Re-Emergent Postural Tremor Without Clinical Resting Tremor in Parkinson's Disease-A Case Report.

Parkinson's disease (PD) tremor has been conceptualized as a tremor of motor stability1: tremor emerges during stable motor states such as rest or sustained posturing, but is suppressed during voluntary movements. The observation that tremor often re-emerges several seconds after posturing has led to the term “re-emergent tremor.” However, re-emergent postural tremor has a higher frequency and worse response to dopaminergic medication than resting tremor.2 This challenges the unifying concept of “tremor of stability” and suggests that resting and postural tremor are associated with distinct (although partly overlapping) neural mechanisms. In support of this idea, we present a de novo PD patient exhibiting re-emergent postural tremor without clinically detectable resting tremor. A 58-year-old left-handed man presented with progressive hand tremor. A mild bilateral action tremor had been present for at least 15 years, with left-sided worsening 7 years ago and progression to severe tremor 2 years ago. He reported no tremor in other body parts or at rest. Tremor exacerbated during cognitive stress and was unaffected by caffeine, alcohol, or beta blockers. He reported no slowness of movement, autonomic dysfunctions, or signs related to REM sleep behavioral disorder. His father exhibited a similar tremor from 55 until 67 years, after which he passed due to cardiac disease. His maternal aunt also experienced (undefined) tremor. Neurological examination showed regular arm-swing and tandem-gait without hypokinetic gait elements, but there was subtle global bradykinesia. Finger tapping and hand movements revealed subtle bradykinesia on the left after multiple (>10) repetitions (Video 1). Limb-rigidity was not detected, also not during co-activation. Several seconds after arm lifting, tremor emerged bilaterally with a markedly asymmetric amplitude (left > right). Tremor resetting and re-emergence occurred with each posture change (eg, outstretched to wing-beating). There was mild bilateral kinetic tremor. Postural tremor showed no distractibility or entrainment. There were no signs of dystonia or ataxia, and further motor and sensory examination showed no abnormalities. Resting tremor was not observed. MRI of the brain was normal. A dopamine transporter scan (I123-FP-CIT SPECT) revealed reduced uptake in the right striatum (Fig. 1A). Based on these findings, we informed him that he likely has PD, while acknowledging that he does not fulfill the MDS-criteria (which requires rest tremor, given the absence of rigidity).3 Tremor was recorded at rest and using cognitive co-activation (mental arithmetic, eg, 350-7) using accelerometers on the dorsum of both hands, in seated and supine positions. Resetting was assessed using a sequence of rest and three postures: arm-extension, wing-beating, and wing-beating with inward palm rotation. There was no clinical evidence of resting tremor in the left arm. However, a power spectral analysis during seated and supine positions revealed a small ~6 Hz peak at rest, which slightly increased with cognitive co-activation (Fig. 1B). During posturing, there was a much larger peak at 5.5 Hz (Fig. 1B). Tremor resetting and re-emergence occurred after each posture-to-posture transition (Fig. 1C, Video 2). A low-amplitude ~7 Hz postural tremor occurred immediately after arm extension and before onset of re-emergent postural tremor, likely reflecting essential tremor (ET, Fig. S1). The patient tried levodopa/carbidopa (200/50 mg three times daily) and pramipexole (0.75 mg once daily) without clear benefit. Re-emergent postural tremor responds worse to dopaminergic medication than resting tremor, which may explain this.2 Although dopaminergic medication was initially tapered off, it was reinstated following clear tremor worsening. If tremor continues to progress, deep brain stimulation or anticholinergics may be considered. This case expands the clinical spectrum of re-emergent tremor in PD: tremor emerged as a “tremor of stability”, but only during posturing. Reports of PD patients exhibiting re-emergent postural tremor without resting tremor are rare,4 and have not examined whether tremor resetting occurred between different postures. Interestingly, the patient's history revealed a longstanding bilateral upper extremity action tremor, suggesting that essential tremor predated nigrostriatal dopamine depletion and contributed to his unusual tremor presentation, in line with a “double-hit” hypothesis involving a vulnerable tremor network. However, we cannot exclude that the longstanding action tremor represented an early “pure postural” PD tremor that initially resembled essential tremor, with a more pronounced re-emergent tremor developing later and obscuring the subtler “pure postural” tremor.2 Clinically, this case shows that resetting is a useful feature to discriminate PD tremor from other tremor types,5, 6 even in the absence of clinically evident resting tremor. Re-emergent tremor is usually assessed using a brief ballistic movement from rest to posturing. Based on this case, we encourage extending this assessment to posture-to-posture transitions, as the presence of resetting may indicate (early) PD. Observations from this patient suggest that postural tremor in PD may have a unique pathophysiology compared to resting tremor. PD tremor likely arises from aberrant basal ganglia activity that acts like a light “switch” that initiates tremor onset.7 This oscillatory activity is then stabilized and amplified in a cerebello-thalamo-cortical circuit, modulating tremor amplitude similar to a light “dimmer.”7 In this patient, the absence of clinically evident resting tremor despite a small ~6 Hz peak in the power spectrum at rest suggests that tremulous activity is present, but insufficiently amplified. One possible explanation for why tremor was amplified only during posturing may relate to the specific role of the cerebellum in PD postural tremor. That is, cerebellar single-pulse transcranial magnetic stimulation could reset re-emergent postural tremor but not resting tremor, suggesting causal cerebellar influences.8, 9 Furthermore, posturing increases corticospinal excitability.10 Hence, we hypothesize that posture-dependent increases in cerebello-thalamo-cortical excitability facilitate the amplification of tremulous signals arising from the basal ganglia, which in this patient resulted in re-emergent postural tremor but not resting tremor. Future neuroimaging studies could test this hypothesis. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. K.R.E.B.: 1A, 1B, 1C, 3A, 3B. R.C.H.: 1A, 1B, 1C, 3B. We thank the patient for allowing to share findings from his case for research and educational purposes. Ethical Compliance Statement: The authors confirm that approval by an institutional review board was not required for this work. A written informed consent of the patient was obtained for the publication of his data. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: The authors declare no funding sources or conflicts of interest that are relevant to this work. Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report. Anonymized data from this case are available upon request only. Figure S1. A subtle postural tremor precedes the onset of re-emergent postural tremor. (A) Late emergence of a 5.5 Hz re-emergent postural tremor following arm extension (visualized for a single trial). (B) Increasing the signal intensity for the same trial (color bar, z-axis) reveals the onset of a ~7 Hz postural tremor directly after arm extension. This tremor likely reflects essential tremor and subsequently transforms into a 5.5 Hz re-emergent postural tremor. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.