Current Case: Spring 2022

Contributed by:
Kelsey M. Smith MD1, Shaun B. Ajinkya MD MPH1, Donnie K. Starnes II MD1, David B. Burkholder MD1, Lily C. Wong-Kisiel MD1, Elson So MD1.
1Mayo Clinic, Rochester, MN

Case Presentation

A 33-year-old man with known Angelman Syndrome and epilepsy presented to the hospital with failure to thrive and worsening of baseline “tremors” over the preceding 6 months, with acute worsening in the week prior to presentation. Prolonged video-EEG was initiated to further assess the movements. Multiple subtle low amplitude, high frequency tremulous movements of both hands, face, and trunk were recorded. Bursts of  generalized sharply contoured 6-9 Hz activity was seen on EEG that frequently but not always correlated with the patient’s tremor. Some of these events were prolonged, lasting for over an hour and associated with decreased responsiveness. An EMG lead was placed on the left wrist where the tremor was the most prominent (Figure 1 and Figure 2)


Figure 1 Legend: EEG with left wrist EMG lead. The EEG shows generalized 6-9 Hz sharply contoured rhythmic activity that precedes the EMG discharges. EEG settings: High frequency filter: 70 Hz, Low frequency filter: 1 Hz, Notch: 60 Hz, Sensitivity: 5 uV/mm. EMG settings: High frequency filter: 50 Hz, Low frequency filter: 1Hz, Notch: off, Sensitivity: 30 uV/mm.

 


Figure 2 Legend: Zoomed in view of EEG with left wrist EMG lead during myoclonus. This shows the preceding cortical discharge prior to the EMG discharges. EEG settings: High frequency filter: 70 Hz, Low frequency filter: 1 Hz, Notch: 60 Hz, Sensitivity: 5 uV/mm. EMG settings: High frequency filter: 50 Hz, Low frequency filter: 1Hz, Notch: off, Sensitivity: 30 uV/mm.

 

Question 1: What do Figure 1 and Figure 2 show?

  1. Cortical myoclonus
  2. Subcortical myoclonus
  3. Spinal myoclonus
  4. None of the above
Answer: (click here)

Correct answer: A. Cortical myoclonus.

Bursts of rhythmic 6-9 Hz discharges on EEG preceding the EMG discharges are consistent with cortical myoclonus (Figure 1 and Figure 2). Cortical myoclonus implies that the myoclonus is related to cortical hyperexcitability. EEG-EMG polygraphy is useful in differentiating cortical from subcortical myoclonus when it is not clear if the EEG discharges are cerebral potentials causing the myoclonus or EMG potentials (myogenic artifact) as a result of the myoclonic movements. Cortical myoclonus is confirmed when EEG discharges correlating with clinical myoclonus precede the EMG potentials, as is seen in our case.1 Multiple medications were tried for the myoclonus in our case including levetiracetam, valproic acid, and benzodiazepines. Despite this, the patient continued to have clinically significant myoclonus. After goals of care discussions, the patient was ultimately transitioned to comfort care and subsequently passed away.

Question 2: What interictal EEG abnormalities can be seen in Angelman Syndrome?

  1. Anteriorly predominant rhythmic 2-3 Hz activity with intermixed spikes and sharp waves
  2. Persistent generalized rhythmic 4-6 Hz activity
  3. Spike and sharp waves with 3-4 Hz activity seen posteriorly on eye closure
  4. All of the above
Answer: (click here)

Correct answer: D. All of the above.

The most common EEG pattern that has been described in Angelman Syndrome is anteriorly predominant rhythmic 2-3 Hz delta with intermixed spikes and sharp waves.2 However, persistent generalized rhythmic 4-6 Hz activity and spike and sharp waves with 3-4 Hz activity seen posteriorly on eye closure have also been described.2 The rhythmic 2-3 Hz delta with intermixed spike and sharp waves can give the appearance of the notched delta pattern which is characteristic of Angelman Syndrome.3 Angelman Syndrome is mostly commonly caused by a deletion within a critical region of 15q11.2-q13 on the maternal chromosome, which occurs in 70% of cases.4 However, mutations within the ubiquitin protein ligase E3A gene (UBE3A) which is located on the 15q11.2–q13 region of the maternal chromosome, paternal uniparental disomy, and imprinting defects in maternal DNS methylation can also cause Angelman syndrome.4 We did not know the genetic mutation in our case as the patient had received all of his prior care at another institution. It has been shown that patients with deletions have a more severe phenotype and more prominent EEG abnormalities.5 Affected regions of 15q11.2-q13 contain genes that code for different subunits of GABAA receptors; therefore, disruption of GABAergic transmission plays a role in epileptogenesis of patients with Angelman syndrome.6, 7

Question 3: What types of myoclonus can be seen in Angelman Syndrome?

  1. Nonepileptic myoclonus
  2. Cortical myoclonus
  3. Myoclonic seizures and status epilepticus
  4. All of the above
Answer: (click here)

Correct answer: D. All of the above.

Nonepileptic myoclonus, cortical myoclonus, and myoclonic seizures and status epilepticus are frequently encountered in patients with Angelman syndrome. Myoclonic seizures frequently begin before age 8.8 Cortical myoclonus, mainly involving the hands and face, has also been reported where the EEG shows rhythmic 5-10 Hz activity which precedes changes on electromyography.9 Myoclonic status epilepticus with ongoing myoclonus and altered mental status associated with functional regression is also described.6 Our patient had primarily cortical myoclonus with the typical EEG findings and prolonged events consistent with myoclonic status epilepticus. Nonepileptic myoclonus is also a common feature of Angelman syndrome, where there is no associated EEG correlate with myoclonus. It was found to be more common during or after puberty, occurring in 40% of individuals over 10 years of age in one study.8

 

References

  1.  Caviness JN. Myoclonus. Continuum (Minneap Minn) 2019;25:1055-1080.
  2. Laan LA, Vein AA. Angelman syndrome: is there a characteristic EEG? Brain Dev 2005;27:80-87.
  3. Korff CM, Kelley KR, Nordli DR, Jr. Notched delta, phenotype, and Angelman syndrome. J Clin Neurophysiol 2005;22:238-243.
  4. Goto M, Saito Y, Honda R, et al. Episodic tremors representing cortical myoclonus are characteristic in Angelman syndrome due to UBE3A mutations. Brain Dev 2015;37:216-222.
  5. Lossie AC, Whitney MM, Amidon D, et al. Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J Med Genet 2001;38:834-845.
  6. Samanta D. Epilepsy in Angelman syndrome: A scoping review. Brain Dev 2021;43:32-44.
  7. Moncla A, Malzac P, Voelckel MA, et al. Phenotype-genotype correlation in 20 deletion and 20 non-deletion Angelman syndrome patients. Eur J Hum Genet 1999;7:131-139.
  8. Pollack SF, Grocott OR, Parkin KA, Larson AM, Thibert RL. Myoclonus in Angelman syndrome. Epilepsy Behav 2018;82:170-174.
  9. Guerrini R, De Lorey TM, Bonanni P, et al. Cortical myoclonus in Angelman syndrome. Ann Neurol 1996;40:39-48.

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