Neurology
Tuberous Sclerosis Complex
Importance of Early Diagnosis in the Management of Tuberous Sclerosis Complex
Overview
The early identification of tuberous sclerosis complex (TSC) allows for the early implementation of interventions and careful monitoring that may help curtail the long-term impact of the disease. In children with TSC, epilepsy and developmental delays are key concerns.
Expert Commentary
Elizabeth A. Thiele, MD, PhD
|
|
“The TSC medical and patient communities feel very strongly that the earlier we can identify patients as having TSC, the greater the impact we can have on their lives and futures, potentially minimizing many aspects of the disorder.”
Over the past 10 to 15 years, our knowledge of TSC and its treatment have grown considerably. Epilepsy is the most common neurologic manifestation of TSC, affecting approximately 90% of patients, and the onset of epilepsy in the majority of individuals with TSC occurs before the age of 2 years, which is a critical time in neurodevelopment. Studies have shown that seizures are a significant variable in other comorbidities of TSC, including cognitive impairment, autism, and other neuropsychiatric disorders. The TSC medical and patient communities feel very strongly that the earlier we can identify patients as having TSC, the greater the impact we can have on their lives and futures, potentially minimizing many aspects of the disorder.
We have studied missed opportunities for diagnosis, and, historically, these have included young children with seizures who presented before the widespread availability of magnetic resonance imaging, at a time when there was not as much knowledge about TSC, and so the diagnosis was not made. Although the early diagnosis of TSC has improved, we still see patients today in our clinic who have lived for decades with TSC without knowing it and without it being diagnosed until something potentially catastrophic occurs. This may arise even in someone who did not have the significant onset of seizures in childhood. For example, a previously undiagnosed adult might have the onset of severe lower back pain from a renal angiomyolipoma rupture, and hemorrhage due to such a rupture may be serious and life threatening. Therefore, knowing that a patient has TSC allows us to help make sure that they stay healthy by monitoring kidney, lung, and other possible organ involvement.
Important considerations in making early diagnoses include having an index of suspicion based on a patient's family history of TSC. In addition, some of the earliest diagnoses of TSC may occur as a result of the detection of cardiac rhabdomyomas, which may be identified during a late-gestation fetal ultrasound. If TSC is suspected, prenatal brain magnetic resonance imaging to look for tubers and genetic testing can be performed.
Genetic testing has had a huge impact on the diagnosis of TSC. There is a program in pediatric epilepsy called Behind the Seizure that facilitates free genetic testing for any child who is under 8 years old who has experienced an unprovoked seizure. This program, in particular, has had a significant effect on the early diagnosis of TSC and other rare disorders.
References
Davis PE, Filip-Dhima R, Sideridis G, et al; Tuberous Sclerosis Complex Autism Center of Excellence Research Network. Presentation and diagnosis of tuberous sclerosis complex in infants. Pediatrics. 2017;140(6):e20164040. doi:10.1542/peds.2016-4040
De Ridder J, Verhelle B, Vervisch J, et al; EPISTOP Consortium. Early epileptiform EEG activity in infants with tuberous sclerosis complex predicts epilepsy and neurodevelopmental outcomes. Epilepsia. 2021;62(5):1208-1219. doi:10.1111/epi.16892
French JA, Lawson JA, Yapici Z, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388(10056):2153-2163. doi:10.1016/S0140-6736(16)31419-2
Hatano T, Egawa S. Renal angiomyolipoma with tuberous sclerosis complex: how it differs from sporadic angiomyolipoma in both management and care. Asian J Surg. 2020;43(10):967-972. doi:10.1016/j.asjsur.2019.12.008
Hulshof HM, Kuijf HJ, Kotulska K, et al; EPISTOP Consortium. Association of early MRI characteristics with subsequent epilepsy and neurodevelopmental outcomes in children with tuberous sclerosis complex. Neurology. 2022;98(12):e1216-e1225. doi:10.1212/WNL.0000000000200027
Invitae. Behind the Seizure. Accessed April 20, 2022. https://www.invitae.com/en/behindtheseizure/
Northrup H, Aronow ME, Bebin EM, et al; International Tuberous Sclerosis Complex Consensus Group. Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatr Neurol. 2021;123:50-66. doi:10.1016/j.pediatrneurol.2021.07.011
Nouri NM, Zak M, Jain P, Whitney R. Epilepsy management in tuberous sclerosis complex: existing and evolving therapies and future considerations. Pediatr Neurol. 2022;126:11-19. doi:10.1016/j.pediatrneurol.2021.09.017
Slowinska M, Jozwiak S, Peron A, et al. Early diagnosis of tuberous sclerosis complex: a race against time. How to make the diagnosis before seizures? Orphanet J Rare Dis. 2018;13(1):25. doi:10.1186/s13023-018-0764-z