A new approach: Valproic acid in Huntington’s Disease. Dose dependent improvement of myoclonic hyperkinesia: an Open-Label, Observational Study in a subgroup

Background: Huntington’s Disease (HD) is characterized by choreatic movements. Chorea is treated with antidopaminergic neuroleptics like tiaprid and tetrabenazine. Especially in patients with signs of parkinsonism antidopaminergic medication often leads to a worsening of symptoms. In earlier studies valproic acid showed no beneficial effect on involuntary movements. Myoclonus is rare in HD and often overseen or misdiagnosed as chorea. It does not sufficiantly respond on antidopaminergic medication. Methods: In this report we present eight patients suffering from myoclonic hyperkinesia as the main symptom. All patients were treated with valproic acid and scored by using UHDRS motor score before and after treatment. Two patients accepted to be additionally videotaped. Results: In seven patients myoclonus and, therefore, UHDRS motorscore improved in a dose dependent manner. In three of these patients antidopaminergic medication could be reduced. Conlusions: In the rare subgroup of HD patients suffering from myoclonus valproic acid is a possible alternative. Valproic acid seems to be more efficient than antidopaminergics in those patients. Besides, valproic acid has no side effects on the extrapyramidal system. Background Huntington’s disease (HD) is an autosomal dominantly transmitted neurodegenerative disorder based on expansions of translated CAG repeats in the huntingtin gene beyond a threshold of 36 to >200 units. The characteristic motor feature of HD is chorea, but parkinsonism and involuntary movements such as dystonia and myoclonus can also be present. Choreatic movements usually are treated with antidopaminergic neuroleptics like tiaprid and tetrabenazine. Especially in patients with signs of parkinsonism, however, antidopaminergic medication often leads to a worsening of symptoms. Dopaminergic drugs or even low-dose levodopa can be administered in patients with the akinetic rigid juvenile variant of HD. Myoclonus is a rare feature of HD. It does not sufficiantly respond on antidopaminergic medication. A few reports of myoclonus in HD have mainly concerned cases of juvenile onset [1-3]. Earlier studies using valproic acid in HD did not show a beneficial effect on involuntary movements particularly with regard to choreatic hyperkinesias ([4] 2 patients; [5, 6] 5 patients; [7] 14 patients; [8] 8 patients; [9] 3 patients; [10] 1 patient). On the other hand, few case reports describing myoclonus in HD, report about an improvement of movement disturbances after administration of valproic acid or other medication than antidopaminergics. Carella et al. described a patient with adult onset HD and prominent action myoclonus. Treatment with valproic acid greatly reduced myoclonus suggesting that the gamma-aminobutyric acid (GABA) system might be involved in the pathophysiology of myoclonus in HD [11]. In another case report two brothers with clinically definite adult Huntington's disease developed disabling myoclonus years after the first signs of the disease, which could be controlled with valproic acid [12]. Thompson et al. describe three patients with HD presenting symptoms before the age of 30, with myoclonus as the predominant clinical feature. The myoclonus improved with piracetam therapy in one patient and a combination of valproic acid and clonazepam in the others [13]. Two further case reports describe an improvement in cases of severe intention myoclonus by clonazepam in adult HD [14, 1]. Funakawa et al. report on a cortical reflex myoclonus in adult onset HD. Oral administration of clonazepam was transiently effective for myoclonus [15]. Apart from this, valproate has also been reported to be effective as a mood stabilizer in HD [16]. We herein describe eight adult HD patients who suffered from severe action myoclonus or myoclonic hyperkinesia leading to physical disability. All patients were treated with valproic acid. To our knowledge, this is the largest collective of this rare feature reported so far. Methods About 90% of 600 HD patients investigated in our center during the last 10 years showed symptoms of chorea, about 60% suffered from choreatic movements as the main somatic symptom. Eight patients suffered from myoclonus as the main clinical symptom and were treated with valproic acid. Patients were scored by Unified Huntington’s Disease Rating Scale (UHDRS) motor score before and after treatment with valproic acid [17, 18]. Two patients accepted to be videotaped initially and after treatment with valproate. One patient was able to give a handwriting test initially and after treatment with valproic acid. If possible peg insertion was performed during treatment in order to evaluate executive dysfunction and motor impairment [19, 20]. All patients had been genetically tested and were symptomatic for HD with choreatic hyperkinesia. Additionally, all patients showed signs of akinesia and rigidity, most of them also suffered from dysphagia. Myoclonus, however, was the predominant clinical symptom. All patients demonstrated a worsening of myoclonus during action, some did also present severe myoclonic hyperkinesias at rest (case 1, 3, 4, 7 and 8) One patient (Case 3) had been treated with valproic acid due to seizures before first investigation (1050 mg/per day, serum level: 31 μg/ml) but the dose had to be increased during treatment. The same patient (listed as case 4) was readmitted 4 years later because of worsening of the symptoms and was treated again by increasing the valproic acid medication (Initial dose 1800 mg, serum level: 37 μg/ml). Characteristica of all patients are described in table 1. Patient Sex CAG AO Motoric AO psych Duration Initial TFC Initial IS % Rigidity Swallowing problems Case 1 M 22/46 28 22 11 2 20 ++ +++ Case 2 F 20/54 37 ND 6 5 70 + Case 3* M 17/48 23 23 8 3 40 ++ ++ Case 4* M 17/48 23 23 12 2 30 ++ +++ Case 5 M 19/48 33 ND 11 4 40 +++ ++ Case 6 M 17/43 50 45 6 3 40 ++ ++ Case 7 F 25/52 31 ND 10 3 40 ++ ++ Case 8 F 17/50 28 26 7 6 70 + Case 9 M 17/50 30 30 11 3 30 +++ +++ Table 1 Clinical data of all patients with valproic acid. AO= age of onset, TFC= Total functional capacity (UHDRS), IS= Independence score (UHDRS), CAG= CAG-ranges (low/high). Swallowing problems (-=none, +=mild, ++=moderate, +++=severe). ND= no data. One patient (*) was treated twice with an increasing dosage of valproic acid within an intervall of 4 years, see text. Results In seven patients (8 cases) myoclonic hyperkinesias and, therefore, UHDRS scores improved in a dose dependent manner (see table 2). Initial mean UHDRS motor score was 73.1 (±11.9), after treatment mean UHDRS motor score was 60.2 ( ±12.8) for all patients (p=0.042; t-test; data showed a normal distribution according to the Kolmogorow-Smirnow test) due to an improvement in overall motor function. In three of these patients antidopaminergic medication could be reduced markedly (case 4, 7 and 8), in the remaining patients antidopaminergic treatment was basically unchanged (table 2). Especially in case 1 and 4 swallowing improved. One patient with a daily dose of only 300 mg valproate did not improve. Changes in comedication during treatment are demonstrated in table 2. Patient Initial UHDRS Second UHDRS Valproic acid (mg/day) Valproic acid serum level (μg/ml) Mood stabilization Improvement of mobility and skilfulness Changes in comedication in mg Case 1 80 72 900 mg 30 +++ + T⇓100 CBZ⇓900 MEL⇓37,5 TE⇔, LO⇔ CL⇑25 Case 2 65 33 1200 mg 87 μg/ml +++ R⇔ Case 3* 79 61 1800 mg 59 μg/ml + + T⇓100 CL⇓44 CLO⇓0,5 LEV⇓1000