Experience in a short-term trial with 4-Aminopyridine in cerebellar ataxia

Abstract

4-Aminopyridine (4-AP) is a reversible blocker of voltagegated potassium channels. Its slow release form has been approved for symptomatic treatment of gait disorder in multiple sclerosis [2]. In a number of small studies, 4-AP and the related compound 3,4-diaminopyridine (3,4-AP) improved downbeat nystagmus and reduced attack frequency in episodic ataxia [9]. In addition, 4-AP decreased gait variability in patients with chronic cerebellar ataxia of different origin [7, 8]. Chronic treatment with 3,4-AP had beneficial effects in a mouse model of spinocerebellar ataxia type 1 (SCA1) [3]. We here report our clinical experiences with 4-AP in 16 patients with chronic cerebellar ataxia. As 4-AP is thought to exert its effect on ataxia by interfering with the activity of cerebellar Purkinje neurons, we treated patients with SCA1, SCA3, SCA6 and sporadic adult-onset ataxia of unknown origin (SAOA), as well as one with a POLG mutation. These disorders are characterized by prominent cerebellar cortical degeneration with Purkinje cell involvement. Three centers participated in the observations. After giving informed consent, 16 patients were treated with the slow release form of 4-AP (Fampyra , 2 9 10 mg/day). Nine of the patients were female. Three patients were diagnosed SCA1, three SCA6, two SCA3, one genetically nonidentified autosomal dominant cerebellar ataxia, one POLG mutation and six of them a SAOA. Age was 60 ± 11.3 years (mean ± SD), disease duration 16.3 ± 17.1 years. To assess the severity of ataxia, we used the Scale for the Assessment and Rating of Ataxia (SARA) [5]. In addition, patients underwent three timed coordination tests, the 8 m walk (8 MW), the 9-hole pegboard (9HPT), and the speech rate test (PATA rate). Performance in these tests allows calculating the SCA Functional Index (SCAFI) [6]. Results of the timed tests are expressed as Z scores. Neurological symptoms other than ataxia were assessed with the Inventory of Non-Ataxia Signs (INAS) [4]. Patients estimated their health-related quality of life on the visual analogue scale of the EQ-5D (EQ-VAS) [1]. Assessments were done at baseline, 4 h and 14 days after treatment. Although two patients discontinued 4-AP due to side effects, the compound was generally well tolerated. This view is also supported by the trend towards an improvement of the EQ-VAS after 14 days. In the remaining 14 patients, SARA (range: 0–40) improved from 14.3 ± 4.7 to 13.0 ± 4.6 points after 4 h (n = 11) and to 13.7 ± 4.6 points after 14 days (n = 14), but these differences failed I. Giordano (&) H. Jacobi M. Minnerop T. Klockgether Department of Neurology, University Hospital of Bonn, Sigmund-Freud-Strase 25, 53105 Bonn, Germany e-mail: ilaria_anna.giordano@ukb.uni-bonn.de