Relationship between resting and action tremors in Parkinson's disease

Introduction

Tremors, the most common movement disorder, are defined as the rhythmic back and forth motion of a body part.[12] Much progress has been made in recent years to better elucidate tremor etiology, pathophysiology, diagnosis, and management.[1] Overall, there exist five main classifications of tremor, the choice of which depends on the associated behavior of the patient.[3] This includes resting, postural, kinetic, intention, and task-specific.[4] Resting tremors (RTs) occur when the limb is fully supported and relaxed, postural is when the limb is positioned against gravity, kinetic can be during any type of movement, intention is worse as one nears the end of a goal-directed movement, and task-specific is only during highly skilled activities.[4]

While RT is classically coupled to a diagnosis of Parkinson's disease (PD), postural and kinetic tremors are frequently seen in patients with essential tremor (ET).[3] However, it is not uncommon for patients with other conditions to present with tremor. Etiologies of pathologic tremor include, but are not limited to Wilson's disease; peripheral neuropathies (e.g., multiple sclerosis, diabetes); diseases of the cerebella and midbrain; as well as drug side effects (e.g., opioids).

PD is a progressive neurodegenerative movement disorder consisting of the following four cardinal features: Tremor, rigidity, akinesthesia/bradykinesthesia, and postural instability.[5] Patients may also complain of nonmotor symptoms, such as dementia, depression, and pain: Especially in advanced stages of disease progression. Tremor is the most common initial finding in patients with PD and is present in up to half of patients at the time of diagnosis.[5] The most traditional manifestation of tremor is an asymmetric RT, described as “pill rolling” in appearance.[6] However, recent studies have looked into the presence of postural and kinetic tremors in PD patients.[47] Of additional interest is any association between action tremor (AT), which is the combination of kinetic and postural tremors, and RT in PD patients. The current consensus on the subject is controversial, with studies by Louis et al. demonstrating a relationship, and Adler et al. arguing against one.[89] The RT in PD is difficult to manage, and may respond to treatments with carbidopa and levodopa, anticholinergic, or in extreme cases, stereotactic thalamotomy.[4] If present, the AT may sometimes improve upon the administration of propranolol.[4]

ET is defined as a syndrome with a slowly progressive postural and/or kinetic tremor.[4] Both arms are normally affected, and a distinctive feature is the presence of a head tremor. ET is the most commonly diagnosed movement disorder.[4] The etiology of ET is unknown, although there does seem to be a genetic component.[49] As mentioned earlier, some studies have supported the role of ET being a risk factor for the onset of PD, although this remains controversial.[8] Since ET rarely causes disability, medical treatment is in general not necessary. However, beta-adrenergic-receptor antagonists, such as propranolol hydrochloride, are the first-line agents when indicated.[4] Second-line agents include metoprolol in the presence of asthma; nadolol for avoiding central nervous system (CNS) side effects; primidone, which is anticonvulsant; and stereotactic thalamotomy or thalamic stimulation in refractory cases.[4]

Although the CNS origin of pathological tremors is well established, the exact mechanism and location of these central oscillators remain unclear.[1] Studies have most consistently shown the presence of multiple central oscillators throughout the basal ganglia (BG) and cerebello-thalamo networks.[10] Indeed, a combination of different cortical and subcortical motor centers has been shown to generate rest, postural, and kinetic tremors.[11]

Overall, the pathophysiology of RT in PD patients remains unclear, as aspects of it seem to contradict the dopamine-deficient etiology of bradykinesthesia and rigidity.[1213] Similarly, dysfunction of the BG is more closely associated to akinesthesia and rigidity than it is with tremor. Emerging evidence suggests the involvement of the cerebello-thalamo-cortical circuit in the underlying pathology of RT.[13] It is generally accepted that RT in PD mainly results from a central mechanism, as there are no suppression effects from peripheral differentiation.[13] Current evidence strongly suggests a number of independent oscillating circuits within cortical, subcortical, spinal, and even peripheral limb centers as the root for PD tremor.[112]

There is much interest in elucidating a relationship between RT and AT in PD patients, as is reflected by the plethora of studies with inconsistent findings. Some studies support the view that AT and RT are related while others suggest they are distinct from one another. In our study, PD patients were assessed retrospectively for the severity and correlates of resting and AT. By evaluating the relationship between resting and AT we hope to draw a clearer understanding on this confusing, yet relevant topic.

Methods

Subjects

A retrospective chart analysis of 157 patients was performed. Participants were diagnosed with idiopathic PD and were aged between 43 and 99 years, with a mean age of 75 years. Of these, 100 had a tremor and were included within our study. More specifically, 65 had rested right upper limb (RRU) tremor, 52 had resting left upper limb (RLU) tremor, 80 had an action right upper limb (ARU) tremor, and 76 had an action left upper limb (ALU) tremor. The breakdown regarding Unified PD Rating Scale (UPDRS) intensity classification can be found on Tables 1–4. Patients were diagnosed and regularly followed by a clinical neurologist with movement disorder training in a community-based PD and movement disorders center between 2005 and 2010. All patients were informed about the nature of the study and gave their written consent for participation. The local ethics review board approved the study.

Table 1 The effects of resting right upper limb and resting left upper limb tremors on action right upper limb tremor. Low and moderate intensity action right upper limb tremor groups were combined (threshold) and compared against various resting tremor locations and severities

Table 2 The effects of resting right upper limb and resting left upper limb tremors on action left upper limb tremor. Low and moderate intensity action left upper limb tremor groups were combined (threshold) and compared against various resting tremor locations and severities

Table 3 The effects of resting right upper limb tremors on resting left upper limb tremors. Low and moderate intensity resting left upper limb tremor groups were combined (threshold) and compared against various resting right upper limb tremor severities

Table 4 The effects of action left upper limb tremors on action right upper limb tremors. Low and moderate intensity action right upper limb tremor groups were combined (threshold) and compared against various action left upper limb tremor severities

Results

Discussion

Most studies have focused on PD RT. However, as our results indicate many PD patients also have AT, which is probably an inherent symptom of the disease. Our data reveal that RT is predictive of AT on the same side, but not the opposing side of the body. The results demonstrate that when RT was present and became more severe in intensity, the occurrence of AT decreased. In addition, the presence of RRU increased the likelihood of RLU. In contrast, the presence of ALU increased the likelihood of ARU.

Our study highlights the importance of the co-occurrence of resting and AT. Although the RT is well studied and documented in PD, it is the AT, however, which is often more disabling for the patient. Patients with kinetic tremor can be handicapped in everyday situations, such as drinking from a glass, grasping an object, writing and other fine motor skills. In contrast to RT, which may represent a social handicap, AT associated with PD is directly correlated with motor disability[16] and contributes to weakness and bradykinesia.[1718]

An early study on AT in PD by Lance et al.[19] noted the presence of AT during voluntary movements and showed considerable evidence for the dissociation of AT and RT. Their results showed that PD patients with AT did not have RT and vice versa. This study also noted that ATs have a higher frequency than RT and the two do not share any harmonic relationship. Although this evidence suggests a dissociation of AT and RT, Sung et al.[20] findings showed that dopaminergic treatment did indeed affect RT but only for PD patients with moderate bradykinesia and rigidity rather than patients with other prominent parkinsonian features. Our study showed that PD patients with RT were highly likely to have AT on the same side of the body, suggesting that individuals with AT will have both the postural and kinetic components along with RT.

Teräväinen and Calne[21] suggested that the pathophysiology of AT may be similar to that of RT. Since during voluntary movement different pathways through the BG are activated compared to the resting state,[22] the occurrence of rest and AT may mainly be determined by the pathways involved in different brain states and the involvement of these pathways in the degenerative processes. From the relatedness between rest and AT, it is likely that pathways may overlap, and that both tremor types share a common pathophysiology. The relationship between neuronal activity patterns in the parkinsonian BG-thalamocortical and the cerebellothalamocortical loop, and the occurrence and severity of rest and AT, as well as the relationship with the other motor symptoms, merits further investigation through simultaneous recordings in different nuclei and movement registration, possibly combined with functional imaging techniques.

Patients were not withdrawn from medication, and the time of medication intake with respect to the measurement session may have been different for the different patients. We expect that medication may have influenced the severity and duration of tremor (both rest and AT), adding to the heterogeneity of the group. Strengths of our study include the large sample size, typical age range, and the presence of a variety of parkinsonian features in our patients. The early studies of Lance et al.[19] and Raethjen et al.[23] included a small number of PD patients who were of younger age. The association of AT and RT in our study support the findings of another study by Louis et al.[8] that looked at the clinical correlates of AT in PD. There is also evidence to suggest that resting and AT share neural substrates.[24] Although our study highly supports that the two tremors are closely related, further research that includes a control group and brain imaging is still required to completely understand the exact neurological basis of this relationship.

Conclusions

AT was associated with RT in PD, suggesting that, at least in part, AT is a manifestation of the underlying BG disease. Therefore, more attention should be paid to kinetic tremor in PD, as it is frequently present and quite disabling with respect to important everyday tasks, such as writing. A better understanding of pathophysiologic and pharmacologic processes can be expected from a more precise differentiation of the different tremor forms at PD, thereby helping those with this debilitating disease.