Facio‐Lingual‐Palatal Myorhythmic Presentation of Anti‐IgLON5 Disease

Anti‐immunoglobulin‐like cell adhesion molecule‐5 (anti‐IgLON5) disease can present with a wide spectrum of neurological manifestations classified into five major clinical phenotypes: sleep disorder, bulbar syndrome, Progressive Supranuclear Palsy (PSP) like and other movement disorders, cognitive impairment with or without chorea and neuromuscular manifestations. ¹ , ² Herein we describe facial‐lingual‐palatal myorhythmia, mild parkinsonism, and generalized fasciculations in a case of Anti‐IgLON5 disease.

A 52‐year‐old male presented with involuntary movements of the tongue and chin for three months which were more prominent at night and disturbed his sleep but disappeared once he slept. There was no history of dysarthria or dysphagia. On close questioning, he reported snoring, insomnia, and daytime drowsiness for the last two years. On examination, in addition to reduced facial expression and reduced arm swing on the left side (Video 1, segment‐1) the patient had slow rhythmic, synchronous movements of the chin, tongue, and palate of around 1 Hz (Video 1, segment‐2) confirmed by surface electromyography (sEMG) and ultrasonography of the submental region (Video 1, segment‐3, 4). The rest of the examination was normal (Table e1).

Video 1.

Segment‐1: The patient had reduced facial expression and reduced arm swing on left side while walking. Segment‐2: Slow, rhythmic, synchronous involuntary myorhythmic movements noted in chin, tongue and palate. Segment‐3: Surface electromyography (EMG) of mentalis and genioglossus muscle demonstrating the slow, rhythmic EMG bursts of around 1 Hz frequency. Segment‐4: Ultrasound of the submental triangle area demonstrating rhythmic contractions of the genioglossus, geniohyoid, and mylohyoid muscles. Segment‐5: Fasciculation of the deltoid muscles clinically and on USG of right deltoid muscle.

Owing to the facial‐lingual‐palatal myorhythmia and sleep disturbance, anti‐IgLON5 disease was considered. Other differentials were Whipple's disease, autoimmune and paraneoplastic encephalitis, and structural brainstem lesions. On investigation (Table e1), magnetic resonance imaging of the brain was normal, the autoimmune and paraneoplastic panel was negative, and serum and cerebrospinal fluid samples were strongly positive for anti‐IgLON5 antibodies confirming the diagnosis of anti‐IgLON5 disease. He was treated with pulse intravenous methylprednisolone and large‐volume plasmapheresis. During this course, he developed fasciculations over the deltoids, chest, and back muscles confirmed with needle EMG and ultrasonography (Video 1, segment‐5). He was also treated with clonazepam, zolpidem, and botulinum toxin injection to genioglossus for myorhythmia and insomnia. He reported around 70% improvement in sleep and the myorhythmia at one‐month follow‐up but the objective improvement was mild.

Facial myorhythmia is a rare initial manifestation of anti‐IgLON5 disease (Table 1). ¹ , ² , ³ , ⁴ , ⁵ The first mention of myorhythmia in a case of anti‐IgLON5 disease was provided by Honorat et al, ² and later, a detailed clinical and electrophysiological description was provided by Morales‐Briceño et al and Asioli et al. ³ , ⁴ In a large cohort, myorhythmia was noted in 6/72 patients. ¹ All patients had at least one other associated feature in the form of sleep disorder, bulbar syndrome, extrapyramidal, and/or cognitive impairment. Myorhythmia in anti‐IgLON5 disease can be secondary to brainstem dysfunction, supported by the evidence of neuronal loss and hyperphosphorylated tau deposition in brainstem. ⁴ , ⁶ However, despite multiple reports of peripheral nervous system involvement, its underlying pathophysiology remains unknown. The slow rhythmic and synchronous movements seen in myorhythmia help differentiate it from other oro‐lingual movements. The myorhythmia in anti‐IgLON5 spares ocular muscles, unlike in Whipple's disease. ¹ Brainstem stroke, autoimmune encephalitis such as anti‐NMDA encephalitis, and multiple sclerosis are the other important considerations in cranial myorhythmia. ⁶ Various other hyperkinetic movement disorders such as chorea, dystonia, tremor, myoclonus, akathisia, myorhythmia, myokymia, and abdominal dyskinesia have been described with the disease. ¹ Immunotherapy has a variable response, with around half demonstrating a partial response.

TABLE 1.

Previous reports of oral/facial/lingual/mandibular/generalized myorhythmia in anti‐IgLON5 disease

Author, year	Case details	Description of myorhythmia	Other findings	Remarks
Honorat et al, 2017 2	Patient‐1: A 69‐yr‐old female initially presented with headache and jaw dystonia. Serum anti‐IgLON5 was positive. CSF was not available for testing	Myorhythmia of the mouth and tongue was observed.	Gait instability, parkinsonism, myoclonus, tremor, supranuclear gaze palsy (up gaze predominant), depression, and memory impairment were noted. There were no sleep disorders. MRI brain was nonspecific (Details not available)	The patient received no immunotherapy and died at 4 mo follow‐up.
Morales‐Briceño et al, 2018 3	A 49‐yr‐old male presented with cold intolerance for 2 yr. Serum (titre:1:3200) and CSF (titre 1:100) anti‐IgLON5 were positive.	At rest, the patient had subtle, continuous, low‐amplitude regular contractions of the mentalis, tongue, and frontalis. Rhythmic palatal movements at a frequency of around 1 Hz were also present.	Vertical and horizontal saccades were hypometric but of normal velocity. Intermittent, isolated, truncal flexion movements at the hip occurring every 2–4 s were observed with the patient lying, sitting, or standing. Mild cognitive impairment, bulbar symptoms, features of RBD, OSA and excessive daytime drowsiness were also present. MRI Brain was normal and CSF–OCB was negative.	The patient was treated with plasma exchange, IVIg, and rituximab. Information regarding follow‐up is unavailable.
Vetter et al, 2018 5	A 79‐yr‐old female presented with parasomnia and progressive bulbar syndrome for 8 mo. Serum and CSF anti‐IgLON5 were positive (1:1000).	The patient had mandibular myorhythmia resulting in lip bites.	The patient additionally had facial forehead myokymia. The MRI brain was unremarkable. CSF analysis showed intrathecal antibody synthesis and elevated tau and phospho‐tau.	Information regarding treatment and follow‐up is unavailable.
Asioli et al, 2021 4	A 68‐yr‐old female presented with gait instability and bilateral limb jerks for 4 yr. Serum and CSF anti‐IgLON5 were positive.	Repetitive, sustained involuntary contractions at rest and during voluntary action involving facial, cervical, upper, and lower limb muscles, resulting in a kiss fashion movement, flexion at the elbow with the extension of hands, and abduction of thighs with the extension of feet was noted. The contractions affected the oro‐pharyngeal region as well, resulting in lingual retraction and elevation of the soft palate, associated with a swallowing‐like movement and guttural sound. These movements persisted during sleep.	Additionally, the patient had apathy and depression, saccadic ocular pursuit, limb dysmetria, diffuse hyperreflexia with lower limb spasticity, mild cognitive impairment with prevalent verbal memory dysfunction, undifferentiated NREM in VPSG, bilateral calcification limited to pallidal nuclei on MRI and CT brain, and mild pleocytosis (7 cells/μl) with no OCB on CSF analysis.	The patient received IVIg and therapeutic plasma exchange but had no improvement. The patient died after 2 yr of presentation.
Gaig et al, 2021*, 1	6 patients were described with myorhythmia. It was the predominant complaint leading to consultation in 2 patients. All had serum anti‐IgLON5 positive. Individual data is not available for CSF anti‐IgLON5.	Myorhythmia, characterized by slow rhythmic movements, was restricted to the tongue and other oral muscles and was the predominant complaint leading to consultations in 2 patients.	Individual data is not available.	Two patients had a partial improvement following immunotherapy.
Current study	A 52‐yr‐old male presented with involuntary movements of tongue and chin of 3 mo with antecedent snoring, insomnia, and daytime sleepiness of 2 yr Serum and CSF anti‐IgLON5 were positive (Titre not available).	Slow, rhythmic, synchronous movements of the chin, tongue and palate of around 1 Hz frequency was observed. Surface electromyography of the mentalis and genioglossus and ultrasound of the submental region demonstrated the same.	Hypomimia and reduced arm swing on the left side was observed. His MRI brain and CSF cytology and biochemistry were normal. VPSG revealed poor sleep efficiency with undifferentiated NREM and obstructive sleep apnoea.	The patient received plasmapheresis, steroid, clonazepam, and 10 units of botulinum toxin to the genioglossus Partial improvement at 1‐mo follow‐up.

Abbreviations: anti‐IgLON5, Antibody to immunoglobulin‐like cell adhesion molecule‐5; CSF, Cerebrospinal fluid; CT, Computerized tomography; IVIg, Intravenous immunoglobulin; MRI, Magnetic resonance imaging; NREM, Non‐rapid eye movements; OSA, Obstructive sleep apnoea; OCB, Oligoclonal band; RBD, Rapid eye movement behavioral disorder; VPSG, Video‐polysomnography.

^*Includes cases described by Asioli et al, 2021.

Author Roles

(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;

S.G.: 1A, 1B, 1C, 3A

V.V.H.: 1A, 1B, 1C, 3A

S.D.K.: 1C, 3B

S.S.P.: IC, 3B

R.D.: IC, 3B

N.K.: 1C, 3B

R.Y.: 1A, 3B

P.K.P.: 1A, 1B, 1C, 3B

Disclosures

Ethical Compliance Statement: Patients' details were anonymized to maintain patient privacy and informed consent was obtained from the patient for the video recording, dissemination and publication. The authors confirm that the an Institution Ethics Committee review waiver was obtained from the institutional review board for the work (NIMHANS/IEC/2023). 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 Parkinson's Disease and Movement Disorders Research Fund, NIMHANS. There are no conflicts of interest to report.

Financial Disclosures for the Previous 12 Months: There are no financial disclosures to report.

Supporting information

Table e1 Clinical and investigations detail of the patient.