What further diagnostic evaluations should be pursued for a 17‑year‑old female with a history of dissociative and generalized seizures, depressive episodes, low IQ, symptom onset before puberty, and recent refractory seizures?

Diagnostic Workup for Adolescent Female with Refractory Seizures, Low IQ, and Psychiatric Comorbidity

This patient requires comprehensive genetic testing with chromosomal microarray (CMA) and Fragile X testing as first-tier investigations, followed by consideration of exome sequencing (ES) if initial testing is unrevealing, alongside video-EEG monitoring to definitively characterize both seizure types.

Genetic Testing Priority

Given the constellation of low IQ, prepubertal symptom onset, and refractory seizures, this patient meets criteria for unexplained developmental delay/intellectual disability (DD/ID) requiring genetic evaluation:

• First-tier genetic testing should include CMA and Fragile X testing 1. The American College of Medical Genetics and Genomics (ACMG) and American Academy of Pediatrics (AAP) recommend these as initial tests for all patients with unexplained DD/ID 1.

• For females with DD/ID, MECP2 sequencing and deletion/duplication analysis should be performed 1. This is particularly relevant given the prepubertal onset and combination of intellectual disability with seizures 1.

• Second-tier testing with exome sequencing (ES) or whole genome sequencing (WGS) should be strongly considered if first-tier tests are unrevealing 1. The 2021 ACMG guidelines specifically state ES/WGS should be a first- or second-tier test in patients with unexplained DD/ID 1.

• Consider metabolic testing if clinical indicators suggest metabolic etiology 1, though this is typically guided by specific clinical features on history and physical examination.

Seizure Characterization with Video-EEG

The coexistence of "dissociative and generalized" seizures requires definitive characterization, as this distinction fundamentally alters management:

• Video-EEG monitoring is the gold standard for distinguishing epileptic seizures from dissociative (functional/psychogenic nonepileptic) seizures 2, 3, 4, 5. This is critical because the two conditions require entirely different treatment approaches and have different prognostic implications for morbidity and quality of life.

• Clinical features suggesting dissociative seizures include: sustained eye closure during episodes (90.2% sensitivity), pelvic thrusting, prolonged duration (median 180 seconds vs 66 seconds for epileptic seizures), fluctuating course, and limb tremors 2. However, these clinical features alone are insufficient for diagnosis without video-EEG confirmation 2, 3.

• Patients can have both epileptic and dissociative seizures concurrently 5, which appears relevant to this case given the description of "both dissociative and generalized" seizures. Video-EEG is essential to characterize each event type 5.

• Delays in obtaining video-EEG are associated with worse outcomes 4, 5. Factors associated with diagnostic delay include multiple antiseizure medication trials, unemployment/non-student status, and psychiatric comorbidities 4, 5—several of which may apply to this patient.

Neuroimaging Considerations

• Brain MRI should be performed if not already completed 1. The ACR Appropriateness Criteria recommend neuroimaging for pediatric seizures, particularly when seizures are refractory or when there are associated neurological findings such as intellectual disability 1.

• MRI is superior to CT for identifying structural abnormalities that may explain both seizures and developmental delay, including cortical malformations, hippocampal sclerosis, or other structural lesions 1.

Clinical Pitfalls to Avoid

Do not continue escalating antiseizure medications without video-EEG confirmation that all events are epileptic in nature 2, 3, 4. Patients with dissociative seizures exposed to multiple antiseizure medications have longer diagnostic delays and worse outcomes 4.

Do not assume psychiatric comorbidity (depression) excludes genetic etiologies 1. Many genetic syndromes causing DD/ID present with both seizures and psychiatric manifestations.

Recognize that dissociative experiences can occur in epilepsy 6, particularly temporal lobe epilepsy, but this does not negate the need for video-EEG to characterize individual events 6.

Algorithmic Approach

1. Immediate: Refer for video-EEG monitoring to definitively characterize all seizure types 2, 3, 4, 5
2. Concurrent: Order CMA and Fragile X testing 1
3. Concurrent: Order MECP2 sequencing and deletion/duplication analysis (female patient with DD/ID) 1
4. If initial genetic testing negative: Proceed to exome sequencing 1
5. If not already done: Obtain brain MRI 1
6. Consider: Metabolic screening if clinical features suggest metabolic disorder 1