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Summary: Purpose: Disabling myoclonus is the main symptom in long-standing Unverricht–Lundborg disease (ULD), and levetiracetam (LEV) appears to be an effective anticonvulsant with promising short-term antimyoclonic properties.
Methods: LEV was prescribed to 13 patients with ULD. We retrospectively analyzed the efficacy of LEV on seizure frequency and on myoclonus, by using a simplified myoclonus rating score, and compared the patients' status before LEV and at the last follow-up. They were two women and 11 men, aged 14 to 52 years (mean, 36.5 years), with a disease duration of 4 to 40 years (mean, 24.3 years). LEV was given at 2,000 to 4,000 mg/d for 0.5 to 26 months (mean, 13.8 months).
Results: One patient stopped LEV within 2 weeks because of side effects and lack of efficacy. None of the other 12 patients reported side effects. The average myoclonus score significantly changed from 3.1 to 2.4 (p = 0.01), but only eight had a measurable improvement.
Conclusions: The best effects were noted in the younger patients. In patients previously treated with high-dose piracetam (PIR), discontinuation of PIR was not always well tolerated, and a combination of PIR at lower doses and LEV appeared to be a practical solution. LEV should probably be considered as a major treatment option early in the course of ULD.
Unverricht–Lundborg disease (ULD) is a typical form of progressive myoclonus epilepsy (PME) (1) with increased prevalence in Scandinavia and around the Mediterranean (2). This recessive disease is associated with a point mutation and/or dodecamer expansion in the cystatin B gene on chromosome 21q (3,4). The clinical presentation includes generalized clonic–tonic–clonic seizures (GTCSs), action myoclonus, and lack of dementia; associated symptoms are few, mostly in the form of mild ataxia (review in ref. 2). The long-term evolution of ULD is often characterized by the abatement of GTCSs and disabling myoclonus, for which treatment options are limited. High doses of piracetam (PIR) have proved to be an effective short- and long-term treatment of myoclonus (5–7). Levetiracetam (LEV), a compound chemically related to PIR, has been shown to have short-term antimyoclonic efficacy in ULD (8). Long-term efficacy was reported in one patient (9) We have used LEV as a long-term treatment in patients with ULD. This study was done without any specific funding and without the involvement of any pharmaceutical company.
PATIENTS AND METHODS
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- PATIENTS AND METHODS
Among patients with ULD regularly followed up at our institutions, and after preliminary positive result in two patients (8), we decided to try add-on LEV in 13 patients who had all been followed up for several years and who were seen at regular, 3- to 6-month intervals. ULD was confirmed by molecular biology in all (4). The records were finally evaluated in October 2002. We examined seizure diaries, EEG tracings, treatment regimens, and the detailed clinical examination performed at each visit, including a systematic simplified myoclonus rating scale (Table 1), and repeated screening of unwanted side effects, social and occupational status, and overall well-being. The patients were seen between 10 and 12 a.m. in the clinic, but the interviews also evaluated the intensity of myoclonus in the early morning and evening. The effect of LEV was assessed at the latest follow-up and compared with the patients' status at initiation of LEV. Statistical analysis was carried out by using the Wilcoxon matched-pairs test.
Table 1. Simplified myoclonus rating used in this study
|Rating||Intensity and consequences of myoclonus|
|1||Minor myoclonus; no interference with daily living|
|2||Mild myoclonus; interference with fine movements and/or|
| || speech, no interference with walking|
|3||Moderate myoclonus; patient still able to walk without support|
|4||Moderate to severe myoclonus; patient able to stand,|
| || unable to walk without support|
|5||Severe myoclonus; patient wheelchair-bound or bedridden|
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The clinical characteristics of patients are summarized on Table 2. The patients were of French, Northern African, and Italian origin (two women and 11 men, aged 14 to 52 years; mean, 36.5 years). The first symptoms occurred at a mean age of 12.2 years (range, 6–17 years), and the mean follow-up since onset was 24.3 years (range, 4–40 years). They were treated with one to five drugs and were variously handicapped, a few having persisting rare GTCSs, but most having disabling myoclonus. LEV was given at 2,000 to 4,000 mg/d, with two equal intakes in the morning and evening, around 8 a.m. and 8 p.m., for a mean period of 13.8 months (range, 0.5–26 months).
Table 2. Patient characteristics
| Patient|| Sex||Geographic origin of grandparents||Age at onset of ULD (yr)||Age at treatment with LEV (yr)|| Social status|
|1||M||Algeria||12||33||Businessman, married, drives|
|2||M||Algeria||17||47||Sheltered employment, married, 3 children|
|3||F||Algeria||17||38||Housewife, no children, fully autonomous|
|4||M||Algeria||15||30||Sheltered employment, lives alone|
|5||F||France||6||35||Total dependency, wheelchair bound, lives with her parents|
|6||M||La Reunion (French)||10||50||Lives in home for handicapped, dependent, walks short distances|
|7||M||Italy||10||14||Student, normal schooling, fully autonomous|
|8||M||Italy||13||24||Lives with parents, disability pension, walks without help|
|9||M||Italy||11||33||Self-employed, fully autonomous, single|
|10||M||Morocco||9||40||Lives with second wife, no employment, disability pension|
|11||M||Algeria||13||46||Lives with aunt, no employment, disability pension|
|12||M||Italy||12||52||Lives with parents, dependent, disability pension, walks with difficulty|
|13||M||Algeria||14||33||Lives with parents, walks, no employment|
Patient 13 stopped LEV (3,000 mg/d) after 2 weeks because of a combination of side effects (drowsiness and restlessness) and lack of improvement. None of the 12 other patients complained of side effects. The social status and the overall well-being of the patients did not change during the LEV treatment period. Patients 3, 4, 11, and 13 had persisting GTCSs at onset of LEV: patients 3 and 11 reported a decrease in seizure frequency, whereas patients 4 and 13 were treated for only 0.5 and 4 months, respectively, and this parameter could not be evaluated. In the other patients, GTCSs had been controlled for several years. All 13 patients reported a decrease of myoclonus, but only eight showed an improvement in the rating scale, the score decreasing from 3.1 to 2.4 (p = 0.01).
A correlation was found between the duration of disease and the effect of LEV: all six patients who received LEV within 25 years of disease onset were improved by 1 or 2 points (average, 1.2) versus only two of the six patients with >25 years of disease (average, 0.3). The five patients without improvement had a mean duration of disease of 30 years, versus 19.3 years for those with measurable improvement. Four of the five patients had been treated with PIR versus only four among the eight patients who were improved.
A particular problem occurred in patients previously treated with high-dose PIR. When PIR was rapidly tapered after the introduction of LEV, patients experienced worsening: this occurred in patients 2, 4, 5, 10, 12, and all but patient 2 had to resume PIR, at a lower dose (patients 5 and 12), at the same dose (patient 10), or at a higher dose (patient 4). Patient 2 decided to stop PIR and was finally at the same level of handicap when LEV had replaced PIR. Patient 12 had chronic diarrhea on high-dose PIR, which abated after reduction in dosage from 12.5 to 6 g/day. Patients 3, 7, 8, and 9 had never been exposed to PIR and reported a clear improvement with LEV. Patient 11 had not tolerated high-dose PIR 5 years ago because of diarrhea and tolerated LEV perfectly.
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ULD is a rare and often severe condition, and controlled studies are difficult to plan. We conducted an open study and managed associated drugs and daily dosages according to each patient's needs and wishes. Under these conditions, the potential influence of confounders cannot be excluded, and therefore our findings concerning the potential efficacy of LEV should be interpreted with caution. Stimulus-sensitive myoclonus is a prominent symptom of ULD in patients from Scandinavia (1,3) and also occurs in Mediterranean patients, but is not a major symptom in the latter group (2); it was not specifically evaluated in these patients. As often seen after one or two decades of follow-up, few patients (three) exhibited persisting GTCSs. Patients 3 and 11 reported a reduction of GTCSs frequency with LEV. The youngest patient was given LEV at age 14 years, and GTCSs had already been controlled with valproate (VPA). The efficacy of LEV against major seizures in ULD is difficult to establish in this series.
Myoclonus partly responds to the recommended association of VPA and benzodiazepines (2,3). Older drugs like primidone (PRM) may be useful, and ethosuximide (ESM) is active against negative myoclonias, which are often found in PMEs in association with positive myoclonias (10). Other drugs used as antimyoclonic agents include baclofen, chloral hydrate, zonisamide (ZNS), and topiramate (TPM) (review in ref. 2). ZNS was made available in France only in 2002, and the effect of TPM was reported but recently: none of our patients received these drugs during this study except patient 12, who received TPM at 200 mg/day with only slight benefit. Alcohol may abate myoclonus for several hours (11). N-acetylcysteine has been reported to slow the course of ULD (12). One of the major recent advances is the demonstration of a dose-related effect of PIR (5–7). Prolonged treatment with PIR remains effective, even if some abatement of efficacy occurs (5). LEV is not simply a more potent form of PIR (13). It was shown to be effective on myoclonus in the short term in two patients with ULD (patients 6 and 10 of the present series) (8) and in the long term in one patient (9).
Long-term efficacy is necessary in a chronic condition like ULD. In this study, LEV proved to be well tolerated, with one exception. In 12 patients who all had long-standing ULD (except one adolescent), LEV was maintained during follow-up because of a favorable combination of efficacy and tolerability. LEV did not totally control GTCSs. The antimyoclonic efficacy was greatest among patients with duration of ULD of <25 years, although some of the older patients also responded. One of the 13 patients had an impressive and very worthwhile 2-point benefit in the myoclonus score. Seven patients improved 1 point, including, significantly, two patients who were unable to walk before. The most severely affected patient did not improve with LEV, but our series is too small to allow correlations between severity of myoclonus and response to LEV.
Four of five patients not previously exposed to PIR had a measurable improvement after LEV introduction, whereas only three of eight patients previously exposed to PIR had a measurable improvement on LEV. Rapid tapering of PIR produced a worsening, which disappeared in most patients reintroducing it at lower doses. LEV cannot simply replace PIR. A combination of LEV at 2,000–3,000 mg/day with a lower dose of PIR, ∼6–15 g/day, is effective and well tolerated. In some patients, PIR may be substituted with LEV without major clinical improvement but without the burden of ingesting large quantities of PIR.
Although LEV was given as an add-on in patients with long-standing ULD in this study, our results suggest that it might be tried much earlier, with better efficacy. It is clearly an economically viable option, because high-dose PIR is costly. It might even be argued that, in light of its overall anticonvulsant activity, LEV may appear as a first-line option in the treatment of ULD in the future. This study, reporting uncontrolled clinical observations, suggests that LEV may be useful for a proportion of patients with ULD, a finding that must be confirmed in a randomized controlled trial.