering, AKT, and DTN. The pathophysiological explanations for the LMT-induced movement disorders are probably related to GABA for DTN and DKN; GABA and Glutamate for MCL; glutamate for PKN and tic. One interesting fact is that the type of LMT-induced movement disorder may be associated with the LMT-dose. In the literature, the majority of the cases did not give a clear picture of the individuals; also, the times of movement disorder onset and recovery were not described. Future studies related to adverse effects with LMT need to evaluate the individuals in a prospective way to provide prognostic information about the development of primary movement disorders.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]