Freely available online Brief Report Primary Orthostatic Tremor: Experience of Perampanel Use in 20 Patients Alexandre Gironell* & Juan Marín-Lahoz Movement Disorders Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Catalonia, ES Abstract Background: Primary orthostatic tremor (POT) is a rare disorder for which current treatments are largely ineffective. Following up on our recent report of com- plete resolution of POT symptoms in a patient using low doses of perampanel, we describe our experience of perampanel in 20 patients. Methods: Twenty patients whose neurologists prescribed perampanel were recruited. Initial dose was 2 mg/day, which was increased to 4 mg/day after the first month. Treatment efficacy was self-scored from +3 to −3 at 1 and 3 months. Results: Eight patients withdrew due to adverse effects. Of the 12 patients who completed the study, 92% indicated that their POT symptoms had improved after 1 month, with 75% indicating moderate to marked improvement (mean score 1.9 ± 0.9). This improvement was not sustained by follow-up at 3 months (mean score 0.9 ± 1.3). A rebound of POT symptoms that lasted 2–6 weeks was observed in most patients who withdrew. Discussion: Our experience with this series of cases points to the potential of low-dose perampanel as a treatment for POT, although poor tolerance and the possibility of a non-persistent therapeutic benefit need to be considered. Controlled studies are needed to confirm these findings. Keywords: Orthostatic tremor, primary orthostatic tremor, tremor, perampanel, unsteadiness Citation: Gironell A, Marín-Lahoz J. Primary orthostatic tremor: experience of perampanel use in 20 patients. Tremor Other Hyperkinet Mov. Tremor Other Hyperkinet Mov. 2019; 9. doi: 10.7916/tohm.v0.720 *To whom correspondence should be addressed. E-mail: agironell@santpau.cat Editor: Elan D. Louis, Yale University, USA Received: August 20, 2019; Accepted: September 20, 2019; Published: October 14, 2019 Copyright: © 2019 Gironell A and Marín-Lahoz J. This is an open-access article distributed under the terms of the Creative Commons Attribution– Noncommercial–No Derivatives License, which permits the user to copy, distribute, and transmit the work provided that the original authors and source are credited; that no commercial use is made of the work; and that the work is not altered or transformed. Funding: None. Financial Disclosures: None. Conflicts of Interest: The authors report no conflicts of interest. Ethics Statement: This study was reviewed by the authors' institutional ethics committee and was considered exempted from further review. Introduction Recently, it has been reported complete resolution of POT symptoms Primary orthostatic tremor (POT) is a disorder characterized by tremor in two patients using low doses of perampanel, an antiepileptic drug that and unsteadiness. It only occurs when the patient is upright and immobile blocks glutamate-mediated postsynaptic excitation.4,5 In the current study, and stops once the patient walks, sits down, or lies down.1 Patients report we describe our experience of using perampanel in 20 patients with POT. a subjective feeling of instability that impacts their quality of life and may Although ours was not a controlled trial, our findings and conclusions affect their activities of daily living, with many such patients experiencing may be of interest due to the low prevalence of this disorder. anxiety, depression, and social phobia.2 This disease is very uncommon.3 Its prevalence, furthermore, is Patients and methods unknown, which means it is very difficult to perform therapeutic trials. Between January 2018 and January 2019, patients with POT were Medication, although it may provide some mild relief, is largely recruited through contact initiated by a French group of patients with ineffective.1 POT. Recruited were 20 patients whose neurologist had acceded to their Tremor and Other Hyperkinetic Movements http://www.tremorjournal.org 1 Columbia University Libraries Gironell A and Marín-Lahoz J Primary Orthostatic Tremor and Perampanel request for a perampanel prescription. Electromyography (EMG) data Discussion were not available for any patient. For our case report series of patients with POT, we observed that Patients were informed that they could withdraw at any time and perampanel improved POT symptoms over 1 month of treatment in were also guaranteed the anonymity and confidentiality of their data. nearly all (92%) of the 12 patients who completed the study, with 75% Informed consent was considered implicit in the patient agreeing to pro- showing moderate to marked improvement. However, this improvement vide essential demographic and clinical data, monitor and record treat- was not sustained over the 3 months of the study. ment efficacy and adverse events, and provide this information to the Currently, the only treatment administered for POT is symptomatic,1 patient coordinator for email transmission to the trial doctors. mainly clonazepam or gabapentin as first-line agents, or primidone, val- Treatment duration was 3 months, and posology was 2 mg/day proic acid, propranolol, or bromazepam.1,7,8 In most cases, however, for the first month, which was increased to 4 mg/day for the remain- medication benefits dissipate over time.1 Non-responders may benefit ing 2 months. Perampanel was taken concurrently with any anti- from bilateral thalamic deep brain stimulation of the ventral intermedi- tremor medication that the patients were taking on while commencing ate nucleus.9 the study. We recently reported complete resolution of POT symptoms in a Treatment efficacy was measured in terms of symptom improve- patient using low doses of perampanel.4 After 18 months of treatment, ment using a simple self-administered subjective scale, based on part the benefits of perampanel persist for this patient at a dose of 2 mg/day. C of Fahn-Tolosa-Marin Tremor Clinical Rating Scale,6 scored as fol- Neurophysiology revealed the persistence of subclinical EMG findings lows: 0 = no change; +1 = slight improvement; +2 = moderate for POT in this patient, which would confirm a symptomatic rather improvement; +3 = marked improvement; −1 = slight worsening; than an etiological effect of this drug. −2 = moderate worsening; and −3 = marked worsening. Adverse Perampanel and its indications, pathophysiology and mechanisms of effects were also recorded. action have been fully documented elsewhere.4,10–15 Patients notified their scores and any adverse event 1 and 3 months Our study pointed to three main drawbacks of perampanel as a after starting treatment with perampanel. Patients who suffered any treatment for POT. First, tolerance was poor, with 40% of recruited adverse effect that lasted more than last clinical control (3 months) were patients withdrawing due to adverse effects (dizziness and instability, followed until symptoms reverted. weight gain, and depression); furthermore, only 4 of the 12 patients who completed the study were able to tolerate doubling the dose to 4 mg/ Results day after the first month. The patients recruited for the study (n = 20) had a mean age of In patients with epilepsy, perampanel appears to be associated with a 68.9 ± 6.3 years, 16 were women, and 17 were being treated with anti- relatively low incidence of serious adverse effects, most especially at low tremor medication. Mean evolution of the disease was 14.4 ± 6.9 years. doses.16,17 Predictable side effects, such as somnolence and dizziness, Of the 20 patients included, 12 completed the study. After 1 month, tend to be observed more frequently at higher doses. While the fact that 11 patients showed some improvement in POT symptoms: three, six, psychiatric adverse effects, mainly irritability and aggression, occur at a and two patients scored their improvement as marked, moderate, and greater rate with the use of perampanel than with a placebo is a poten- mild, respectively, and a single patient reported no change. tial concern, the incidence of serious psychiatric effects is nevertheless After 3 months, however, the degree of improvement decreased, with low. In our study, poor tolerance, as manifested in dizziness and instabil- only a single patient indicating marked improvement, four and five ity, weight gain, and depression, may have been due to perampanel patients indicating moderate and mild improvement, respectively, and interaction with the concomitant anti-tremor medication (clonazepam, two patients reporting no change. gabapentin, pregabalin, lorazepam, and/or oxycodone) taken by 17 of The mean improvement score was 1.9 ± 0.9 after 1 month, falling to the included 20 patients. 0.9 ± 1.3 after 3 months. Non-persistence of the therapeutic effect was A second issue with perampanel as a treatment for POT was that the observed in 50% of patients. therapeutic benefit failed to persist in around 50% of our patients after Of the 20 included patients, eight withdrew in a mean of 10 ± 5 days 3 months of treatment. This effect has not been described for peram- due to adverse effects: dizziness and instability with increased falls panel used to treat patients with epilepsy, but has been reported for (n = 8), weight gain (n = 2), and depression (n = 2). No further patients POT pharmacological trials with other anti-epileptic drugs1; this possi- withdrew, although following the dose increase to 4 mg/day after the bly points to a greater tolerance of anticonvulsant drugs by patients with first month, 8 of the remaining 12 patients reverted to 2 mg/day due to POT. The reason for the non-persistence of therapeutic benefit is not mild dizziness and instability. clear. One possibility is the existence of a placebo effect lasting for some A rebound in POT symptoms (worse unsteadiness symptoms than weeks. Another possibility is that the reduced efficacy may result from a patients ever had before) lasting 2–6 weeks was observed in six of the eight dose increase from 2 to 4 mg/day. Efficacy may be greater at low doses, patients who withdrew. Of the 12 patients who completed the study, eight as higher doses would increase the adverse effects and hide anti-tremor opted to continue with perampanel treatment after the study. efficacy. Further studies are needed to clarify this issue. The demographic and clinical characteristics of the patients are A final drawback with perampanel was the lengthy rebound of POT summarized in Table 1. symptoms in most of the patients who discontinued perampanel. Tremor and Other Hyperkinetic Movements http://www.tremorjournal.org 2 Columbia University Libraries Gironell A and Marín-Lahoz J Primary Orthostatic Tremor and Perampanel Table 1. Patient Characteristics No. Age, sex Evolution Concurrent Perampanel mg/ Improvement Rebound Adverse effects (years) treatment day at 3 months score 1 month 3 months 1 65, F 17 GBP 2 +2 +1 No Weight gain, instability 2+ 66, F 5 None 2 +3 +3 N/A Mild dizziness 3* 78, F 31 CLN N/A N/A N/A Yes Dizziness, asthenia 4* 78, M 15 None N/A N/A N/A Yes Instability, dizziness 5* 65, F 24 CLN N/A N/A N/A Yes Tremor, dizziness 6* 72, F 5 CLN, PRG N/A N/A N/A Yes Tremor, instability 7* 75, M 17 CLN N/A N/A N/A N/A Instability 8 + 70, F 20 CLN, PRG 2 +2 +2 N/A None 9 + 71, F 14 CLN 4 +2 +2 N/A None 10* 75, M 8 TAR, LOR N/A N/A N/A Yes Depression 11* 53, F 11 None N/A N/A N/A N/A Depression 12 + 75, F 20 CLN 4 +2 +1 N/A None 13 66, F 15 CLN 2 +1 0 No Instability 14* 62, F 20 PRG N/A N/A N/A Yes Instability 15+ 68, F 7 GBP, CLN 4 +3 +2 N/A Weight gain 16 + 65, F 5 CLN 2 +3 +1 N/A None 17 60, F 10 CLN 2 0 0 No None 18 + 70, M 15 CLN 2 +2 +2 N/A None 19+ 75, F 10 GBP 4 +1 +1 N/A None 20 70, F 20 PRG 2 +2 +1 No Mild dizziness Abbreviations: CLN, clonazepam; F, female; GBP, gabapentin; LOR, lorazepam; M, male; N/A, not applicable OXC, oxycodone; PRG, pregabalin. * Indicates withdrawal. + Indicates continuation beyond the study period. 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