Aminopyridines for the treatment of neurologic disorders

Purpose of review:To identify the different indications for the treatment of neurologic disorders with the potassium channel blockers 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP).Recent findings:4-AP is an effective symptomatic treatment for downbeat nystagmus (DBN), episodic ataxia type 2 (EA2) (5–10 mg TID), and impaired gait in multiple sclerosis (MS) (10 mg BID). 3,4-DAP (5 mg/d–20 mg TID) improves symptoms in Lambert-Eaton myasthenic syndrome (LEMS) (randomized placebo-controlled trials for all 4 entities). 4-AP may also be effective in cerebellar gait ataxia of different etiologies (2 case series), upbeat nystagmus, and limb ataxia in MS (single cases). In the recommended dosages, they are well tolerated. The assumed mode of action is a blockade of mainly Kv1.5: in DBN, this increases the excitability of Purkinje cells (PC), and in EA2, restores the precision of resting discharge of PC. In MS, 4-AP improves the conduction of action potentials in demyelinated axons, and in LEMS, 3,4-DAP facilitates the transmission at the neuromuscular endplate by prolonging the action potential duration.Summary:There is sufficient evidence that APs are indicated for the symptomatic treatment of DBN, EA2, gait ataxia due to MS and cerebellar disorders, and LEMS with a reasonable risk-benefit profile.

Cerebellar Ataxia

This chapter deals with disorders of the cerebellum and its connections. These conditions may be identified by the mode of onset—whether acute, subacute, chronic, or episodic. The chronic ataxias are inherited in various patterns: autosomal dominant; autosomal recessive; X-linked. Autosomal dominant inherited ataxias discussed include spinocerebellar ataxia, autosomal dominant episodic ataxia, and glucose transporter type I deficiency syndrome. Some episodic ataxias have variable inheritance. Other episodic ataxias without a clear genetic basis are detailed including mitochondrial spinocerebellar ataxia and epilepsy; coenzyme Q deficiency; progressive cerebellar ataxia with palatal tremor; and progressive cerebellar gait ataxia, myoclonic epilepsy, and intention tremor. Also various disorders associated with ataxia are enumerated.

Relative Contributions of Balance and Voluntary Leg-Coordination Deficits to Cerebellar Gait Ataxia

Different cerebellar regions participate in balance control and voluntary limb coordination, both of which might be important for normal bipedal walking. We wanted to determine the relative contributions of balance versus leg-coordination deficits to cerebellar gait ataxia in humans. We studied 20 subjects with cerebellar damage and 20 control subjects performing three tasks: a lateral weight-shifting task to measure balance, a visually guided stepping task to measure leg- coordination, and walking. We recorded three-dimensional joint position data during all tasks and center of pressure coordinates during weight-shifting. Each cerebellar subject was categorized as having no detectable deficits, a balance deficit only, a leg-placement deficit only, or both deficits. We then determined the walking abnormalities associated with each of these categories. Five of 10 measures of gait ataxia were abnormal in cerebellar subjects with a balance deficit, but only 1 was abnormal in cerebellar subjects with a leg-placement deficit. Furthermore, subjects with a balance deficit performed worse than subjects with a leg-placement deficit on 9 of the 10 gait measures. Finally, performance on the balance task, but not the leg-placement task, explained a significant proportion of the variance in walking speed for the entire cerebellar group. We conclude that balance deficits are more closely related to cerebellar gait ataxia than leg-placement deficits. Our findings are consistent with animal literature, which has suggested that cerebellar control of balance and gait are interrelated, and dissociable from cerebellar control of voluntary, visually guided limb movements.