An Unusual Motor OFF in Parkinson's Disease

Paroxysmal tonic upgaze (PTU) has been described in children associated with structural and genetic etiologies.1, 2 Oculogyric crises (OGC) and conjugate ocular deviations have been reported as levodopa induced ocular dyskinesia earlier.3, 4 Episodic tonic upgaze occurring in the OFF state in Parkinson's disease (PD) has not been described earlier. A 62-year-old man with 8-year history of PD presented with episodes of tonic upgaze throughout and exclusive to the entire OFF period (Video 1). His OFF-UPDRS-III score was 78. These episodes were characterized by brief, tonic upward conjugate sustained eye deviation lasting few seconds with chin depression during the episode, without any preceding urge. He did not have any other abnormal eye movements. He was able to partially bring his eyes down voluntarily, but was not able to fixate during the episode. The last part of the video demonstrates right hand rest tremor with bilateral bradykinesia suggestive of limb motor OFF. These episodes completely resolved with levodopa. He denied any dyskinesias. There was no relevant dopamine blocker intake, encephalitis, or family history. Magnetic resonance imaging brain was normal. Tonic gaze deviations have been reported as a peak dose phenomenon in levodopa treated PD and need to be differentiated clinically (Table 1).1 There has been a single case report of nonclassical OGC as an OFF manifestation in PD5 provoked on upward deviation, unlike our patient who had brief episodes of upgaze without fulfilling the OGC criteria,3 and was best characterized as PTU.1 The inhibitory output of the substantia nigra pars reticulata projects to the intermediate and deep layers of the superior colliculus (SC). The SC, in addition, receives excitatory glutamatergic inputs from frontal eye fields (FEF) forming the corticomesencephalic tract (Fig. 1). Impaired firing pattern of the basal ganglia output results in SC disinhibition, which when activated with excessive cortical excitatory input, may lead to tonic gaze deviation.4, 5 It can be speculated that oculomotor abnormalities in OFF state involve abnormalities in SC and parietal cortex in addition to the oculomotor circuits' classically implicated in PD involving the FEF and caudate nucleus. The etiologies of episodic tonic upgaze encompass structural (corpus callosum, mesencephalic lesions, and hypomyelinating leukoencephalopathy), genetic (CACNA1A, GRID2 or SEPSECS, ATP1A3 mutations), and metabolic (sepiapterin reductase deficiency) causes.4, 5 This is probably reflective of the pathophysiological differences in the degree and distribution of dopaminergic denervation. PD is characterized by milder dopaminergic deficit and degeneration confined to the nigrostriatal system, at least in earlier stages.4 The usual pattern of cell loss in PD suggests initial dopaminergic innervation in the dorsal striatum (representing limbs) compared to ventral striatum (representing eyes and face), which is involved in later stages.5 Therefore, oculomotor abnormality in the OFF period probably reflects more extensive mesencephalic dysfunction and severe dopaminergic denervation of the nigrostriatal system, suggesting a distinct pathophysiological phenotype of PD. Long term cumulative data is required to confirm this clinic-pathophysiological correlation and predict disease outcomes with other non-motor symptom burden in the presence of this intriguing motor fluctuation. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. S.J.: 1A, 1B, 1C, 2A, 2B M.J: 1A, 1B, 1C, 2B Ethical Compliance Statement: The present work respects ethical guidelines. The author confirms that the approval of an institutional review board was not required for this work. Written consent was obtained for showing the patients' video. 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 that there are no funding sources or conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.