FULL-LENGTH ORIGINAL RESEARCH
Early and effective treatment of KCNQ2 encephalopathy *Tiziana Pisano, †Adam L. Numis, ‡Sin ead B. Heavin, §¶Sarah Weckhuysen, #Marco Angriman, §¶Arvid Suls, **Barbara Podesta, ††Ronald L. Thibert, †Kevin A. Shapiro, *‡‡Renzo Guerrini, ‡Ingrid E. Scheffer, *Carla Marini, and †§§Maria Roberta Cilio Epilepsia, **(*):1–7, 2015 doi: 10.1111/epi.12984
SUMMARY
Tiziana Pisano is a senior consultant at the pediatric neurology unit of the Meyer Children’s Hospital, Florence, Italy.
Objectives: To describe the antiepileptic drug (AED) treatment of patients with early infantile epileptic encephalopathy due to KCNQ2 mutations during the neonatal phase and the first year of life. Methods: We identified 15 patients and reviewed the electroclinical, neuroimaging, and AED treatment data. Results: Seizure onset was between 1 and 4 days of age with daily tonic asymmetric, focal and clonic seizures in nine patients and status epilepticus in the remaining six. Electroencephalography (EEG) showed multifocal epileptiform abnormalities in nine patients and a burst-suppression pattern in six. All patients were trialed with adequate daily doses of several AEDs before they reached seizure freedom. Six patients (40%) achieved seizure control within 2 weeks of carbamazepine (CBZ) administration and five (33%) were seizure-free with phenytoin (PHT). The last four patients (27%) were successfully treated with topiramate (TPM) (two patients), levetiracetam (LEV) (one), and a combination of LEV with TPM (one). Most patients reached seizure freedom within the first year of life and remained seizure-free thereafter. Twelve patients had moderate-to-severe developmental delay at follow-up. However, the two patients whose seizures ceased within a few days of onset showed only mild cognitive impairment. Significance: Our findings suggest that drugs acting on sodium channels including CBZ and PHT should be considered as first-line treatment in patients with KCNQ2 encephalopathy. Voltage-gated sodium and potassium channels co-localize at the neuronal membrane. Therefore, the efficacy of drugs acting as sodium-channel blockers could be linked to their modulating effect on both channels. The type of KCNQ2 mutation might influence AED response as well as developmental outcome. Early recognition of KCNQ2 encephalopathy followed by the most appropriate and effective treatment may be important for reducing the neurodevelopmental impairment associated with this disorder. KEY WORDS: Epilepsy, KCNQ2 encephalopathy, Antiepileptic drug treatment.
Accepted March 3, 2015. *Neurology Unit and Laboratories, A. Meyer Children’s Hospital, Florence, Italy; †Department of Neurology, University of California, San Francisco, San Francisco, California, U.S.A.; ‡Departments of Medicine and Paediatrics, Florey Institute, Austin Health and Royal Children’s Hospital, University of Melbourne, Melbourne, Victoria, Australia; §Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; ¶Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; #Central Hospital of Bolzano, Bolzano, Italy; **Child Neurology and Psychiatry Unit, S. Croce and S. Carlo Hospital, Cuneo, Italy; ††Pediatric Epilepsy Program, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A.; ‡‡University of Florence, Florence, Italy; and §§Department of Pediatrics, University of California San Francisco, San Francisco, California, U.S.A. Address correspondence to Carla Marini, Neurology Unit, A. Meyer Children’s Hospital, Viale Pieraccini 24, Florence, Italy. E-mail: [email protected] Wiley Periodicals, Inc. © 2015 International League Against Epilepsy
1
2 T. Pisano et al. Early infantile epileptic encephalopathies (EIEEs) are a heterogeneous group of severe epilepsies with multiple seizure types beginning in infancy with a poor motor and cognitive prognosis.1,2 EIEEs may be caused by structural abnormalities, either congenital or acquired, and most often have a genetic etiology. Online Mendelian Inheritance in Man (OMIM) recognizes 24 EIEE with mutations in specific genes (http:// www.ncbi.nlm.nih.gov/omim). In the past few years, the application of whole exome/genome sequencing techniques has led to an explosion of epilepsy gene discoveries, and new EIEE genes are identified almost every month.3,4 Molecular genetic analyses have also highlighted the challenges in genotype–phenotype correlation. Indeed, mutations in the same gene can cause both benign and severe epilepsies. KCNQ2 gene encoding a voltage-gated potassium (K) channel and first associated with benign familial neonatal seizures (BFNS),5–7 is also responsible for about 10% of EIEE with neonatal onset.8–10 BFNS and KCNQ2 encephalopathy represent the opposite ends of a spectrum of epilepsies with neonatal onset. BFNS constitutes the benign end: seizures spontaneously resolve after a few weeks or months and patients have a normal motor and cognitive outcome. At the opposite extreme is KCNQ2 encephalopathy, with intractable seizures and severe developmental delay. In a recent study, Numis et al.11 observed a dramatic response, with seizure freedom, to carbamazepine (CBZ) in three patients with KCNQ2 encephalopathy. Here, we seek to confirm this finding in a larger cohort of patients and provide evidence that treatment with phenytoin (PHT), either intravenous or orally, is also effective in the early treatment. In this report, we reviewed electroclinical data of 15 patients with KCNQ2 encephalopathy in particular with regard to the response to antiepileptic drug (AED) treatment at onset in the neonatal period, and in the first year of life.
Methods Patient recruitment We identified 15 patients with EIEE due to heterozygous KCNQ2 mutations through an international collaboration involving four centers. Nine patients have been included in previously published papers (patient 68; patients 1, 2, 7, and 89; patients 9 and 1012; and patients 12 and 1311). One patient from our previous report11 was not included because of an early death in the first month of life due to respiratory infection. Clinical information was obtained directly from the parents, medical records or the referring physicians. The original clinical, ictal, and interictal video–electroencephalography (EEG) data, brain magnetic resonance imaging (MRI), and AED treatment of all patients were reviewed by pediatric neurologists and neurophysiologists (TP, Epilepsia, **(*):1–7, 2015 doi: 10.1111/epi.12984
ALN, MA, RT, IES, CM, and MRC). Developmental delay and cognitive impairment were assessed using developmental milestones, current functioning, and neurological examination. The degree of cognitive impairment was assessed qualitatively with a developmental quotient (DQ) based on acquisition of developmental milestones, with scores of 70 and below indicative of cognitive impairment. In nine patients, DQ was quantitatively assessed with the Griffiths or Brunet Lezine development scale.13 KCNQ2 mutations were identified using Sanger sequencing as described previously.8 The study was approved by the human research ethics committee of the Meyer Children’s Hospital, Austin Health and Royal Children’s Hospital, University of Antwerp, and Benioff Children’s Hospital.
Results Clinical history The study included 15 patients (8 male) ages 6 months to 12 years (mean 4.7 years; median 3.5 years); follow-up ranged from 10 months to 9 years (mean and median 2.8 years). Table 1 summarizes the electroclinical features of each patient and AEDs are listed in the sequence that they were prescribed. In addition to the AEDs listed in Table 1, and following the guidelines for neonatal treatment of seizures,14 12 patients were also trialed with adequate dose of pyridoxine, 7 received pyridoxal-phosphate, 2 received biotin, and one received folinic acid. Benzodiazepines including clobazam and midazolam were also used in most patients. Seizure onset was between the first and fourth days of life (mean and median 2 days). Nine patients (60%) had daily seizures (>15/day); their EEG recordings showed multifocal epileptiform abnormalities in six (67%) and burst-suppression (BS) pattern in three (33%). The remaining six patients (40%) presented with status epilepticus (SE). EEG recordings showed a BS pattern in three (50%) and multifocal epileptiform abnormalities in three. In most patients, seizures were characterized by asymmetric tonic posturing, often accompanied by apnea, and at times followed by focal clonic activity. Fourteen patients were trialed with several AEDs before they reached seizure freedom (see below and Table 1); one patient continues to have about two seizures per week. Cognitive and motor development At onset, all patients showed axial hypotonia. During follow-up, cognitive impairment emerged for all patients and was mild in three (20%), moderate in five (33%), and severe in seven (47%). Severe impairment of motor function including spastic quadriplegia and diplegia was also observed in nine patients (60%).
3 AED Treatment in KCNQ2 Encephalopathy Treatment Figure 1 illustrates the AED history of each patient; ultimately, all but one patient were seizure-free. Six patients (40%), four with SE and two with intractable seizures, achieved seizure freedom within 2 weeks of CBZ administration that was added at ages ranging from 12 days to 13 months, and at daily doses ranging from 15 to 20 mg/ kg/day (see Table 1: patients 3, 4, 9, 12, 13, and 15). Two patients (4 and 13, see Table 1) had failed to respond to PHT in the neonatal period despite adequate titration and dosage of the drug. All patients remained on CBZ, CBZ withdrawal was attempted in patient 4 at age 5 years, but seizures recurred within 2 weeks and CBZ was reintroduced. Five patients (33%) were seizure-free following intravenous (two patients) or oral (three patients) PHT administration. Intravenous administration of PHT was given with a single bolus of 18 mg/kg, whereas oral intake ranged from 5 to 7 mg/kg/day. In two patients, PHT was given for neonatal SE and produced complete and persistent seizure control within hours, with disappearance of the BS pattern. Both patients were then changed to CBZ for ongoing treatment at doses ranging from 15 to 20 mg/kg/day. Of the remaining three neonates treated with PHT, patient 6 was seizure-free from 2 to 13 months until PHT was weaned, and seizures recurred within 5 days of discontinuing PHT. PHT was reintroduced and she became seizurefree again at 14 months. However, at 3.5 years of age, 16 h after pertussis immunization and still on PHT, she presented with a 25-min convulsive seizure, complicated by hepatic and renal failure and pancreatitis, requiring prolonged intensive care admission. Treatment with PHT and levetiracetam A Figure 1. Antiepileptic drug (AED) treatment of each patient. The vertical axis displays the seizure frequency ranging from status epilepticus (SE) or daily seizures to seizure-free. The horizontal axis represents the AEDs; each line corresponds to a patient. (A) AED profile of six patients who became seizure-free on carbamazepine (CBZ). (B) AED profile of five patients who became seizure-free on phenytoin (PHT). (C) AED profile of four patients who became seizure-free on topiramate (TPM), on levetiracetam (LEV), or levetiracetam with topiramate. SE, status epilepticus; sz, seizures; VPA, valproic acid; VGB, vigabatrin; OXC, oxcarbazepine Epilepsia ILAE
(LEV) rendered her seizure-free. At 4.4 years, PHT was decreased from 3.7 to 2 mg/kg/day and seizures recurred; PHT was subsequently increased to the original dose. At 5 years, CBZ was commenced, but it caused sedation and irritability and so it was discontinued. At 5.3 years, the introduction of oxcarbazepine also caused sedation and irritability and was discontinued. LEV was also weaned at this time. At 6 years, PHT was increased to 4.2 mg/kg/day, again fully controlling seizures. Patient 7 was seizure-free from 2 to 9 months on PHT but seizures recurred within 1 week after it was discontinued. The patient was then switched to LEV (13 mg/kg/day) and valproate (38.5 mg/ kg/day) for ongoing treatment. Patient 14 received PHT at age 5 months, which resulted in seizure freedom, and was then switched to rufinamide monotherapy at 13 months and is still seizure-free at 23 months. Two patients (13%, patients 8 and 11) responded to topiramate (TPM). Patient 11 became seizure-free at age 2 years on TPM at 6.25 mg/kg/day; it was the fourth AED to be introduced and he had not had CBZ or PHT. However, patient 8, after an initial response to TPM at a dose of 9.6 mg/kg/day continued to have two focal seizures per week during sleep; he also had not had CBZ or PHT. In the remaining two patients (13%, patients 10 and 5), monotherapy with LEV (40 mg/kg/day) and a combination of LEV (50 mg/kg/day) with TPM (9 mg/kg/day) produced seizure freedom at ages 2 years and 2 months, respectively. Neuroimaging Brain imaging was normal in six patients (40%). The remaining nine patients (60%) showed variable T1 and/or B
C
Epilepsia, **(*):1–7, 2015 doi: 10.1111/epi.12984
Age at sz onset (d)
1
1
3
1
1
1
2
2
3
1
2
4
ID/sex
1F
2M
Epilepsia, **(*):1–7, 2015 doi: 10.1111/epi.12984
3F
4F
5M
6F
7F
8M
9M
10F
11M
12M
1.8 y
12.2 y
4.7 y
2.7 y
4.10 y
10.1 y
6.10 y
11 m
8.6 y
3.7 y
3.5 y
3.6 y
Age at time of the study
(SE) Tonic asymmetric, apnea
Tonic–clonic
Clonic
Tonic asymmetric, apnea Tonic, lips pursing, eyes clenching, cyanosis Tonic asymmetric
Tonic
Focal
SE (tonic asymmetric, apnea)
Tonic asymmetric
SE (tonic asymmetric, apnea)
SE (tonic asymmetric, apnea)
Sz type at onset
MultiF ED, intermixed attenuations
MultiF ED
MultiF ED
Temporal ED
BS
MultiF ED
BS
MultiF ED
BS
BS
BS
BS
EEG at onset
PB (20 mg/kg/d), VPA (25 mg/kg/d), VGB (120 mg/kg/d); TPM (6 mg/kg/d, effective) PB IV (20 mg/kg repeated loads + 7 mg/kg/d for 45 d), LEV IV (50 mg/kg/d for 60 d) TPM 22 mg/kg/d or 45 d, VGB (150 mg/kg/d for 14 d) CBZ (20 mg/kg/d, effective)
PB, LEV, TPM (2 mg/kg/d) (effective but AE), CBZ (20 mg/kg/d, effective) VGB, PHT, VPA, LEV (40 mg/kg/d, effective)
PB IV (20 mg/kg) load, PHT IV (18 mg/kg, effective) PHT oral (7 mg/kg/d), CBZ (15 mg/kg/d) PB IV (20 mg/kg) load, PHT IV (18 mg/kg, effective), PHT oral (7 mg/kg/d), CBZ (15 mg/kg/d) PB IV (20 mg/kg load, 7 mg/kg/d os) for 2 w, LEV (50 mg/kg/d) for 2 w, VGB (100 mg/kg/d) for 1 m, CBZ (20 mg/kg/d, effective) PB IV (20 mg/kg) for 2 d, PHT IV (18 mg/kg) load; LEV IV (45 mg/kg) CBZ (15 mg/kg/d, effective) PB (8 mg/kg/d) for 23 d, PHT (6 mg/kg/d) for 12 d (partially effective), LEV 50 mg/kg/d), TPM (9 mg/kg/d), LEV and TPM, effective) PB, LEV (32 mg/kg/d) CBZ (AE), OXC (AE), PHT (4 mg/kg/d, effective) LEV (13 mg/kg/d) and VPA (38.5 mg/kg/d) for ongoing treatment PB IV (effective but AE), LEV (13 mg/kg/d), VPA (38.5 mg/kg/d) PHT (5 mg/kg/d) PB, LEV (50 mg/kg/d), VPA (30 mg/kg/d), TPM (9.6 mg/kg/d, effective)
AED treatment
SF at 3.5 m
SF at 2 y
SF at 2 y
SF at 11 m
2 sz 9 week
SF at 2 m
SF at 2 m
SF at 2 m
Moderate cognitive impairment Severe cognitive impairment and quadriplegia Moderate cognitive impairment Severe cognitive impairment and quadriplegia Severe cognitive impairment and quadriplegia Severe cognitive impairment and quadriplegia
Severe cognitive impairment and quadriplegia
Severe cognitive impairment and quadriplegia Mild global impairment
Moderate cognitive impairment and diplegia
SF at 11 m
SF at 2 m
Moderate cognitive impairment
Mild cognitive impairment
Psychomotor development outcome
SF at 2 m
SF at 7 d
Epilepsy outcome
Table 1. Patients electroclinical features
c.1734G>C p.Met578Ile
c.613A>G p.Ile205Val
c.587G>A p.Ala196Val c.602C>T p.Arg201His
6y
c.638G>A p.Arg213Gln (inherited from mosaic father) c.1666A>G p.Lys556Glu c.973A>G p.Arg325Gly
Continued
1y
8y
2y
1.5 y
3.5 y
9y
11 m
7y
2.10 y
2.9 y
2.8 y
Follow-up
c.802C>T p.Leu268Phe
c.881C>T p.Ala294Val
c.1655A>C p.K552TI
c.629G>A p.Arg210His
c.629G>A p.Arg210His
KCNQ2 mutation
4
T. Pisano et al.
5
MultiF ED (SE) Tonic asymmetric 2 15M
10 m
MultiF ED Tonic asymmetric 5m 3 14F
T2 hyperintensities in the basal ganglia, thalami, or hippocampus (Table 1; patients 1, 12, 14, and 15), thinning of the corpus callosum (Table 1; patients 2, 6, 7 and 13), or diffuse hypomyelination with volumetric reduction of the frontal lobes (Table 1; patients 5 and 13). In four of these nine patients (Table 1; patients 6, 12, 14, and 15), follow-up MRI studies at 23, 33, and 42 months were normal.
BS, burst suppression; d, day; ED, epileptiform discharge; F, female; m, months; M, male; MultiF, multifocal; SE, status epilepticus; SF, seizure-free; sz, seizures; y, year; w, week.
10 m c.841G>T p.Gly281Trp (novel) Mild cognitive/moderate motor impairment and quadriplegia SF at 14 d
2y c. 1678 C>T p.Arg560Trp Mild to moderate cognitive impairment SF at 5 m
2.5 y c.973 A>G p.Arg325Gly Severe cognitive impairment and quadriplegia SF at 1.1 y
PB (20 mg/kg load then 5 mg/kg for 2 y), LEV (50 mg/kg/d) for 60 d, PHT IV 18 mg/kg then 7 mg/kg for 14 d, VGB (80 mg/kg/d) for 30 d, TPM (5 mg/kg/d load, then 7 mg/kg/d for 1 y, CBZ (20 mg/kg/d, effective) PB IV (20 mg/kg load + 8.5 mg/kg/d for 15 m), LEV IV (20 mg/kg + 75 mg/kg/d for 4 m), TPM (12 mg/kg/d) for 2 m, PHT (13 mg/kg/d, effective), RUF for ongoing treatment PB (30 mg/kg load + 5 mg/kg/d for 11 d) LEV 30 mg/kg load + 30 mg/kg/d for 3 d), CBZ (20 mg/kg/d, effective) MultiF ED, intermixed attenuations (SE) Tonic asymmetric, apnea 1 13M
2.6 y
AED treatment EEG at onset Sz type at onset ID/sex
Age at time of the study Age at sz onset (d)
Table 1. Continued.
Epilepsy outcome
Psychomotor development outcome
KCNQ2 mutation
Follow-up
AED Treatment in KCNQ2 Encephalopathy
Genetic findings All patients had a heterozygous KCNQ2 missense mutation; 14 were de novo and one was inherited from a mosaic father who had the mutant allele in 30% of his lymphocytes and was mildly affected with a history consistent with BFNS. He had seizures from day 4 to 11 weeks of life, followed by six tonic–clonic seizures between 4 and 32 years of age. He also had myokymia and remained on CBZ. Two mutations recurred (two patients with each) and were associated with the same electroclinical and imaging phenotype.
Discussion The 15 patients reported herein share the typical electroclinical and MRI features of KCNQ2 encephalopathy (8 were reported previously8,9,11,12). The hallmark of this disorder is the onset of refractory seizures within the first few days of life. Seizures are tonic, and often asymmetric with ocular symptoms, apnea, and other autonomic signs. At onset, EEG shows multifocal epileptiform activity or a BS pattern. Brain imaging may reveal hypoplasia of the corpus callosum, hyperintensity in the basal ganglia, and diffuse hypomyelination.8 Motor and cognitive deficits are evident from birth and continue with different degrees of severity in all patients.9 There is only one report that focuses on AED treatment in KCNQ2 encephalopathy,11 together with limited information about drug therapy in other studies.9,15 About 50 patients with KCNQ2 encephalopathy have been reported to date, with the efficacy of AED being variable and, to date, no recommendations have been made about how to optimally treat this severe condition.15,16 The aim of this study was to review the AED treatment of a large series of patients with KCNQ2 encephalopathy. We searched for possible drugs or drug associations that might be more effective than others to treat both SE and recurrent seizures. All patients described had seizure onset in the first week of life and failed to respond to several AEDs. Because patients were treated at different centers and had variable ages at the time of study, AED treatment was heterogeneous and different drugs and doses were used. We observed that 53% of the patients were seizure-free on CBZ (six at onset and two switched to CBZ following PHT), whereas 33% responded to PHT. In two of these patients, PHT was administered intravenously during the acute phase of SE producing immediate seizure control. The remaining 27% of the patients responded to TPM and LEV, Epilepsia, **(*):1–7, 2015 doi: 10.1111/epi.12984
6 T. Pisano et al. and only one patient had recurrent seizures during followup. Two patients were treated with steroids without any efficacy. One previously reported patient with KCNQ2 encephalopathy became seizure-free with adrenocorticotropic hormone (ACTH) therapy at 3 months of life.16 Patients with KCNQ2 mutations associated with a BFNS phenotype have seizures that remit spontaneously in the first year of life, even though, in a small percentage of families, recurrence may occur later in life. The evidence that patients with KCNQ2 encephalopathy also become seizure-free at a certain age might suggests that, independent of AED treatment, seizures have restricted temporal expression related to KCNQ2 function. However, 93% of our patients were seizure-free, whom 80% by 13 months of age, and 13% were seizure-free in the first 2 weeks of life. Of interest, these two patients only had mild cognitive impairment. Although seizure remission has been reported in some patients with KCNQ2 encephalopathy,8,9 only one patient was seizurefree by 3 months of age, and the median age of seizure freedom was 24 months.8,9 All patients reported here had a high seizure burden before responding to CBZ or PHT. In addition, seizure recurrence in three patients following a brief phase of sodium-channel (Na-channel) blocker discontinuation emphasizes the extreme drug sensitivity of this disorder. Maintenance of seizure freedom is important to minimize developmental regression associated with refractory seizures or SE. All of our patients had developmental impairment with a spectrum of severity ranging from mild to severe, and including spastic quadriplegia. Although preliminary, our data on neurodevelopmental outcome suggest that children with early optimized treatment producing seizure control may have a better outcome compared with the others. The nature of the KCNQ2 mutation might also influence the overall outcome, including seizures and neurodevelopment as demonstrated by in vitro experimental studies, therefore, suggesting the presence of phenotype–genotype correlations.17 PHT and CBZ are sodium-channel blockers with a wellknown mechanism of action.18 Drugs targeting sodium channels block the movement of sodium ions through the channels during propagation of the action potential and thus block and prevent the development of seizure activity.19 Seemingly disparate, voltage-gated sodium channels and KCNQ potassium channels co-localize and are bound at critical locations of the neuronal membrane.20 The response to sodium-channel blockers in patients with potassiumchannel disorders could be explained by structure–function approaches showing that modulation of one channel may significantly affect the function of the channel complex.21 A better understanding of why and how these AEDs are effective in KCNQ2 encephalopathy may improve the pathophysiologic knowledge of this severe disorder. Several cellular targets have been proposed to be relevant to the therapeutic activity of TPM, and these include voltEpilepsia, **(*):1–7, 2015 doi: 10.1111/epi.12984
age-gated sodium channels,22 like CBZ and PHT. LEV acts on SV2A, a vesicle-docking protein, and we cannot explain the response to this drug in two patients.23 Retigabine, which is not yet approved for use in the pediatric population, is a promising drug and has a mechanism of action that markedly differs from that of any of the current AEDs.24 Retigabine acts as a neuronal KCNQ/kv7K channel opener and may provide a targeted treatment for KCNQ2 encephalopathy.25 Unfortunately, it has recently been associated with the side effect of blue discoloration in the digits and retina, which will delay trials of it or await the development of an analog with a safer profile.26 We suggest that CBZ and PHT are considered as first-line therapy for SE in neonates with KCNQ2 encephalopathy. With the ready availability of intravenous administration and blood level monitoring, the efficacy and substantial experience to date, PHT is ideal for SE in this disorder. However, the nonlinear kinetics and the long-term adverse effects make oral PHT less suitable for chronic treatment. CBZ has proven to be rapidly effective in our patients with recurrent seizures as well as in those with SE. CBZ is rarely used in neonates; however, we have shown that in KCNQ2 encephalopathy, CBZ can be an effective treatment even in the neonatal period. We believe that a targeted therapeutic approach should be considered in the neonatal epilepsies, since in many aspects they differ from the most common acute neonatal seizures for which protocols have been already been established.14 Yet, for those neonates with seizures that are not attributable to a specific cause and for whom a genetic etiology is suspected, early trial of PHT and CBZ should be considered. Finally, the importance of early recognition of this phenotype cannot be overstated as some of our patients were successfully treated with PHT or CBZ in the first few days of life, well before the results of genetic testing were available. Our retrospective study reports on 15 patients from four institutions. The limitations of referral bias and different treatment strategies are noted in such a series. Although institutional paradigms of neonatal seizure management vary, herein we report that antiepileptic agents with voltagegated sodium-channel blockade, specifically CBZ and PHT, may be considered as first line for treating patients with KCNQ2 encephalopathy, allowing for improved insight on drug-specific effects on seizures in patients with this rare disorder. Given the high seizure burden and developmental delay, we hope to improve recognition of this electroclinical phenotype so that these agents, which are seldom used in acute neonatal seizure management, are trialed early in the disease course. Therapies for treating rare diseases need their efficacy and safety evaluated, but due to the small number of potential trial participants, a standard randomized-controlled trial is often not feasible without large multinational collaboration. Prospective studies with appropriate design are warranted to confirm our observation.
7 AED Treatment in KCNQ2 Encephalopathy
Acknowledgments We thank the patients and their families for participating in our research. We thank Piras Maria Francesca for technical support. The study was supported by the RF-2009-152669 grant from the Italian Ministry of Health and Education and the National Health and Medical Research Council of Australia. AS is a postdoctoral fellow of the National Fund for Scientific Research Flanders (FWO). Prof Guerrini received honoraria from Biocodex, UCB, Eisai Inc., ValueBox, and ViroPharma, and research support from the Italian Ministry of Health, the European Community Sixth and Seventh Framework Thematic Priority Health, the Italian Ministry of Education, University and Research, the Tuscany Region, the Telethon Foundation, and the Mariani Foundation. Prof Scheffer has received support from, and/or has served as a paid consultant for UCB, Athena Diagnostics, GlaxoSmithKline, Janssen-Cilag EMEA, and Transgenomics and Biocodex.
Disclosure of Conflict of Interest Dr. Pisano, Dr. Numis, Dr. Heavin, Dr. Weckhuysen, Dr. Angriman, Dr. Suls, Dr. Podesta, Dr. Marini, and Prof Cilio report no disclosures. 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.
References 1. Cross JK, Guerrini R. The epileptic encephalopathies. Handb Clin Neurol 2013;111:619–626. 2. Esmaeeli Nieh S, Sherr EH. Epileptic encephalopathies: new genes and new pathways. Neurotherapeutics 2014;11:796–806. 3. Epi4K Consortium, Epilepsy Phenome/Genome Project, Allen AS, et al. De novo mutations in epileptic encephalopathies. Nature 2013;501:217–221. 4. EuroEPINOMICS-RES Consortium, Epi4K Consortium, Epilepsy Phenome/Genome Project. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet 2014;95:360–370. 5. Leppert M, Anderson VE, Quattlebaum T, et al. Benign familial neonatal convulsions linked to genetic markers on chromosome 20. Nature 1989;337:647–648. 6. Singh NA, Charlier C, Stauffer D., et al. A novel potassium channel gene, KCNQ2, is mutated an inherited epilepsy of newborns. Nat Genet 1998;18:25–29. 7. Biervert C, Steinlein OK. Structural and mutational analysis of KCNQ2, the major gene locus for benign familial neonatal convulsions. Hum Genet 1999;104:234–240.
8. Weckhuysen S, Mandelstam S, Suls A, et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol 2012;71:15–25. 9. Weckhuysen S, Ivanovic V, Hendrickx R, et al. Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients. Neurology 2013;81:1697–1703. 10. Milh M, Boutry-Kryza N, Sutera-Sardo J, et al. Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2. Orphanet J Rare Dis 2013;8:80. 11. Numis AL, Angriman M, Sullivan JE, et al. KCNQ2 encephalopathy: delineation of the electroclinical phenotype and treatment response. Neurology 2014;82:368–370. 12. Carvill GL, Heavin SB, Yendle SC, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet 2013;45:825–830. 13. Murray G, Jones P, Kuh D, et al. Infant developmental milestones and subsequent cognitive function. Ann Neurol 2007;62:128–136. 14. Volpe JJ. Neonatal seizures. In Volpe JJ (Ed) Neonatal neurology. 5th Ed. Philadelphia, PA: WB Saunders, 2008:203–244. 15. Kato M, Yamagata T, Kubota M, et al. Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation. Epilepsia 2013;54:1282–1287. 16. Serino D, Specchio N, Pontrelli G, et al. Video/EEG findings in a KCNQ2 epileptic encephalopathy: a case report and revision of literature data. Epileptic Disord 2013;15:158–165. 17. Miceli F, Soldovieri MV, Ambrosino P, et al. Genotype–phenotype correlations in neonatal epilepsies caused by mutations in the voltage sensor of K(v)7.2 potassium channel subunits. Proc Natl Acad Sci U S A 2013;110:4386–4391. 18. Ambrosio AF, Silva AP, Malva JO, et al. Carbamazepine inhibits Ltype Ca2+ channels in cultured rat hippocampal neurons stimulated with glutamate receptor agonists. Neuropharmacology 2010;38:1349– 1359. 19. Arya R, Glauser TA. CNS pharmacotherapy of focal epilepsy in children: a systematic review of approved agents. Drugs 2013;27:273– 286. 20. Pan Z, Kao T, Horvath Z, et al. A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. J Neurosci 2006;26:2599–2613. 21. Nguyen HM, Miyazaki H, Hoshi N, et al. Modulation of voltage-gated K+ channels by the sodium channel ß1 subunit. Proc Natl Acad Sci U S A 2012;109:18577–18582. 22. Shank RP, Gardocki JF, Streeter AJ, et al. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia 2000;41:3–9. 23. Lyseng-Williamson KA. Levetiracetam: a review of its use in epilepsy. Drugs 2011;71:489–514. 24. Barrese V, Miceli F, Soldovieri MV, et al. Neuronal potassium channel openers in the management of epilepsy: role and potential of retigabine. Clin Pharmacol 2010;2:225–236. 25. Gunthorpe MJ, Large CH, Sankar R. The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy. Epilepsia 2012;53:412–424. 26. Splinter MY. Efficacy of retigabine in adjunctive treatment of partial onset seizures in adults. J Cent Nerv Syst Dis 2013;5:31–41.
Epilepsia, **(*):1–7, 2015 doi: 10.1111/epi.12984
Early and effective treatment of KCNQ2 encephalopathy *Tiziana Pisano, †Adam L. Numis, ‡Sin ead B. Heavin, §¶Sarah Weckhuysen, #Marco Angriman, §¶Arvid Suls, **Barbara Podesta, ††Ronald L. Thibert, †Kevin A. Shapiro, *‡‡Renzo Guerrini, ‡Ingrid E. Scheffer, *Carla Marini, and †§§Maria Roberta Cilio Epilepsia, **(*):1–7, 2015 doi: 10.1111/epi.12984
SUMMARY
Tiziana Pisano is a senior consultant at the pediatric neurology unit of the Meyer Children’s Hospital, Florence, Italy.
Objectives: To describe the antiepileptic drug (AED) treatment of patients with early infantile epileptic encephalopathy due to KCNQ2 mutations during the neonatal phase and the first year of life. Methods: We identified 15 patients and reviewed the electroclinical, neuroimaging, and AED treatment data. Results: Seizure onset was between 1 and 4 days of age with daily tonic asymmetric, focal and clonic seizures in nine patients and status epilepticus in the remaining six. Electroencephalography (EEG) showed multifocal epileptiform abnormalities in nine patients and a burst-suppression pattern in six. All patients were trialed with adequate daily doses of several AEDs before they reached seizure freedom. Six patients (40%) achieved seizure control within 2 weeks of carbamazepine (CBZ) administration and five (33%) were seizure-free with phenytoin (PHT). The last four patients (27%) were successfully treated with topiramate (TPM) (two patients), levetiracetam (LEV) (one), and a combination of LEV with TPM (one). Most patients reached seizure freedom within the first year of life and remained seizure-free thereafter. Twelve patients had moderate-to-severe developmental delay at follow-up. However, the two patients whose seizures ceased within a few days of onset showed only mild cognitive impairment. Significance: Our findings suggest that drugs acting on sodium channels including CBZ and PHT should be considered as first-line treatment in patients with KCNQ2 encephalopathy. Voltage-gated sodium and potassium channels co-localize at the neuronal membrane. Therefore, the efficacy of drugs acting as sodium-channel blockers could be linked to their modulating effect on both channels. The type of KCNQ2 mutation might influence AED response as well as developmental outcome. Early recognition of KCNQ2 encephalopathy followed by the most appropriate and effective treatment may be important for reducing the neurodevelopmental impairment associated with this disorder. KEY WORDS: Epilepsy, KCNQ2 encephalopathy, Antiepileptic drug treatment.
Accepted March 3, 2015. *Neurology Unit and Laboratories, A. Meyer Children’s Hospital, Florence, Italy; †Department of Neurology, University of California, San Francisco, San Francisco, California, U.S.A.; ‡Departments of Medicine and Paediatrics, Florey Institute, Austin Health and Royal Children’s Hospital, University of Melbourne, Melbourne, Victoria, Australia; §Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; ¶Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; #Central Hospital of Bolzano, Bolzano, Italy; **Child Neurology and Psychiatry Unit, S. Croce and S. Carlo Hospital, Cuneo, Italy; ††Pediatric Epilepsy Program, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A.; ‡‡University of Florence, Florence, Italy; and §§Department of Pediatrics, University of California San Francisco, San Francisco, California, U.S.A. Address correspondence to Carla Marini, Neurology Unit, A. Meyer Children’s Hospital, Viale Pieraccini 24, Florence, Italy. E-mail: [email protected] Wiley Periodicals, Inc. © 2015 International League Against Epilepsy
1
2 T. Pisano et al. Early infantile epileptic encephalopathies (EIEEs) are a heterogeneous group of severe epilepsies with multiple seizure types beginning in infancy with a poor motor and cognitive prognosis.1,2 EIEEs may be caused by structural abnormalities, either congenital or acquired, and most often have a genetic etiology. Online Mendelian Inheritance in Man (OMIM) recognizes 24 EIEE with mutations in specific genes (http:// www.ncbi.nlm.nih.gov/omim). In the past few years, the application of whole exome/genome sequencing techniques has led to an explosion of epilepsy gene discoveries, and new EIEE genes are identified almost every month.3,4 Molecular genetic analyses have also highlighted the challenges in genotype–phenotype correlation. Indeed, mutations in the same gene can cause both benign and severe epilepsies. KCNQ2 gene encoding a voltage-gated potassium (K) channel and first associated with benign familial neonatal seizures (BFNS),5–7 is also responsible for about 10% of EIEE with neonatal onset.8–10 BFNS and KCNQ2 encephalopathy represent the opposite ends of a spectrum of epilepsies with neonatal onset. BFNS constitutes the benign end: seizures spontaneously resolve after a few weeks or months and patients have a normal motor and cognitive outcome. At the opposite extreme is KCNQ2 encephalopathy, with intractable seizures and severe developmental delay. In a recent study, Numis et al.11 observed a dramatic response, with seizure freedom, to carbamazepine (CBZ) in three patients with KCNQ2 encephalopathy. Here, we seek to confirm this finding in a larger cohort of patients and provide evidence that treatment with phenytoin (PHT), either intravenous or orally, is also effective in the early treatment. In this report, we reviewed electroclinical data of 15 patients with KCNQ2 encephalopathy in particular with regard to the response to antiepileptic drug (AED) treatment at onset in the neonatal period, and in the first year of life.
Methods Patient recruitment We identified 15 patients with EIEE due to heterozygous KCNQ2 mutations through an international collaboration involving four centers. Nine patients have been included in previously published papers (patient 68; patients 1, 2, 7, and 89; patients 9 and 1012; and patients 12 and 1311). One patient from our previous report11 was not included because of an early death in the first month of life due to respiratory infection. Clinical information was obtained directly from the parents, medical records or the referring physicians. The original clinical, ictal, and interictal video–electroencephalography (EEG) data, brain magnetic resonance imaging (MRI), and AED treatment of all patients were reviewed by pediatric neurologists and neurophysiologists (TP, Epilepsia, **(*):1–7, 2015 doi: 10.1111/epi.12984
ALN, MA, RT, IES, CM, and MRC). Developmental delay and cognitive impairment were assessed using developmental milestones, current functioning, and neurological examination. The degree of cognitive impairment was assessed qualitatively with a developmental quotient (DQ) based on acquisition of developmental milestones, with scores of 70 and below indicative of cognitive impairment. In nine patients, DQ was quantitatively assessed with the Griffiths or Brunet Lezine development scale.13 KCNQ2 mutations were identified using Sanger sequencing as described previously.8 The study was approved by the human research ethics committee of the Meyer Children’s Hospital, Austin Health and Royal Children’s Hospital, University of Antwerp, and Benioff Children’s Hospital.
Results Clinical history The study included 15 patients (8 male) ages 6 months to 12 years (mean 4.7 years; median 3.5 years); follow-up ranged from 10 months to 9 years (mean and median 2.8 years). Table 1 summarizes the electroclinical features of each patient and AEDs are listed in the sequence that they were prescribed. In addition to the AEDs listed in Table 1, and following the guidelines for neonatal treatment of seizures,14 12 patients were also trialed with adequate dose of pyridoxine, 7 received pyridoxal-phosphate, 2 received biotin, and one received folinic acid. Benzodiazepines including clobazam and midazolam were also used in most patients. Seizure onset was between the first and fourth days of life (mean and median 2 days). Nine patients (60%) had daily seizures (>15/day); their EEG recordings showed multifocal epileptiform abnormalities in six (67%) and burst-suppression (BS) pattern in three (33%). The remaining six patients (40%) presented with status epilepticus (SE). EEG recordings showed a BS pattern in three (50%) and multifocal epileptiform abnormalities in three. In most patients, seizures were characterized by asymmetric tonic posturing, often accompanied by apnea, and at times followed by focal clonic activity. Fourteen patients were trialed with several AEDs before they reached seizure freedom (see below and Table 1); one patient continues to have about two seizures per week. Cognitive and motor development At onset, all patients showed axial hypotonia. During follow-up, cognitive impairment emerged for all patients and was mild in three (20%), moderate in five (33%), and severe in seven (47%). Severe impairment of motor function including spastic quadriplegia and diplegia was also observed in nine patients (60%).
3 AED Treatment in KCNQ2 Encephalopathy Treatment Figure 1 illustrates the AED history of each patient; ultimately, all but one patient were seizure-free. Six patients (40%), four with SE and two with intractable seizures, achieved seizure freedom within 2 weeks of CBZ administration that was added at ages ranging from 12 days to 13 months, and at daily doses ranging from 15 to 20 mg/ kg/day (see Table 1: patients 3, 4, 9, 12, 13, and 15). Two patients (4 and 13, see Table 1) had failed to respond to PHT in the neonatal period despite adequate titration and dosage of the drug. All patients remained on CBZ, CBZ withdrawal was attempted in patient 4 at age 5 years, but seizures recurred within 2 weeks and CBZ was reintroduced. Five patients (33%) were seizure-free following intravenous (two patients) or oral (three patients) PHT administration. Intravenous administration of PHT was given with a single bolus of 18 mg/kg, whereas oral intake ranged from 5 to 7 mg/kg/day. In two patients, PHT was given for neonatal SE and produced complete and persistent seizure control within hours, with disappearance of the BS pattern. Both patients were then changed to CBZ for ongoing treatment at doses ranging from 15 to 20 mg/kg/day. Of the remaining three neonates treated with PHT, patient 6 was seizure-free from 2 to 13 months until PHT was weaned, and seizures recurred within 5 days of discontinuing PHT. PHT was reintroduced and she became seizurefree again at 14 months. However, at 3.5 years of age, 16 h after pertussis immunization and still on PHT, she presented with a 25-min convulsive seizure, complicated by hepatic and renal failure and pancreatitis, requiring prolonged intensive care admission. Treatment with PHT and levetiracetam A Figure 1. Antiepileptic drug (AED) treatment of each patient. The vertical axis displays the seizure frequency ranging from status epilepticus (SE) or daily seizures to seizure-free. The horizontal axis represents the AEDs; each line corresponds to a patient. (A) AED profile of six patients who became seizure-free on carbamazepine (CBZ). (B) AED profile of five patients who became seizure-free on phenytoin (PHT). (C) AED profile of four patients who became seizure-free on topiramate (TPM), on levetiracetam (LEV), or levetiracetam with topiramate. SE, status epilepticus; sz, seizures; VPA, valproic acid; VGB, vigabatrin; OXC, oxcarbazepine Epilepsia ILAE
(LEV) rendered her seizure-free. At 4.4 years, PHT was decreased from 3.7 to 2 mg/kg/day and seizures recurred; PHT was subsequently increased to the original dose. At 5 years, CBZ was commenced, but it caused sedation and irritability and so it was discontinued. At 5.3 years, the introduction of oxcarbazepine also caused sedation and irritability and was discontinued. LEV was also weaned at this time. At 6 years, PHT was increased to 4.2 mg/kg/day, again fully controlling seizures. Patient 7 was seizure-free from 2 to 9 months on PHT but seizures recurred within 1 week after it was discontinued. The patient was then switched to LEV (13 mg/kg/day) and valproate (38.5 mg/ kg/day) for ongoing treatment. Patient 14 received PHT at age 5 months, which resulted in seizure freedom, and was then switched to rufinamide monotherapy at 13 months and is still seizure-free at 23 months. Two patients (13%, patients 8 and 11) responded to topiramate (TPM). Patient 11 became seizure-free at age 2 years on TPM at 6.25 mg/kg/day; it was the fourth AED to be introduced and he had not had CBZ or PHT. However, patient 8, after an initial response to TPM at a dose of 9.6 mg/kg/day continued to have two focal seizures per week during sleep; he also had not had CBZ or PHT. In the remaining two patients (13%, patients 10 and 5), monotherapy with LEV (40 mg/kg/day) and a combination of LEV (50 mg/kg/day) with TPM (9 mg/kg/day) produced seizure freedom at ages 2 years and 2 months, respectively. Neuroimaging Brain imaging was normal in six patients (40%). The remaining nine patients (60%) showed variable T1 and/or B
C
Epilepsia, **(*):1–7, 2015 doi: 10.1111/epi.12984
Age at sz onset (d)
1
1
3
1
1
1
2
2
3
1
2
4
ID/sex
1F
2M
Epilepsia, **(*):1–7, 2015 doi: 10.1111/epi.12984
3F
4F
5M
6F
7F
8M
9M
10F
11M
12M
1.8 y
12.2 y
4.7 y
2.7 y
4.10 y
10.1 y
6.10 y
11 m
8.6 y
3.7 y
3.5 y
3.6 y
Age at time of the study
(SE) Tonic asymmetric, apnea
Tonic–clonic
Clonic
Tonic asymmetric, apnea Tonic, lips pursing, eyes clenching, cyanosis Tonic asymmetric
Tonic
Focal
SE (tonic asymmetric, apnea)
Tonic asymmetric
SE (tonic asymmetric, apnea)
SE (tonic asymmetric, apnea)
Sz type at onset
MultiF ED, intermixed attenuations
MultiF ED
MultiF ED
Temporal ED
BS
MultiF ED
BS
MultiF ED
BS
BS
BS
BS
EEG at onset
PB (20 mg/kg/d), VPA (25 mg/kg/d), VGB (120 mg/kg/d); TPM (6 mg/kg/d, effective) PB IV (20 mg/kg repeated loads + 7 mg/kg/d for 45 d), LEV IV (50 mg/kg/d for 60 d) TPM 22 mg/kg/d or 45 d, VGB (150 mg/kg/d for 14 d) CBZ (20 mg/kg/d, effective)
PB, LEV, TPM (2 mg/kg/d) (effective but AE), CBZ (20 mg/kg/d, effective) VGB, PHT, VPA, LEV (40 mg/kg/d, effective)
PB IV (20 mg/kg) load, PHT IV (18 mg/kg, effective) PHT oral (7 mg/kg/d), CBZ (15 mg/kg/d) PB IV (20 mg/kg) load, PHT IV (18 mg/kg, effective), PHT oral (7 mg/kg/d), CBZ (15 mg/kg/d) PB IV (20 mg/kg load, 7 mg/kg/d os) for 2 w, LEV (50 mg/kg/d) for 2 w, VGB (100 mg/kg/d) for 1 m, CBZ (20 mg/kg/d, effective) PB IV (20 mg/kg) for 2 d, PHT IV (18 mg/kg) load; LEV IV (45 mg/kg) CBZ (15 mg/kg/d, effective) PB (8 mg/kg/d) for 23 d, PHT (6 mg/kg/d) for 12 d (partially effective), LEV 50 mg/kg/d), TPM (9 mg/kg/d), LEV and TPM, effective) PB, LEV (32 mg/kg/d) CBZ (AE), OXC (AE), PHT (4 mg/kg/d, effective) LEV (13 mg/kg/d) and VPA (38.5 mg/kg/d) for ongoing treatment PB IV (effective but AE), LEV (13 mg/kg/d), VPA (38.5 mg/kg/d) PHT (5 mg/kg/d) PB, LEV (50 mg/kg/d), VPA (30 mg/kg/d), TPM (9.6 mg/kg/d, effective)
AED treatment
SF at 3.5 m
SF at 2 y
SF at 2 y
SF at 11 m
2 sz 9 week
SF at 2 m
SF at 2 m
SF at 2 m
Moderate cognitive impairment Severe cognitive impairment and quadriplegia Moderate cognitive impairment Severe cognitive impairment and quadriplegia Severe cognitive impairment and quadriplegia Severe cognitive impairment and quadriplegia
Severe cognitive impairment and quadriplegia
Severe cognitive impairment and quadriplegia Mild global impairment
Moderate cognitive impairment and diplegia
SF at 11 m
SF at 2 m
Moderate cognitive impairment
Mild cognitive impairment
Psychomotor development outcome
SF at 2 m
SF at 7 d
Epilepsy outcome
Table 1. Patients electroclinical features
c.1734G>C p.Met578Ile
c.613A>G p.Ile205Val
c.587G>A p.Ala196Val c.602C>T p.Arg201His
6y
c.638G>A p.Arg213Gln (inherited from mosaic father) c.1666A>G p.Lys556Glu c.973A>G p.Arg325Gly
Continued
1y
8y
2y
1.5 y
3.5 y
9y
11 m
7y
2.10 y
2.9 y
2.8 y
Follow-up
c.802C>T p.Leu268Phe
c.881C>T p.Ala294Val
c.1655A>C p.K552TI
c.629G>A p.Arg210His
c.629G>A p.Arg210His
KCNQ2 mutation
4
T. Pisano et al.
5
MultiF ED (SE) Tonic asymmetric 2 15M
10 m
MultiF ED Tonic asymmetric 5m 3 14F
T2 hyperintensities in the basal ganglia, thalami, or hippocampus (Table 1; patients 1, 12, 14, and 15), thinning of the corpus callosum (Table 1; patients 2, 6, 7 and 13), or diffuse hypomyelination with volumetric reduction of the frontal lobes (Table 1; patients 5 and 13). In four of these nine patients (Table 1; patients 6, 12, 14, and 15), follow-up MRI studies at 23, 33, and 42 months were normal.
BS, burst suppression; d, day; ED, epileptiform discharge; F, female; m, months; M, male; MultiF, multifocal; SE, status epilepticus; SF, seizure-free; sz, seizures; y, year; w, week.
10 m c.841G>T p.Gly281Trp (novel) Mild cognitive/moderate motor impairment and quadriplegia SF at 14 d
2y c. 1678 C>T p.Arg560Trp Mild to moderate cognitive impairment SF at 5 m
2.5 y c.973 A>G p.Arg325Gly Severe cognitive impairment and quadriplegia SF at 1.1 y
PB (20 mg/kg load then 5 mg/kg for 2 y), LEV (50 mg/kg/d) for 60 d, PHT IV 18 mg/kg then 7 mg/kg for 14 d, VGB (80 mg/kg/d) for 30 d, TPM (5 mg/kg/d load, then 7 mg/kg/d for 1 y, CBZ (20 mg/kg/d, effective) PB IV (20 mg/kg load + 8.5 mg/kg/d for 15 m), LEV IV (20 mg/kg + 75 mg/kg/d for 4 m), TPM (12 mg/kg/d) for 2 m, PHT (13 mg/kg/d, effective), RUF for ongoing treatment PB (30 mg/kg load + 5 mg/kg/d for 11 d) LEV 30 mg/kg load + 30 mg/kg/d for 3 d), CBZ (20 mg/kg/d, effective) MultiF ED, intermixed attenuations (SE) Tonic asymmetric, apnea 1 13M
2.6 y
AED treatment EEG at onset Sz type at onset ID/sex
Age at time of the study Age at sz onset (d)
Table 1. Continued.
Epilepsy outcome
Psychomotor development outcome
KCNQ2 mutation
Follow-up
AED Treatment in KCNQ2 Encephalopathy
Genetic findings All patients had a heterozygous KCNQ2 missense mutation; 14 were de novo and one was inherited from a mosaic father who had the mutant allele in 30% of his lymphocytes and was mildly affected with a history consistent with BFNS. He had seizures from day 4 to 11 weeks of life, followed by six tonic–clonic seizures between 4 and 32 years of age. He also had myokymia and remained on CBZ. Two mutations recurred (two patients with each) and were associated with the same electroclinical and imaging phenotype.
Discussion The 15 patients reported herein share the typical electroclinical and MRI features of KCNQ2 encephalopathy (8 were reported previously8,9,11,12). The hallmark of this disorder is the onset of refractory seizures within the first few days of life. Seizures are tonic, and often asymmetric with ocular symptoms, apnea, and other autonomic signs. At onset, EEG shows multifocal epileptiform activity or a BS pattern. Brain imaging may reveal hypoplasia of the corpus callosum, hyperintensity in the basal ganglia, and diffuse hypomyelination.8 Motor and cognitive deficits are evident from birth and continue with different degrees of severity in all patients.9 There is only one report that focuses on AED treatment in KCNQ2 encephalopathy,11 together with limited information about drug therapy in other studies.9,15 About 50 patients with KCNQ2 encephalopathy have been reported to date, with the efficacy of AED being variable and, to date, no recommendations have been made about how to optimally treat this severe condition.15,16 The aim of this study was to review the AED treatment of a large series of patients with KCNQ2 encephalopathy. We searched for possible drugs or drug associations that might be more effective than others to treat both SE and recurrent seizures. All patients described had seizure onset in the first week of life and failed to respond to several AEDs. Because patients were treated at different centers and had variable ages at the time of study, AED treatment was heterogeneous and different drugs and doses were used. We observed that 53% of the patients were seizure-free on CBZ (six at onset and two switched to CBZ following PHT), whereas 33% responded to PHT. In two of these patients, PHT was administered intravenously during the acute phase of SE producing immediate seizure control. The remaining 27% of the patients responded to TPM and LEV, Epilepsia, **(*):1–7, 2015 doi: 10.1111/epi.12984
6 T. Pisano et al. and only one patient had recurrent seizures during followup. Two patients were treated with steroids without any efficacy. One previously reported patient with KCNQ2 encephalopathy became seizure-free with adrenocorticotropic hormone (ACTH) therapy at 3 months of life.16 Patients with KCNQ2 mutations associated with a BFNS phenotype have seizures that remit spontaneously in the first year of life, even though, in a small percentage of families, recurrence may occur later in life. The evidence that patients with KCNQ2 encephalopathy also become seizure-free at a certain age might suggests that, independent of AED treatment, seizures have restricted temporal expression related to KCNQ2 function. However, 93% of our patients were seizure-free, whom 80% by 13 months of age, and 13% were seizure-free in the first 2 weeks of life. Of interest, these two patients only had mild cognitive impairment. Although seizure remission has been reported in some patients with KCNQ2 encephalopathy,8,9 only one patient was seizurefree by 3 months of age, and the median age of seizure freedom was 24 months.8,9 All patients reported here had a high seizure burden before responding to CBZ or PHT. In addition, seizure recurrence in three patients following a brief phase of sodium-channel (Na-channel) blocker discontinuation emphasizes the extreme drug sensitivity of this disorder. Maintenance of seizure freedom is important to minimize developmental regression associated with refractory seizures or SE. All of our patients had developmental impairment with a spectrum of severity ranging from mild to severe, and including spastic quadriplegia. Although preliminary, our data on neurodevelopmental outcome suggest that children with early optimized treatment producing seizure control may have a better outcome compared with the others. The nature of the KCNQ2 mutation might also influence the overall outcome, including seizures and neurodevelopment as demonstrated by in vitro experimental studies, therefore, suggesting the presence of phenotype–genotype correlations.17 PHT and CBZ are sodium-channel blockers with a wellknown mechanism of action.18 Drugs targeting sodium channels block the movement of sodium ions through the channels during propagation of the action potential and thus block and prevent the development of seizure activity.19 Seemingly disparate, voltage-gated sodium channels and KCNQ potassium channels co-localize and are bound at critical locations of the neuronal membrane.20 The response to sodium-channel blockers in patients with potassiumchannel disorders could be explained by structure–function approaches showing that modulation of one channel may significantly affect the function of the channel complex.21 A better understanding of why and how these AEDs are effective in KCNQ2 encephalopathy may improve the pathophysiologic knowledge of this severe disorder. Several cellular targets have been proposed to be relevant to the therapeutic activity of TPM, and these include voltEpilepsia, **(*):1–7, 2015 doi: 10.1111/epi.12984
age-gated sodium channels,22 like CBZ and PHT. LEV acts on SV2A, a vesicle-docking protein, and we cannot explain the response to this drug in two patients.23 Retigabine, which is not yet approved for use in the pediatric population, is a promising drug and has a mechanism of action that markedly differs from that of any of the current AEDs.24 Retigabine acts as a neuronal KCNQ/kv7K channel opener and may provide a targeted treatment for KCNQ2 encephalopathy.25 Unfortunately, it has recently been associated with the side effect of blue discoloration in the digits and retina, which will delay trials of it or await the development of an analog with a safer profile.26 We suggest that CBZ and PHT are considered as first-line therapy for SE in neonates with KCNQ2 encephalopathy. With the ready availability of intravenous administration and blood level monitoring, the efficacy and substantial experience to date, PHT is ideal for SE in this disorder. However, the nonlinear kinetics and the long-term adverse effects make oral PHT less suitable for chronic treatment. CBZ has proven to be rapidly effective in our patients with recurrent seizures as well as in those with SE. CBZ is rarely used in neonates; however, we have shown that in KCNQ2 encephalopathy, CBZ can be an effective treatment even in the neonatal period. We believe that a targeted therapeutic approach should be considered in the neonatal epilepsies, since in many aspects they differ from the most common acute neonatal seizures for which protocols have been already been established.14 Yet, for those neonates with seizures that are not attributable to a specific cause and for whom a genetic etiology is suspected, early trial of PHT and CBZ should be considered. Finally, the importance of early recognition of this phenotype cannot be overstated as some of our patients were successfully treated with PHT or CBZ in the first few days of life, well before the results of genetic testing were available. Our retrospective study reports on 15 patients from four institutions. The limitations of referral bias and different treatment strategies are noted in such a series. Although institutional paradigms of neonatal seizure management vary, herein we report that antiepileptic agents with voltagegated sodium-channel blockade, specifically CBZ and PHT, may be considered as first line for treating patients with KCNQ2 encephalopathy, allowing for improved insight on drug-specific effects on seizures in patients with this rare disorder. Given the high seizure burden and developmental delay, we hope to improve recognition of this electroclinical phenotype so that these agents, which are seldom used in acute neonatal seizure management, are trialed early in the disease course. Therapies for treating rare diseases need their efficacy and safety evaluated, but due to the small number of potential trial participants, a standard randomized-controlled trial is often not feasible without large multinational collaboration. Prospective studies with appropriate design are warranted to confirm our observation.
7 AED Treatment in KCNQ2 Encephalopathy
Acknowledgments We thank the patients and their families for participating in our research. We thank Piras Maria Francesca for technical support. The study was supported by the RF-2009-152669 grant from the Italian Ministry of Health and Education and the National Health and Medical Research Council of Australia. AS is a postdoctoral fellow of the National Fund for Scientific Research Flanders (FWO). Prof Guerrini received honoraria from Biocodex, UCB, Eisai Inc., ValueBox, and ViroPharma, and research support from the Italian Ministry of Health, the European Community Sixth and Seventh Framework Thematic Priority Health, the Italian Ministry of Education, University and Research, the Tuscany Region, the Telethon Foundation, and the Mariani Foundation. Prof Scheffer has received support from, and/or has served as a paid consultant for UCB, Athena Diagnostics, GlaxoSmithKline, Janssen-Cilag EMEA, and Transgenomics and Biocodex.
Disclosure of Conflict of Interest Dr. Pisano, Dr. Numis, Dr. Heavin, Dr. Weckhuysen, Dr. Angriman, Dr. Suls, Dr. Podesta, Dr. Marini, and Prof Cilio report no disclosures. 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.
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