The Mechanism of Tremor Modulating Properties of Propranolol and Primidone in Essential Tremor: A Study With Transcranial Magnetic Stimulation and Eye Blink Classical Conditioning Paradigm

Background: Although ET is the most common of movement disorders, its pathophysiology has not yet been fully explained. Central nervous system functional studies have shown that oscillatory activity within the cerebello-thalamo-cortical networks plays a key role in ET's pathophysiology. The origin of this oscillatory activity and the potential role of the primary motor cortex in its formation or modulation remains unknown. Neuropathological studies found degenerative structural changes in the cerebellum of ET patients. Propranolol and primidone are the first-line therapies for ET and the sole medications for treating ET with the level A recommendations according to the latest guidelines of the American Academy of Neurology. Propranolol is a beta-blocker class of medication and primidone is a barbiturate. In spite of solid evidence of their effectiveness in ET patients, the mechanisms of their central action are not yet fully understood. It is believed that propranolol mediates its therapeutic action through peripheral beta-2 adrenergic receptors of skeletal muscles and muscle spindles and through central beta-adrenergic and serotoninergic receptors. After oral intake, primidone is partially metabolized to phenylethylmalonamide (PEMA) and phenobarbital. Even though the studies have shown that PEMA does not have anti-tremor activity, primidone is much more effective in alleviating tremor than phenobarbital alone. In addition, it has been shown that the anti-tremor effect of primidone occurs sooner than its metabolite phenobarbital is produced. This may be due to the non-metabolized primidone compound having an anti-tremor activity or due to PEMA's and phenobarbital's synergistic activity. No association between anti-tremor activity and the concentration of primidone or phenobarbital in the serum has been found. While phenobarbital activity is well known to be mediated through binding to gamma-aminobutyric acid (GABA) A receptors, the mechanism of action of non-metabolized primidone is poorly understood.

Aims: To study the mechanisms of primidone and propranolol action in ET with the use of TMS. The investigators believe that studying mechanisms of action of medications that have been shown to reduce ET can further improve the understanding of ET pathophysiology. Since the cerebellum is thought to be involved in ET pathophysiology the EBCC paradigm will be used to evaluate cerebellar dysfunction in ET patients and to show whether cerebellar dysfunction influences the effectiveness of propranolol and primidone.

Patients and inclusion/exclusion criteria: Fifty patients will be recruited from the outpatient clinic for extrapyramidal disorders. Only patients with the diagnosis of ET made according to the newest consensus statement on the classification of tremors and only patients who will be initiated on propranolol or primidone will be included. Exclusion criteria for TMS will be used. Patients having a history of seizures or mental illness, patients with a cardiac pacemaker, metal material in the head (except dental material in the mouth), or with medication pumps and pregnant women will be excluded from the study.

Study protocol: Patients treated with propranolol or primidone will be studied prior to treatment and 3 - 6 months after treatment initiation. Patients will not be allowed to start any new medication with the action on the central nervous system, while included in the study. Tremor will be assessed clinically using the TETRAS scale and by EMG and accelerometry recordings. Positive treatment response will be defined as a 30% or more decrease in tremor amplitude. At baseline cerebellar function will be assessed clinically with the SARA scale and electrophysiologically using the EBCC paradigm. TMS will be used to study motor cortex excitability.

Methods: