Lennox-Gastaut Syndrome (LGS) is a severe epilepsy syndrome, with onset typically before 8 years of age and comprising a variety of seizure types. LGS is often accompanied by specific changes on electroencephalography (EEG) and cognitive impairment. Herein, we describe a patient with late-onset LGS who had onset after 8 years of age. For a comprehensive analysis, previous cases of late-onset LGS were reviewed and compared to this case.

The onset of LGS is typically before 8 years of age, with a peak at 4–5 years (3). Late-onset LGS, occurring in adolescents or adults (> 8 years old), is relatively rare and accounts for 10–15% of all LGS cases (4, 5). Thus, we collected data on all cases of late-onset LGS that have been reported since 1991; the 42 identified cases are summarized in Table 1 (6–13). The age of seizure onset ranged from 6 weeks to 28 years, while the age at LGS diagnosis ranged from 8 to 64 years, The lag time between seizure onset and LGS diagnosis is mostly due to ictal semiology and electroclinical findings not having been fulfilled, suggesting that electroclinical changes in LGS follow a gradual evolutionary process, as in this case. It generally takes 1–2 years from seizure onset to a definite diagnosis of LGS (14, 15) because of differences in etiology, clinical characteristics, and disease progression between patients. This emphasizes the importance of individual electroclinical follow-up for early diagnosis of LGS. Additionally, for patients with a definite LGS diagnosis, a retrospective analysis of the characteristics of their electroclinical evolution is necessary and useful for precise treatment.

Among the identified 42 cases of late-onset LGS, 13 showed chromosome variations. Of the 29 remaining cases, 17 showed normal cognition and had a disease course of 5–32 years, while 12 showed cognitive impairment (mild cognitive impairment in two cases) and a course of 5–25 years. This indicates that unlike early-onset LGS, cognitive function, and daily viability are relatively preserved in late-onset LGS; additionally, cognitive function is not significantly related to disease course (4, 5, 8). This case had a disease course of 9 years, but the patient's cognitive function had only moderately declined. Furthermore, neurological examination results were mentioned in 38 of the 42 cases, among which four patients had abnormal neurological signs related to intracranial infection, cerebral infarction, perinatal injury, etc. Additionally, the EEG background was mentioned in 16 of the 42 cases, among which 10 showed normal EEG background, and six showed nonspecific slow waves. These findings suggest that late-onset LGS mostly shows no positive neurological signs or special abnormalities in the EEG background, as observed in this case.

Among the 42 cases, MRI findings were negative in 17, nonspecific or subcortical changes were found in 12, local cortical lesions were found in 5, and MRI findings were not mentioned in the remaining 8, suggesting that the cortical structure in late-onset LGS mostly showed no specific changes. However, this substantially differs from previous reports on classical LGS, which indicate that more than 2/3 of patients show cortical structural lesions on MRI (3, 16), including focal, multifocal, and diffuse abnormalities, with static pathological lesions predominating (e.g., focal cortical dysplasia), while progressive or metabolic lesions are relatively rare (17, 18). This may reflect a difference between early- and late-onset LGS, but it may also be related to a case inclusion bias and skill in image reading; thus, this potential distinction needs to be confirmed by accumulating more cases. However, the progression of neuroimaging technology and the quality of MRI scans may also contribute to focal structural lesion identification. In this case, nothing was found in the initial clinical work-up, and the epileptic focus was found during the re-evaluation process by high-resolution structural MRI and later confirmed by SEEG and RFTC, indicating the important role of high-resolution structural MRI in the etiological diagnosis and treatment of late-onset LGS. Routine MRI should include three-dimensional T1, T2 FLAIR, and coronal thin-layer scanning of the long axis of the vertical hippocampus (3).

In the 29 cases without chromosome variations, the prognosis was not mentioned in 6 cases, 11 cases had independent viability, 2 cases had well-controlled seizures, and the remaining 10 cases had a poor prognosis, including frequent seizures, encephalopathy, sudden unexpected death in epilepsy, etc. This indicates that the prognosis of late-onset patients is relatively good. Furthermore, although most of the 42 identified cases had tried more than three antiepileptic drugs, none underwent surgery, which may be related to an unclear etiology. In total, 10 cases had tried VNS, which was clearly mentioned as effective in only 1 case, suggesting that VNS has a poor effect on late-onset LGS, as observed in this case, which showed obvious improvement after surgery, suggesting the effectiveness and necessity of early surgery for patients with late-onset LGS with definite focal lesions (15, 18).

For 1 year after the RFTC, not only were the patient's seizures well controlled, but his cognition improved and the EEG spikes “calmed down” gradually for 2 years. Such changes were first mentioned in 1979 (19). These observations not only suggest that electroclinical changes in late-onset LGS are the result of secondary alterations in brain networks (20), but also confirm the efficacy of RFTC. However, his seizure recurred and he eventually underwent left occipital resection and has been seizure free until now. This indicated the limited efficacy and scope of RFTC compared to craniotomy in lesion damage and pathological network disconnection in some cases with accurate lesion targets, which may be the main reason explaining the low rate of seizure-free cases with RFTC (21). However, the improvement of clinical outcomes after RFTC may further suggest the correct location of epileptic foci and good prognosis after craniotomy, as in this case. Nevertheless, RFTC is superior in some small foci that can be located precisely and destroyed completely but are inaccessible by surgery, and has the advantages of less damage to brain function, fewer complications, and faster postoperative recovery (22, 23).

In summary, LGS, with onset after 8 years of age known as late-onset LGS, may be caused by focal lesions. Individualized follow-up is necessary. Late-onset LGS and classical LGS have some differences in terms of clinical manifestation, cognitive changes, prognosis, and treatment. MRI is important in determining the etiology of late-onset LGS and is useful for early treatment. Comparing to craniotomy, RFTC is limited and less effective in lesion damage. However, clinical improvement after RFTC would support the appropriate identification of seizure onset zone location indicated by SEEG results and therefore help with surgical plan for cortical resection.

We spent a lot of money and time in the treatment of our son's disease before the second evaluation. After the RFTC, our son's seizures were miraculously controlled and he could go to school again. This was beyond our expectations.

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