Tremor in Parkinson's Disease: From Pathophysiology to Advanced Therapies

Abstract

Background: Tremor is one of the most prevalent symptoms in Parkinson's Disease (PD). The progression and management of tremor in PD can be challenging, as response to dopaminergic agents might be relatively poor, particularly in patients with tremor-dominant PD compared to the akinetic/rigid subtype. In this review, we aim to highlight recent advances in the underlying pathogenesis and treatment modalities for tremor in PD.

Methods: A structured literature search through Embase was conducted using the terms "Parkinson's Disease" AND "tremor" OR "etiology" OR "management" OR "drug resistance" OR "therapy" OR "rehabilitation" OR "surgery." After initial screening, eligible articles were selected with a focus on published literature in the last 10 years.

Discussion: The underlying pathophysiology of tremor in PD remains complex and incompletely understood. Neurodegeneration of dopaminergic neurons in the retrorubral area, in addition to high-power neural oscillations in the cerebello-thalamo-cortical circuit and the basal ganglia, play a major role. Levodopa is the first-line therapeutic option for all motor symptoms, including tremor. The addition of dopamine agonists or anticholinergics can lead to further tremor reduction. Botulinum toxin injection is an effective alternative for patients with pharmacological-resistant tremor who are not seeking advanced therapies. Deep brain stimulation is the most well-established advanced therapy owing to its long-term efficacy, reversibility, and effectiveness in other motor symptoms and fluctuations. Magnetic resonance-guided focused ultrasound is a promising modality, which has the advantage of being incisionless. Cortical and peripheral electrical stimulation are non-invasive innovatory techniques that have demonstrated good efficacy in suppressing intractable tremor.

Keywords: DBS; Levodopa-resistant; Parkinson’s Disease; Tremor.

Figure 1

Flow diagram summarizing the steps involved in the literature search.

Figure 2

Cerebral neuronal and neurochemical basis of tremor in Parkinson’s Disease. The figure shows the main circuits of the dimmer-switch model (A), which includes the cerebello-thalamo-cortical circuit (in red) and the basal ganglia-cortical circuit (in green). The basal ganglia (B) is the key structure that triggers the initiation of tremor. The striatum increases inhibitory output to the globus pallidus internus (Gpi), which in turn stimulates the anterior ventrolateral (VLa) nucleus of the thalamus. This trigger further propagates to the cerebral cortex, where convergence of both circuits occurs. This convergence stimulates the cerebello-thalamo-cortical circuit, which alters tremor amplitude. The figure also shows the main nuclei proposed to have major neurochemical role in tremor pathogenesis: 1. Degeneration in the retrorubral area (RRA) leads to reduced dopaminergic projections to the subthalamic region, the basal ganglia, and the ventrolateral thalamus 2. Reduced serotonergic projections result from degenerative raphe nuclei (RN). 3. Increased noradrenergic projection from the locus coeruleus (LC).

Figure 3

Algorithm for the treatment of Parkinson Disease with predominant symptomatic tremor. ^† No strong evidence to support long term, sustained efficacy, and safety. Currently, the modality is mostly applied within the scope of clinical trials and registries.