Sporadic subependymal giant cell astrocytoma with somatic TSC2 mutation: A case report.

Subependymal giant cell astrocytoma (SEGA) is a rare circumscribed astrocytic glioma that occurs in approximately 25% of all tuberous sclerosis (TSC) cases. Herein, we discuss an atypical presentation of SEGA, including the genetic alterations, impact on clinical presentation, and the determinants of each medical and surgical treatment option. A 14-year-old girl presented with intermittent headache and a right intraventricular mass originating near the foramen of Monro. The tumor's proximity to critical structures necessitated maximum safe resection, which improved her symptoms. Histological findings indicated SEGA, and genetic sequencing revealed a TSC2 mutation. However, complete clinical and radiological evaluations failed to reveal TSC. Two months later, a new subependymal nodule was incidentally found. She had a recurrent left occipital horn lesion and diffuse smooth leptomeningeal enhancement with no spine drop metastases. She was administered everolimus as the tumor was considered unresectable. Subsequent imaging revealed a reduction in both residual and new lesions.

Follow-up report of fundus findings of tuberous sclerosis-associated retinal astrocytoma of two siblings.

A late adolescent with tuberous sclerosis (TS) presented with reduced vision in one eye to our tertiary care university hospital 4 years ago. Fundus examination revealed multiple retinal astrocytic hamartomas (RAHs) in both eyes. His younger sibling, who also had TS, was found to have RAH on retinal screening. The swept-source optical coherence tomography (SS-OCT) findings were typical of RAH. We further noted that some of the RAH lesions showed segmental whitening of the outer walls of the arterioles, which traversed through them. The segmental whitening may suggest the enveloping of normal retinal vessels by the tumour. En-face and B-scan SS-OCT angiography of patients with TS showed vascularity within the tumour. The vessels within the tumour appeared to be in continuity with the retinal vasculature. Both siblings were reviewed annually. At the end of 4 years, there was no change in visual acuity, tumour size, number, vascularity and behaviour.

Malignant tumors in tuberous sclerosis complex: a case report and review of the literature.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disease that arises from TSC1 or TSC2 genetic mutations. These genetic mutations can induce the development of benign tumors in any organ system with significant clinical implications in morbidity and mortality. In rare instances, patients with TSC can have malignant tumors, including renal cell carcinoma (RCC) and pancreatic neuroendocrine tumor (PNET). It is considered a hereditary renal cancer syndrome despite the low incidence of RCC in TSC patients. TSC is typically diagnosed in prenatal and pediatric patients and frequently associated with neurocognitive disorders and seizures, which are often experienced early in life. However, penetrance and expressivity of TSC mutations are highly variable. Herein, we present a case report, with associated literature, to highlight that there exist undiagnosed adult patients with less penetrant features, whose clinical presentation may contain non-classical signs and symptoms, who have pathogenic TSC mutations. CASE PRESENTATION: A 31-year-old female with past medical history of leiomyomas status post myomectomy presented to the emergency department for a hemorrhagic adnexal cyst. Imaging incidentally identified a renal mass suspicious for RCC. Out of concern for hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome, the mass was surgically removed and confirmed as RCC. Discussion with medical genetics ascertained a family history of kidney cancer and nephrectomy procedures and a patient history of ungual fibromas on the toes. Genetic testing for hereditary kidney cancer revealed a 5'UTR deletion in the TSC1 gene, leading to a diagnosis of TSC. Following the diagnosis, dermatology found benign skin findings consistent with TSC. About six months after the incidental finding of RCC, a PNET in the pancreatic body/tail was incidentally found on chest CT imaging, which was removed and determined to be a well-differentiated PNET. Later, a brain MRI revealed two small cortical tubers, one in each frontal lobe, that were asymptomatic; the patient's history and family history did not contain seizures or learning delays. The patient presently shows no evidence of recurrence or metastatic disease, and no additional malignant tumors have been identified. CONCLUSIONS: To our knowledge, this is the first report in the literature of a TSC patient without a history of neurocognitive disorders with RCC and PNET, both independently rare occurrences in TSC. The patient had a strong family history of renal disease, including RCC, and had several other clinical manifestations of TSC, including skin and brain findings. The incidental finding and surgical removal of RCC prompted the genetic evaluation and diagnosis of TSC, leading to a comparably late diagnosis for this patient. Reporting the broad spectrum of disease for TSC, including more malignant phenotypes such as the one seen in our patient, can help healthcare providers better identify patients who need genetic evaluation and additional medical care.

Review of the spectrum of tuberous sclerosis complex: The Saudi Arabian Experience.

OBJECTIVES: To determine the prevalence of tuberous sclerosis complex (TSC) in the paediatric Saudi population and to characterise the range of clinical symptoms, neurocutaneous findings, neuroimaging results, and complications of the disease. METHODS: A total of 61 genetically confirmed TSC patients from the National Guard Health Affairs (NGHA) in Saudi Arabia were the subject of this retrospective descriptive analysis. The data were presented using descriptive measures. RESULTS: The mean age at diagnosis was found to be 4.9 years. Subependymal nodules (86.9%), numerous cortical tubers and/or radial migration lines (63.9%), and hypomelanotic macules (63.9%) were the 3 most common significant criteria. The vast majority (86.9%) of those diagnosed had epilepsy, of which 50% were considered medically intractable. Nearly half of our subjects underwent genetic testing, which revealed that TSC2 predominated over TSC1. Symptoms of Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders (TAND) were present in 66.7% of TSC1 patients and 73.9% of TSC2 patients. CONCLUSION: The findings of this study demonstrate that the clinical spectrum of TSC among Saudi children is consistent with the body of existing literature. The TSC2 was more prevalent than TSC1. The most frequent signs were cutaneous and neurological. Monitoring TSC patients regularly is crucial to identify any issues as soon as possible.

Kidney transplantation in patients with tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is a disorder of the mammalian target of the rapamycin (mTOR) pathway associated with the development of multisystem tumors, including renal angiomyolipoma (AML). These renal tumors are benign by nature but locally invasive and carry a risk for the progression of chronic kidney disease (CKD) to end stage kidney disease (ESKD). The frequency of subsequent renal transplantation in this population is largely uncharacterized, although single-center data suggests that 5%-15% of adult TSC patients are kidney transplant recipients. METHODS: This retrospective cohort study utilized United Network for Organ Sharing (UNOS) data. We included candidates waitlisted between 1987 and 2020 for a first kidney transplant with TSC-associated kidney failure. We utilized descriptive statistics to characterize the frequency of first-time kidney transplant waitlisting and transplantation among persons with TSC and the Fine-Gray subdistribution hazard model to evaluate characteristics associated with progression from waitlist. RESULTS: We identified 200 TSC-associated kidney failure patients within the waitlist cohort. Of these, 12 were pediatric patients. Two-thirds (N = 134) of waitlisted persons were female. One hundred forty patients received a transplant with a median waitlist time of 2 years. Younger age at waitlisting was associated with a greater probability of progressing to transplant (HR 0.98 [95% CI: 0.96-0.99]). 91.8% of kidney transplant recipients survived 1-year post-transplant with a functioning allograft. CONCLUSIONS: The majority of patients with TSC who are waitlisted for a kidney transplant progress onto transplantation with excellent 1-year post transplant patient and allograft survival.

Exploring an objective measure of overactivity in children with rare genetic syndromes.

BACKGROUND: Overactivity is prevalent in several rare genetic neurodevelopmental syndromes, including Smith-Magenis syndrome, Angelman syndrome, and tuberous sclerosis complex, although has been predominantly assessed using questionnaire techniques. Threats to the precision and validity of questionnaire data may undermine existing insights into this behaviour. Previous research indicates objective measures, namely actigraphy, can effectively differentiate non-overactive children from those with attention-deficit hyperactivity disorder. This study is the first to examine the sensitivity of actigraphy to overactivity across rare genetic syndromes associated with intellectual disability, through comparisons with typically-developing peers and questionnaire overactivity estimates. METHODS: A secondary analysis of actigraphy data and overactivity estimates from The Activity Questionnaire (TAQ) was conducted for children aged 4-15 years with Smith-Magenis syndrome (N=20), Angelman syndrome (N=26), tuberous sclerosis complex (N=16), and typically-developing children (N=61). Actigraphy data were summarized using the M10 non-parametric circadian rhythm variable, and 24-hour activity profiles were modelled via functional linear modelling. Associations between actigraphy data and TAQ overactivity estimates were explored. Differences in actigraphy-defined activity were also examined between syndrome and typically-developing groups, and between children with high and low TAQ overactivity scores within syndromes. RESULTS: M10 and TAQ overactivity scores were strongly positively correlated for children with Angelman syndrome and Smith-Magenis syndrome. M10 did not substantially differ between the syndrome and typically-developing groups. Higher early morning activity and lower evening activity was observed across all syndrome groups relative to typically-developing peers. High and low TAQ group comparisons revealed syndrome-specific profiles of overactivity, persisting throughout the day in Angelman syndrome, occurring during the early morning and early afternoon in Smith-Magenis syndrome, and manifesting briefly in the evening in tuberous sclerosis complex. DISCUSSION: These findings provide some support for the sensitivity of actigraphy to overactivity in children with rare genetic syndromes, and offer syndrome-specific temporal descriptions of overactivity. The findings advance existing descriptions of overactivity, provided by questionnaire techniques, in children with rare genetic syndromes and have implications for the measurement of overactivity. Future studies should examine the impact of syndrome-related characteristics on actigraphy-defined activity and overactivity estimates from actigraphy and questionnaire techniques.

Measurement of Developmental and Behavioral Concerns in Toddlers With Tuberous Sclerosis Complex.

BACKGROUND: The TAND (Tuberous Sclerosis Complex [TSC]-Associated Neuropsychiatric Disorders) Checklist was developed as a clinical screener for neurodevelopmental disorders in TSC. Most studies have described patterns in older children and adults. This study sought to better understand behavioral concerns as measured by the TAND Checklist in young children with TSC. METHODS: We examined patterns of caregiver responses to the TAND Checklist in 90 toddlers with TSC (12 to 23 months n = 60; 24 to 36 months n = 30) through data collected during baseline visits across two TSC early intervention studies. RESULTS: Over 90% of caregivers reported at least one behavioral concern related to TAND. The number of concerns increased with age. Delayed language was the most frequently reported concern across ages (12 to 23 months: 58.3%, 24 to 36 months: 86.7%). Questions related to behavioral concerns were largely relevant in this age range, but questions in other areas, such as neuropsychological or academic function, were not. CONCLUSIONS: TAND symptoms are very common in toddlers with TSC, and these symptoms may increase with age. The TAND Checklist is a useful tool for identifying behavioral concerns efficiently, but several items and sections are not suited to younger children. Results support the development of an abbreviated form of the TAND Checklist for toddlers.

Clinical practice recommendations for kidney involvement in tuberous sclerosis complex: a consensus statement by the ERKNet Working Group for Autosomal Dominant Structural Kidney Disorders and the ERA Genes & Kidney Working Group.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the presence of proliferative lesions throughout the body. Management of TSC is challenging because patients have a multifaceted systemic illness with prominent neurological and developmental impact as well as potentially severe kidney, heart and lung phenotypes; however, every organ system can be involved. Adequate care for patients with TSC requires a coordinated effort involving a multidisciplinary team of clinicians and support staff. This clinical practice recommendation was developed by nephrologists, urologists, paediatric radiologists, interventional radiologists, geneticists, pathologists, and patient and family group representatives, with a focus on TSC-associated kidney manifestations. Careful monitoring of kidney function and assessment of kidney structural lesions by imaging enable early interventions that can preserve kidney function through targeted approaches. Here, we summarize the current evidence and present recommendations for the multidisciplinary management of kidney involvement in TSC.

Lymphangioleiomyomatosis in patients with tuberous sclerosis: a national centre audit.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is common in tuberous sclerosis complex (TSC) yet under recognised with management mostly based upon evidence obtained from patients with sporadic LAM. We performed a prospective audit of patients with TSC-LAM attending a national referral centre to inform management guidelines. METHODS: The UK LAM Centre was established in 2011 and conducts a prospective audit of pre-defined quality outcomes for all subjects. Audit data are reported on all patients with TSC-LAM and a comparator population of patients with sporadic LAM. RESULTS: Between 2011 and 2022, 73 patients were seen with TSC-LAM. All were women with a mean (SD) age of 39 (12) years. Referral rates were similar over the study period including after the introduction of CT screening. Median age of diagnosis with TSC was 11 years (range 0-70) with one third diagnosed with TSC as adults. Compared with all TSC patients in the 'TOSCA' registry, TSC-LAM patients tended to have been diagnosed with TSC at an older age, had fewer neuro-cognitive manifestations and were more likely to have angiomyolipoma. The most common presentations of TSC-LAM were following workup for angiomyolipoma, pneumothorax or dyspnoea with only one fifth detected after CT screening. Baseline FEV1 and DLCO at first assessment were reduced to 77 and 63% predicted respectively and were similar to patients with sporadic LAM. During follow-up, FEV1 fell by a mean of 81 ml/year and DLCO fell by 0.309 mmol/ml/kPa/year in patients not being treated with an mTOR inhibitor. 55% required treatment with either sirolimus or Everolimus for LAM or angiomyolipoma respectively. For those treated with an mTOR inhibitor, mean FEV1 fell by 3 ml/year and DLCO increased by 0.032 mmol/ml/kPa/year and was similar to sporadic LAM. Risk of death due to LAM or need for lung transplant in patients with TSC-LAM was 0.67%/year. CONCLUSIONS: Despite screening recommendations, LAM is often diagnosed in TSC after symptoms develop which may delay treatment. Complications including pneumothorax and loss of lung function are significant and similar to sporadic LAM. Work is needed to implement the recommended CT screening for LAM and improve respiratory care for TSC-LAM.

Tuberous sclerosis complex in adulthood: focus on epilepsy prognosis.

OBJECTIVE: Typically diagnosed in early childhood or adolescence, TSC is a chronic, multisystemic disorder with age-dependent manifestations posing a challenge for transition and for specific surveillance throughout the lifetime. Data on the clinical features and severity of TSC in adults and on the prognosis of epilepsy are scarce. We analyzed the clinical and genetic features of a cohort of adult patients with TSC, to identify the prognostic predictors of seizure remission after a long follow-up. METHOD: We conducted a retrospective analysis of patients diagnosed with TSC according to the updated international diagnostic criteria. Pearson's chi-square or Fisher's exact test and Mann Whitney U test were used to compare variables among the Remission (R) and Non-Remission (NR) group. Univariate and multivariate logistic regression analyses were performed. RESULTS: We selected 43 patients with TSC and neurological involvement in terms of epilepsy and/or brain lesions, attending the Epilepsy Center of our Institute: of them, 16 (37.2%) were transitioning from the pediatric care and 6 (13.9%) were referred by other specialists. Multiorgan involvement includes cutaneous (86.0%), nephrological (70.7%), hepatic (40.0%), ocular (34.3%), pneumological (28.6%) and cardiac (26.3%) manifestations. Thirty-nine patients (90.7 %) had epilepsy. The mean age at seizure onset was 4 ± 7.3 years: most patients (29, 76.3 %) presented with focal seizures or spasms by age 3 years; only 2 (5.3 %) had seizure onset in adulthood. Twenty-seven patients (69.2 %) experienced multiple seizure types overtime, 23 (59.0 %) had intellectual disability (ID). At last assessment, 14 (35.9 %) were seizure free (R group) and 25 (64.1 %) had drug-resistant seizures (NR group). At logistic regression univariate analysis, ID (OR 7.9, 95 % CI 1.8--34.7), multiple seizure types lifelong (OR 13.2, 95 % CI 2.6- 67.2), spasms/tonic seizures at presentation (OR 6.5, 95 % CI 1.2--35.2), a higher seizure frequency at onset (OR 5.4, 95 % CI 1.2--24.3), abnormal neurological examination (OR 9.8, 95 % CI 1.1--90.6) and pathogenic variants in TSC2 (OR 5.4, 95 % CI 1.2--24.5) were significantly associated with non-remission. In the multivariate analysis, both ID and multiple seizure types lifelong were confirmed as independent predictors of poor seizure outcome. CONCLUSIONS: In our cohort of adult patients with TSC, epilepsy remains one of the main neurological challenges with only 5.3% of cases manifesting in adulthood. Approximately 64% of these patients failed to achieve seizure remission. ID and multiple seizure types were the main predictors of poor outcome. Nephrological manifestations require continuous specific follow-up in adults.

The effect of pregnancy on renal angiomyolipoma; a world of knowledge to gain, specifically in women with TSC.

BACKGROUND: Women are counseled preconceptionally about the potential risks of rAML progression and chance of complications during and due to pregnancy. However, a systematic search investigating the evidence on which this advice is based does not exist. The aim of this systematic review is to determine the effect of pregnancy on renal angiomyolipoma (rAML) size and risk of haemorrhage in patients with tuberous sclerosis complex (TSC). METHODS: We searched PubMed, EMBASE, Medline and ClinicalTrials.gov using terms for "renal angiomyolipoma" and "pregnancy". English-language articles published between January 1st 2000, and December 31st 2020 of which full-text was available were included. The initial search resulted in 176 articles. After the screening process we included 45 case reports and 1 retrospective study. For the retrospective study we assessed the risk of bias using the Newcastle-Ottawa Scale. We included articles about renal AML and pregnancy with and without an established diagnosis of TSC. From these articles we recorded the rAML sizes and rAML complications. RESULTS: Seven case reports, from a total of 45 case reports, provided follow-up data on renal AML size (these were all cases of renal AML without a known diagnosis of TSC). Of these cases, renal AML size decreased in one patient, was stable in one patient, increased in three patients and fluctuated in two others. Renal AML size of women who suffered a haemorrhage were significantly larger (12.1 ± 4.6 cm) than rAMLs of women who did not suffer a haemorrhage (8.3 ± 3.2 cm). Data from the retrospective study showed no difference in renal complications between the women with and without a history of pregnancy. Haemorrhage occurred in 30% of the women with a history of pregnancy (n = 20) and in 11% in the patients without a history of pregnancy (n = 2), however this retrospective study had methodological limitations. CONCLUSION: The effect of pregnancy on renal AML size and complications in patients with TSC is unclear. More research is needed to determine the risk of pregnancy on TSC-associated kidney disease in TSC patient.

Patients' and physicians' awareness of clinical symptoms and disease severity in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a rare inherited disease with the potential to affect virtually every organ system. Clinical presentation is age- and partly sex-dependent and varies broadly with respect to disease manifestations including treatment-refractory epilepsy, intellectual disability and TSC-associated neuropsychiatric disorders, chronic kidney disease or progressive lung function decline. Given the complexity of this disease, multidisciplinary care in specialized TSC centres is recommended. We aimed to elucidate the state of knowledge of patients/caregivers and physicians on individual disease manifestations. We further examined whether the association to a TSC centre has an impact on the comprehensive consideration of potential disease manifestations. Therefore, a survey was performed in a cohort of German TSC patients and their physicians. Complete information was available for 94 patients with a median age of 18 years [range 1-55] and a sex distribution of 53.2% (male): 48.8% (female). Using almost identical questionnaires for patients/caregivers and their respective physician, there was a good correlation for disease assessments associated with relevant morbidity and mortality like epilepsy, renal angiomyolipoma, cardiac rhabdomyomas or intellectual disability. Correlation was moderate for several neuropsychiatric disorders and only poor for hypomelanotic macules, dental pits or retinal achromic patches. Estimation of overall disease severity using a numeric rating scale correlated highly significantly (Pearson correlation coefficient = 0.767; p < 0.001) between patients/caregivers and physicians. In general, physicians more likely quoted items as 'unknown' than patients (822 answers vs. 435 answers in the respective groups). Questionnaires completed by physicians who were associated with a specialized TSC centre declared a significantly lower proportion of items as unknown (mean 8.7% vs. 20.5%; p < 0.001). These findings indicate that patients treated by specialized TSC centres seem to obtain a more comprehensive surveillance. Furthermore, it shows that there were reasonable surveillance strategies in general and sufficient patient/caregiver interaction and education in the examined cohort. However, for the most prominent disease characteristics there was a good awareness within both the patients/caregivers and the physicians group.

Giant cell angiofibroma of gingiva in tuberous sclerosis complex: a case report and literature review.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare, complex genetic disorder characterized by hamartomas and neoplastic lesions in various organ systems. With the development of radiology and gene testing, the diagnostic criteria for TSC were updated in 2012 at the International Consensus Conference. Intraoral fibromas have long been associated with TSC. However, the incidence of giant cell angiofibroma (GCA) in TSC patients is extremely rare. Here, we report the first case of GCA in the gingival tissue of a patient with TSC. CASE PRESENTATION: A 41-year-old woman first visited the Department of Oral and Maxillofacial Surgery, Chonnam National University Dental Hospital, complaining of gingival enlargement. Clinical examination revealed several manifestations associated with TSC, including intraoral fibromas, facial angiofibromas, dental enamel pits, ungual fibromas, "confetti" skin lesions, hypomelanotic macules, and a shagreen patch. Intraoral examination revealed a 6.0 × 5.0 cm gingival overgrowth on the left mandible. Surgical excision was performed, and subsequent histopathological examination confirmed the diagnosis of GCA. There was no evidence of recurrence within the 24- months of surgery. CONCLUSIONS: We report the first case of GCA in the gingival tissue of a patient with TSC. This report would contribute to an improved understanding of this rare disease. However, further case reports are necessary to clarify the relationship between GCA and TSC.

Nutritional status as a predictive factor for paediatric tuberous sclerosis complex-associated kidney angiomyolipomas: a retrospective analysis.

The purpose of this study is to determine the predictive factors of tuberous sclerosis complex (TSC)-associated kidney disease and its progression in children. Retrospective review of children with TSC in a tertiary children's hospital was performed. Relevant data were extracted, and Cox proportional hazards regression was used to establish predictors of kidney lesions. Logistic regression was conducted to identify factors predicting chronic kidney disease (CKD) and high-risk angiomyolipomas (above 3 cm). Kidney imaging data were available in 145 children with TSC; of these, 79% (114/145) had abnormal findings. The only significant predictive factor for cyst development was being female (HR = 0.503, 95% CI 0.264-0.956). Being female (HR = 0.505, 95% CI 0.272-0.937) and underweight (HR = 0.092, 95% CI 0.011-0.800) both lowers the risk of having angiomyolipomas, but TSC2 mutations (HR = 2.568, 95% CI 1.101-5.989) and being obese (HR = 2.555, 95%CI 1.243-5.255) increases risks. Ten (12%) of 81 children with kidney function tested demonstrate CKD stages II-V, and only angiomyolipomas above 3 cm predict CKD. Additionally, 13/145 (9%) children had high-risk angiomyolipomas, whereby current age (adjusted odds ratio (aOR) 1.015, 95% CI 1.004-1.026) and being overweight/obese (aOR 7.129, 95% CI 1.940-26.202) were significantly associated with angiomyolipomas above 3 cm. CONCLUSIONS: While gender and genotype are known predictors, this study includes the novel finding of nutritional status as a predictor of TSC-associated kidney disease. This study sheds light on a possible complex interplay of hormonal influences, obesity, and kidney angiomyolipomas growth, and further investigations focusing on the impact of nutritional status on TSC-associated kidney disease are warranted. WHAT IS KNOWN: • Gender and genotype are well-studied predictive factors in TSC kidney disease. WHAT IS NEW: • Nutritional status may influence the development and the progression of kidney lesions in children with TSC and should not be overlooked. • Management guidelines of TSC-associated kidney disease can address nutritional aspects.

A quantitative cross-sectional study of the burden of caring for patients with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex-associated epilepsy in Japan.

INTRODUCTION: Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC)-associated epilepsy are rare conditions associated with severe childhood-onset epilepsy. Caregivers play a critical role in the patients' care and may experience significant psychosocial and socioeconomic burden. This cross-sectional study determined the burden of caring for patients with these rare epilepsy conditions in Japan. METHODS: A quantitative online survey was used to assess patients' and caregivers' characteristics and the caregivers' emotional state, among others. Several validated questionnaires were used: the Hospital Anxiety and Depression Scale (HADS; 0-21 score) assessed the caregivers' emotional wellbeing, the Pediatric Quality of Life Inventory Family Impact Module (PedsQL FIM; 0-100 score) assessed the health-related quality of life (HRQoL) of the caregivers and their families, and the Work Productivity and Activity Impairment General Health (WPAI:GH; 0-100 % score) questionnaire assessed work productivity. RESULTS: A total of 36 caregivers responded (median [interquartile range (IQR)] age 43.5 [39.5, 48.3] years; 33/36 [92 %] female; 13/36 [36 %] working part-time and 13/36 [36 %] not working). Participants cared for 7/36 (19 %), 19/36 (53 %), and 10/36 (28 %) patients with LGS, DS, and TSC, respectively (median [IQR] age, 11.0 [6.8, 16.3] years; age at first seizure, 0 [0, 0] years). Patients received a median (IQR) of 4 (3, 5) treatment drug types. Patients experienced median (IQR) 3.0 (0, 21.0) epileptic seizures in the previous week; 28/36 (78 %) had severe intellectual disabilities, and 34/36 (94 %) had developmental delays. Caregivers reported stress (17/36 [47 %]), sleep problems (13/36 [36 %]), and anxiety (12/36 [33 %]). They spent a median (IQR) of 50.0 (17.5, 70.0) hours caregiving in the previous week, with 3.0 (1.0, 11.0) hours of seizure-specific care. Caregivers reported that their lives would be easier with a median (IQR) of 1.5 (0, 5.0) hours fewer per week caring for patients during/following seizures. Median HADS scores were 9.5 ('suspected anxiety diagnosis') and 7.5 ('no depression') for caregivers, and PedsQL FIM Total median score was 60.1, indicating HRQoL impairment for the caregiver and their family. WPAI:GH scores for paid workers indicated important work impairment. Higher caregiving hours (≥ 21 h vs. < 21 h in the previous week) resulted in higher caregiver burden as indicated by the HADS Total score (p = 0.0062) and PedsQL FIM Total score (p = 0.0007). CONCLUSIONS: Caregivers of patients with LGS, DS, or TSC in Japan experience a significant time burden, reduced HRQoL, and high level of work/activity impairment. Caregivers provide round-the-clock care to patients and rely on family and specialized caring services to help manage the increased caregiving time, which tends to be associated with greater emotional burden and HRQoL impact.

Perampanel for the treatment of epilepsy with genetic aetiology: Real-world evidence from the PERMIT Extension study.

Genetic factors contribute to the aetiology of epilepsy in >50% of cases, and information on the use of antiseizure medications in people with specific aetiologies will help guide treatment decisions. The PERMIT Extension study pooled data from two real-world studies (PERMIT and PROVE) to investigate the effectiveness and safety/tolerability of perampanel (PER) when used to treat people with focal and generalised epilepsy in everyday clinical practice. This post-hoc analysis of PERMIT Extension explored the use of PER when used to treat individuals presumed to have epilepsy with a genetic aetiology. Assessments included retention rate (evaluated at 3, 6 and 12 months), effectiveness (responder and seizure freedom rates; evaluated at 3, 6, 12 months and the last visit [last observation carried forward) and tolerability (adverse events [AEs]). Of the 6822 people with epilepsy included in PERMIT Extension, 1012 were presumed to have a genetic aetiology. The most common genetic aetiologies were idiopathic generalised epilepsy (IGE; 58.2%), tuberous sclerosis (1.1%), Dravet syndrome (0.8%) and genetic epilepsy with febrile seizures plus (GEFS+; 0.5%). Retention rates at 3, 6 and 12 months in the total genetic aetiology population were 89.3%, 79.7% and 65.9%, respectively. In the total genetic aetiology population, responder rates at 12 months and the last visit were 74.8% and 68.3%, respectively, and corresponding seizure freedom rates were 48.9% and 46.5%, respectively. For the specific aetiology subgroups, responder rates at 12 months and the last visit were, respectively: 90.4% and 84.4% (IGE), 100% and 57.1% (tuberous sclerosis), 100% and 71.4% (Dravet syndrome), and 33.3% and 20.0% (GEFS+). Corresponding seizure freedom rates were, respectively: 73.1% and 64.6% (IGE), 33.3% and 22.2% (tuberous sclerosis), 20.0% and 28.6% (Dravet syndrome), and 0% and 0% (GEFS+). The incidence of AEs was 46.5% for the total genetic aetiology population, 48.8% for IGE, 27.3% for tuberous sclerosis, 62.5% for Dravet syndrome, and 20% for GEFS+. Tolerability findings were consistent with PER's known safety profile. PER was effective and generally well tolerated when used in individuals with a presumed genetic epilepsy aetiology in clinical practice. PER was effective across a wide range of genetic aetiologies.