Eyelid Closure Downbeat Nystagmus: A Rare Cause of Insomnia

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Gour Wang, MD Eyelid Closure Downbeat Nystagmus: A Rare Cause of Insomnia Philip W. Tipton, MD, Brynn K. Dredla, MD, Pablo R. Castillo, MD, Elizabeth A. Mauricio, MD, João Lemos, MD, Eric R. Eggenberger, DO E yelid closure downbeat nystagmus (ECDN) is an involuntary extraocular movement abnormality characterized by a slow upward drift of the eyes, followed by a fast downward corrective saccade that is only present when the eyes are closed. This has most often been associated with structural disruption of vestibular circuitry (1). In recent years, downbeat nystagmus (DBN) has been reported in association with motor neuron disease (MND) and given the name finger extension weakness and DBN with MND (FEWDON-MND) (2). Despite occasional case reports within the medical literature, the underlying pathophysiology of this phenomenon is unclear. We present a case of insomnia related to ECDN in a patient with concomitant distal weakness and response to immunomodulatory therapy, suggesting an autoimmune etiology. REPORT OF CASE A 71-year-old man presented with new-onset insomnia, related to bothersome eye movements at sleep onset, even during the day if he tried to take a nap. He reported gradual worsening during the preceding year and progressive hand weakness with muscle twitching for 2 years. He maintained regular sleep times, and his Epworth Sleepiness Scale score was 3. His wife noticed loud snoring. The eye movements were modestly improved after starting clonazepam. Formal neuro-ophthalmological assessment revealed spontaneous vertical eye movements characterized by a slow upward component and a fast downward component that occurred when the patient closed his eyes (See Supplemental Digital Content, Video, http://links.lww.com/WNO/A403). Nystagmus was not elicitable with lateral/horizontal gaze or Departments of Neurology (PWT, BKD, EAM) and Pulmonary Medicine (PRC), Mayo Clinic, Jacksonville, Florida; Department of Neurology (JL), Coimbra University Hospital Centre, Coimbra, Portugal; and Department of Ophthalmology (ERE), Mayo Clinic, Jacksonville, Florida. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Philip W. Tipton, MD, Department of Neurology, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224; E-mail: [e-mail] e194 convergence while the eyes were opened or with provocative maneuvers, such as fixation block or hyperventilation. These findings were consistent with ECDN. Other pertinent findings include normal saccades and smooth pursuit in all directions and normal vestibulo-ocular reflex suppression. His neurologic examination was also notable for distal limb weakness, including significant finger extension weakness, distal muscle atrophy, fasciculations, and reduced or absent deep tendon reflexes. Sensation was preserved. There were no upper motor neuron findings. There were no tremors, including palatal tremor. Laboratory testing revealed the elevated levels of ganglioside antibodies (IgM GM1 asialo and monosialo), which can be seen in multifocal motor neuropathy. Mild elevations were also noted in angiotensin-converting enzyme, antinuclear antibodies, dsDNA, ribonucleoprotein IgG, a2 globulin, g globulin, and glutamic acid decarboxylase 65 (GAD65). Other laboratory test results, including complete blood count, renal function, hepatic function, thyroid function, vitamin B12, folate, Lyme serology, rapid plasma reagin, SS-A/B, inflammatory markers, hemoglobin A1c, creatinine kinase, serum protein electrophoresis, complement levels, and a paraneoplastic panel, were normal. The patient underwent electromyography, which demonstrated findings consistent with a multifocal motor neuropathy with conduction block. Polysomnography demonstrated snoring without clinically significant obstructive sleep apnea, evidenced by a normal apnea–hypopnea index of 3.5. MRI of the cervical and lumbar spine was unremarkable, whereas that of the brain showed only mild midline cerebellar atrophy with no abnormal contrast enhancement (Fig. 1). An electroencephalogram showed vertical involuntary eye movement artifact of 5–6 Hz with eyelid closure that attenuated with the onset of N1 sleep (Fig. 2). The patient’s weakness and ECDN improved to some degree with intravenous immunoglobulin. He was ultimately transitioned to subcutaneous immunoglobulin for maintenance therapy. 4-Aminopyridine was also prescribed, which, along with clonazepam, allowed for further improvement in ECDN and subjective improvements in sleep. DISCUSSION DBN has been well described in the medical literature and is typically related to disruption of the vestibular Tipton et al: J Neuro-Ophthalmol 2021; 41: e194-e196 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. MRI of the brain: T1-weighted sagittal MRI of the brain of a patient showing only mild atrophy of the cerebellar vermis (A). Normal T2-weighted axial MRI of the brain at the level of the medulla (B, C) and pons (D–F). system due to focal brain lesions involving the cerebellum or caudal brainstem. Eye movements are typically spared in MND; however, there are recent reports of FEWDON-MND, although the patients described in this series did not experience nystagmus with the eyes closed (2). Our patient was diagnosed with multifocal motor neuropathy and ECDN that was partially responsive to immunotherapy based on the patient’s subjective reporting. ECDN was previously described in 1 patient, who had multiple sclerosis and a lesion within the paramedian basis pontis (1). ECDN may be the result of ephaptic activation of ventral tegmental tracts, which yoke the vestibular system to extraocular motor nuclei. ECDN was also reported in a cohort of patients with oculopalatal tremor, which results from disruption of the Guillain–Mollaret triangle (3). In our case, the globe’s movements under eye closure consisted of an upward slow phase and a downward fast phase, which FIG. 2. Electroencephalogram of vertical eye movements: Electroencephalogram of a patient with no background abnormalities while eyes are open but the development of vertical eye movement artifacts upon eyelid closure. Black line correlates with the period during which the patient’s eyelids were closed. Left oculogram and right oculogram are placed under the left and right eyes, respectively. Tipton et al: J Neuro-Ophthalmol 2021; 41: e194-e196 e195 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence led us to characterize this involuntary eye movement as DBN. However, in the absence of eye movement recording, vertical opsoclonus cannot be fully discarded as a possibility. It is interesting that our patient’s MRI showed no abnormalities because the proposed mechanisms for ECDN involve focal brain pathology often identified with MRI. There have been several reports of DBN caused by viral infections. One case of DBN associated with herpes simplex virus had no postmortem structural brain changes, despite the presence of viral particles within brainstem neurons (4). This suggests that eye movement abnormalities may result from a functional disruption of neural circuitry in the absence of overt macroscopic structural damage. Paraneoplastic DBN has been identified in the absence of MRI findings but with cerebellar hypermetabolism on 2-deoxy2-[F18]fluoro-D-glucose positron emission tomography, leading to a diagnosis of metastatic lung carcinoma (5). Our patient’s positive response to immunotherapy is suggestive of an autoimmune process. We found elevated levels of ganglioside GM1 antibodies, which have not been associated with ECDN and mildly elevated serum GAD65 levels, which are nonspecific but often associated with other pathological antibodies. Although the commercially available autoantibody panels have grown large, new antibodies continue to be discovered regularly. It is unclear whether our patient’s symptoms are related to one of these antibodies or a separate unidentified antibody. We report insomnia due to ECDN and multifocal motor neuropathy in a patient, who improved with immunotherapy. This may represent a variant of the previously described FEWDON-MND. Our findings should prompt physicians to perform a thorough multisystem evaluation of patients and seek expert consultation when needed. Increased awareness of ECDN will likely result in greater detection rates and provide the necessary participants to fuel larger scale studies to increase our understanding of the underlying pathophysiology en route to more effective treatments. e196 P. W. Tipton: Composed the article and prepared the manuscript. P. R. Castillo: Patient evaluation. E. A. Mauricio: Patient evaluation and editing the manuscript. E. R. Eggenberger: Patient evaluation, advised for the manuscript content, and provided video. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: P. W. Tipton, B. K. Dredla, P. R. Castillo, and E. R. Eggenberger; b. Acquisition of data: P. W. Tipton, P. R. Castillo, and E. R. Eggenberger; c. Analysis and interpretation of data: P. W. Tipton, B. K. Dredla, P. R. Castillo, E. A. Mauricio, J. Lemos, and E. R. Eggenberger. Category 2: a. Drafting the manuscript: P. W. Tipton, B. K. Dredla, P. R. Castillo, E. A. Mauricio, J. Lemos, and E. R. Eggenberger; b. Revising it for intellectual content: P. W. Tipton, B. K. Dredla, P. R. Castillo, E. A. Mauricio, Dr. Lemos, and E. R. Eggenberger. Category 3: a. Final approval of the completed manuscript: P. W. Tipton, B. K. Dredla, P. R. Castillo, E. A. Mauricio, J. Lemos, and E. R. Eggenberger. ACKNOWLEDGMENTS The authors thank Kirsten Yelvington and William Tatum, D.O., for acquisition of the EEG tracing. REFERENCES 1. Lemos J, Pereira D, Amorim M, Santiago B, Paiva A, Cunha L. Downbeat nystagmus elicited by eyelid closure. J NeuroOphthalmol. 2014;34:350–353. 2. 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