Ocular Tremor in Parkinson's Disease: Inherent or Compensatory?

August 10, 2017

It remains unclear whether ocular tremors are inherent in Parkinson’s or not.

Observations of ocular tremor in patients with Parkinson's disease (PD) have triggered intensive debate over the past 5 years on whether it represents an early clinical marker of PD or a compensatory vestibulo-ocular reflex (VOR) to head tremor.

In a review recently published in Frontiers in Neurology, Diego Kaski, MRCP, PhD, and Professor Adolfo Bronstein, MD, PhD, FRCP, both of  Imperial College London and authors of numerous articles on the topic, laid out evidence in support of both arguments.1 To date, no study has conclusively proven either theory to be correct.

Ocular tremor was first described by Duval and Beuter in 1998, in 3 of 5 patients with monocular oscillations localized to the side of the body most affected by PD.2 The frequency of the oscillations, which the investigators believed were pathophysiologic in origin, aligned closely with resting limb tremor in those patients, but the amplitudes did not match. The investigators concluded that an “attractor effect” from the movement of the resting limb tremor was responsible.

Dr Kaski and Professor Bronstein noted that this study was largely ignored until 2012, when Gitchel et al identified a “pervasive ocular tremor” in all of 112 PD patients studied.3 Recorded oscillations showed a continuous fixation instability with an average frequency of 5.7 Hz (relative to limb tremors ranging from 4 Hz to 7 Hz) and mean horizontal and vertical amplitudes of 0.27 and 0.33, respectively.

Theory 1: Ocular Tremor Is Inherent in PD

Several pieces of evidence from these and other studies support an inherent role of ocular tremor in PD, including:

• The lack of a direct relationship between resting limb tremor and amplitude of ocular oscillations in the Duval and Beuter study pointing to independent mechanisms between the two
• Duval and Beuter had participants bite down on a tongue depressor attached to the chair in order to stabilize the head, which could have caused activation of the VOR and that would have explained their findings of asymmetrical oscillations between the eyes
• All patients in the Gitchel study, including those who were not medicated, showed evidence of ocular tremor
• Using a magnetic tracker to detect head movement in a subset of 62 patients, the Gitchel study did not identify any evidence of motion
• A second study by Gitchel et al4 identified ocular tremor in PD, irrespective of whether the head was fixed
• No evidence of ocular tremor was found in patients with essential tremor5

Theory 2: Ocular Tremor Is Due to Head Oscillation

In their own work, Dr Kaski and Professor Bronstein provided substantial evidence against an inherent basis for ocular tremor, suggesting instead that it was more likely the result of compensatory mechanisms to head tremor in PD. Fundoscopic examinations showed ocular oscillations in patients with head tremor and bilaterally impaired VOR, resulting in pendular pseudonystagmus. They pointed to a lack of observations in Parkinson's studies over the past 30 years6,7 (with the exception of Duval and Beuter) as the first clue. In these cases, the patients reported oscillopsia that was clinically evident. Kaski et al1 determined that oscillopsia is indicative of an intact VOR and is specifically not reported by patients with PD and head tremor.

In another study of 2 eye clinic patients with head tremor, Kaski and colleagues8 reported ocular oscillations that revolved in the opposite direction of head movement and were minimized by restraint, leaving them to conclude that the ocular tremor was a compensatory response — in complete opposition to conclusions reached by Gitchel et al.

Other clinical features that support nonpathologic mechanisms include:

• Observations that nearly every form of ocular oscillation is affected by eye movements such as saccades and blinks3 — with the exception of pervasive ocular tremor—suggesting a lack of involvement of the ocular motor system9
• Expectations that the high frequency of ocular tremor in PD would induce oscillopsia,9 and that pervasive ocular tremor should be visible during direct ophthalmoscopy10
• Uniocular tremor observed in a patient with asymptomatic oculopalatal tremor secondary to a brain bleed affecting the inferior olivary nucleus,11 which challenged Gitchel's presumption of tremor as a fundamental feature of preclinical PD

The extensive disagreement between the 2 scientific camps on the origins of ocular tremor has become at times publicly confrontational, as indicated by a letter published in Parkinsonism Related Disorders in 2014,4 in which Baron, Gitchel, and Wetzel argued that:

“Our manuscripts consistently provide comprehensive scientific evidence that ocular tremor is a fundamental feature of Parkinson's disease, which is not influenced by head movement or peripheral tremor.15,29 This finding arguably has major implications for diagnosing PD, offering a much sought after, dependable, and non-invasive biomarker. Unfortunately, Kaski, Saifee, and colleagues continue to question the validity of our findings.8,12 Now that we have provided evidence of absolute head stability from numerous independent sensors in multiple patients, they suggest that the ocular tremor could represent improper filtering of signals.”

The Kaski-Bronstein review,1 while accepting some of the arguments put forward by the Gitchel papers, also reiterated concerns over potential recognition of pervasive ocular tremor as a predictive biomarker of PD, strongly suggesting the need for research from other laboratories “to identify whether head tremor is indeed a ubiquitous finding in PD, and whether such tremor could be identified using eye movement recordings,” they wrote.

References

1. Kaski D, Bronstein AM. Ocular tremor in Parkinson's disease: discussion, debate, and controversy. Front Neurol. 2017;8:134.
2. Duval C, Beuter A. Fluctuations in tremor at rest and eye movements during ocular fixation in subjects with Parkinson's disease. Parkinsonism Relat Disord. 1998;4:91-97.
3. Gitchel GT, Wetzel PA, Baron MS. Pervasive ocular tremor in patients with Parkinson disease. Arch Neurol. 2012;69:1011-1017.
4. Gitchel GT, Wetzel PA, Qutubuddin A, Baron MS. Experimental support that ocular tremor in Parkinson's disease does not originate from head movement. Parkinsonism Relat Disord.2014;20:743-747.
5. Gitchel GT, Wetzel PA, Baron MS. Slowed saccades and increased square wave jerks in essential tremor. Tremor Other Hyperkinet Mov (NY). 2013;3.
6. Otero-Millan J, Schneider R, Leigh RJ, Macknik SL, Martinez-Conde S. Saccades during attempted fixation in parkinsonian disorders and recessive ataxia: from microsaccades to square-wave jerks. PLoS One. 2013;8:e58535.
7. Chen AL, Riley DE, King SA, et al. The disturbance of gaze in progressive supranuclear palsy: implications for pathogenesis. Front Neurol. 2010;1:147.
8. Kaski D, Saifee TA, Buckwell D, Bronstein AM. Ocular tremor in Parkinson's disease is due to head oscillation. Mov Disord. 2013;28:534-537.
9. Leigh RJ, Zee DS. The Neurology of Eye Movements. 5th ed. New York, NY: Oxford University Press; 2015. 
10. Younge BR, McLaren JW, Brown WL. Retinal image stability in head tremor and nystagmus: counterintuitive observations. J Neuroophthalmol. 2007;27:107-114.
11. Jang L, Borruat FX. Micronystagmus of oculopalatal tremor. Neurology. 2013;80:e27.
12. Saifee TA, Kaski D, Buckwell D, Bronstein AM. Tremor of the eye in Parkinson's disease: merely a measure of the head movement. Parkinsonism Relat Disord. 2014;20:1447e8./

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