Studies on pathophysiology and effects of botulinumtoxin in focal dystonia

Abstract

The pathophysiology of focal dystonia, such as cervical dystonia (CD) and writer's cramp (WR) is far from determined and the development of effective treatment is thus impeded. The dystonia in WR is often action-specific, and most dystonic patients experience an action-induced worsening of the symptoms. Patients with CD and WR were studied at rest and during activity by different neurophysiological methods Intramuscular botulinum toxin (BTX) injection are increasingly utilized in the treatment of the focal dystonias. The effects of BTX in CD patients were studied with electromyography (EMG) and with measurements of clinical efficacy.

Bursts of involuntary activity were recorded with EMG in CD patients' sternocleidomastoid muscles (SCMs), both at rest and during a slight muscle contraction Transcranial magnetic stimulation (TMS) induced motor evoked potentials (MEPs) with abnormally short latencies in the SCMs of CD patients. The onset of TMS induced suppression of EMG activity occurred abnormally late in the CD patients' SCMs. The CD patients' clinical signs were compatible with a unilateral central dysfunction, whereas the abnormal results of TMS were seen bilterally both at rest and during SCM contraction. Studies of precision grip function in patients with WR showed impaired abilities to coordinate grip and lift force trajectories, and to correct erroneously programmed grip force according to sensory feedback. The WR patients further ha abnormally large grip force increases in response to a sudden load increase. The findings in the EMG, TMS and precision grip studies suggest an impaired motor control in dystonia due to increased motoneuronal excitability and deficiencies of inhibitory regulation.

Dystonic signs increased, and positron emission tomography showed increased regional cerebral blood flow (rCBF) in the left primary sensory-motor and premotor cortical areas, the left thalamus and the right cerebellum, as WR patients wrote for longer periods. These rCBF increases suggest an increased activation of a cerebro-cerebellar motor circuit in dystonia. The WR patients concurrently progressively decreased the rCBF in the left supramarginal and angular gyri.

Control subjects had no progressive changes of rCBF during prolonged writing, but their rCBF changes during writing(compared to during drawing) resembled the WR patients' pattern of progressive rCBF changes during prolonged writing. The normal cerebral processes during writing seem thus to be exaggerated in WR, which may contribute to the task-specific dysfunction. Data from CD status scales according to Tsui and to Fahn correlated well with patient's rating of the BTX treatment effect. BTX injections improved but failed to normalize CD patients' quality of life. EMG of single motor units in SCMs repeatedly injected with BTX indicated persitent reduction of the number of size of functional muscle fibres, but otherwise restored functional neuromuscular organization when CD symptoms had relapsed.