The Possible Role of Anti-Epileptic Drugs (AEDS) in Treating Levodopa Induced Dyskinesia (LID)

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Parkinson’s disease (PD) is a neurodegenerative disorder with a lifetime risk of 1%- 2% [1, 2]. Patients present with motor as well as non-motor symptoms and signs [1, 3, 4]. PD main motor signs are tremor, rigidity, bradykinesia, gait instability and more. Non-motor disturbances include sleep, autonomic problems and cognitive decline [1, 4]. PD is usually treated by drugs that enhance dopaminergic neurotransmission, such as levodopa and dopamine receptor agonists. These anti-parkinsonian drugs markedly improve motor performance, especially at the early stages of the disease. In contrast, in the more advanced stages of PD, patients only partially respond to the presently available pharmacological and neurosurgical treatments and develop severe adverse events to anti-Parkinsonian drugs [1, 5, [6, 7, 56]. One important complication of levodopa and dopamine receptor agonists is the levodopainduced dyskinesia (LID). LID develops in almost all long-standing PD patients treated with levodopa or dopamine receptor agonists, and manifests as involuntary movements induced by the anti- Parkinsonian drugs [8, 9].

LIDs are common and difficult to treat [9]. In general, they can be classified as chorea which is hyperkinetic dance-like movements and dystonia referring to sustained abnormal muscle contractions [10]. Additional motor manifestations in LID include ballism and choreoathetosis [8, 51] . With increasing duration of treatment, the frequency as well as the severity of the dyskinesia exacerbate [11]. LID appear in 20–30% of patients receiving levodopa for less than two years. Over half of patients with PD will develop dyskinesia within six months of treatment [8, 10] . Eventually, most (up to 80%) of levodopa-treated PD patients has LID within five years [8,9].

The pathophysiological mechanisms underlying LID are poorly understood. At the network level, LID may be the result of reduced activity of STN and GPi neurons. The decreased activity of GPi causes dis-inhibition to activity in the motor cortex, especially SMA [12, 13] . At the cellular level, LID has been associated with pulsatile stimulation of dopamine receptors, dysregulation of genes and proteins in neurons resulting in changes in neural discharge patterns between BG and cortex [8, 14] . Furthermore, metabolic activity in thalamic nuclei of ventral anterior (VA) and ventrolateral (VL) is significantly decreased in LID [8]. It is lower than that observed in normal and parkinsonian untreated animals. More importantly, it is below than that found in non-dyskinetic, levodopa treated animals [15]. These findings indicate that hypo-activity of BG output nuclei (GPi and SNr) may be related to LID development by inducing hyperactivity of the motor cortex especially the supplementary motor area (SMA). Indeed, electrophysiological evidences proposed that LID is associated with marked decrease in firing frequency of the GPi neurons both in parkinsonian monkeys [8, 16] and in PD patients [17]. Furthermore, changes in firing pattern, and not only in firing frequency, may be involved in LID [16] . Both D1 and D2 dopamine receptor agonists disrupt neural firing pattern indicating that irregular firing patterns, more than change in firing rate, are crucial in LID [8].

Therefore, the electrophysiological mechanisms involved in LID include combination of significant decrease in GPi firing rate and a modification of the firing patterns. Mechanisms involving dysfunction of dopamine release, changes in dopamine receptor signaling and changes in non-dopamine systems were described as well [18, 19, 20] . Many strategies tried to treat LID such as opoidreceptors antagonist [21], NMDA and AMPA receptors antagonists [22, 23, 24, 25], H3 Histamine receptor antagonists, adenosine A2a receptors antagonists [26] and more with little tangible success. Interestingly, Anti-epileptic drugs (AEDs) were also tried in order to treat LID and despite the relatively small amount of studies, promising effects may exist.

Anti-epileptic drugs (AEDs) are widespread medications affecting neural activity at the cellular as well as network level by diverse mechanisms. The exact mechanism of action of part of them is largely unknown. Besides treating epilepsy, they have been widely used for other purposes like in major psychiatric disorders, migraine and more [27, 28, [29, 30, 31]. The motivation beyond using AEDs for treating LIDs rises from electrophysiological findings discussed above including changes in firing rate like hypoactivation of GPi and dis-inhibition of motor cortex in LID. Theoretically, AEDs may aid reversing the dis-inhibited motor cortex in LID. Interestingly, most of the evidences about the effectiveness of AEDs in LID has been investigated mainly for second-generation drugs, maybe because their better safety profile. There are very little studies about firstgeneration drugs like phenytoin, carbamazepine, etc.

Levetiracetam is a relatively well-tolerated AED with a poorly understood mechanism of action. Most likely is has more than one potential mechanism of action such as synaptic vesicle 2A modulation, modulating voltage-gated calcium channels [32] and potassium channels [33]. In LID, it has been shown to abolish the abnormal movements in rat models of LID and MPTP-lesioned macaques in a dose-dependent pattern [34, 35, 36]. Few clinical trials investigated the efficacy of levetiracetam in treating LID. A randomized placebo- controlled double-blind pilot study in nine PD patients suggested improvements of these patients reflected by increasing the time free from dyskinesia [36, 37]. In addition, wider multicenter double-blind placebo- controlled trial in 38 LID patients demonstrated a significant decrease in dyskinesia time with levetiracetam at doses of 500 and 1000 mg per day [38] .Pre-clinical animal studies and additional case reports indicate that Levetiracetam may reduce other types of dyskinesia rather than LID such as fever- induced chorea as well as paroxysmal choreoathetosis [40]. On the other hand, other studies showed that levetiracetam was not well tolerated in PD patients with LID mainly because of its side effects as well as worsening of the dyskinesia [39].

Topiramate acts in many mechanisms including voltage gated sodium channel blockade, modulating GABA and Glutamate synaptic transmission, carbonic anhydrase inhibitor and more [32]. Contradicting evidences were reported about its effect on LID patients. On the one hand, it was demonstrated to reduce LID in rat and non-human primate models [36, 41, 42]. On the other hand, a small-randomized double-blind trial in 15 patients with LID demonstrated that topiramate did not improve the dyskinesia and even exacerbates it [43]. Zonisamide has also multiple mechanisms of action including voltage gated sodium and calcium channels blockade, inhibiting of glutamate release, increase in dopamine synthesis, MAO-B inhibition and more [32]. A notable doubleblind trial of 422 patients showed that zonisamide improves PD dyskinesia and diminished the time of wearing off [44] . However, the positive effect on LID was not consistent across groups (improvement only in the 50 mg group, but not in the 25 mg and 100 mg groups) [53, 54].

Valporate is a first-generation AED. Its mechanism of action is complicated and poorly understood [32]. Few studies in the past examined its efficacy in treating LID concluding that it may yield moderate improvement in the dyskinesia, but this was not significant [48]. Furthermore, previous studies investigated valproate as a treatment for tardive dyskinesia in psychiatric patients with very small effects [49]. Other studies demonstrated no effects [50] . Gabapentin was also investigated and failed to improve LIDs [53, 55]. Other AEDs were not directly investigated for LID but for other types of dyskinesia. For example, low dose of oxacarbamezapine was shown to reduce Paroxysmal Kinesigenic Dyskinesia in 4 patients [45]. However, Carbamazepine (similar to oxacarbamezapine) itself is known to cause dyskinesia, as carbamazepine-induced dyskinesia is the second most common AED induced dyskinesia [46, 47]. Lamotrigine also was suggested to be effective in Paroxysmal Kinesigenic Dyskinesias [52].

Conclusion

To conclude, LID is a common and a difficult to treat complication in PD patients receiving L-dopa or dopamine agonists. Only part of AEDs were directly addressed to improve this dyskinesia. Levetritacem is the drug with the most evidences for treating LID with positive effects in most of the clinical studies. Others were not properly investigated with only small trials lacking statistical power and consistency in findings. Counting on the pathophysiological mechanism, AEDs and especially the voltagegated sodium channels blockers may help alleviate LID by reversing the dis-inhibited motor cortex and the irregular firing patterns of neurons in the motor cortex as well as striatum. Such drugs include phenytoin, Lacosamide, carbamazepine and Lamotrigine. Therefore, we recommend that larger trials will be conducted exploring the real effects of those drugs in LID patients.

Acknowledgements

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