Discussion
The patient was initially thought to have a generalised epilepsy that responded to treatment. EEG supported the diagnosis. Follow-up EEGs were normal, and it was presumed that the epilepsy had receded with time. On renewed plenary evaluation of the original EEGs from the year of the first seizure, the previously described photoparoxysmal response was no longer interpreted as significant. These previous recordings only provided eight channels, and not 25 as today, thus the coverage of brain activity was less. There was no description of torsade de pointes in the accompanying one-channel ECG in relation to the pathological changes described or her subjective symptoms. Repeated ECGs taken at the emergency department were also described as normal.
Long QT syndrome is most commonly a genetic channelopathy caused by a mutation in genes coding for proteins in ion channels of the heart. At least 12 genes are currently known to cause long QT syndrome, as well as more than 35 genes where a mutation leads to prolonged QT interval (4). The most studied mutations are in the genes KCNQ1, KCNH2 and SCN5A, which are related to potassium and sodium channels. The mutations cause repolarisation disturbances, resulting in prolonged QT interval.
Symptoms are syncope due to ventricular arrhythmias, typically torsade de pointes, but may also be bradycardia and deafness, as in Jervell and Lange-Nielsen syndrome. A certain degree of correlation between genotype and phenotype is often seen (5). In some cases, the manifestation may present as sudden unexpected cardiac death. Due to their hereditary nature, these cases require molecular autopsy to locate family members with the disease who may be amenable to treatment (6). Disease history, family history and ECG are the pillars of diagnosis.
The QT interval is corrected for heart frequency by using Bazett´s formula: QTc = QT / √ RR (c = corrected). Normal QTc values are < 0.44, with a considerable overlap between normally prolonged QTc and pathologically prolonged QT interval. The 99th percentile for men is 0.47 seconds and for women 0.48 seconds, but there are also variations with age (7). Diagnosing long QT syndrome may be difficult (8).
There are both European and international guidelines that advise on the diagnosis of long QT syndrome (3, 9). The guidelines differ slightly in details, but diagnosis is mainly based on the presence of a known pathogenic mutation (in the majority) or QTc > 500 ms on repeated measurements or a LQTS-risk score of > 3. The diagnosis may be considered if a LQTS score = 2–3 (10). Table 1 (2) shows the criteria for calculation of such a score, which have have been tested in a large population of children (Schwartz criteria) (11). The Schwartz criteria have since been modified. The criteria are especially important in the absence of genetic testing or when genetic testing is negative (2). An important aspect of these criteria, is that long QT syndrome may be diagnosed with QTc as low as 450 ms in men (Table 1).
Table 1
Schwartz criteria for diagnosing long QT syndrome, after Schwartz PJ, Crotti L. QTc Behavior During Exercise and Genetic Testing for the Long-QT Syndrome (2). Score: ≤ 1 low probability of LQTS, 1.5–3 intermediate probability of LQTS, ≥ 3.5 high probability of LQTS. 1In the absence of medications or disorders known to affect these electrocardiographic features. 2QTc calculated using Bazett's formula where QTc=QT/√RR. 3Mutually exclusive. 4Resting heart rate below the 2nd percentile for age. 5The same family member cannot be counted in both A and B.
| ECG findings1 |
Points |
| A QTc2 |
|
| ≥ 480 ms |
3 |
| 460–479 ms |
2 |
| 450–459 ms (men) |
1 |
| QTc ≥ 480 ms in minute 4 after completed stress test |
1 |
| C Torsade de pointes3 |
2 |
| D T-wave alternans |
1 |
| E Jagged T-wave in 3 leads |
1 |
| F Low cardiac frequency for age4 |
0.5 |
| Disease history |
|
| A Syncope3 |
|
| With stress |
2 |
| Without stress |
1 |
| B Congenital deafness |
0.5 |
| Family history |
|
| A Family members with confirmed LQTS5 |
1 |
| B Sudden unexplained cardiac death in close family members under the age of 305 |
0.5 |
Typically the inheritance in long QT syndrome is autosomal dominant. The incidence is probably between 1: 2 000 and 1: 2 500 (11, 12). In recent years, genetic testing has become more easily accessible and has become an important tool in diagnosing genetic causes of sudden cardiac death.
Indications for genetic testing of long QT syndrome are first of all a strong clinical suspicion based on clinical findings or family history, in addition to prolonged QT interval in ECG. Furthermore, it may be suspected in asymptomatic individuals with an obviously prolonged QTc (> 0.50 sec) where no other cause is present. The third group that should be investigated is first degree relatives in families where a distinct pathogenic mutation is proven (10).
Clinical manifestations may occur at any time of life, but are most common before the age of 30. Depending on subtype, several different triggers are known – physical exercise and especially swimming in long QT syndrome type 1, emotional triggers and especially auditory stimulating factors in type 2, rest and sleep in type 3 (5).
The clinical background for the assumption of a common pathophysiological substrate between epilepsy and long QT syndrome has mainly been limited to case reports (13–16). The proteins that are coded in the KCNH2 gene are also found in ion channels in the astrocyte membrane of the hippocampus. This association is postulated as a possible explanation for the link between long QT syndrome and epilepsy (14–17). Further, it is shown that patients with long QT syndrome type 2 more often have a history that includes epileptic seizures and are more often treated with antiepileptic drugs than patients with long QT syndrome types 1 and 3 (17).
In a prevalence study of patients with long QT syndrome, it was found that 15 % of those with clinical seizures or seizure-like episodes had epileptiform activity in EEG recordings (18). Exome sequencing of patients with sudden unexpected death in epilepsy have shown mutations in clinically relevant genes coding for arrhythmia and epilepsy (19).
Animal studies have also described mutations in the KCNQ1 gene causing epileptic seizures with concomitant epileptiform activity in EEG, and in addition malignant cardiac arrhythmia (20). In a large-scale study of genetic biomarkers and the risk of seizures in long QT syndrome, it was found that LQTS2 mutations in the KCNH2 pore region were positive predictors of both arrhythmias and seizures. In contrast, mutations in the cyclic nucleotide-binding domain (cNBD) of KCNH2 gave a negative risk of seizures but not arrhythmias. LQTS2, KCNH2-pore, KCNH2-cNBD, QTc and sex were independent predictors of seizures (21). Furthermore, the literature describes a patient with presumed long QT syndrome whose ICD required explantation and who is now treated by an epileptologist (22).
It is important to diagnose long QT syndrome and investigate close family members due to the availability of good and effective ways to prevent serious events. Drugs that prolong the QT interval must be avoided in patients with a proven mutation and in all patients diagnosed with long QT syndrome. In cases where these drugs are given, proper follow-up must be provided. Web pages are available with updated lists of the relevant drugs (23).
Whether our patient originally had genuine epilepsy that was outgrown is uncertain, but incidental presence of both diseases is of course possible. However, epileptiform activity was only determined in a single EEG recording in the year of her first seizure. This was more or less refuted in the retrospective plenary assessment, but that took place in a new and different EEG era. The fact that long QT syndrome was diagnosed in adulthood does not exclude the diagnosis of epilepsy in her teenage years.
When the episodes of loss of consciousness returned and a plausible cause presented itself in the patient history, reinitiation of antiepileptic medication would have been an easy step to take. In this particular case, such an approach could have brought about serious consequences by exacerbating the existing arrhythmia and increasing the risk of sudden death associated with torsade de pointes. The risk associated with antiepileptic drugs, either alone or in combination, has been described (24).
This patient case is a reminder of the importance of a constant re-evaluation of any diagnosis in a patient at any time in the course of disease. Additionally, it underlines the importance of measuring the corrected QT interval in loss of consciousness that is not obviously explained by the circumstances. In the case of recurring seizures that are not unequivocally consistent with a cardiac aetiology, a control EEG should be performed with repeated intermittent photic stimulation.