Abstract
Objective
We retrospectively investigated a cohort of patients with ring chromosome 20 syndrome (r20), aiming to provide information on the prognosis of r20 regarding seizures, cognitive function, comorbidities, and social living.
Methods
Patients diagnosed with r20 in our hospital were identified, and clinical data were extracted from medical records. We used the following seizure outcome classification: favorable seizure outcome, a condition in which seizures do not interfere with daily life, including no seizures, subclinical discharges, sleep seizures or mild focal aware seizures; poor seizure outcome, a condition in which seizures interfere with daily life. Clinical variables were compared between favorable and poor seizure outcome groups.
Results
Forty‐seven patients (64% female) were studied. Mean age ± standard deviation (SD) at epilepsy onset was 7.5 ± 3.7 (range 1–15) years. Mosaicism rate was 33 ± 24% (range 1%–97%). Fourteen patients (30%) were classified in the favorable seizure outcome group and 33 (70%) in the poor seizure outcome group. Multivariable analysis identified lower mosaicism rate and higher rate of lamotrigine use as independent factors associated with a favorable seizure outcome. The most effective drug was lamotrigine (69%), followed by valproate (43%) and other sodium channel blockers. Intellectual disability was present in 27 patients (57%), autism spectrum disorder in 8 (17%), and psychiatric symptoms in 10 (21%). Of 30 adult patients, 7 (23%) were employed, 5 (17%) were employed previously but unemployed at the last follow‐up, 3 (10%) were employed as disabled, 6 (20%) received employment support, 3 (10%) were college students, and 6 (20%) had no employment history. Twenty‐five patients (83%) lived with their families. Two patients (7%) were married.
Significance
In 30% of r20 patients, drug treatment improved seizures to a degree minimally disruptive to daily life. Lamotrigine use was associated with favorable seizure outcome. Social constraints in employment, residence, and marriage were significant, indicating the need for comprehensive epilepsy care.
Keywords: chromosome mosaicism, comorbidities, employment, nonconvulsive status epilepticus, treatment response
Key points.
This retrospective cohort study of 47 patients investigated the outcomes of seizure, cognitive function, comorbidities, and social living of patients with ring chromosome 20 syndrome.
In 30% of patients, seizures improved to a condition not or minimally disruptive to daily living.
Favorable seizure outcome was significantly associated with lower mosaicism and higher lamotrigine use.
Fifty‐seven percent of patients had intellectual disability, 17% had autism spectrum disorder, and 21% had psychiatric symptoms.
Social constraints in employment, independent living, driving, and marriage were common.
1. INTRODUCTION
The ring chromosome 20 syndrome (r20) is a rare and refractory epilepsy syndrome. Since the report of the first case of ring chromosome 20 in 1972, 1 fewer than 200 cases have been reported worldwide. 2 Despite many reports on electroencephalography (EEG) findings and seizure types including non‐convulsive status epilepticus (NCSE) in r20, 3 , 4 , 5 there are few studies on long‐term seizure outcome and treatment response. In a cohort study of 25 patients with r20 followed for 2–18 years at six Italian epilepsy centers, 24 patients had epilepsy and 3 (12.5%) became seizure‐free. 6 Analysis of a group with favorable long‐term outcome (no seizures, with or without medications) and a group with unfavorable course (refractory focal seizures and NCSE) showed that later seizure onset was associated with better outcome. This report suggests that good prognosis is rare, and identifies age at epilepsy onset as a nonmodifiable prognostic factor, which possibly correlates with mosaicism rate. This cohort probably had relatively mild cases, judging from the significantly older disease onset age and significantly lower mosaicism rate compared to 75 patients analyzed in the literature review reported in the same article. 6 This would raise a concern that the prognosis of the r20 population may be even worse.
On the other hand, our clinical experience gave us the impression that the seizure prognosis and overall quality of life of patients with r20 may not be so poor. There is still a paucity of long‐term data available to answer the concerns and questions that patients and their families may have regarding seizures, cognitive development, and future social outcome. We therefore investigated the detailed seizure outcome, treatment response, cognitive development, comorbidities, and social outcomes of a cohort of patients with r20, aiming to provide information on future life prospects for the patients, their families, and medical professionals involved in their care.
2. MATERIALS AND METHODS
2.1. Patients
We conducted a retrospective cohort study at the National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Japan, on patients who visited our Center between April 1975 and March 2024, with a diagnosis of r20 based on clinical information and chromosome examination. This center is the first national epilepsy center established in Japan, treating the largest number of patients with epilepsy from children to adults in Japan, and patients are referred from all over Japan and sometimes from abroad. This syndrome is not currently included in the International League Against Epilepsy (ILAE) classification and definition of epilepsy syndromes, 7 , 8 and there are no international diagnostic criteria for the syndrome. Therefore, we used the Diagnostic Criteria for Ring Chromosome 20 Syndrome designated by the Japanese Ministry of Health, Labour and Welfare (Act on Medical Care and Social Supports for Patients with Intractable/Rare Diseases). 9 (See Data S1 for its English translation.)
Patient demographics, seizure type, ictal semiology, and other clinical information were extracted from medical charts, and patients were divided into two groups according to the seizure outcome classification described in subsequent text. Treatment response was also investigated, and the association between treatments used in more than 10 patients and seizure outcome was analyzed statistically. Descriptive statistics were performed on a subgroup of adults who were 18 years of age or older at the last follow‐up, for employment, residential status, marriage, childbearing (women only), and driver's license status. Time of the last follow‐up was the time of the last visit or contact with the hospital, or March 2024, if follow‐up was ongoing.
The karyotype was confirmed by the G‐Band method using lymphocytes collected from peripheral blood. The number of cells examined was usually 20 or 30, increasing to a maximum of 100 cells when r20 was strongly suspected clinico‐electrographically.
All patients underwent routine EEG examination initially and repeatedly during follow‐up (duration of 30–60 min, for a median of 3 times) and were, except one case, admitted to the hospital for prolonged video‐EEG examination during the course of treatment (median duration 7 nights 8 days, for a median of 3 times). The duration of NCSE in this study was defined as at least 5 min; <5 min was considered a single seizure where appropriate.
Effectiveness of drug, surgery, or dietary therapy was determined based on the medical records. Effectiveness was estimated not only by a decrease in number of seizures, but also by a shortening of seizure duration and reduction in severity of impaired consciousness during seizures. Specifically, treatment was judged to be effective if the seizure frequency was reduced by 50% or more, or if the seizure duration was reduced by 50% or more. Treatment was also judged to be effective if seizure severity was improved; such as when the patient no longer had impairment of consciousness, was aware during seizure, remembered a seizure afterwards, or no longer fell over during a tonic seizure. In cases where quantitative data were not available due to insufficient entries in medical records, effectiveness was determined based on qualitative descriptions. If treatment was effective but became ineffective due to tolerance, or if treatment was effective but was discontinued due to adverse effects, the treatment was not evaluated as effective. Cases showing exacerbation or unknown outcome were evaluated as ineffective. In patients who had undergone multiple intelligence tests, the results of that closest to the time of the last follow‐up was adopted. Cognitive regression was considered to be present if there was documented deterioration of a cognitive milestone that was reached previously during the interictal phase. Eight patients in the present cohort had been reported previously. 3 , 10 , 11 , 12
2.2. Classification of seizure outcome
NCSE, the hallmark seizure type of r20, may show varying degrees of impairment of consciousness. Although some NCSEs are clinically distinct, others may appear to be clinically subtle, although ictal EEG waves are present. In addition, during the course of treatment, the duration of seizures may become short or the degree of impairment may become mild; consequently, seizures are barely noticeable to others and/or do not interfere with the patient's daily life. In this study, we developed a seizure outcome classification taking into account the severity of impairment and the influence on daily life, rather than only according to the presence or absence of seizures. The definitions of different outcomes are shown below.
2.2.1. Favorable seizure outcome
A condition in which seizures do not interfere with daily life, including:
No seizures or subclinical discharges only.
Patient is aware of seizures, and seizures are mild in nature. For example, the patient does not need rest during and after the seizures.
The seizures are not noticeable to others, regardless of whether the patient is able to accurately report his/her symptoms. Even if the seizures are noticed by others, manifestations are subtle, and the patient or caregiver clearly states that the seizures do not interfere with the patient's daily life.
Seizures occur during sleep and do not affect daytime activities, including post‐seizure status.
2.2.2. Poor seizure outcome
A condition in which seizures interfere with daily life, including:
Seizures causing impaired consciousness while the patient is awake.
Seizures are quite unpleasant; such as pain or fear, or requiring rest, or other changes in behavior due to drowsiness, or poor physical condition, even in the absence of impaired consciousness.
Seizures occur during sleep but are followed by prolonged post‐ictal symptoms (including headache, muscle pain, and confusion) that interfere with subsequent waking behaviors.
A flowchart of seizure type classification is shown in Data S5.
2.3. Statistical analysis
Continuous variables with Gaussian distribution were described by mean and standard deviation (SD), and continuous variables with non‐Gaussian distribution by median (interquartile range [IQR]). Counts and percentages were used for categorical variables. Statistical comparisons between the favorable seizure outcome and poor seizure outcome groups were performed for demographic data, seizure types, ictal semiology, and other epilepsy‐related features. Continuous variables with Gaussian distribution were analyzed by the t‐test, and those with non‐Gaussian distribution by the Mann–Whitney's U test. Categorical variables were analyzed by the chi‐square test or Fisher's exact test, as appropriate.
Based on a previous report 2 and the present results, multivariate analysis was performed using logistic regression analysis for four parameters; sex, age at last follow‐up, mosaicism rate, and history of lamotrigine (LTG) use, as independent variables associated with seizure outcome. Results were considered statistically significant for two‐sided p < .05. All statistical computations were performed using SPSS 25.0 for Windows (SPSS Inc.).
2.4. Institutional approval
The study protocol was approved by the ethics committee of NHO Shizuoka Institute of Epilepsy and Neurological disorders (No. 2023‐30).
3. RESULTS
3.1. Demographic data and seizure outcome
A total of 47 patients were included in the study. Demographic and clinical data are shown in Table 1. Thirty patients were female (63.8%). All patients had epilepsy. Mean age at epilepsy onset was 7.5 ± 3.7 (range 1–15) years, and median age at the last follow‐up was 23.0 (IQR 13.0–33.0, range 9–70) years. Median duration of disease (from age at epilepsy onset to age at last follow‐up) was 13.0 (IQR 7–26) years. The mosaicism rate for r20 (n = 43) was 32.5 ± 23.7% (range 1%–97%), and no patient was confirmed as being non‐mosaicism. The latest intelligence quotient (IQ; n = 38) was 66.4 ± 16.0. Intellectual disability was observed in five of the nine patients with unknown IQ, and together with 22 patients with IQ < 70, 27 of 47 patients (57.4%) had intellectual disability. Developmental delay before epilepsy onset was present in 7 patients (14.9%), cognitive regression in 14 (29.8%), autism spectrum disorder in 8 (17.0%), and psychiatric symptoms in 10 (21.3%). There were no fatalities. Yearly change in the number of diagnoses of r20 is shown in Data S4.
TABLE 1.
Demographic and clinical data of all patients classified according to seizure outcome.
| Overall (n = 47) | Favorable seizure outcome (n = 14) | Poor seizure outcome (n = 33) | p Value | |
|---|---|---|---|---|
| Age at epilepsy onset, mean ± SD | 7.5 ± 3.7 | 10.4 ± 2.6 | 6.2 ± 3.4 | < .001 |
| Female, n (%) | 30 (63.8) | 5 (35.7) | 25 (75.8) | .009 |
| Age at last follow‐up, median (IQR) | 23.0 (13.0–33.0) | 20.5 (17–33) | 25.0 (13–33) | .98 |
| Percent mosaics, mean ± SD [n = 43] | 32.5 ± 23.7 | 17.6 ± 11.2 | 39.7 ± 24.9 | < .001 |
| Latest IQ, mean ± SD [n = 38] | 66.4 ± 16.0 | 74.6 ± 9.6 | 62.1 ± 17.0 | .006 |
| Developmental delay before epilepsy onset, n (%) | 7 (14.9%) | 2 (14.3) | 5 (15.2) | 1 |
| Cognitive regression, n (%) | 14 (29.8%) | 3 (21.4) | 11 (33.3) | .5 |
| ASD, n (%) | 8 (17.0%) | 4 (28.6) | 4 (12.1) | .22 |
| Psychiatric symptoms, n (%) | 10 (21.3%) | 5 (35.7) | 5 (15.2) | .14 |
| ASM‐induced a | 5 (10.6%) | 4 (28.6) | 1 (3.0) | .023 |
| Non–ASM‐induced b | 6 (13.8%) | 3 (21.4) | 3 (9.1) | .34 |
Note: The numbers of patients in the favorable and poor seizure outcome groups were, respectively, 14 and 29 for mosaicism rate (43 total), and 14 and 24 for latest IQ (38 total). One patient had both ASM‐induced and non–ASM‐induced psychiatric symptoms. There was no formal diagnosis of conduct disorder or developmental disorder, but significant problematic behavior was observed regularly in two patients, with one failing to follow ward rules (drinking, leaving ward without permission), and the other bullying, sexual harassment, restlessness, leaving ward without permission. Bold font denotes statistical significance (p < .05).
Abbreviations: ASD, autism spectrum disorder; ASM, antiseizure medication; IQ, intelligence quotient; IQR, interquartile range; SD, standard deviation.
Caused by LEV in two patients (irritability, depression, and problematic behavior), ESM in one (irritability, restlessness, and communication disorder), GBP in one (problematic behavior) in the favorable seizure outcome group. Caused by CLB in one patient (irritability) in the poor seizure outcome group.
Include hallucinations, delusions, obsessive‐compulsive disorder, emotional instability, and suicidal idea.
The favorable seizure outcome group consisted of 14 patients (29.8%). Among the patients with favorable seizure outcome, three patients reportedly had no clinical seizures. But these patients showed electrographic seizures (subclinical discharges) even at the last follow‐up, and it is difficult to determine that they are completely free from seizures. The remaining 33 patients (70.2%) had poor seizure outcome. Detailed seizure outcomes of individual patients are shown in Data S2. In the comparison of demographic and clinical data including comorbidities between the favorable and poor seizure outcome groups, the favorable seizure outcome group had older epilepsy onset age, fewer women, lower mosaicism rate, higher IQ, and more drug‐induced psychiatric symptoms.
3.2. Seizure types and ictal semiology
Seizure types, ictal semiology, and other findings related to epilepsy are listed in Table 2. NCSE manifested in all patients. Ictal fear was observed in 10 patients (21.3%) and ictal laughing in four patients (8.5%). Of the four patients with ictal laughing, three had impaired consciousness and the presence or absence of mirth was unknown, the remaining one had no data regarding consciousness and mirth. Ictal pain was noted in two patients (4.3%); one described the pain as needle pricks in both hands, both legs, and sometimes in the unilateral limbs; and the other patient described pain as if a piece of glass had pierced the left arm, chest, and leg.
TABLE 2.
Seizure types, ictal semiology, and other features related to epilepsy.
| Seizure type | Overall (n = 47) | Favorable seizure outcome (n = 14) | Poor seizure outcome (n = 33) | p Value |
|---|---|---|---|---|
| NCSE | 47 (100.0) | 14 (100.0) | 33 (100.0) | |
| NCSE with tonic component | 9 (19.1) | 3 (21.4) | 6 (18.2) | 1 |
| NCSE with myoclonic component | 22 (46.8) | 3 (21.4) | 19 (57.6) | .023 |
| NCSE without motor component | 31 (66.0) | 12 (85.7) | 19 (57.6) | .094 |
| Tonic seizure | 21 (44.7) | 6 (42.9) | 15 (45.5) | .87 |
| Focal impaired awareness seizure | 18 (38.3) | 8 (57.1) | 10 (30.3) | .083 |
| BTCS including focal, generalized or unknown onset | 18 (38.3) | 5 (35.7) | 14 (42.4) | .67 |
| FBTCS | 8 (17.0) | 4 (28.6) | 4 (12.1) | .21 |
| Head nodding seizure a | 2 (4.3) | 1 (7.1) | 1 (3.0) | .51 |
| Ictal semiology | ||||
| Hyperkinetic movement | 6 (12.8) | 2 (14.3) | 4 (12.1) | 1 |
| Ictal fear | 10 (21.3) | 4 (28.6) | 6 (18.2) | .46 |
| Ictal laughing | 4 (8.5) | 4 (28.6) | 0 (0.0) | .006 |
| Ictal visual hallucination | 5 (10.6) | 1 (7.1) | 4 (12.1) | 1 |
| Ictal pain | 2 (4.3) | 1 (7.1) | 1 (3.0) | .51 |
| Non‐epileptic events (No clinical‐EEG correlation) b | 5 (10.6) | 2 (14.3) | 3 (9.1) | .63 |
| Transiently seizure‐free c | 5 (10.6) | 1 (7.1) | 4 (12.1) | 1 |
Note: Data are presented as n (%) unless otherwise indicated. Bold font denotes statistical significance (p < .05).
Abbreviations: BTCS, bilateral tonic–clonic seizure; EEG, electroencephalography; FBTCS, focal to bilateral tonic–clonic seizure; NCSE, non‐convulsive status epilepticus.
Head‐nodding seizures suggestive of epileptic spasms according to descriptions. Both patients were not confirmed by video‐EEG.
Events without EEG changes, although manifesting unresponsiveness observed by others.
Transiently seizure‐free was defined as seizure‐free for a minimum duration of 3 times the longest pretreatment inter‐seizure interval, or 12 months, whichever is longer. Seizure‐free period was 10 years in one patient, 6 years in two patients, 4 years in one patient, and 1 year in one patient. Two patients were untreated, and the remaining three patients were taking antiseizure medications.
In the comparison of seizure types and ictal semiology between favorable and poor seizure outcome, NCSE with myoclonic component was less common in the favorable outcome group (21.4% vs 57.6%, p = .023) and ictal laughing was more common in the favorable outcome group (28.6% vs 0%, p = .006).
3.3. Treatments
The numbers of patients using various antiseizure medications (ASMs) and other treatment modalities, and the effectiveness rates are shown in Figure 1. The frequently used ASMs (n > 20) were valproate (VPA), carbamazepine (CBZ), phenytoin (PHT), LTG, zonisamide (ZNS), clobazam (CLB), and levetiracetam (LEV). Drugs with the highest effectiveness rates (effectiveness ≥30%) were VPA, PHT, LTG, mexiletine, dipotassium clorazepate, and rufinamide (RUF).
FIGURE 1.
Effectiveness rates of various treatments for seizure control. The data are sorted by the number of patients treated, except for surgical procedures, which are grouped separately. The number at the top of the bar denotes the number of patients who received the treatment, and the number at the bottom of the yellow bar shows the effectiveness rate. AZA, acetazolamide; CBZ, carbamazepine; CC, corpus callosotomy; CLB, clobazam; CZP, clonazepam; DZP, diazepam; ESM, ethosuximide; GBP, gabapentin; LCM, lacosamide; LEV, levetiracetam; LTG, lamotrigine; MST, multiple subpial transection; NZP, nitrazepam; OXC, oxcarbazepine; PB, phenobarbital; PER, perampanel; PHT, phenytoin; PRM, primidone; RUF, rufinamide; SLT, sulthiame; TPM, topiramate; VNS, vagus nerve stimulation; VPA, valproate; ZNS, zonisamide.
When the relationship between seizure outcome and drugs used by ≥10 patients was analyzed, only LTG was significantly more frequently used in the favorable seizure outcome group (78.6% vs 45.5%, p = .037). The ASM regimens at the last follow‐up are shown in Data S3. Multivariate analysis using seizure outcome as the dependent variable, and age at last follow‐up, sex, mosaicism rate, and LTG use as independent variables identified lower mosaicism rate (β = −0.11, odds ratio [OR] = 0.90, 95% confidence interval [CI] = 0.82–0.97, p = .010), and higher frequency of LTG use (β = 2.9, OR = 17.8, 95% CI = 1.9–164.5, p = .011) as independent factors significantly associated with favorable seizure outcome. Sex (β = −0.97, OR = 0.38, 95% CI = 0.059–2.4, p = .31), and age at last follow‐up (β = −0.064, OR = 0.94, 95% CI = 0.86–1.02, p = .15) were not significant factors.
3.4. Social outcomes
Social outcomes are shown in Table 3. The subgroup of adults (18 years and older, n = 30) 19 were female (63.3%) and 11 were male (36.7%). Mean age at seizure onset was 8.1 ± 4.1 years, and median age at the last follow‐up was 29.5 (IQR 24–40) years. Mosaicism rate was 29.4 ± 24.0% (n = 29), and IQ was 67.1 ± 17.7 (n = 25). Nine patients (30.0%) were in the favorable seizure outcome group, and 21 (70.0%) were in the poor seizure outcome group. The demographic and clinical data of the adult subgroup were similar to the overall group.
TABLE 3.
Social outcomes.
| n (%) | |
|---|---|
| Education (all patients, n = 47) | |
| Regular class | 26 (55.3) a |
| Special class or school for handicapped | 21 (44.7) a |
| Graduated from college/university (adults, n = 30) | 7 (23.3) |
| Employment status (adults, n = 30) | |
| Employed | 7 (23.3) |
| Employed but left the job | 5 (16.7) |
| Employed as disabled | 3 (10.0) |
| Employment support | 6 (20.0) |
| College/university student | 3 (10.0) |
| No employment history | 6 (20.0) |
| Residence status (adults, n = 30) | |
| Living with family | 25 (83.3) |
| Living alone | 3 (10.0) |
| Institutionalized | 2 (6.7) |
| Marital status (adults, n = 30) | |
| Married | 2 (6.7) |
| History of childbirth (adult female, n = 19) | |
| Childbirth | 1 (5.3) |
| Driver's license (adults, n = 30) | |
| Obtained license | 1 (3.3) |
Note: None of the patients living with their families were married or living with their spouses or children. One woman experienced childbirth two times, and her two children had no known history of epilepsy and chromosomal abnormality. None of the men had children. One patient who had a driver's license had uncontrolled disabling seizures and had not been diagnosed with ring chromosome 20 syndrome at the time of license renewal. This person did not drive.
School‐aged children are defined as from 6 years to 18 years. Adults are defined as age 18 years and older in this study.
Regarding education, 26 (55.3%) of all patients attended regular classes in mainstream schools. In the adult subgroup, 7 (23.3%) of 30 patients had graduated from college or university, and 3 (10%) were college or university students. Among adults, a history of regular employment was found in 12 patients (40%), but only 7 (23.3%) were continuously employed at the last follow‐up. As for residential status, 25 (83.3%) of the adult patients were living with family members. Two (7%) were married.
4. DISCUSSION
We performed a retrospective study of seizure outcome, as well as developmental, cognitive, and social outcomes in a large cohort of 47 patients with r20. Based on a unique seizure outcome classification tailored to r20, 30% of the patients were classified in the favorable seizure outcome group. Favorable outcome was associated with lower rate of mosaicism and higher rate of LTG use. This study also investigated comorbidities, seizure types and semiology, efficacy rates of various ASMs, and social outcomes of r20, providing new data on the clinical profile and treatment of r20, as well as presenting hopes and challenges for the patients.
4.1. Seizure outcome
The present study showed that seizures that interfere with daily life were largely controlled in ~30% of patients. In the study of Vignoli et al., 6 which analyzed a total of 99 patients with r20 and epilepsy, including 24 patients from their cohort and 75 from their literature review, 9 patients (9.1%) were reported to respond to drug treatment. Although our seizure outcome classification differs from theirs, and the numerical results of the two studies cannot be compared directly, our finding that 30% of the patients had a favorable seizure outcome (seizures with no or minimal disruption of daily life) is clinically meaningful. This information may also give more hope to patients with r20, their families, and the health care providers who support them, than just knowing that complete seizure control is difficult. Among the various ASMs, only LTG use was significantly associated with favorable seizure outcome, and this is important when recommending ASM for r20.
Other factors shown to be associated with seizure outcome were ASM‐induced psychiatric symptoms, NCSE with myoclonic component, and laughter during seizures. Regarding ASM‐induced psychiatric symptoms, LEV, ethosuximide (ESM), and gabapentin (GBP) were the causative agents used in the favorable outcome group (Table 1). Because LTG was frequently used in the same period as GBP and LEV (GBP, LTG, and LEV were launched in 2006, 2008, and 2010, respectively), use of LEV and GBP is probably the confounding factor for the association of ASM‐induced psychiatric symptoms with favorable seizure outcome identified by the univariate analysis. The association between NCSE with myoclonic component and poor seizure outcome may be related to the difference in percent mosaicism. A comparison of 20 patients having NCSE with myoclonic component vs 23 without myoclonic component (only patients with known mosaicism rate included) showed a percent mosaicism of 41.8 ± 22.2% vs 24.4 ± 22.4% (p = .015), with a significantly higher mosaicism rate in NCSE with myoclonic component. Dimova et al. 13 reported a case of ictal laughing in r20. Their patient had relatively mild disease with epilepsy onset at age 9 years, IQ of 88, and mosaic rate of 25%. Comparing our 4 patients with and 39 without ictal laughing, the mosaic rate was 20.8 ± 13.8 vs 33.7 ± 24.3% (p = .16), with no significant difference. However, the mosaic rate tended to be lower in patients with ictal laughing. Future verification is needed because the present study may be underpowered because of the limited sample size.
In univariate analysis, there were significantly more female patients in the poor seizure outcome group. In our cohort, the age at disease onset was 8.5 ± 3.7 years for male and 6.9 ± 3.6 years for female patients (p = .165), and the mosaic rate was 25.8 ± 20.1% in male and 36.8 ± 25.2% in female patients (p = .14). Although there were no significant differences in both comparisons, female patients tended to be younger at disease onset and have higher mosaic rate. The larger number of women with severe disease may have affected the outcome. There was no significant sex difference in LTG use (53.3% in female vs 58.8% in male patients, p = .72) and in VPA use (86.7% in female vs 94.1% in male patients, p = .64).
4.2. Effectiveness of ASMs for r20
Lamotrigine was effective in ~70% of the patients, suggesting that it is more effective than other ASMs and non‐medical treatment modalities (Figure 1). However, due to the limited sample size and the problem of multiple comparisons, statistical comparisons were not performed. Of the 26 patients who received LTG, 11 (42.3%) had a favorable seizure outcome, and of the 21 patients who did not receive LTG, 3 (14.3%) had a favorable seizure outcome. Of the 24 patients with known mosaicism and a history of LTG use, the mosaicism rate was 41.8 ± 33.8% in the LTG ineffective group (n = 6), and 35.9 ± 25.2% in the effective group (n = 18), with no statistically significant difference between the two groups (p = .71). These results suggest that the mosaic rate is not significantly lower in patients who responded to LTG.
VPA was also effective in ~40% of the patients. Although the effectiveness of LTG and VPA has been reported in the past, 5 , 6 this study provides quantitative evidence for the effectiveness of these ASMs in a large cohort of r20 patients is of clinical importance. There are case reports of anecdotal success of ASMs such as GBP, 14 ZNS,15 and perampanel (PER), 16 but the efficacy rates of these agents were not high in our study. Publication bias is a limitation of case reports, indicating the need for more reliable data. A prospective, randomized, controlled trial would be ideal to provide better evidence, but it is not feasible given the rarity of r20.
Looking at the overall picture of ASM efficacy, excluding VPA, sodium channel blockers appear to be more effective than agents with other mechanisms of action. On the other hand, drugs with unique mechanisms of action, such as ZNS, topiramate, LEV, PER, and GBP, appear to have lower efficacy rates. These findings are interesting and may be helpful for drug selection.
4.3. Social outcomes
The fact that more than one‐half of the patients continued to attend regular classes in mainstream schools may imply that the majority of patients with r20 do not exhibit regression, and that seizures may be relatively acceptable in school life.
In the adult subgroup (n = 30), seven patients had graduated from mainstream university, college, or vocational school, and three were still in college. One‐third of the patients had access to higher education, which may not be sufficient but may offer some hope to the patients and their families who do not have such information and were simply told that the patients have an intractable disease. Driving, employment, and independence are the major concerns of patients with epileptic seizures. 17 In the adult subgroup, 12 patients (40%) were able to find regular employment at least once, but 5 (41.7%) subsequently left for some reasons and were unable to return to work, indicating both opportunities and challenges with regard to employment for patients with r20. In addition, only three patients (10%) lived alone and one (3.3%) obtained a driver's license. Despite that ~30% of the patients with r20 have a favorable seizure outcome, these patients are significantly constrained in terms of employment and independent living.
Two patients (6.7%) were married. The median age at the last follow‐up was 29.5 years in the adult subgroup. When compared with the marriage rate of 27.4% in the 25‐ to 29‐year age group in the general Japanese population according to the Japanese 2020 census, 18 the marriage rate among patients with r20 was markedly low. Although low marriage rates among patients with epilepsy have been reported in many countries 19 , 20 , 21 , 22 and there are reports indicating that seizure control rate and seizure type may not affect marital status, 22 , 23 , 24 the low marriage rate in this study was striking.
It is conceivable that in r20 patients, in addition to seizures, comorbidities such as intellectual disabilities, developmental disorders, and psychiatric symptoms may affect employment and independence, including marital prospects. To reduce social constraints, non‐ASM treatments such as psychological treatment, rehabilitation, education, and social support, as well as a multidisciplinary approach, are needed.
4.4. Limitations
One of the limitations of this study is that it is a single‐center, retrospective study, which may bias the patient population and treatment. Furthermore, our hospital functions as a quaternary epilepsy center 25 and receives referrals of refractory patients. However, the mosaicism rate (correlates with epilepsy severity and outcome) of our cohort was within the range reported by Vignoli et al. 6 for their cohort (n = 25) and their literature review (n = 75), suggesting that the severity of epilepsy in our cohort may not be greatly different from that in cohorts from other facilities, probably reflecting no marked selection bias. Another limitation is that the information was collected from medical records, which may introduce information bias. In particular, the frequency of each clinical variable may be underestimated. The seizure outcome classification in this study did not include outcomes that may affect the patient's quality of life and disease burden, such as the risk of sudden unexpected death in epilepsy (SUDEP), adverse effects of medications, comorbidities, impact of disease and/or ASMs on childbearing, and financial costs. These non‐seizure outcomes are also targets of comprehensive epilepsy care and need to be considered in clinical practice. The clinical data do not necessarily reflect the changes and advances in medicine up to the present day. For example, LTG was launched in Japan in 2008, with a tendency that fewer older patients had a history of use. The concept of neurodevelopmental disorders, represented by autistic spectrum disorders, has become more recognized over time 26 ; the diagnostic criteria have also evolved, and more patients are diagnosed with these disorders in recent years due to a variety of factors. Therefore, older patients may be underdiagnosed. Nonetheless, the fact that this study provides novel evidence on treatment, seizures, and social outcomes of r20 patients is meaningful for patients, caregivers, and health care providers.
5. CONCLUSION
This largest cohort study to date reveals detailed seizure outcome, treatment response, comorbidities, and social outcomes in the long term for r20. In ~30% of the patients, seizures became minimally disruptive to daily life, and this favorable outcome was significantly associated with LTG use as a modifiable factor. This is a hopeful result for patients with r20, whose prognosis has been, until now, considered as unclear or emphasized as intractable. Social constraints such as employment, residence status, and marriage are obvious, reiterating the need for comprehensive care including multidisciplinary approach for comorbidities.
AUTHOR CONTRIBUTIONS
Kentaro Tokumoto had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: all authors. Acquisition, analysis, or interpretation of data: all authors. Drafting of the manuscript: Kentaro Tokumoto and Yushi Inoue. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: Kentaro Tokumoto. Administrative, technical, or material support: Yushi Inoue. Study supervision: Kentaro Tokumoto and Yushi Inoue.
FUNDING INFORMATION
This work was supported by Ministry of Health, Labour and Welfare Research Program on Rare and Intractable Diseases (grant number JPMH23FC1013).
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
ETHICS STATEMENT
The study protocol was approved by the ethics committee of NHO Shizuoka Institute of Epilepsy and Neurological Disorders (No. 2023‐30).
Supporting information
Data S1–S5.
ACKNOWLEDGMENTS
The authors would like to acknowledge the cooperation of the patients and their parents/caregivers who participated in the study. We also thank the medical staff of Shizuoka Institute of Epilepsy and Neurological Disorders.
Tokumoto K, Nishida T, Ikeda H, Ikeda H, Kawaguchi N, Mizutani S, et al. Long‐term seizure and psychosocial outcomes of patients with ring chromosome 20 syndrome: A cohort study of 47 cases. Epilepsia. 2025;66:2444–2453. 10.1111/epi.18370
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1–S5.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author on reasonable request.