Cannabidiol Intervention for Non‐Epileptic Myoclonus in Angelman Syndrome: A Case Report

Angelman Syndrome (AS) is a neurogenetic disorder characterized by reduced activity of the ubiquitin‐protein ligase E3A enzyme—resulting from deletion or mutation of the maternally inherited 15q11.2–13.1 region, paternal uniparental disomy of chromosome 15, or an imprinting error. ¹ AS can significantly impact a patient's motor function, speech, and behavior with prevalent symptoms of developmental delay, seizures, frequent laughter, excitability, ataxia, speech impairment, non‐epileptic myoclonus (NEM), and other movement disorders. ¹ , ² NEM can be challenging to treat long‐term, as this condition is commonly refractory to the current medication options of levetiracetam, clobazam, and clonazepam. ² Cannabidiol (CBD) has shown promise in providing mixed therapeutic benefits for patients with movement disorders. ³ We present an AS patient with refractory NEM, with marked clinical improvement on non‐pharmaceutical CBD oil.

Case Report

The patient is a 15‐year‐old female diagnosed with Angelman Syndrome, characterized by a heterozygous UBE3A mutation in exon 16 (c.2503_2507dupCTTAA). Her symptoms are characterized by baseline tremor, intermittent episodes of increased myoclonic tremor, daily episodes of NEM shaking, and loss of tone (Video 1 and 2). Her episodes of NEM are typically triggered when she is startled in sleep, getting out of the car, and going up or down stairs. Her poorly controlled NEM severely impacted her activities of daily living and sleep quality.

Video 1.

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Episode of non‐epileptic myoclonus. Shaking episodes would occur daily. View of upper body and then legs. Mom comes in to help assist the patient.

Video 2.

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Another shaking episode of non‐epileptic myoclonus. Mom is helping to calm the patient through the episode.

Initially, at 10 years of age, clonazepam was initiated for myoclonic events, with positive effects, but the NEM episodes persisted and remained significantly disabling. Over the next several years, she underwent trials of lamotrigine, valproic acid, propranolol, baclofen, and gabapentin, none of which produced positive effects and were subsequently weaned off, before initiating trihexyphenidyl which helped control her tremors. Following a discussion with her medical team, the use of non‐pharmaceutical CBD oil was used in a trial, alongside the conventional medications, to alleviate the myoclonic attacks and improve her overall quality of life. She trialed a low dose of non‐pharmaceutical CBD oil 20 mg once daily at 11 years of age, but discontinued after 2 months due to persistent episodes, despite some improvement. One year later, non‐pharmaceutical CBD oil 20 mg once daily was attempted again and eventually ramped up to an increased dose taken three times daily (25, 30, and 25 mg), and significant improvements were seen in her myoclonus and overall livelihood (Table 1).

TABLE 1.

A variety of traditional medications used in non‐epileptic myoclonus management were attempted prior to the trial of CBD oil. A significant resolution of myoclonus and associated symptoms were seen after adding CBD oil to the patient's therapeutic regimen

Date	CLO	LAM	VPA	CBD	PRO	BCF	GAB	TRI	Comments
Mar 2019	0.5 mg
May 2019	0.5 mg BID
Aug 2019	↓	50 mg trial
Mar 2020	↓	Stop	1 g BID						Lamotrigine stopped: some decrease of NEM episodes at 50 mg, but no further decrease at a therapeutic dose of 112.5 mg BID and was stopped for VPA
Sep 2020	0.5 mg (am) 0.25 mg (pm)		750 mg BID	20 mg
Oct 2020	↓		Stop	↓					VPA stopped due to mild weight gain
Nov 2020	↓			Stop					Mild improvement on CBD, but episodes persisted
Jan 2021	Stop								Increased frequency of NEM episodes without Clonazepam
Feb 2021	0.375 mg (am) 0.25 mg (pm)								Clonazepam alone cannot control episodes
Mar 2021	↓								Improved myoclonic tremor with Propranolol
Jun 2021	0.375 mg (am) 0.375 mg (pm)				5 mg (am)
Oct 2021	0.375 mg (am) 0.375 mg (pm) 0.25 mg (4 am)				↓				Clonazepam with Propranolol inadequate to manage NEM episodes
Nov 2021	↓			20 mg	↓				Disturbed sleep persists with CBD and melatonin a
Apr 2022	0.375 mg (am) 0.25 mg (pm)			↓	Stop	10 mg (am)			Improved sleep with dose modification of Clonazepam; Propranolol stopped due to lack of efficacy with decreasing NEM episodes
Aug 2022	↓			↓		↓	100 → 600 mg trial		Brief relief of sleep with Gabapentin, no effect after 2 months
Oct 2022	↓			↓		↓	Stop	2.4 mg trial	Trihexyphenidyl started for management of myoclonic tremors
May 2023	↓			↓		Stop		↓	Baclofen stopped due to lack of efficacy with decreasing NEM episodes
Oct 2023	↓			25 mg (am) 30 mg (afternoon) 25 mg (bedtime)				↓	Resolution of myoclonus with higher dose CBD

Abbreviations: BCF, Baclofen; CBD, Cannabidiol oil; CLO, Clonazepam; GAB, Gabapentin; LAM, Lamotrigine; PRO, Propranolol; TRI, Trihexyphenidyl; VPA, Valproic Acid.

^a Patient was started on 10 mg Melatonin at bedtime November 2021 and has continued using this dose.

The increased dose of CBD oil was followed by a noticeable decrease in the frequency of myoclonic episodes, despite no significant changes in the patient's daily living, stressors, and family care. Her caregivers observed that before clonazepam and CBD treatment, she experienced 9 NEM episodes each night, which reduced to 5–6 episodes after initiating clonazepam, which were further reduced to 0–1 per night after adding CBD. While the use of clonazepam did provide benefit to the patient, the episodes of NEM persisted and the number of episodes was not dramatically decreased until the addition of CBD oil to her regimen. Her reduction of myoclonic episodes increased her confidence in walking unassisted, climbing stairs without support, and even learning to run (Video 3).

Video 3.

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Post cannabidiol treatment. Segment 1: Patient walking down the stairs with slight assistance. Segment 2: Patient walking unassisted.

Discussion

Classically, AS presents with developmental delay, speech impairment, epilepsy, sleep dysfunction, and movement disorders. ¹ Sleep disturbances include frequent night walking, early waking, and a decrease in the duration of REM sleep. ¹ The most common movement disorders seen include ataxia, tremors, and myoclonus, in epileptic and non‐epileptic forms of myoclonus. ¹ , ⁴ Non‐epileptic forms of myoclonus are characterized by myoclonic jerks that last from seconds to several hours, typically starting in the hands and spreading to the rest of the body. ⁴

Currently, the treatment for non‐epileptic cortical myoclonus include levetiracetam, lamotrigine, clonazepam, and valproic acid. ⁵ Through anecdotal reports, parents of patients with AS have described reduced symptoms with the use of CBD. In clinical practice, CBD was shown to be effective in Dravet and Lennox–Gastaut Syndrome in randomized clinical trials, leading to approval by the Food and Drug Administration (FDA) for these epileptic syndromes. ⁶ One possible mechanism for CBD's role in treating NEM is through the modulation of GABAergic signaling. ⁷ The use of CBD in combination with other anti‐seizure medications (ASM) is generally well‐tolerated, with some necessary adjustments to the dosing strengths of the commonly used ASMs, particularly clobazam. ⁸

Evidence from AS model mice supports a role for CBD in the treatment of epilepsy. In AS model mice, CBD attenuated hyperthermia‐ and acoustically‐induced seizures and reduced intracortical local field potential (LFP) power, exhibiting the potential to normalized AS‐related EEG abnormalities. When examining CBD's effects on behavioral and motor deficits associated with AS in mice, CBD had a dose‐dependent sedative effect leading to decreased locomotor activity, poor motor coordination, and reduced marble‐burying behavior. ⁹ CBD has also demonstrated an anxiolytic effect in both preclinical studies and a double‐blind randomized controlled trial. ⁷ While not a primary focus in this patient's treatment plan, anxiety is a significant comorbidity observed in individuals with Angelman syndrome that is often a focus for treatment. ¹⁰ Further investigation into CBD's sedative and anxiolytic effects and its relationship with NEM episodes is needed to better understand the mechanism behind the reduction of episodes seen.

To our knowledge, CBD treatment in managing NEM in Angelman Syndrome has yet to be reported in literature. Our current understanding of the mechanism and use of CBD is still limited and is additionally complicated by the social complexities associated with CBD usage. Further studies could provide valuable insights into the utilization of CBD for NEM and could be considered for other AS patients experiencing inadequate control of their myoclonic events.

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.

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

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

M.A.: 3A

E.Z.: 3A

C.S.: 3B

K.M.: 1A, 3A, 3B

Disclosures

Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. The authors confirm that informed consent of the patient and caregiver (mom) was obtained. 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: No specific funding was received for this work. The authors declare that there are no 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.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.