Responding to the Need of the Hour: Natural History Studies

Abstract

Natural History Study of STXBP1-Developmental and Epileptic Encephalopathy Into Adulthood

Stamberger H, Crosiers D, Balagura G, Bonardi CM, Basu A, Cantalupo G, Chiesa V, Christensen J, Bernardina BD, Ellis CA, Furia F, Gardiner F, Giron C, Guerrini R, Klein KM, Korff C, Krijtova H, Leffner M, Lerche H, Lesca G, Lewis-Smith D, Marini C, Marjanovic D, Mazzola L, Ruggiero SM, Mochel F, Ramond F, Reif PS, Richard-Mornas A, Rosenow F, Schropp C, Thomas RH, Vignoli A, Weber Y, Palmer E, Helbig I, Scheffer IE, Striano P, Møller RS, Gardella E, Weckhuysen S. Neurology. 2022;99(3):e221-e233. doi:10.1212/WNL.0000000000200715

Background and objectives:

Pathogenic STXBP1 variants cause a severe early-onset developmental and epileptic encephalopathy (STXBP1-DEE). We aimed to investigate the natural history of STXBP1-DEE in adults focusing on seizure evolution, the presence of movement disorders, and the level of functional (in)dependence.

Methods:

In this observational study, patients with a minimum age of 18 years carrying a (likely) pathogenic STXBP1 variant were recruited through medical genetics departments and epilepsy centers. Treating clinicians completed clinical questionnaires and performed semistructured video examinations while performing tasks from the (modified) Unified Parkinson Disease Rating Scale when possible.

Results:

Thirty adult patients were included for summary statistics, with video recordings available for 19 patients. The median age at last follow-up was 24 years (range 18-58 years). All patients had epilepsy, with a median onset age of 3.5 months. At last follow-up, 80% of adults had treatment-resistant seizures despite long periods of seizure freedom in 37%. Tonic-clonic, focal, and tonic seizures were most frequent in adults. Epileptic spasms, an unusual feature beyond infancy, were present in 3 adults. All individuals had developmental impairment. Periods of regression were present in 59% and did not always correlate with flare-ups in seizure activity. Eighty-seven percent had severe or profound intellectual disability, 42% had autistic features, and 65% had significant behavioral problems. Video examinations showed gait disorders in all 12 patients able to walk, including postural abnormalities with external rotation of the feet, broad-based gait, and asymmetric posture/dystonia. Tremor, present in 56%, was predominantly of the intention/action type. Stereotypies were seen in 63%. Functional outcome concerning mobility was variable ranging from independent walking (50%) to wheelchair dependence (39%). Seventy-one percent of adults were nonverbal, and all were dependent on caregivers for most activities of daily living.

Discussion:

STXBP1-DEE warrants continuous monitoring for seizures in adult life. Periods of regression are more frequent than previously established and can occur into adulthood. Movement disorders are often present and involve multiple systems. Although functional mobility is variable in adulthood, STXBP1-DEE frequently leads to severe cognitive impairments and a high level of functional dependence. Understanding the natural history of STXBP1-DEE is important for prognostication and will inform future therapeutic trials.

Commentary

Catastrophic neonatal epilepsies that previously included early myoclonic epilepsy and early infantile epileptic encephalopathy (EIEE/Ohtahara syndrome) are now regrouped as early infantile developmental and epileptic encephalopathies (EIDEE). ¹ Greater than 50% of EIDEE have a genetic etiology ² opening doors for modifying outcomes using precision medicine approaches. It has become clear that focusing on seizure control alone as an outcome measure does not offer a holistic solution in altering the “lived experience” of individuals and families with DEE. STXBP1 associated DEE is one such condition that causes not only debilitating seizures but also disorders of movement, tone, sleep, and behavior. Multiple facets of this DEE need modification to improve the lives of the patient, family, and community at large. ^3,4

The ultimate goal of precision medicine techniques is to modify the disease mechanistically. Disease modification in a DEE in its true sense can only be possible once clinical trial design is reimagined beyond seizure control. ⁵ This means disease phenotypes across all ages need to be very well understood, clinically relevant outcome measures need to be identified and the trajectory of the disease made predictable. Although small case series and case reports help widen the scope of the known phenotype, smaller datasets run the risk of selection bias, and less meaningful conclusions. Disease concept models, as discussed in a recent preprint by the group of Helbig in Philadelphia, are one way to help identify outcomes of importance before designing a clinical trial. ⁶ Natural history studies (NHS) are another means to make a disease as known and predictable as possible. In a highly informative publication about the importance of NHS, authors Palmer et al ⁷ point out that either retrospective cross-sectional or prospective longitudinal NHS are urgently needed for rare DEE. Retrospective studies are more economical and can be completed in a shorter duration—however are prone to biased assessments of patients that are either severely affected or perhaps less affected depending on when they present to the treating physician. Additionally, retrospectively identified patients may not have the benefit of having been exposed to the more recently used effective therapies (e.g., Dravet syndrome and earlier exposure to fenfluramine). Natural history studies help with clear patient identification and identify biomarkers and clinically meaningful outcomes that can inform future trials. STXBP1 related DEE has seen a lot of recent publications as a potential target for the next clinical trial. ^{4,8 -10}

While the epilepsy and developmental outcomes of patients with STXBP1 across a wide range of ages was recently published by Balagura et al, ³ Stamberger et al focused only on adults ages 18 and up with STXBP1 ¹¹ in a cross sectional, retrospective NHS. Authors recruited 32 adults through an international collaboration of epileptologists and geneticists to include patients with genetically proven: pathogenic or likely pathogenic mutations in STXBP1. Clinical data was collected using 3 standardized questionnaires filled by referring clinicians: one each on (a) epileptology and development; (b) movement disorders and extrapyramidal disorders; (c) mobility, communication, and functional independence in adulthood. Additionally, semistructured video examinations while performing tasks from the (modified) Unified Parkinson Disease Rating Scale were performed when possible.

Important Results From This Study:

1. Epilepsy and development: (A) Seizures start very early in life: 80% patients started having seizures within first year of life with median age at onset of seizures being 3.5 months. (B) Prolonged seizure control is possible: At last follow-up 17% patients had been seizure-free for 10 to 25 years with seizure freedom achieved between ages of 8 months to 11 years. (C) Temporary withdrawal of anti seizure medication (ASM) was possible. However, seizures returned and (D) 80% of adults had active epilepsy at last follow up with daily-weekly seizures in most of the patients. (E) Although there was some evolution in seizure types, focal seizures, tonic seizures, tonic–clonic seizures and epileptic spasms were the main seizure types with 3 adults continuing to have epileptic spasms. (F) Rare patients had normal EEGs throughout the duration of this study.

2. Developmental trajectory: Developmental delay was present in 76% patients before the first year of life. Additionally behavioral disorders continue into adulthood and 20% of this cohort were in need of medication for psychiatric diagnoses.

3. Movement disorders and gait disturbance: About 50% patients had maintained ability to walk (10/19) but gait disturbances were common. Hypomimia, bradykinesia, and rigidity were described.

4. Gastrointestinal disorders were the most common non-neurological symptoms.

5. Communication, mobility, and functional independence in adulthood was significantly affected with 71% individuals being nonverbal. Regression in communication and mobility occurred in 26% in the adolescent group without clear correlation with seizure exacerbation. The developmental regression occurred as a slow progression of symptoms versus a precipitous drop in functional ability. All patients were largely dependent for activities of daily living with only 15% of the patients maintaining ability to live at home.

6. Genotype phenotype correlation: None was noted.

7. Longevity: The oldest patient in this cohort was 58 years. Two deaths reported in the cohort were not related to epilepsy.

What Does This Study Highlight for Me as a Clinician?

Although >50% patients with an EIDEE and seizures within the neonatal and early infantile age could be expected to die in early childhood, this study indicates that patients with STXBP1 can live into the fifth decade of life. Additionally, epileptic spasms could continue into adult life. Most patients seem to have poor developmental outcomes without any direct correlation to treatment of epileptic spasms. Majority of the patients are going to remain almost completely dependent for activities of daily living. Thus, aggressive therapy aimed at eliminating all spasms after an initial trial of standard approaches should be tempered. Additionally, considering the slow progression of this condition with a hint at neurodegenerative findings; patients in their adolescent ages could still be candidates for intervention through clinical trials.

Charuta Joshi MBBS, FAES, CSCN(EEG)
Department of Pediatrics, The University of Texas Southwestern Medical Center