Abstract
Article abstract— Ring chromosome 20 mosaicism is associated with dysmorphic features, mental retardation, and intractable seizures, including recurrent episodes of nonconvulsive status epilepticus. The authors’ findings in four children, all without dysmorphic features, indicate that mental deterioration and frequent subtle nocturnal frontal lobe seizures, associated with a characteristic EEG pattern, represent prominent additional clinical features not previously described in this syndrome. This emphasizes the importance of full-night video-EEG in children with frontal lobe seizures and cognitive deterioration.
Ring chromosome 20 mosaicism (r(20)) is a rare chromosomal anomaly associated with dysmorphic features, mental retardation, autistic behavior, and intractable epilepsy.1 Distinct electroclinical features have been reported in these patients, although with contradictory findings.2-4⇓⇓ Six patients with r(20) but without dysmorphic features showed frequent episodes of nonconvulsive status epilepticus (NCSE) associated with a typical EEG pattern, characterized by runs of long-lasting bilateral paroxysmal high-voltage slow waves with occasional spikes over the frontal lobes.2,3⇓ Other investigators considered this EEG pattern as genetically determined and not necessarily related to an active seizure disorder.4
We present the electroclinical features of four children with r(20) without dysmorphic signs. All showed diurnal episodes of NCSE but also frequent nocturnal frontal lobe seizures (NS), characterized predominantly by subtle stretching, turning, or rubbing movements that, without video-EEG, would be indistinguishable from physiologic arousal behavior. Taking the EEG discharges (highly characteristic bursts of diffuse but frontally dominant high-voltage fast activity) as a lead, however, the video showed these to represent a spectrum of characteristic minimal to moderate motor signs, identifying them as “subtle nocturnal seizures” (SNS). In some patients, SNS represented the only seizure type. This newly described feature may provide a link to other epilepsy syndrome phenotypes that involve chromosome 20, especially those with NS.
Methods.
Between 1994 and 1999, we identified four patients with r(20). Comprehensive evaluation of the children included MRI, multiple 24-hour video-EEG, and at least one neuropsychological assessment, usually combined with video-EEG. Cytogenetic analysis showed r(20) mosaicism (one normal chromosome 20 and one r(20) (46,XY, r(20) or 46,XX, r(20)) in all four patients. Clinical signs were not correlated to the r(20) lymphocyte percentage, which varied from 12 to 68%. No epilepsy-related microdeletions or subtelomeric deletions were detected. Details of the genetic studies will be published separately. Clinical data and video-EEG findings are summarized in tables 1 and 2⇓ and the figure.
Clinical data
EEG findings
Figure. (A) Patient 4. EEG fragment during nonconvulsive status epilepticus shows continuous irregular multifocal but predominantly frontal spike and wave discharges, especially on the left. (B) Patient 1. Shown is nocturnal frontal lobe seizure with overt clinical signs (awakening, staring, some tonic stiffening, followed by clonic movements of eyelids, around the mouth, and in all extremities, then by agitation and disorientation). Note diffuse attenuation and low-voltage fast activity, evolving into high-voltage rhythmic slow wave over the frontal region. (C) Patient 4. Subtle nocturnal seizure with minimal motor activity is shown, clinically indistinguishable from physiologic arousal activity. Note characteristic bursts of diffuse but frontally emphasized high-voltage fast (beta) activity, evolving into bifrontal high-voltage subdelta waves. This pattern was identified in all subtle nocturnal seizures in all four patients.
Case reports.
Patient 1.
A previously normal and healthy 11-year-old girl developed major behavioral problems and cognitive decline, diagnosed as atypical pervasive developmental disorder. Six months later, she developed epilepsy with frontal lobe NS and NCSE, manifesting as an altered state of vigilance with loss of emotional facial expression, diminished spontaneous behavior and speech, and a slow response to questions. Neuropsychological assessment (total IQ [TIQ] = 63) confirmed the cognitive deterioration; during NCSE, it showed significant slowing on simple visual and auditory reaction time tests but otherwise no overt cognitive disturbances. Follow-up video-EEG confirmed the intractability of daily recurrent diurnal NCSE in the afternoon and multiple SNS. The patient had to give up regular school and currently works in a sheltered environment. Her behavior has improved but still shows autistiform features.
Patient 2
This 14-year-old girl with mild mental handicap (TIQ = 75) was diagnosed with cryptogenic frontal lobe epilepsy at the age of 3 years. Until seizure onset, her psychomotor development had been normal. Video-EEG monitoring identified diurnal complex partial seizures with frontal lobe features, daily recurrent episodes of NCSE in the late afternoon, and frequent (20 to 80) SNS during night. During NCSE, there were marked mental slowing and some confusion without further cognitive impairment. After 3-year follow-up, the recurrent NCSE and the frequent SNS still persist.
Patient 3
An 11-year-old boy with unremarkable past medical history presented with recurrent periods of confusion and mental slowing, shown by video-EEG to represent NCSE. During these episodes, he remained responsive but manifested considerable mental slowing and loss of facial expression. Neuropsychological test results (TIQ = 90) were markedly influenced by NCSE. Although there was no known history of seizures, video-EEG demonstrated multiple SNS. Total suppression of the recurrent NCSE was achieved, but the SNS remain refractory. On repeated neuropsychological assessment, overall performance was not markedly improved (TIQ = 96) but mental speed, reaction time, and motor fluency showed significant improvement.
Patient 4
An 8-year-old girl was barred from regular school because of severe educational and autistic behavioral problems, associated with daily recurrent periods with mental slowing, restlessness, and distractibility, 3 months after the onset of epilepsy with frequent diurnal seizures. NS were not reported. Video-EEG captured a period with clouded consciousness, mutism, restlessness, some automatisms, and EEG evidence of NCSE, multiple diurnal frontal lobe seizures and >20 NS, most of them SNS. NCSE recurred daily during late afternoon or evening. Neuropsychological assessment (TIQ = 70) indicated severe deterioration.
Discussion.
The documentation of frequent SNS with characteristic EEG features as a predominant symptom in all four patients expands the electroclinical phenotype of r(20) syndrome and emphasizes the importance of full-night sleep video-EEG in children with a history suggesting frontal lobe seizures and cognitive deterioration. Documentation of typical electroclinical features, notably SNS, should prompt karyotyping studies, even in children without dysmorphic features.
This predominance of NS in r(20) epilepsy syndrome was not noted in previous reports that focused on periodic NCSE with EEG findings emphasizing frontal lobe involvement as a pivotal symptom, although complex partial or convulsive seizures from sleep are mentioned in Patients 2 and 6.2,3,5⇓⇓ Our electroclinical findings confirm those reported previously by the Japanese investigators but identify an additional pattern of generalized paroxysmal fast activity, associated with SNS, that has not been described in r(20) syndrome before. A similar EEG pattern is often observed during tonic seizures in patients with Lennox–Gastaut syndrome; however, no such seizures were observed in our patients. Our video-EEG findings during NCSE are in sharp contrast with those reported in three patients.4 In these cases, the EEG changes were considered nonsymptomatic. Episodes of EEG NCSE were consistently associated with subtle but demonstrable evidence of impaired cognitive behavior. Although we observed a typical circadian pattern, with the amount of epileptiform activity most abundant during the afternoon and evening periods, this was not associated with overt changes in alertness unless evolving into NCSE.
The predominance of subtle nocturnal frontal lobe seizures in patients with r(20) suggests a possible relationship with other epilepsy syndromes related to genes located on the distal long arm of chromosome 20. The gene for the syndrome of autosomal dominant nocturnal frontal lobe epilepsy has been mapped to chromosome 20q13.2-q13.36 associated with a missense mutation in the neuronal nicotinic acetylcholine receptor A4 subunit (CHRNA4), also mapped to 20q.7,8⇓ Other candidate genes are the KCNQ2 gene related to benign neonatal convulsions9 and the melanocortin receptor gene (MC3R), which has been mapped to 20q13.2-q13.310 and could be involved in the marked circadian pattern of the epileptiform activity in these patients. In our patients, no microdeletions were detected in either the CHRNA4 or the KCNQ2 gene. The MC3R gene is currently being investigated.
Prognosis in this epilepsy syndrome is poor. Cognitive and behavioral regression was time locked to the onset of the seizure disorder in all children (3 to 11.5 years), and those three with normal intellectual and behavioral levels before seizure onset became dependent on special education afterward. The neuropsychological level of these children remained subnormal (TIQ = 70 to 95), confirming permanent regression from previous normal level. Two patients still have major behavioral problems with autistic features not present before seizure onset. In the largest r(20) series, subnormal TIQ scores (47 to 95) are reported in all six patients and major behavioral problems in two, but mental or behavioral regression following seizure onset (mean age of 5 years) is not mentioned.2 Our findings suggests the existence of a distinct phenotype of r(20) syndrome, characterized by childhood onset of epilepsy, with frequent NCSE, SNS, typical EEG features, and cognitive deterioration and without conspicuous dysmorphic features.
Acknowledgments
Acknowledgment
The authors thank Dr. O. Steinlein for her support in the genetic investigation, E. Dekker (REEGT) for technical assistance during the EEG, and Prof. F.H. Lopes da Silva for critical reading of the manuscript.
- Received September 18, 2000.
- Accepted May 12, 2001.
Disputes & Debates: Rapid online correspondence
- Reply to Serrano-Castro
- Expanding heterogeneity of seizure pattern in ring chromosome 20 syndrome
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