The physiological basis of therapies for cerebellar ataxias

Abstract

Cerebellar ataxias represent a group of heterogeneous disorders impacting on activities of daily living and quality of life. Various therapies have been proposed to improve symptoms in cerebellar ataxias. This review examines the physiological background of the various treatments currently administered worldwide. We analyze the mechanisms of action of drugs with a focus on aminopyridines and other antiataxic medications, of noninvasive cerebellar stimulation, and of motor rehabilitation. Considering the cerebellum as a controller, we propose the novel concept of 'restorable stage'. Because of its unique anatomical architecture and its diffuse connectivity in particular with the cerebral cortex, keeping in mind the anatomophysiology of the cerebellar circuitry is a necessary step to understand the rationale of therapies of cerebellar ataxias and develop novel therapeutic tools.

Keywords: aminopyridines; cerebellar ataxias; motor rehabilitation; non-invasive cerebellar stimulation; therapy.

Figure 1.

Algorithm for the diagnosis and treatment of patients with acute cerebellar ataxias. ACA/AC, acute cerebellar ataxia/acute cerebellitis; CT, computed tomography; hemorrhage, cerebellar hemorrhage; infarction, cerebellar infarction; injuries, cerebellar injuries; IMCA, immune-mediated cerebellar ataxia; MRI, magnetic resonance imaging; MS, multiple sclerosis; rtPA, recombinant tissue plasmin activator; Wernicke, Wernicke encephalopathy.

Figure 2.

Algorithm for the diagnosis and treatment of patients with subacute, chronic or insidious cerebellar ataxia (CA). Chiari, Chiari syndrome; IMCA, immune-mediated cerebellar ataxia; MRI, magnetic resonance imaging; MS, multiple sclerosis.

Figure 3.

A scheme of cerebellar neural circuits. CF, climbing fiber; GABAergic IN, GABAergic interneuron; GC, granule cell; MF, mossy fiber; PC, Purkinje cell; PF, parallel fiber. +, excitation (excitatory neurons: open circles); –, inhibition (inhibitory neurons: filled circles).

Figure 4.

A scheme of the decline of cerebellar functions and the concept of ‘restorable stage’. Proper therapies could restore cerebellar functions in patients whose cerebellum is at ‘restorable stage’, meaning that there is still a sufficient preservation of cerebellar functions. After a given threshold of neuronal loss or dysfunction in the cerebellar circuitry, cerebellar functions cannot be restored anymore because the loss of computational capacities of the remaining cerebellar modules is too severe. Motor Cx, motor cortex.