Non‐Persistence of Tremorolytic Effect of Perampanel in Essential Tremor: Real‐World Experience with 50 Patients

ABSTRACT

Background

We describe our experience of using perampanel to treat essential tremor (ET) over 12 months.

Methods

We enrolled 50 ET patients in an open‐label trial. Perampanel was titrated to 4 mg/day as adjuvant therapy. The main outcome measures were baseline, +1, +3, +6, and + 12 month scores of the Tremor Clinical Rating Scale (TCRS) and the Glass scale (GS).

Results

Twenty patients withdrew because of adverse effects. At +1 month, 27 of 30 patients improved: 68% reduction in both TCRS 1 + 2 (P < 0.001) and TCRS 3 (P < 0.001); TCRS 4 + 1.8 and GS 1.1 point reduction. By +12 months non‐persistence of therapeutic effect occurred in 70% of patients: the mean reduction in TCRS 1 + 2 was 33% (P = 0.03), TCRS 3 (0.04), TCRS 4 + 0.8, GS 0.2 points reduction.

Conclusions

We report important peramapanel acute tremorolytic effects, but poor tolerance to adverse effects and a non‐sustained therapeutic effect in most patients.

Drug treatment for essential tremor (ET) is often unsatisfactory and more treatment options are clearly needed. ¹ Perampanel, licensed and marketed as an antiepileptic drug that blocks glutamate‐mediated postsynaptic excitation, has shown efficacy in pilot studies of ET and in primary orthostatic tremor (POT). ² , ³ , ⁴ , ⁵ , ⁶ However, in a recent study evaluating perampanel for POT, it was observed that, although therapeutic efficacy was very high in the early weeks of treatment, the benefit failed to persist in ~50% of patients by ~3 months of treatment. ⁶ It is not known if this loss of efficacy also occurs with ET.

In this article we describe acute and chronic effects of using perampanel to treat ET in a 12‐month open‐label trial. Although ours was not a controlled trial, our real‐world findings and conclusions may be of interest.

Patients and Methods

From September 2019 to January 2020, we consecutively enrolled 50 patients diagnosed with ET by a Movement Disorders Unit neurologist at the Sant Pau Hospital (Barcelona). The study protocol was approved by the Hospital Ethics Committee. Informed consent to participate was obtained from all patients.

Only patients with moderate or severe tremor (Glass scale II, III, or IV) were included. ET was diagnosed according to the Movement Disorders Society (MDS) consensus statement (1998), ⁷ and all patients met neurophysiological criteria for ET. ⁸

Exclusion criteria included psychiatric illness, liver disease, substance abuse, epilepsy, and dystonia. Additionally, excluded were professional drivers and operators of heavy machinery, individuals taking tremorgenic drugs, and individuals in whom there was a suspected interaction between perampanel and other drugs. Patients were requested not to smoke or take alcohol or caffeine in the 24 hours before testing.

Perampanel was taken concurrently with any anti‐tremor medication that the patient was taking on commencing the study. Forty of 50 patients were taking anti‐tremor medication (mean daily doses in brackets): 25 propranolol (80 mg), 10 topiramate (200 mg), 5 gabapentin (1200 mg), 5 alprazolam (3 mg), 8 zonisamide (200 mg), and 15 primidone (300 mg). The anti‐tremor drug dose was not changed in the month before, or during the trial.

Perampanel was dosed over a period of 8 weeks according to the regime used in previous ET studies. ² , ³ Dosage was titrated at 2 mg daily at night for the first month, rising to 4 mg daily at night from the second month.

The main outcome measure was ET severity as quantified by the validated Tremor Clinical Rating Scale (TCRS) ⁹ and the validated Glass scale. ¹⁰ Scores were compared for day 1 (before drug intake) and + 1 month, +3 months, +6 months, and + 12 months (last dose taken the night before). Scores of TCRS parts 1 and 2 were summed because they include clinical examination of tremor (visual inspection and patient performance). ¹¹ All patients were clinically assessed by the same examiner (A.G.).

To evaluate the main outcomes (TCRS and Glass scale scores) baseline versus +1 month, baseline versus +3 months, baseline versus +6 months and baseline versus +12 months, we used the non‐parametric asymptotic Wilcoxon–Pratt signed‐rank test, given that assumptions for parametric testing were not satisfied. Any P < 0.05 was considered significant. All statistical tests were performed using R 3.4.3. ¹²

Results

The 50 patients (30 women) recruited for the study had a mean age of 67.39 ± 6.0 years, and 40 were being treated with anti‐tremor medication. Mean evolution of the disease was 30.8 ± 10.0 years. All 50 patients had a family history of tremor.

Of the 50 included patients, 30 completed the four follow‐up visits of the study. Twenty withdrew, in a mean of 18 ± 7 days, because of adverse effects: dizziness and instability with increased falls (n = 16), weight gain (n = 2), and depression (n = 2). No further patients withdrew, although, following the dose increase to 4 mg/day after the first month, 10 of the remaining 30 patients reverted to 2 mg/day because of mild dizziness and instability. Results for the patients that completed the study (see Table 1) are summarized as follows:

• At +1 months, some improvement in ET symptoms was evident in 27 of 30 (90%) patients that tolerated perampanel: a significant 68% reduction in both the TCRS 1 + 2 score (P < 0.001) and the TCRS 3 score (P < 0.001); a reduction of 1.1 points in the Glass scale score; and a mean TCRS 4 score of +1.8.

• At +3 months, improvement had slowed down, although the improvement in clinical scores was still significant: a 57% reduction in the TCRS 1 + 2 score (P < 0.001) and the TCRS 3 score (P < 0.001); a Glass scale score reduction of 0.7; and a mean TCRS 4 score of +1.5.

• At +6 months: a 44% reduction in the TCRS 1 + 2 score (P < 0.001) and the TCRS 3 score (P < 0.001); a Glass scale score reduction of 0.7; and a mean TCRS 4 score of +0.9.

• At +12 months: a 33% reduction in the TCRS 1 + 2 score (P < 0.035) and the TCRS 3 score (P < 0.041); a Glass scale score reduction of 0.2; and a mean TCRS 4 score of +0.8.

TABLE 1.

Efficacy endpoint outcomes

	Baseline	Months over baseline
		+1	+3	+6	+12
TCRS scores
1 + 2	55.13 (5.84)	17.65 (7.3)*	23.7 (5.5)*	30.80 (3.9)*	36.90 (4.8) +
3	22.7 (3.6)	7.27 (3.3)*	9.77 (3.8)*	12.72 (3.3)*	15.21 (3.3) +
4		+1.8	+1.5	+0.9	+0.8
Glass scale score	3.2 (0.2)	2.1 (0.2)*	2.5 (0.1)*	2.8 (0.2) +	3.0 (0.2)

Note: Means (standard errors). P‐values reflect comparison of mean changes from baseline:

Abbreviation: TCRS, Tremor Clinical Rating Scale.

⁺ P < 0.05,

^* P < 0.001.

There were no differences when analyzing results of patients that tolerate 4 mg/day (n = 20) and patients that reverted to 2 mg/day (n = 10).

Non‐persistence of the therapeutic effect after 12 months was observed in 70% of patients (Fig. 1). Of the 30 patients who completed the study, 10 opted to continue with perampanel treatment after the study. Once the study concluded, titration of perampanel was increased to 6 mg/day in 5 patients taking 4 mg/day; none reported any tremor improvement after 4 weeks, and 2 reverted to the previous dose because of adverse effects.

FIG. 1.

TCRS 1 + 2 scores over the study period.

Discussion

In this open‐label study we found that perampanel had a tremorolytic effect on ET. In the 30 patients who tolerated the drug, perampanel improved ET symptoms over 1 month of treatment in 90% of cases. This improvement was moderate to marked (68% improvement of clinical scores). Over the study period (12 months), however, this improvement was not sustained, because the tremorolytic effect progressively decreased.

Perampanel is a non‐competitive AMPA‐type glutamate receptor antagonist. AMPA receptors increase the degree of inferior olivary coupling, which, in turn, increases Purkinje cell complex spike synchrony, possibly associated with increased movement amplitude and tremor. ¹³ , ¹⁴ , ¹⁵ AMPA receptor antagonists suppress tremor in the harmaline animal model, whereas an allosteric AMPA receptor activator (PF‐4778574) causes tremor in primates and other species. ¹⁶ , ¹⁷ , ¹⁸

In humans, several case reports have demonstrated perampanel to have a tremorolytic effect on POT. ⁴ , ⁵ , ⁶ Two main studies have been conducted on the use of perampanel for ET. In an open‐label 8‐week trial with 12 patients, Gironell et al ² found that perampanel (titrated at 2 mg/day at night in the first month, rising to 4 mg/day at night from the second month) improved tremor symptoms in all patients who tolerated the drug, with subjective tremor improving by around 70% in half of those patients. For a recent 14‐week double‐blind randomized crossover trial in 26 patients, Handforth et al ³ reported that perampanel (titration 2–8 mg/day) was statistically superior to placebo in terms of both clinical tremor and activities of daily living. Both those studies coincided in pointing to poor tolerance to the adverse effects of perampanel; 35% ² and 40% ³ recruited patients withdrew because of adverse effects (mainly dizziness and instability, weight gain, and mood changes), and dose reduction was necessary in 33% ² and 41% ³ of patients, with the latter study concluding that the incidence of adverse events was notable, especially at doses >4 mg/day, and, furthermore, recommending doses of 4 mg/day or less in future studies.

In patients with epilepsy, perampanel appears to be associated with a relatively low incidence of serious adverse effects, most especially at low doses. ¹⁹ , ²⁰ , ²¹ In ET studies, poor tolerance may be because of perampanel interaction with the concomitant anti‐tremor medication. Another possibility is that it may be partially age‐related, because many patients with ET are ages >65 years. ²² Finally, inherent balance and psychiatric abnormalities described as non‐motor symptoms of ET may explain why imbalance and irritability were more common in patients with ET than in older patients with epilepsy. ²³ , ²⁴ , ²⁵

In this study, we found that the therapeutic benefit failed to persist in around 50% of our patients after 3 months of treatment. Loss of efficacy was progressive, but was evident in 70% of patients after 12 months. After 12 months, nonetheless, the tremorolytic effect was sustained in nearly 30% of patients. Although this effect has not been described for perampanel used to treat epilepsy, ²¹ it has been reported for perampanel used to treat POT. ⁶

Non‐persistence of pharmacological efficacy in the treatment of ET is a recurrent problem. Few pharmacological studies have analyzed more than 6 months ET treatment follow‐up (chronic effects) and even fewer with the latest generation antiepileptic drugs with some tremorolytic properties (gabapentin, topiramate, or zonisamide). The non‐persistence of efficacy has been studied mainly for antiepileptic drugs (primidone), but also for propranolol and thalamic deep brain stimulation. ²⁶ , ²⁷ Crystal et al, ²⁸ Shale and Fahn, ²⁹ and O'Brien et al ³⁰ reported some non‐persistence of the pharmacological effect of primidone in case reports. In a 12‐month study of chronic effects in 50 patients, Koller et al²⁷found that efficacy was not maintained in 12.5% and 13% of patients on propranolol and primidone, respectively, whereas Sasso et al ³¹ found that primidone maintained efficacy after 12 months, although statistically only on accelerometric evaluation.

The reason for the non‐persistence of therapeutic benefit is not clear. One possibility is the existence of a placebo effect lasting for some weeks. Another possibility is the dose increase from 2 mg/day to 4 mg/day; efficacy may be greater at low doses, because higher doses would increase adverse effects and mask anti‐tremor efficacy. In a handful of our patients, a higher dose of 4 mg/day did not enhance anti‐tremor efficacy. Finally, disease progression may account for some loss of pharmacological effect, although the usual rate of advancement of ET is very slow. ³²

The main limitation of our study is its non‐controlled design. Another limitation is that ET diagnosis was done following MDS 1998 criteria instead of 2018. Finally, concomitant treatment with antiepileptic drugs may have increased perampanel adverse effects and, therefore, intolerance.

In conclusion, for our long‐term evaluation of perampanel used to treat ET, we report important acute tremorolytic effects, but poor tolerance to adverse effects and a non‐sustained therapeutic effect in most patients. Controlled studies are needed to confirm these findings.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of The First Draft, B. Review and Critique.

A.G.: 1A, 1B, 1C, 3A.

B.P.S.: 1C, 3B.

J.Perez: 1C, 3B.

J.M.L.: 2A, 2B, 2C, 3C.

J.Pagonabarraga: 2C, 3B.

Disclosures

Ethical Compliance Statement

Study approved by the Sant Pau Hospital (Barcelona) Ethics Committee. Informed consent to participate was obtained written from all patients. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines

Funding Sources and Conflicts of Interest

No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work

Financial Disclosures for the Previous 12 Months

The authors declare that there are no additional disclosures to report