Rhythmic Eyelid Closure Responsive to <scp>STN‐DBS</scp>: Blepharoclonus, Blepharospasm, Eyelid Opening Apraxia, or Eyelid Tremor?

Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) is an effective treatment for the motor complications of Parkinson's disease (PD).1 People with PD can present with eyelid movement disorders, of which blepharospasm and eyelid opening apraxia (EOA) are well characterized,2 whereas other eyelid abnormalities—including blepharoclonus and eyelid tremor—have been poorly defined.3 Here we describe a 58-year-old man with a 10-year history of tremor-dominant PD characterized by involuntary eyelid movements responsive to STN-DBS (Fig. 1A) and provide a brief overview of the differential diagnosis of such phenomenology. Frequent bilateral rhythmical eyelid movements and bilateral upper-limb resting and postural tremor were noted during the first programming visit in the med-off condition. The eyelid movements had been present before surgery and were poorly responsive to levodopa. Notably, after a prolonged forceful eyelid closure, there was no sustained contraction of the orbicularis oculi (OO) or hyperactivation of the frontalis muscle. To better characterize this phenomenology, electromyography was recorded with surface electrodes over the left biceps, triceps, bilateral extensor carpi radialis, flexor carpi ulnaris, and OO muscles. Arm tremor was also recorded with an accelerometer on the left hand, with arms in resting and outstretched position (Fig. 1B,C). The patient was evaluated in med-off condition, DBS-OFF, DBS-left ON, DBS-right ON, and DBS-ON bilaterally (Table S1). In the DBS-OFF condition, there was a rhythmical bilateral eyelid movement, presenting in bursts with an average frequency of 4.3 Hz (coherence of 0.87 between both eyelids) and a bilateral resting tremor of the left and right arms with an average frequency of 5.5 and 4.5 Hz, respectively (Video 1; Fig. 1C). There was no coherence in frequency between tremor in both arms nor between arms at rest and OO activity. In the outstretched position, there was a low coherence between OO activity and the ipsilateral arm as well as between OO activity and the contralateral arm (Table S1). These findings were suggestive of different oscillation generators for each arm, a well-known feature of parkinsonian tremor,4 and different oscillators between the arms and the eyes. Voluntary bilateral rhythmic hand movement elicited no entrainment of eyelid contractions. With left-DBS ON, there was a reduction in the right-side tremor both postural and at rest. The duration of OO contraction bursts decreased with arms in resting position but not with arms outstretched. With right-DBS ON, there was nearly complete suppression of the left-arm resting tremor and a significant reduction in the duration of eyelid contraction bursts. With both arms outstretched, a moderate decrease in left-arm postural tremor was observed, accompanied by a slight increase in the duration of the eyelid contraction burst. With bilateral DBS-ON, there was significant reduction in arm tremor and no more eyelid movements (Video 1). Notably, response of eyelid tremor to bilateral stimulation was superior to unilateral stimulation, aligning with observations for other midline tremors in PD.5 The lack of coherence between hand and eyelid tremor as well as the rapid effect of DBS even when blindly turned ON or OFF ruled out a possible functional etiology of these tremors. Apart from tremor, other movement disorders can involve the eyelid. Blepharospasm is caused by hyperactivity of the OO muscles and may initially present with an increased blinking rate that evolves over time into more sustained eyelid closure.6 EOA, defined as the patient's inability to voluntarily initiate the opening of the eyelids without a visible contraction of the OO, rarely occurs in PD, typically during the later stages of the disease or after STN-DBS.7 Blepharoclonus was defined by Obeso et al. as an “inappropriate, brief, repetitive and clonic contraction of the orbicularis oculi,” usually preceding or associated to blepharospasm.8 Subsequently, the term “blepharoclonus” has been used to describe a clonic OO activation elicited during voluntary gentle eye closure,9 an observation relatively common in PD.3 Based on the rhythmic and oscillating nature of the eyelid movements (Fig. 1B,C) and the presence of a single peak in the frequency spectral analysis, we argue that the eyelid involuntary movement in our patient is consistent with tremor. Although a grade I blepharospasm may manifest only with an increased blink rate, the frequencies described in such a condition (blinking ranges 17–131 per min) are lower than those recorded in our patient.10 Our patient had no difficulty in initiating the opening of the eyes, thus ruling out EOA. Finally, the involuntary eyelid movement of our patient was not provoked by the attempt to close his eyelids but occurred during normal visual fixation. Therefore, we believe that blepharoclonus can be ruled out as well. Eyelid tremor is a rare, and probably underrecognized, type of parkinsonian tremor. A proper clinical examination and a neurophysiological assessment can be helpful in distinguishing it from its main mimics. Further studies are needed to better understand the prevalence, pathophysiology, and treatment response of this condition. All authors had full access to all the data and accept responsibility to submit for publication. 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. G.G.: 1B, 1C, 3A A.B.: 1B, 1C, 3A T.G.: 1C, 3A R.Ci.: 1B, 3B R.E.: 1B, 3B R.Ch.: 1B, 3B A.F.: 1A, 3B Ethical Compliance Statement: RBD number: 24-5180—Clinical progression of patients with movement disorders. Informed consent was obtained from the subject described in this letter. 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: This work was partly supported by the Chair in Neuromodulation (A.F.) at the University of Toronto and University Health Network, Toronto, Ontario, Canada. The authors have no conflicts of interest to declare. Financial Disclosures for the Previous 12 Months: G.G. reports no disclosures. A.B. reports receiving honoraria from the American Academy of Neurology and AbbVie; consultancy fees from AbbVie, Abbott, and Boston Scientific; and a research grant from the Fernand Lazard Foundation. All disclosures are not relevant to this paper. T.G. reports a research grant from the Canada Dystonia Medical Foundation. All disclosures are not relevant to this paper. R.Ci. has received speaking honoraria from Zambon Italia, Zambon SAU, and Bial Italia Srl; advisory board fees from Bial; and research support from the Italian Ministry of Health; R.Ci. is the editor in chief of the neuromuscular and movement disorders section of Brain Sciences and is the associate editor of Parkinsonism and Related Disorders and Frontiers in Neurology. R.E. reports no disclosures. R.Ch. reports honoraria from Ipsen, AbbVie, and Merz; research grants from CIHR, the Parkinson Foundation, the Dystonia Medical Research Foundation, and the National Organization for Rare Disorders. A.F. reports the following: consultancies from AbbVie, Ceregate, Medtronic, Boston Scientific, Iota, Inbrain, and Inbrain Pharma; honoraria from AbbVie, Medtronic, Boston Scientific, Sunovion, Chiesi farmaceutici, UCB, and Ipsen; and grants from the University of Toronto, Weston Foundation, AbbVie, Medtronic, Boston Scientific, and CIHR. Table S1. Electrophysiological findings depending on arm position and STN-DBS condition. 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.