Abstract
Objective
Lennox‐Gastaut syndrome (LGS) is an archetypal developmental and epileptic encephalopathy, for which novel treatments are emerging. Diagnostic criteria for LGS have recently been defined by the International League Against Epilepsy (ILAE). We aimed to apply these criteria in a real‐world setting.
Methods
We applied ILAE diagnostic criteria to a cohort of patients diagnosed with LGS by epileptologists following inpatient video‐EEG monitoring (VEM) at tertiary comprehensive epilepsy centers between 1995 and 2015. We also assessed mortality in this cohort.
Results
Sixty patients diagnosed with LGS and had complete records available for review were identified. Among them, 29 (48%) patients met ILAE diagnostic criteria for LGS (ILAE‐DC group). Thirty‐one did not meet criteria (non‐ILAE‐DC) due to the absence of documented tonic seizures (n = 7), EEG features (n = 12), or both tonic seizures and EEG features (n = 10), intellectual disability (n = 1), or drug resistance (n = 1). The ILAE‐DC group had a shorter duration of epilepsy at VEM than the non‐ILAE‐DC group (median = 12.0 years vs. 23.7 years, respectively; p = 0.015). The proportions of patients with multiple seizure types (100% vs. 96.7%), ≤2.5 Hz slow spike‐and‐wave EEG activity (100% vs. 90%), seizure‐related injuries (27.6% vs. 25.8%), and mortality (standardized mortality ratio 4.60 vs. 5.12) were similar between the groups.
Significance
Up to 52% of patients diagnosed with LGS following VEM may not meet recently accepted ILAE criteria for LGS diagnosis. This may reflect both the limitations of retrospective medical record review and a historical tendency of applying the LGS diagnosis to a broad spectrum of severe, early‐onset drug‐resistant epilepsies with drop attacks. The ILAE criteria allow the delineation of LGS based on distinct electroclinical features, potentiating accurate diagnosis, prognostication, and management formulation. Nonetheless, mortality outcomes between those who did and did not meet ILAE diagnostic criteria for LGS were similarly poor, and both groups suffered high rates of seizure‐related injury.
Plain Language Summary
More than half of patients diagnosed with Lennox‐Gastaut Syndrome (LGS) at three Australian epilepsy monitoring units between 1995 and 2015 did not meet the recently devised International League Against Epilepsy (ILAE) diagnostic criteria for LGS. Mortality was equally high in those who did and did not meet the ILAE diagnostic criteria, and seizure‐related injury was common. The ILAE diagnostic criteria will guide accurate diagnosis, management, prognostication, and research in patients with LGS, however may be limited in their practical application to patients with a longer duration of epilepsy, or to those for whom detailed assessment is difficult.
Keywords: diagnosis, Lennox‐Gastaut syndrome, multicenter study, video‐EEG monitoring
Key points.
Historically, a Lennox‐Gastaut Syndrome (LGS) diagnosis was applied to a broad spectrum of severe, early onset drug‐resistant epilepsies with drop attacks.
The International League Against Epilepsy (ILAE) recently accepted diagnostic criteria for LGS, which will allow appropriate diagnosis, management, and prognostication in LGS.
Up to 52% of patients diagnosed with LGS after VEM may not meet the recently accepted ILAE criteria for LGS diagnosis.
Mortality outcomes were similarly poor in those diagnosed with LGS after VEM who did meet the new ILAE diagnostic criteria versus those who did not.
1. INTRODUCTION
Lennox‐Gastaut syndrome (LGS) is an archetypal developmental and epileptic encephalopathy (DEE). LGS typically has onset in childhood, characterized by tonic seizures and at least one other seizure type, developmental impairment, and characteristic electroencephalography (EEG) features. These features evolve over time. 1 , 2 , 3 , 4 LGS has heterogenous etiologies, and atypical cases with late onset, or normal cognition may lead to diagnostic difficulty. 3 Accurate diagnosis and distinction from other DEEs may be challenging, 2 , 4 and, until recently has been hindered by the absence of clear diagnostic criteria. The result has been that historically, patients with intellectual impairment and drug‐resistant seizures causing drop attacks, have been loosely labeled as having “LGS”. LGS is generally drug‐resistant, 3 with relatively few treatments showing efficacy in randomized controlled trials. 4 , 5 , 6 However, new therapies for LGS are emerging, and therefore, more accurate diagnosis in clinical practice has taken on increased importance. 7 , 8 , 9
Criteria for the diagnosis of LGS have recently been defined by the International League Against Epilepsy (ILAE), addressing a longstanding gap. 10 These criteria outline distinct electroclinical features needed for a diagnosis of LGS, with important treatment implications. We aimed to apply the new diagnostic criteria in children and adults previously labeled as having LGS by epileptologists following inpatient video‐EEG monitoring (VEM) over a 20‐year span in a multicenter study. We also describe the characteristics and mortality rates in our cohort.
2. METHODS
2.1. Participants
This 20‐year retrospective cohort study identified patients diagnosed with LGS from 5509 individuals admitted to one of three tertiary hospital VEM units in Melbourne, Australia, between January 1, 1995 and December 31, 2015. This included 2306 adults assessed at The Royal Melbourne Hospital, 1244 adults at St Vincent's Hospital, and 1424 adults and 535 children at Austin Health. Epilepsy was diagnosed and classified in 3175 patients by multidisciplinary epilepsy team consensus, as previously described. 11
We reviewed medical records of patients with a LGS diagnosis following VEM admission. Patients were categorized into three groups: Entire Cohort, which comprised all patients diagnosed with LGS following VEM; and two mutually exclusive subgroups that included only those with data available for assessment against the recently accepted ILAE diagnostic criteria: those meeting ILAE diagnostic criteria (ILAE‐DC group), 10 and those diagnosed with LGS following VEM, but who did not fulfill the ILAE diagnostic criteria (non‐ILAE‐DC group). The ILAE mandatory criteria are (a) onset before 18 years of age, (b) tonic seizures with at least one additional seizure type (atypical absence, atonic, myoclonic, focal impaired awareness, generalized tonic–clonic seizures; nonconvulsive status epilepticus; epileptic spasms), (c) mild to profound intellectual disability, (d) drug‐resistant epilepsy, and (e) diffuse slow spike‐and‐wave complexes (SSW) at ≤2.5 Hz and generalized paroxysmal fast activity (GPFA) in sleep on EEG.
2.2. Clinical data
Clinical, developmental, and epilepsy history documented at VEM admission was analyzed from medical records. Duration of epilepsy at time of VEM was calculated from the time of first known seizure. Data from EEG reports obtained included the presence of SSW and GPFA or polyspikes. If the frequency of the SSW was not specified, the EEG was reviewed by an epileptologist, with ≤3.0 Hz SSW otherwise assumed.
2.3. LGS etiology
The etiology of LGS was classified according to the following:
Structural causes with an anatomical abnormality stratified as: (a) genetic or presumed genetic structural or (b) acquired structural.
Genetic or “presumed genetic” causes with no epileptogenic neuroanatomical abnormality on investigation; a “presumed genetic” cause was one where aetiological investigations were negative and no genetic abnormality was known.
Acquired nonstructural causes;
Unknown cause, where data regarding genetic, neuroanatomical, and metabolic investigations were unavailable.
2.4. Mortality outcomes and seizure‐related injury
The procedures for determining if patients had died, their cause of death, and SUDEP status have been previously described. 11 In brief, these were determined by linkage to the Australia National Death Index up to May 6, 2018, with cause of death refined and SUDEP determined by linkage to the Australian National Coronial Information System. Serious seizure‐related injury documented at time of VEM was defined as head injury, fracture, or other unspecified “serious” injuries listed in the medical record as a result of a seizure.
2.5. Statistical analyses
Mann–Whitney test was performed to assess differences in age and epilepsy duration at the time of VEM between ILAE‐DC and non‐ILAE‐DC groups. Significance level was set at p < 0.05. Standardized mortality ratio (SMR) was estimated using published age‐, sex‐ and year‐specific population mortality rates available from the Australian Bureau of Statistics. Statistical analyses were performed using Stata version 16 (StataCorp).
2.6. Ethical approvals
This study was approved by relevant Human Research Ethics Committees and Institutional Review Boards, as detailed previously. 11
3. RESULTS
Seventy‐three patients were diagnosed with LGS following admission to Austin Health (n = 58), The Royal Melbourne Hospital (n = 13), and St Vincent's Hospital (n = 2). Sufficient data were available to review against the ILAE diagnostic criteria for LGS in 60 patients. Median duration of admission in the 60 patients with data available was 4 days (interquartile range [IQR] = 2–5 days). Twenty‐nine were included in the ILAE‐DC group and 31 in the non‐ILAE‐DC group. The ILAE‐DC group, non‐ILAE‐DC group, and the 13 cases diagnosed with LGS on VEM with missing or insufficient data available for inclusion in the studies analyses stratified by mean age and hospital site are available in Table 1. The median duration of admission was 4 days in each group, (IQR = 3–5 and 2–5 days, respectively). Of the respective ILAE‐DC and non‐ILAE‐DC groups, 17.2% (n = 5) and 9.6% (n = 3) were studied over 20 years ago, between 1995 and 2000, 17.2% (n = 5) and 45.2% (n = 14) between 2001 and 2005, 20.1% (n = 6) and 25.8% (n = 8) between 2006 and 2010, and 44.8% (n = 13) and 19.4% (n = 6) between 2011 and 2015.
TABLE 1.
Breakdown of patients in the ILAE‐DC group, non‐ILAE‐DC group, and those missing data for inclusion in analyses, stratified by hospital site and age at VEM.
| ILAE‐DC group (n = 29) | Non‐ILAE‐DC group (n = 31) | Patients with insufficient or missing data (n = 13) | ||||
|---|---|---|---|---|---|---|
| n | Age at VEM (years), median (IQR) | n | Age at VEM (years), median (IQR) | n | Age at VEM (years), median (IQR) | |
| Austin Hospital (n = 58) | 28 | 17.5 (9.5–22) | 23 | 24 (6–42) | 7 | 21 (17–46) |
| Royal Melbourne Hospital (n = 13) | 1 | 24 | 7 | 28 (21–36) | 5 | 40 (25–46) |
| St Vincent's Hospital Melbourne (n = 2) | 0 | – | 1 | 20 | 1 | 39 |
Abbreviations: ILAE, International League Against Epilepsy; ILAE‐DC group, International League Against Epilepsy Diagnostic Criteria group; IQR, interquartile range; VEM, video‐EEG monitoring.
Clinical data relevant to the ILAE criteria are in Table 2. Fourteen of 24 (58.3%) children (aged <18 years), and 15 of 36 (41.6%) adult patients with sufficient data available satisfied an LGS diagnosis by the ILAE criteria and were included in the ILAE‐DC group. Of 31 patients in the non‐ILAE‐DC group, 18 cases (58%) met all but one ILAE criterion for LGS diagnosis. Twelve (38.7%) patients could not be included in the ILAE‐DC group because they failed to meet the ILAE EEG diagnostic criteria alone. This included one patient without documented SSW ≤2.5 Hz, eight without documented GPFA/polyspikes, and three with neither. Sixteen (51.6%) patients did not have tonic seizures documented in the medical records or captured during VEM. Ten patients (32.3%) did not meet both tonic seizure and EEG criteria. One (3.2%) patient did not meet the criteria for intellectual impairment, or drug resistance at the time of VEM, respectively.
TABLE 2.
Demographic data and characteristics of LGS patients admitted for VEM.
| (a) The entire cohort (n = 60) | (b) ILAE‐DC group (n = 29) | (c) Non‐ILAE‐DC group (n = 31) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n (n with data available) | % | Mean (yrs) | Range (yrs) | n (n with data available) | % | Mean (yrs) | Range (yrs) | n (n with data available) | % | Mean (yrs) | Range (yrs) | |
| Demographic data | ||||||||||||
| Sex (male) | 38 | 63.3 | – | – | 19 | 65.5 | – | – | 19 | 61.3 | ||
| Age at VEM | – | – | 23.5 | 2.0–56 | – | – | 20.3 | 3.0–52 | – | – | 26.6 | 2.1–56.1 |
| Children (aged <18 years) | 24 | 40.0 | – | – | 14 | 48.3 | – | – | 10 | 32.3 | ||
| Age at epilepsy onset | – | – | 4.3 | 0–18 | – | – | 4.7 | 0.3–17 | – | – | 3.9 | 0.3–18.0 |
| Epilepsy duration | – | – | 18.6 | 1.0–50 | – | – | 14.4 | 1.9–50 | – | – | 22.6 | 1.1–47.2 |
| Intellectual/cognitive impairment | 59 a | 98.3 | – | – | 29 | 100 | – | – | 30 | 97.0 | – | – |
| LGS etiology | ||||||||||||
| Genetic/presumed genetic | 32 | 53.3 | – | – | 14 | 48.3 | – | – | 18 | 58.1 | – | – |
| Structural | 19 | 31.7 | – | – | 11 | 37.9 | – | – | 8 | 25.8 | – | – |
| Structural—genetic/presumed genetic | 15 | 25.0 | – | – | 7 | 24.1 | – | – | 8 | 25.8 | – | – |
| Structural—acquired | 4 | 6.7 | – | – | 4 | 13.8 | – | – | 0 | 0.0 | – | – |
| Acquired—other | 1 | 1.7 | – | – | 1 | 3.4 | – | – | 0 | 0.0 | – | – |
| Unknown | 8 | 13.3 | – | – | 3 | 10.3 | – | – | 5 | 16.1 | – | – |
| Seizure history | ||||||||||||
| Tonic–clonic seizures (a) | 46 | 76.7 | – | – | 21 | 72.4 | – | – | 25 | 80.6 | – | – |
| Tonic seizures (b) | 44 | 73.3 | – | – | 29 | 100 | – | – | 15 | 48.3 | – | – |
| Atonic seizures (c) | 25 | 41.7 | – | – | 14 | 48.3 | – | – | 11 | 35.5 | – | – |
| Drop attacks unspecified (d) | 19 | 31.7 | – | – | 11 | 37.9 | – | – | 8 | 25.8 | – | – |
| Atypical absence seizures (e) | 43 | 71.7 | – | – | 20 | 69.0 | – | – | 23 | 74.2 | – | – |
| Myoclonic seizures (f) | 24 | 40.0 | – | – | 11 | 37.9 | – | – | 13 | 41.9 | – | – |
| Multiple seizure types | 59 | 98.3 | – | – | 29 | 100 | – | – | 30 | 96.7 | – | – |
| ≥2 seizure types (a–f), for ≥6 months † | 55 (59) | 93.2 | – | – | 27 (28) | 96.4 | – | – | 28 (31) | 90.3 | – | – |
| ≥2 drop seizures (a–c) per week, for 28 days † | 46 (55) | 83.6 | – | – | 23 (25) | 92.0 | – | – | 23 (30) | 76.7 | – | – |
| Serious seizure‐related injury | 16 | 26.7 | – | – | 8 | 27.6 | – | – | 8 | 25.8 | – | – |
| ASM use | ||||||||||||
| ASM number at VEM | – | – | 3.1 | 0–6 | – | – | 3.2 | 2–5 | – | – | 3.1 | 0–6 |
| ASM number trialed prior to VEM | – | – | 3.7 | 0–9 | – | – | 3.3 | 0–8 | – | – | 4.1 | 0–9 |
| ≥2 ASM's trialed † | 59 | 98.3 | – | – | 29 | 100 | – | – | 30 | 96.7 | – | – |
| Valproate | 42 | 70.0 | – | – | 23 | 79.3 | – | – | 19 | 61.3 | – | – |
| Lamotrigine | 24 | 40.0 | – | – | 12 | 41.4 | – | – | 12 | 38.7 | – | – |
| Clonazepam | 21 | 35.0 | – | – | 11 | 37.9 | – | – | 10 | 32.2 | – | – |
| Carbamazepine | 17 | 28.3 | – | – | 9 | 31 | – | – | 8 | 25.8 | – | – |
| EEG features | ||||||||||||
| ≤2.5 Hz SSW | 56 | 93.3 | – | – | 29 | 100 | – | – | 27 | 87.1 | – | – |
| ≤3 Hz SSW † | 59 | 98.3 | – | – | 29 | 100 | – | – | 30 | 96.7 | – | – |
| GPFA/polyspikes | 41 | 68.3 | – | – | 29 | 100 | – | – | 12 | 38.7 | – | – |
| Previous epilepsy surgery | 10 | 16.7 | – | – | 4 | 13.8 | – | – | 6 | 19.4 | – | – |
| Corpus callosotomy | 2 b | 3.3 | – | – | 1 | 3.4 | – | – | 1 b | 3.2 | – | – |
| Resection | 3 | 5.0 | – | – | 0 | 0 | – | – | 3 | 9.7 | – | – |
| VNS insertion | 5 b | 8.3 | – | – | 3 | 10.3 | – | – | 2 b | 6.5 | – | – |
| Meeting all criteria marked with (†) 10 | 40 (54) | 74.1 | – | – | 21 (24) | 87.5 | – | 18 (29) | 62.1 | – | – | |
Abbreviations: ASM, antiseizure medication; EEG, electroencephalogram; ILAE, International League Against Epilepsy; ILAE‐DC group, International League Against Epilepsy Diagnostic Criteria group; LGS, Lennox‐Gastaut syndrome; SSW, slow spike‐and‐wave; VEM, video‐EEG monitoring; VNS, vagal nerve stimulator; yrs, years.
One patient with relative preservation of intellectual function. One patient intellectually normal.
One patient underwent both corpus callosotomy and VNS insertion.
3.1. Demographic data and LGS etiology
Table 2 summarizes demographic data, epilepsy history, and etiology for each group. The median age at VEM in the ILAE‐DC group was 18.0 years (IQR = 10.4–24.0) compared with 27.5 years (IQR = 13.7–41.8) in the non‐ILAE‐DC group (p = 0.098). Data regarding the median duration of epilepsy at the time of VEM was available in 28 of 29 patients in the ILAE‐DC group and 30 of 31 patients in the non‐ILAE‐DC. The duration of epilepsy at the time of VEM was significantly shorter in the ILAE‐DC group compared to the non‐ILAE‐DC group (median 12.0 years; IQR = 4.87–19.3 vs. median 23.7 years; IQR = 12.6–34.7, respectively; p = 0.015).
3.2. Seizure types and EEG findings
Lifetime seizure history is summarized in Table 2 for each group. In the non‐ILAE‐DC group, tonic seizures were reported at VEM admission in 48.4% (n = 15) of cases. In addition to tonic seizures, all of these 15 cases also experienced at least one of the following seizure types: atypical absence seizures (n = 11), atonic seizures (n = 2), myoclonic seizures (n = 5), focal impaired aware seizures (n = 5), generalized tonic–clonic seizures (n = 11), or epileptic spasms (n = 2). In those without documented tonic seizures in the non‐ILAE‐DC group (n = 16), atonic seizures (n = 9), myoclonic seizures (n = 8), focal impaired aware seizures (n = 2), generalized tonic–clonic seizures (n = 14), and “drop attacks” of unspecified nature (n = 5) were common. There were no documented epileptic spasms in this subgroup. Multiple seizure types were reported in 96.7% of cases across the non‐ILAE‐DC group. Serious seizure‐related injury was documented in 27.6% and 25.8% at VEM in the non‐ILAE‐DC and ILAE‐DC groups, respectively. In the non‐ILAE‐DC group with EEG data available, SSW of ≤2.5 Hz was documented in 87.1% of cases and GPFA or polyspikes were documented in 38.7% of patients.
3.3. Treatment history
Fifty‐nine of 60 (98.3%), 29/29 (100%), and 30/31 (96.7%) patients with available data failed ≥2 ASMs in the entire cohort, the ILAE‐DC and non‐ILAE‐DC groups, respectively (Table 2). Valproate, lamotrigine, clonazepam, and carbamazepine were the most commonly used ASMs across all three groups. Previous epilepsy surgery was documented in 16.7%, 13.8%, and 19.4% of patients in each respective group.
3.4. Mortality and serious seizure‐related injury
The SMR for the entire cohort, the ILAE‐DC group, and the non‐ILAE‐DC group were 4.91 (95% CI = 2.46–9.82), 4.61 (95% CI = 1.49–14.3), and 5.12 (95% CI = 2.13–12.3), respectively (Table 3). In the Entire Cohort, females (SMR = 13.2, 95% CI = 5.48–31.7) and those aged 18–29 years (SMR = 5.38, 95% CI = 1.34–21.5), and 30–49 years (SMR = 9.89, 95% CI = 4.12–23.7) experienced significantly elevated mortality compared with the general population. Serious seizure‐related injury was common, reported in 26.7%, 27.6%, 25.8% of the entire cohort, ILAE‐DC, and non ILAE‐DC groups, respectively.
TABLE 3.
Standardized mortality ratio (SMR) of LGS patients admitted for VEM.
| Deaths observed | Deaths expected | SMR | 95% confidence interval (CI) | |
|---|---|---|---|---|
| Entire cohort (n = 60) | 8 | 1.63 | 4.91 | 2.46–9.82 |
| Sex | ||||
| Male | 3 | 1.25 | 2.4 | 0.77–7.44 |
| Female | 5 | 0.38 | 13.18 | 5.49–31.7 |
| Age group | ||||
| 0–17 | 1 | 0.29 | 3.48 | 0.49–24.7 |
| 18–29 | 2 | 0.37 | 5.38 | 1.35–21.5 |
| 30–49 | 5 | 0.51 | 9.89 | 4.11–23.8 |
| 50+ | 0 | 0.47 | 0 | – |
| ILAE‐DC group (n = 29) | 3 | 0.65 | 4.61 | 1.49–14.3 |
| Non ILAE‐DC group (n = 31) | 5 | 0.98 | 5.12 | 2.13–12.3 |
Abbreviations: LGS, Lennox‐Gastaut syndrome; SMR, standardized mortality ratio; VEM, video‐EEG monitoring.
Of the eight deceased patients across the Entire Cohort, three underwent autopsy. Autopsy confirmed definite SUDEP in one case, identifying a histological area of cardiac ischemic fibrosis in the setting of patent coronary arteries. The two remaining autopsies determined metastasis and urosepsis, respectively, as the cause of death. Overall, the primary cause of death was identified as definite or possible SUDEP (n = 2), status epilepticus (n = 1), aspiration pneumonitis (n = 1), neoplasia (n = 2), cerebral palsy, with aspiration pneumonitis as the secondary cause of death (n = 1), and urosepsis (n = 1).
4. DISCUSSION
We analyzed the phenotypic features of patients with a diagnosis of LGS following VEM and assessed how many meet the recent ILAE diagnostic criteria for LGS. We compared the mortality between patients who fulfilled the criteria (ILAE‐DC) compared with those who did not (non‐ILAE‐DC). VEM admission represents the gold standard for evaluating a patient's eligibility to meet the ILAE LGS criteria but is only applicable to those patients who are able to tolerate admission.
With the caveat that some patients in our cohort were evaluated more than 20 years ago, we found that only 48% of patients diagnosed with LGS by epileptologists following VEM met all mandatory ILAE criteria for LGS. In a recent similar study, only 32% of patients diagnosed with LGS in an outpatient epilepsy clinic met the ILAE criteria. 12 The results of the current study are likely due to multiple possible reasons. Only 73.3% of patients in this study had tonic seizures documented in the admission history or captured during VEM. It is possible that incorrect terminology had been used. Indeed, in our cohort, 31.7% of cases had “drop attacks” noted in the medical record without further description. Unfortunately, this is a limitation of retrospective medical record review and may have meant some patients who had true LGS could not be shown to meet ILAE diagnostic criteria. Similarly, the cross‐sectional nature of this medical record data will compound this. The evolving EEG and phenotypic features often seen in LGS may contribute to failure to capture key criteria at the time of review, 4 , 13 , 14 especially in patients with a longer duration of epilepsy.
Our data are also likely to reflect a historical tendency for LGS diagnoses to be applied to a broad spectrum of patients with severe, early onset epilepsies with drug‐resistant seizures and drop attacks. 1 Previous attempts by expert panels to establish universally accepted diagnostic criteria showed variable emphasis on combinations of seizure types, EEG features, and cognitive or behavioral abnormalities, 1 , 2 , 15 emphasizing the degree of heterogeneity and diagnostic complexity for LGS. Our results in a retrospective cohort of patients diagnosed from 1995 onwards likely reflect these issues, and our data shows significant clinical overlap between the ILAE‐DC and non‐ILAE‐DC groups. Among those in the non‐ILAE‐DC group, 18/31 (58%) cases met all but one ILAE criterion for LGS diagnosis (SSW ≤2.5 Hz, GPFA/polyspikes, Intellectual impairment, tonic seizures with at least one additional seizure type, or drug resistant epilepsy). The incidence of tonic seizures (48.3%), SSW (87.1%), GPFA or polyspikes (38.7%) and intellectual impairment (96.8%) were variable. Most patients in the non‐ILAE‐DC group had multiple seizure types, and were pharmaco‐resistant (96.8% each). Given the challenges in diagnosing LGS as highlighted by our study, the specific ILAE criteria for LGS are a welcome important advance for the diagnosis and management of LGS.
Interestingly, patients who did not meet all of the ILAE‐DC criteria tended to have a longer duration of epilepsy than those who did. However, these patients were not statistically significantly older. It has been previously reported that both seizure types and SSW discharges may reduce in frequency over time, 3 , 13 , 14 , 16 potentially making them less likely to be reported in patients living with LGS for longer. Our limited analysis may suggest that the reported evolution of phenotypic and electroclinical features in LGS are more dependent on disease progression than patient age. This highlights the need to acknowledge the complex, evolving phenotype of LGS over time and the need for early engagement with epileptologists, rigorous longitudinal phenotyping and, if indicated, re‐evaluation to establish if patients meet the diagnostic criteria. Failure to do so may result in a subset of patients, particularly those living with epilepsy for longer, being unintentionally denied access to emerging therapies.
The ILAE criteria for LGS will enable accurate diagnosis of patients, facilitate accurate prognostication, and guide management and treatment distribution in a patient group with complex and drug‐resistant epilepsy. Diagnostic workup should be comprehensive and multimodal, and when necessary over multiple time points to achieve diagnostic accuracy. This should include careful seizure histories to classify seizure types and educate families and carers about recognition of seizures. Home video‐recordings over consecutive nights, and overnight ambulatory EEG alongside VEM will aid in detection of nocturnal events and characteristic EEG features, and collectively help to ensure accurate diagnosis. Consistent with other cohorts, our data suggests a significant proportion of patients may not meet key diagnostic criteria despite a thorough workup, 17 yet will have equally poor outcomes. These patients may have other DEEs which suggests a need to assess the utility of new, emerging treatments in a broader group of DEEs. Our observation may also reflect a practical, real‐world limitation to the application of the ILAE diagnostic criteria in a clinically evolving group of patients and, in particular, in patients living with epilepsy for longer. In cases where a clear epilepsy syndrome cannot be identified, each individual patient and their limitations to clear diagnosis should be carefully considered by an epileptologist alongside the ILAE criteria on a case‐by‐case basis to ensure evidence based, best practice treatment is provided.
Our study of the mortality of patients diagnosed with LGS following VEM, found an SMR 4.5‐fold greater than the general population, 10‐fold greater in females, and 6‐ to 7‐fold higher in those aged 18–49 years. Mortality was similar between the entire cohort, the ILAE‐DC and non‐ILAE‐DC groups. As much as 50% of the mortality appeared to be seizure‐related (SUDEP, status epilepticus and aspiration pneumonia), and at least one‐quarter of patients had had a previous serious seizure‐related injury. SUDEP is associated with an increased frequency of generalized tonic–clonic seizures, 18 which LGS patients frequently experience. Hospital epilepsy cohorts tend to have higher rates of mortality and SUDEP than primary care or population‐based epilepsy cohorts. 19 , 20 This is presumably related to epilepsy severity and higher rates of drug resistance, although cohorts from the general population or primary care have also been found to have high rates of drug resistance. 21 , 22
This study has a range of limitations. Retrospective review of hospital medical records over a long time period is limited by data loss, poor documentation may limit the accuracy of available data, and the sample size limits the strength of conclusions drawn from mortality analyses. Sleep disturbance in an inpatient setting may underestimate the incidence of GPFA or tonic seizures, reducing the proportion of patients meeting the recent ILAE criteria. Importantly, many LGS patients with severe epilepsy and intellectual disability do not tolerate VEM, or even a routine EEG, posing an arguably even greater challenge in reaching a definitive diagnosis.
5. CONCLUSION
Patients with LGS need universally accepted, pragmatic, diagnostic criteria to enable appropriate management formulation, prognostication, and clinical trials. The criteria outlined by the ILAE will allow this by delineating LGS from other DEEs as a clear cluster of electroclinical features. As many as 52% of epileptologist‐diagnosed LGS diagnoses following VEM did not fulfill the ILAE criteria. This is likely multifactorial. These findings likely reflect the limitations of retrospective, cross‐sectional medical record review in patients with an evolving phenotype, and also highlight a historical tendency for LGS diagnoses in practice to refer more broadly to early onset epilepsy with intractable seizures and falls. The ILAE diagnostic criteria may be limited in their practical application to patients with a longer duration of epilepsy, or to those for whom detailed assessment is difficult. Given the similar clinical and prognostic features of the ILAE‐DC and non‐ILAE‐DC groups, investigation of LGS should be multimodal and when needed, conducted at multiple time points to ensure accurate diagnosis. Patients without a diagnosis following extensive workup should be carefully considered on a case‐by‐case basis to ensure appropriate management is provided. Further investigation into the utility of emerging treatments in the broader DEE group of patients is also warranted.
AUTHOR CONTRIBUTIONS
Drafted and revised the manuscript for intellectual content, a major role in acquisition of data, contributed to the interpretation of data: Russell Nightscales; Performed statistical analyses, revised the manuscript for intellectual content, and contributed to the interpretation of data: Zhibin Chen; Major role in acquisition of data, contributed to the interpretation of data, and revised the manuscript for intellectual content: Sarah Barnard; Major role in the acquisition of data, and revised the manuscript for intellectual content: Clarissa Auvrez, Gerard Tao; Critical revision of the manuscript for intellectual content: Shobi Sivathamboo, Maria Rychkova; Role in data collection, critical revision of the manuscript for intellectual content: Caitlin Bennett; Provided scientific direction, reviewed clinical data, contributed to the interpretation of data, and critical revision of the manuscript for intellectual content: Wendyl D'Souza, John‐Paul Nicolo, Piero Perucca; Provided scientific direction, contributed to the interpretation of data, and critical revision of the manuscript for intellectual content: Samuel F. Berkovic; Role in study design, provided scientific direction, reviewed clinical data, contributed to the interpretation of data, and critical revision of the manuscript for intellectual content: Terence J. O'Brien, Ingrid Scheffer; Corresponding author, role in study design, drafting, and critical revision of the manuscript for intellectual content: Patrick Kwan.
CONFLICT OF INTEREST STATEMENT
R. Nightscales, S. Barnard, C. Auvrez, G. Tao, C. Bennett, and M. Rychkova report no disclosures relevant to the manuscript. Z. Chen was supported by an Early Career Fellowship from the National Health and Medical Research Council (GNT1156444). S. Sivathamboo is supported by Research Program Grants from the National Institute of Health (1U54AT012307‐01 and 1R01NS123928‐01). She reports salary support paid to her institution from Jazz Pharmaceuticals for clinical trial‐related activities; she receives no personal income for these activities. W. D'Souza receives salary support from The University of Melbourne. He has received travel, investigator‐initiated, scientific advisory board, and speaker honoraria from UCB Pharma Australia & Global; investigator‐initiated, scientific advisory board, travel, and speaker honoraria from Eisai Australia & Global; advisory board honoraria from Liva Nova; educational grants from Novartis Pharmaceuticals, Pfizer Pharmaceuticals, and Sanofi‐Synthelabo; educational; travel and fellowship grants from GSK Neurology Australia; and honoraria from SciGen Pharmaceuticals. He has shareholdings in the device company EpiMinder. S.F. Berkovic is supported by a Program Grant from the National Health and Medical Research Council of Australia (APP1091593). He reports grants from Eisai, UCB Pharma, and SciGen; has a patent for SCN1A licensed to various diagnostic companies with no financial return, a patent for PRRT2 gene licensed to Athena Diagnostics, and a patent for Diagnostic and Therapeutic Methods for Epilepsy and Mental Retardation Limited to Females (EFMR) licensed to Athena Diagnostics. J‐P. Nicolo has received consulting fees to his institution from Eisai and UCB Pharma, both unrelated to the submitted work. T.J. O'Brien is supported by a Program Grant (APP1091593) and Investigator Grant (APP1176426) from the National Health and Medical Research Council of Australia and the Victorian Medical Research Acceleration Fund. He reports grants and consulting fees to his institution from Eisai, UCB Pharma, Praxis, Biogen, ES Therapeutics, and Zynerba. P. Perucca is supported by the Emerging Leadership 2 Investigator Grant from the NHMRC (APP2017651), the Epilepsy Foundation, The University of Melbourne, Monash University, Brain Australia, the Weary Dunlop Medical Research Foundation, and the Norman Beischer Medical Research Foundation. He has received speaker honoraria or consultancy fees to his institution from Chiesi, Eisai, GRIN Therapeutics, the limbic, LivaNova, Novartis, Sun Pharma, Supernus, and UCB Pharma, outside the submitted work. He is an Associate Editor for Epilepsia Open. I.E. Scheffer has served on scientific advisory boards for BioMarin, Chiesi, Eisai, Encoded Therapeutics, GlaxoSmithKline, Knopp Biosciences, Nutricia, Rogcon, Takeda Pharmaceuticals, UCB, Xenon Pharmaceuticals; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, Liva Nova, Nutricia, Zuellig Pharma and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin, Encoded Therapeutics and Eisai; has served as an investigator for Anavex Life Sciences, Cerecin Inc, Cerevel Therapeutics, Eisai, Encoded Therapeutics, EpiMinder Inc, Epygenyx, ES‐Therapeutics, GW Pharma, Marinus, Neurocrine BioSciences, Ovid Therapeutics, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix and Zynerba; and has consulted for Care Beyond Diagnosis, Epilepsy Consortium, Atheneum Partners, Ovid Therapeutics, UCB, Zynerba Pharmaceuticals, BioMarin, Encoded Therapeutics and Biohaven Pharmaceuticals; and is a Non‐Executive Director of Bellberry Ltd and a Director of the Australian Academy of Health and Medical Sciences and the Australian Council of Learned Academies Limited. She may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has a patent for SCN1A testing held by Bionomics Inc and licensed to various diagnostic companies; has a patent molecular diagnostic/theranostic target for benign familial infantile epilepsy (BFIE) [PRRT2] 2011904493 and 2012900190 and PCT/AU2012/001321 (TECH ID:2012‐009). P. Kwan was supported by a Medical Research Future Fund Practitioner Fellowship (MRF1136427). His institution has received research grants from Eisai, GW Pharmaceuticals, SK Life Sciences, UCB Pharma, and LivaNova and has received travel, speaker honoraria, or consultancy fees from Angelini, Eisai, SK Life Sciences, and UCB Pharma.
ETHICS STATEMENT
Australian Human Research Ethics Committee approval for the study was provided by St Vincent's Hospital, Melbourne Health (The Royal Melbourne Hospital), and Austin Health (The Austin Hospital). Approval for data linkage to the Australian National Death Index was granted by the Australian Institute of Health and Welfare (AIHW) Ethics Committee. Access to the Australian National Coronial Information System was granted by the Justice Human Research Ethics Committee.
CONSENT FOR PUBLICATION
We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
ACKNOWLEDGMENTS
This study was funded by GW pharmaceuticals (now part of Jazz Pharmaceuticals) and supported by Chiesi Australia. The study funders played no role in study design, data collection, or data interpretation.
Nightscales R, Chen Z, Barnard S, Auvrez C, Tao G, Sivathamboo S, et al. Applying the ILAE diagnostic criteria for Lennox‐Gastaut syndrome in the real‐world setting: A multicenter retrospective cohort study. Epilepsia Open. 2024;9:602–612. 10.1002/epi4.12894
Contributor Information
Russell Nightscales, Email: R.Nightscales@alfred.org.au.
Patrick Kwan, Email: patrick.kwan@monash.edu.
DATA AVAILABILITY STATEMENT
Data used in this analysis are available from the corresponding author upon request from any qualified researcher for a period of 12 months following publication.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data used in this analysis are available from the corresponding author upon request from any qualified researcher for a period of 12 months following publication.