Diagnosis and Treatment of Common Forms of Tremor

Andreas Puschmann, M.D.; Zbigniew K. Wszolek, M.D.

Disclosures

Semin Neurol. 2011;31(1):65-77. 

In This Article

Pathophysiology of Tremor

Progress has been achieved in mapping tremors to certain structures or pathways in the nervous system, even though the exact pathophysiology of tremor is still incompletely understood. Two basic principles have been postulated in tremorogenesis. One emphasizes a functional hyperexcitability and rhythmic oscillation of neuronal loops in the absence of structural changes. This hyperexcitability has been studied with neurophysiologic techniques in humans and animals, and modeled in dynamic mathematical paradigms.[6] Complete reversibility of some tremor symptoms after alcohol ingestion or with medication has been interpreted as evidence for an overwhelmingly or exclusively functional disturbance. The second principle is that of a permanent structural pathology with signs of neurodegeneration. This concept has more recently received renewed attention after systematic pathologic studies of patients with essential tremor revealed characteristic pathologic changes.[4]

Two sets of neuronal networks are of particular importance (Fig. 1). One is the corticostriatothalamocortical loop through the basal ganglia, whose physiologic task is the integration of different muscle groups for complex movement programs. This loop also ensures that an ongoing movement program will not be terminated or disturbed by minor or irrelevant external influences. The other circuit involves the red nucleus, inferior olivary nucleus (ION), and the dentate nucleus, forming the triangle of Guillain and Mollaret (Guillain-Mollaret triangle). This circuit's main physiologic task is to fine-tune voluntary precision movements. Among its components, probably the ION plays the most important role in the genesis of tremor. The neurons of the ION receive their input from the red nucleus, and project as climbing fibers to Purkinje cells in the cerebellar cortex. The individual ION neurons are connected by gap junctions and can thereby act as a synchronized neuronal ensemble.[7] In healthy individuals, ION neurons exhibit regular oscillatory depolarizations mediated by calcium-channels.[8] These oscillations serve an important physiologic purpose as pacemakers in the timely processing and temporal coordination of the cerebellar modulation of precision movements as well as in cerebellar motor learning.[7] A line of evidence suggests that such synchronized oscillations of ION neurons also are involved in the genesis of tremor. The β-carboline alkaloids harmine, harmaline, and tetrahydroharmine from the Harmal plant (Peganum harmala, "Syrian Rue"), increase ION neuron excitability. Although the seeds and roots of this plant also have hallucinogenic and antinociceptive properties, and have been used as an entheogen for many centuries,[9] a transient cerebellar syndrome with dysmetria and nystagmus as well as intention and postural tremor were documented after ingestion of high doses.[10] This effect is also seen in animals, and in fact harmaline is frequently used to model essential tremor in animals.[11] In such animals, harmaline-induced tremors are abolished by lesioning the ION, emphasizing harmaline's impact on the triangle of Guillain and Mollaret.[12] In addition to chemical substances, structural lesions affecting this circuit can cause tremor. Lesions damaging afferents to the ION are responsible for symptomatic palatal tremor associated with reactive hypertrophic degeneration of the ION.[13] Hypertrophy of the ION is also seen in the rare syndrome of progressive ataxia and palatal tremor, further implicating ION in tremorogenesis.[14]

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