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Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: An open-label, prospective, interventional study
European Journal of Paediatric Neurology xxx (xxxx) xxx
Contents lists available at ScienceDirect
European Journal of Paediatric Neurology
Original article
Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: An open-label, prospective, interventional study Kelsey Poisson a, b, *, Matthew Wong b, Chon Lee b, c, Maria Roberta Cilio d, e a
Division of Neurology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH, 45229, USA Department of Neurology, Wake Forest Baptist Medical Center, 1 Medical Center Blvd, Winston Salem, NC, 27157, USA Department of Neurology, University of North Carolina Medical Center, 170 Manning Dr, Chapel Hill, NC, 27599, USA d Department of Neurology, Benioff Children's Hospital, University of California San Francisco, 1975 4th St, San Francisco, CA, USA, 94118 e Department of Pediatrics and Institute of Clinical and Experimental Research, University Hospital Saint-Luc, University of Louvain, Avenue Hippocrate 10, 1200, Bruxelles, Belgium b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 17 June 2019 Received in revised form 25 October 2019 Accepted 29 December 2019
Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) is a rare, developmental and epileptic encephalopathy most commonly associated with mutations in KCNT1, a potassium channel. Polymorphous migrating focal seizures begin within 6 months of life and are pharmacoresistant to standard anticonvulsants. Additional therapies are needed to decrease seizure frequency and subsequent developmental deterioration associated with EIMFS. Cannabidiol (CBD) has recently arisen in public interest due to its potential in treatment-resistant epilepsies as demonstrated in randomized controlled trials for Dravet Syndrome and Lennox-Gastaut Syndrome. Here we evaluate the response of three patients, all diagnosed with EIMFS secondary to KCNT1 mutations, to pharmaceutical grade CBD. Two patients showed no benefit and have since voluntarily stopped CBD. One patient showed no overall reduction in seizure frequency, however showed a notable reduction in seizure intensity with possible developmental progression. Further studies are needed to assess the potential benefit of CBD in treatment-resistant epilepsies such as EIMFS, with a focus on early identification and intervention. © 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Keywords: Epilepsy of infancy with migrating focal seizures Cannabidiol Treatment resistant epilepsy Epileptic encephalopathy
1. Introduction Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) is a rare, developmental and epileptic encephalopathy presenting within 6 months of life with polymorphous, migrating focal seizures [1e4]. Initial sporadic focal motor seizures evolve within weeks to months into near-continuous seizure clusters and developmental deterioration. Seizures in EIMFS are typically treatmentresistant. However, some improvement has been reported with bromides [5], stiripentol and clonazepam [6], levetiracetam [7], rufinamide [8], ketogenic diet [9], quinidine [10,11], and cannabidiol (CBD) [12] in various combinations. Ion channel mutations have been implicated as a major cause of
* Corresponding author. Division of Neurology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 2015, Cincinnati, OH, 45229, USA. E-mail address: [email protected] (K. Poisson).
developmental and epileptic encephalopathies. In particular, EIMFS is commonly associated with gain-of-function mutations in KCNT1, a gene that encodes a neuronal sodium-gated potassium channel subunit; numerous mutations and one deletion within KCNT1 have been described as causative of EIMFS [13,14]. Other implicated genes include SCN2A [15], SCN1A [16], SLC25A22 [17], and SLC12A5 [18]. Cannabis, and specifically its major non-psychoactive component CBD, has arisen in public interest due to its potential in treatment-resistant epilepsies. Ongoing anecdotal evidence, parental testimony, open-label trials, and randomized-controlled trials suggest a role for CBD in treatment-resistant epilepsy in children, particularly in Dravet Syndrome [19], Lennox Gastaut Syndrome [20], Tuberous-Sclerosis Complex [21], and most recently CDKL5 deficiency, Aicardi, Dup15q, and Doose Syndromes [22]. Data from Phase 3 placebo-controlled trials showed a reduction of convulsive seizures in Dravet Syndrome by 39% [19] and drop seizures in Lennox Gastaut Syndrome by 44% [20]. Long-term
https://doi.org/10.1016/j.ejpn.2019.12.024 1090-3798/© 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: K. Poisson et al., Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: An open-label, prospective, interventional study, European Journal of Paediatric Neurology, https://doi.org/10.1016/ j.ejpn.2019.12.024
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K. Poisson et al. / European Journal of Paediatric Neurology xxx (xxxx) xxx
outcomes of patients with a variety of epilepsies and epilepsy syndromes have shown a variable retention rate from 67% [23] to 34% [24]. Highly purified CBD has been approved in the U.S. as Epidiolex® (GW Research Ltd, Cambridge, UK) for seizures associated with Lennox-Gastaut Syndrome and Dravet Syndrome in patients 2 years of age. Additional rigorous data is needed to clarify whether response to CBD is syndrome-specific and/or effective particularly in some rare epilepsies. Only one case report exists describing the successful use of CBD in EIMFS which lead to sustained reduced seizure frequency and developmental gains [12]. However, the genetic etiology could not be confirmed and genetic testing of KCNT1 was not performed. Here we evaluate the response of three patients, all diagnosed with EIMFS due to KCNT1 mutations, to pharmaceutical grade CBD, either plant-derived (Epidiolex®, GW Research Ltd, Cambridge, UK) or synthetic (pharmaceutical-grade cannabidiol chemically synthesized by INSYS Manufacturing LLC). The characteristics of the patients are detailed in Table 1. 2. Methods Patients were trialed on CBD in add-on to their baseline AEDs. Patients 1 and 2 received CBD through the GW Pharma expanded access program. Patient 3 received pharmaceutical grade synthetic CBD through a company-sponsored trial (INSYS Development Company). Plant-derived CBD (Epidiolex®, GW Research Ltd, Cambridge, UK) contained 100 mg/mL CBD as a 98% pure extract of constant composition. Synthetic CBD was chemically synthesized by INSYS Manufacturing LLC, according to Current Good Manufacturing Practice. Seizure frequency was documented in seizure diaries during a 4-week pre-treatment period (baseline), over the first 12-week treatment period, and over the following 12 weeks of treatment. Seizure types were then categorized as type 1 (motor arrest), type 2 (oral automatisms and/or eye deviation), type 3 (generalized clonic movements), and type 4 (asymmetric tonic posturing). Side effects as well as Caregiver Global Impression of Change (CGIC) were also documented. CGIC scale ranged from a score of 1 (very much improved), 2 (much improved), 3 (a little improved), 4 (no change), 5 (a little worse), 6 (much worse) or 7 (very much worse). Pharmaceutical-grade plant-derived CBD oral solution was titrated to a maximum dose of 25 mg/kg/d. Pharmaceutical-grade synthetic CBD oral solution was titrated to a maximum dose of 30 mg/kg/day. The doses of concomitant AEDs remained unchanged during the treatment with CBD, unless clinically significant increases of plasma level occurred. The study was approved by the human research ethics committee of the UCSF Benioff Children's Hospital and Wake Forest Baptist Medical Center Human Research Institutional Review Board. 3. Results At baseline and over the course of treatment, families and caregivers tracked the number of each seizure type per day, side effects, and global impression of change using a numerical scale. Overall seizure frequency increased during the treatment period in two patients (Patient 1, þ13%; Patient 2, þ20%) as compared to baseline, while patient 3 experienced no change. Patient 2 had a 20% increase in asymmetric tonic seizures with apnea and desaturation. Patient 1 did not reach maximum dose during the 12week treatment period due to increased somnolence. This patient experienced a 12% reduction in overall seizure frequency only at week 16 of treatment, after reaching the maximum dose of 25 mg/ kg/day. While he had a 3-fold increase in motor arrest seizures, he had a clinically meaningful reduction in seizure intensity. As shown
in Fig. 1, after reaching maximum dose, patient 1 had a 93% reduction in type C and a 48% reduction in type D seizures which represented the most severe semiologies. In addition to seizure diaries, patients 2 and 3 also had prolonged video-EEG monitoring before and after 5 and 6 months of treatment respectively, which confirmed the lack of response to CBD with no change in seizure frequency and no improvement in background activity. None of our patients had serious adverse events. Patient 1 experienced somnolence at a dose of 20 mg/kg/day, but after lowering the dose he was able to tolerate a slower titration to the maximum dose. With addition of CBD, Patient 2 experienced a 20% increase in seizure frequency and somnolence associated with increased plasma levels of bromide (from 140 to 170 mg/dL) and phenobarbital (from 43 to 55 mg/L). Patient 3 did not experience side effects. Families and caregivers did not note any consistent change in behavior in patients 2 and 3 during treatment and elected to stop CBD after 5 and 11 months of treatment, respectively. CGIC rating of 4 “unchanged” was given for patient 3; CGIC was not evaluated for Patient 2. Parents of patient 1 documented that CBD made a noticeable difference in his demeanor, with CGIC rating from 1 to 2 “much to very much improved”. After 6 months of treatment, he was described as more interactive and had attained new milestones including babbling, smiling, and fixing. 4. Discussion To our knowledge, this is the first report of CBD use in KCNT1associated EIMFS, where a diagnosis by clinical and EEG criteria was corroborated by genetic testing. We used both plant-based and synthetic pharmaceutical-grade CBD to evaluate seizure frequency, seizure intensity, global impression of change, and adverse events over a treatment period. Interestingly, a recent study evaluated the effects of pharmaceutical-grade synthetic CBD in pediatric patients with treatment-resistant epilepsies and found similar adverse events as reported for plant-derived CBD [25]. One report exists describing the beneficial effect of CBD in breaking continuous seizures in a 4-month old infant with EIMFS as well as his subsequent developmental progression and sustained reduction in seizure frequency [12]. However, this patient was tested only for mutations in the SCN1A gene, while KCNT1 was not analyzed. In contrast, our three patients had no reduction in overall seizure frequency during the treatment period. Patients 1 and 2 experienced a slight increase in seizure frequency, which likely represents the natural fluctuation in seizure frequency commonly seen in EIMFS patients rather than a direct effect of CBD. Because our patients had documented KCNT1 pathogenic variants, it is possible that CBD may be more effective in specific channelopathies, as suggested by its effect in Dravet Syndrome [19]. Another potential explanation for the lack of response to CBD in our three patients relates to the timing of intervention, as CBD was started more than a year after seizure onset as compared to the other case [12]. Further investigation is warranted to assess if CBD may be more effective in reducing seizure frequency if given earlier in the course of the disease. Patient 1 had a 12% reduction in seizure frequency after reaching the maximum dose of CBD. While we cannot exclude that this was due to the natural fluctuation in seizure frequency, CBD may be dose or timing dependent. Prior randomized controlled trials have evaluated response to 20 mg/kg/day of CBD [19] and open label trials have used up to 50 mg/kg/day [26]. Because of the lack of effective therapies for seizure control in EIMFS, it may be worth evaluating the response to higher doses of CBD. Interestingly, patient 1 had a dramatic reduction in seizure intensity (93% reduction in seizure type C involving cyanosis) after reaching the maximum dose. CBD may be more effective at targeting certain seizure types
Please cite this article as: K. Poisson et al., Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: An open-label, prospective, interventional study, European Journal of Paediatric Neurology, https://doi.org/10.1016/ j.ejpn.2019.12.024
Sex Genetics KCNT1 Mutation Report Status Clinical Characteristics Gestational age at birth Seizure Onset (day of life) Seizure frequency (current) Seizure Types
Development Other Clinical EEG Characteristics Interictal background
Ictal
Medications trialed (* denotes benefit) Cannabidiol trial Age at initiation Duration of treatment Concomitant AED Preparation and maximal dose
Baseline seizure frequency (seizures/week)
Treatment seizure frequency (change in seizures/week from baseline)
Ongoing seizure frequency (change in seizures/week from baseline)
Caregiver global impression of change (1e7)
Case 1
Case 2
Case 3
M
M
F
W476R De novo, novel, adjacent to reported gain of function mutation (R474H)
A259D De novo, novel
Q550del De novo, previously reported
Full term Day 1 14 seizures/day Motor arrest; asymmetric tonic; clonic extremity movements, irregular breathing and cyanosis
Full term Day 14 25 seizures/day Asymmetric tonic, apnea and desaturation; eye deviation
Profound DD (DQ<25) Severe diffuse hypotonia
Full term Day 1 100 seizures/day Asymmetric tonic, apnea and desaturation; eye deviation; subclinical Profound DD (DQ <25) Spastic tetraplegia
Lack of organization, diffuse background slowing, frequent to abundant multifocal independent spikes, polyspikes and spike wave discharges
Lack of organization, diffuse background slowing, abundant multifocal independent SW, random asynchronous attenuations.
Multifocal seizures with multiple morphologies, most commonly rhythmic delta activities with superimposed fast activities, then slowing in frequency and increasing in amplitude. PB, PHT, LVT, TPM, B6, KGD*, OXC, pentobarbital
Cessation of interictal SW, background attenuation with superimposed faster frequencies, multifocal in onset, then emergence of rhythmic sharpened alpha. CLB, CZP, KBR*, KGD, LEV, TPM, PB, PHT, B6, FLN, quinidine
Lack of organization, diffuse background slowing, abundant multifocal independent SW, PSW, SSW, and random asynchronous attenuations. Cessation of interictal SW, background attenuation with multifocal onset and then emergence of rhythmic sharpened alpha with evolution to delta þ/- SW. CLB, KBR*, KGD, LEV, PB, PHT, TPM, B6, CBZ, rufinamide, quinidine
47 months Ongoing (3 þ years) KGD 25 mg/kg/day Plant-derived Pharmaceutical grade
21 months 5 months KGD, PB, KBR 25 mg/kg/day Plant-derived Pharmaceutical grade
Type Type Type Type Type Type Type Type Type Type Type Type 1-2
Type 2:210 Type 4: 350
15 months 11 months LEV, KBR 30 mg/kg/day Synthetic Pharmaceutical grade Type 2: 35 Type 4: 140
Type 2: 0 Type 4: þ70
Type 2: 0 Type 4: 0
Type 2: 0 Type 4: 0
Type 2: 0 Type 4: 0
Not queried
4
1: 2: 3: 4: 1: 2: 3: 4: 1: 2: 3: 4:
20 39 4.5 36 þ17 0 0 3 þ13 4 4 17
Profound DD (DQ <25) Spastic tetraplegia K. Poisson et al. / European Journal of Paediatric Neurology xxx (xxxx) xxx
Please cite this article as: K. Poisson et al., Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: An open-label, prospective, interventional study, European Journal of Paediatric Neurology, https://doi.org/10.1016/ j.ejpn.2019.12.024
Table 1 Genetic, clinical, and EEG characterization of EIMFS patients.
Abbreviations. DD: Developmental Delay; DQ: Developmental Quotient. EEG: MF: Multifocal, SW: Spike-wave; SSW: Slow spike-wave; PSW: Polyspike-wave. Medications: CBZ: carbamazepine; CLB: clobazam; CZP: clonazepam; KGD: ketogenic diet; FLN: folinic acid; LEV: levetiracetam; PB: phenobarbital; PHT: phenytoin; KBR: potassium bromide; B6: pyridoxine; TPM: topiramate; OXC: oxcarbazepine.
3
4
K. Poisson et al. / European Journal of Paediatric Neurology xxx (xxxx) xxx
Fig. 1. Change in seizure frequency following CBD treatment in Patient 1: Average number of seizures per week as calculated during 4-week pre-treatment period (Baseline frequency), 12-week treatment period (Treatment frequency), and 8-week period after reaching maximum dose (Post-max dose frequency).
or decreasing seizure severity rather than overall seizure frequency. Developmentally, patients 2 and 3 did not make progress while taking CBD and elected to discontinue use. Conversely, the family of patient 1 was very optimistic about the perceived therapeutic benefit of CBD. Patient 1 reportedly had improved muscle tone and attained new milestones within 6 months of CBD treatment; he currently remains on CBD. While encouraging, it is difficult to elucidate whether developmental gains were the direct result of a reduction in seizure intensity, or whether seizure frequency stabilizing at lower relative levels in his disease course may have enabled this progress. We also acknowledge that the placebo effect for this highly publicized compound may have played a role in parental reporting of developmental progress, making the CGIC scale difficult to interpret. No major adverse events were reported. Patient 2 had increased phenobarbital and bromide levels which ultimately required dose adjustment. Concomitant bromides and CBD have not been previously investigated in the literature. To our knowledge, CBD has not been previously reported to change phenobarbital levels in humans; in one animal study phenobarbital levels did not change with addition of CBD [27]. Somnolence, as experienced by patient 1, is a previously reported side effect of CBD often attributed to altered metabolism of anti-epileptic drugs such as clobazam resulting in higher levels. Because patient 1 was not on any concomitant anti-epileptic drugs, somnolence may be directly caused by CBD. A slower titration schedule may also be required to minimize side effects due to CBD. The major limitations of our study were the small number of patients, and that it was open-label and uncontrolled. However, clinical studies in orphan diseases such as EIMFS vary from those in non-rare conditions and are less likely to use randomization, blinding and active comparators [28]. In addition, the issue of the placebo response in pediatric trials of cannabidiol was especially relevant at the time of our study, prior to approval of Epidiolex®. Further investigation is warranted to evaluate for potential
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Please cite this article as: K. Poisson et al., Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: An open-label, prospective, interventional study, European Journal of Paediatric Neurology, https://doi.org/10.1016/ j.ejpn.2019.12.024
Contents lists available at ScienceDirect
European Journal of Paediatric Neurology
Original article
Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: An open-label, prospective, interventional study Kelsey Poisson a, b, *, Matthew Wong b, Chon Lee b, c, Maria Roberta Cilio d, e a
Division of Neurology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH, 45229, USA Department of Neurology, Wake Forest Baptist Medical Center, 1 Medical Center Blvd, Winston Salem, NC, 27157, USA Department of Neurology, University of North Carolina Medical Center, 170 Manning Dr, Chapel Hill, NC, 27599, USA d Department of Neurology, Benioff Children's Hospital, University of California San Francisco, 1975 4th St, San Francisco, CA, USA, 94118 e Department of Pediatrics and Institute of Clinical and Experimental Research, University Hospital Saint-Luc, University of Louvain, Avenue Hippocrate 10, 1200, Bruxelles, Belgium b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 17 June 2019 Received in revised form 25 October 2019 Accepted 29 December 2019
Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) is a rare, developmental and epileptic encephalopathy most commonly associated with mutations in KCNT1, a potassium channel. Polymorphous migrating focal seizures begin within 6 months of life and are pharmacoresistant to standard anticonvulsants. Additional therapies are needed to decrease seizure frequency and subsequent developmental deterioration associated with EIMFS. Cannabidiol (CBD) has recently arisen in public interest due to its potential in treatment-resistant epilepsies as demonstrated in randomized controlled trials for Dravet Syndrome and Lennox-Gastaut Syndrome. Here we evaluate the response of three patients, all diagnosed with EIMFS secondary to KCNT1 mutations, to pharmaceutical grade CBD. Two patients showed no benefit and have since voluntarily stopped CBD. One patient showed no overall reduction in seizure frequency, however showed a notable reduction in seizure intensity with possible developmental progression. Further studies are needed to assess the potential benefit of CBD in treatment-resistant epilepsies such as EIMFS, with a focus on early identification and intervention. © 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Keywords: Epilepsy of infancy with migrating focal seizures Cannabidiol Treatment resistant epilepsy Epileptic encephalopathy
1. Introduction Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) is a rare, developmental and epileptic encephalopathy presenting within 6 months of life with polymorphous, migrating focal seizures [1e4]. Initial sporadic focal motor seizures evolve within weeks to months into near-continuous seizure clusters and developmental deterioration. Seizures in EIMFS are typically treatmentresistant. However, some improvement has been reported with bromides [5], stiripentol and clonazepam [6], levetiracetam [7], rufinamide [8], ketogenic diet [9], quinidine [10,11], and cannabidiol (CBD) [12] in various combinations. Ion channel mutations have been implicated as a major cause of
* Corresponding author. Division of Neurology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 2015, Cincinnati, OH, 45229, USA. E-mail address: [email protected] (K. Poisson).
developmental and epileptic encephalopathies. In particular, EIMFS is commonly associated with gain-of-function mutations in KCNT1, a gene that encodes a neuronal sodium-gated potassium channel subunit; numerous mutations and one deletion within KCNT1 have been described as causative of EIMFS [13,14]. Other implicated genes include SCN2A [15], SCN1A [16], SLC25A22 [17], and SLC12A5 [18]. Cannabis, and specifically its major non-psychoactive component CBD, has arisen in public interest due to its potential in treatment-resistant epilepsies. Ongoing anecdotal evidence, parental testimony, open-label trials, and randomized-controlled trials suggest a role for CBD in treatment-resistant epilepsy in children, particularly in Dravet Syndrome [19], Lennox Gastaut Syndrome [20], Tuberous-Sclerosis Complex [21], and most recently CDKL5 deficiency, Aicardi, Dup15q, and Doose Syndromes [22]. Data from Phase 3 placebo-controlled trials showed a reduction of convulsive seizures in Dravet Syndrome by 39% [19] and drop seizures in Lennox Gastaut Syndrome by 44% [20]. Long-term
https://doi.org/10.1016/j.ejpn.2019.12.024 1090-3798/© 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: K. Poisson et al., Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: An open-label, prospective, interventional study, European Journal of Paediatric Neurology, https://doi.org/10.1016/ j.ejpn.2019.12.024
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outcomes of patients with a variety of epilepsies and epilepsy syndromes have shown a variable retention rate from 67% [23] to 34% [24]. Highly purified CBD has been approved in the U.S. as Epidiolex® (GW Research Ltd, Cambridge, UK) for seizures associated with Lennox-Gastaut Syndrome and Dravet Syndrome in patients 2 years of age. Additional rigorous data is needed to clarify whether response to CBD is syndrome-specific and/or effective particularly in some rare epilepsies. Only one case report exists describing the successful use of CBD in EIMFS which lead to sustained reduced seizure frequency and developmental gains [12]. However, the genetic etiology could not be confirmed and genetic testing of KCNT1 was not performed. Here we evaluate the response of three patients, all diagnosed with EIMFS due to KCNT1 mutations, to pharmaceutical grade CBD, either plant-derived (Epidiolex®, GW Research Ltd, Cambridge, UK) or synthetic (pharmaceutical-grade cannabidiol chemically synthesized by INSYS Manufacturing LLC). The characteristics of the patients are detailed in Table 1. 2. Methods Patients were trialed on CBD in add-on to their baseline AEDs. Patients 1 and 2 received CBD through the GW Pharma expanded access program. Patient 3 received pharmaceutical grade synthetic CBD through a company-sponsored trial (INSYS Development Company). Plant-derived CBD (Epidiolex®, GW Research Ltd, Cambridge, UK) contained 100 mg/mL CBD as a 98% pure extract of constant composition. Synthetic CBD was chemically synthesized by INSYS Manufacturing LLC, according to Current Good Manufacturing Practice. Seizure frequency was documented in seizure diaries during a 4-week pre-treatment period (baseline), over the first 12-week treatment period, and over the following 12 weeks of treatment. Seizure types were then categorized as type 1 (motor arrest), type 2 (oral automatisms and/or eye deviation), type 3 (generalized clonic movements), and type 4 (asymmetric tonic posturing). Side effects as well as Caregiver Global Impression of Change (CGIC) were also documented. CGIC scale ranged from a score of 1 (very much improved), 2 (much improved), 3 (a little improved), 4 (no change), 5 (a little worse), 6 (much worse) or 7 (very much worse). Pharmaceutical-grade plant-derived CBD oral solution was titrated to a maximum dose of 25 mg/kg/d. Pharmaceutical-grade synthetic CBD oral solution was titrated to a maximum dose of 30 mg/kg/day. The doses of concomitant AEDs remained unchanged during the treatment with CBD, unless clinically significant increases of plasma level occurred. The study was approved by the human research ethics committee of the UCSF Benioff Children's Hospital and Wake Forest Baptist Medical Center Human Research Institutional Review Board. 3. Results At baseline and over the course of treatment, families and caregivers tracked the number of each seizure type per day, side effects, and global impression of change using a numerical scale. Overall seizure frequency increased during the treatment period in two patients (Patient 1, þ13%; Patient 2, þ20%) as compared to baseline, while patient 3 experienced no change. Patient 2 had a 20% increase in asymmetric tonic seizures with apnea and desaturation. Patient 1 did not reach maximum dose during the 12week treatment period due to increased somnolence. This patient experienced a 12% reduction in overall seizure frequency only at week 16 of treatment, after reaching the maximum dose of 25 mg/ kg/day. While he had a 3-fold increase in motor arrest seizures, he had a clinically meaningful reduction in seizure intensity. As shown
in Fig. 1, after reaching maximum dose, patient 1 had a 93% reduction in type C and a 48% reduction in type D seizures which represented the most severe semiologies. In addition to seizure diaries, patients 2 and 3 also had prolonged video-EEG monitoring before and after 5 and 6 months of treatment respectively, which confirmed the lack of response to CBD with no change in seizure frequency and no improvement in background activity. None of our patients had serious adverse events. Patient 1 experienced somnolence at a dose of 20 mg/kg/day, but after lowering the dose he was able to tolerate a slower titration to the maximum dose. With addition of CBD, Patient 2 experienced a 20% increase in seizure frequency and somnolence associated with increased plasma levels of bromide (from 140 to 170 mg/dL) and phenobarbital (from 43 to 55 mg/L). Patient 3 did not experience side effects. Families and caregivers did not note any consistent change in behavior in patients 2 and 3 during treatment and elected to stop CBD after 5 and 11 months of treatment, respectively. CGIC rating of 4 “unchanged” was given for patient 3; CGIC was not evaluated for Patient 2. Parents of patient 1 documented that CBD made a noticeable difference in his demeanor, with CGIC rating from 1 to 2 “much to very much improved”. After 6 months of treatment, he was described as more interactive and had attained new milestones including babbling, smiling, and fixing. 4. Discussion To our knowledge, this is the first report of CBD use in KCNT1associated EIMFS, where a diagnosis by clinical and EEG criteria was corroborated by genetic testing. We used both plant-based and synthetic pharmaceutical-grade CBD to evaluate seizure frequency, seizure intensity, global impression of change, and adverse events over a treatment period. Interestingly, a recent study evaluated the effects of pharmaceutical-grade synthetic CBD in pediatric patients with treatment-resistant epilepsies and found similar adverse events as reported for plant-derived CBD [25]. One report exists describing the beneficial effect of CBD in breaking continuous seizures in a 4-month old infant with EIMFS as well as his subsequent developmental progression and sustained reduction in seizure frequency [12]. However, this patient was tested only for mutations in the SCN1A gene, while KCNT1 was not analyzed. In contrast, our three patients had no reduction in overall seizure frequency during the treatment period. Patients 1 and 2 experienced a slight increase in seizure frequency, which likely represents the natural fluctuation in seizure frequency commonly seen in EIMFS patients rather than a direct effect of CBD. Because our patients had documented KCNT1 pathogenic variants, it is possible that CBD may be more effective in specific channelopathies, as suggested by its effect in Dravet Syndrome [19]. Another potential explanation for the lack of response to CBD in our three patients relates to the timing of intervention, as CBD was started more than a year after seizure onset as compared to the other case [12]. Further investigation is warranted to assess if CBD may be more effective in reducing seizure frequency if given earlier in the course of the disease. Patient 1 had a 12% reduction in seizure frequency after reaching the maximum dose of CBD. While we cannot exclude that this was due to the natural fluctuation in seizure frequency, CBD may be dose or timing dependent. Prior randomized controlled trials have evaluated response to 20 mg/kg/day of CBD [19] and open label trials have used up to 50 mg/kg/day [26]. Because of the lack of effective therapies for seizure control in EIMFS, it may be worth evaluating the response to higher doses of CBD. Interestingly, patient 1 had a dramatic reduction in seizure intensity (93% reduction in seizure type C involving cyanosis) after reaching the maximum dose. CBD may be more effective at targeting certain seizure types
Please cite this article as: K. Poisson et al., Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: An open-label, prospective, interventional study, European Journal of Paediatric Neurology, https://doi.org/10.1016/ j.ejpn.2019.12.024
Sex Genetics KCNT1 Mutation Report Status Clinical Characteristics Gestational age at birth Seizure Onset (day of life) Seizure frequency (current) Seizure Types
Development Other Clinical EEG Characteristics Interictal background
Ictal
Medications trialed (* denotes benefit) Cannabidiol trial Age at initiation Duration of treatment Concomitant AED Preparation and maximal dose
Baseline seizure frequency (seizures/week)
Treatment seizure frequency (change in seizures/week from baseline)
Ongoing seizure frequency (change in seizures/week from baseline)
Caregiver global impression of change (1e7)
Case 1
Case 2
Case 3
M
M
F
W476R De novo, novel, adjacent to reported gain of function mutation (R474H)
A259D De novo, novel
Q550del De novo, previously reported
Full term Day 1 14 seizures/day Motor arrest; asymmetric tonic; clonic extremity movements, irregular breathing and cyanosis
Full term Day 14 25 seizures/day Asymmetric tonic, apnea and desaturation; eye deviation
Profound DD (DQ<25) Severe diffuse hypotonia
Full term Day 1 100 seizures/day Asymmetric tonic, apnea and desaturation; eye deviation; subclinical Profound DD (DQ <25) Spastic tetraplegia
Lack of organization, diffuse background slowing, frequent to abundant multifocal independent spikes, polyspikes and spike wave discharges
Lack of organization, diffuse background slowing, abundant multifocal independent SW, random asynchronous attenuations.
Multifocal seizures with multiple morphologies, most commonly rhythmic delta activities with superimposed fast activities, then slowing in frequency and increasing in amplitude. PB, PHT, LVT, TPM, B6, KGD*, OXC, pentobarbital
Cessation of interictal SW, background attenuation with superimposed faster frequencies, multifocal in onset, then emergence of rhythmic sharpened alpha. CLB, CZP, KBR*, KGD, LEV, TPM, PB, PHT, B6, FLN, quinidine
Lack of organization, diffuse background slowing, abundant multifocal independent SW, PSW, SSW, and random asynchronous attenuations. Cessation of interictal SW, background attenuation with multifocal onset and then emergence of rhythmic sharpened alpha with evolution to delta þ/- SW. CLB, KBR*, KGD, LEV, PB, PHT, TPM, B6, CBZ, rufinamide, quinidine
47 months Ongoing (3 þ years) KGD 25 mg/kg/day Plant-derived Pharmaceutical grade
21 months 5 months KGD, PB, KBR 25 mg/kg/day Plant-derived Pharmaceutical grade
Type Type Type Type Type Type Type Type Type Type Type Type 1-2
Type 2:210 Type 4: 350
15 months 11 months LEV, KBR 30 mg/kg/day Synthetic Pharmaceutical grade Type 2: 35 Type 4: 140
Type 2: 0 Type 4: þ70
Type 2: 0 Type 4: 0
Type 2: 0 Type 4: 0
Type 2: 0 Type 4: 0
Not queried
4
1: 2: 3: 4: 1: 2: 3: 4: 1: 2: 3: 4:
20 39 4.5 36 þ17 0 0 3 þ13 4 4 17
Profound DD (DQ <25) Spastic tetraplegia K. Poisson et al. / European Journal of Paediatric Neurology xxx (xxxx) xxx
Please cite this article as: K. Poisson et al., Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: An open-label, prospective, interventional study, European Journal of Paediatric Neurology, https://doi.org/10.1016/ j.ejpn.2019.12.024
Table 1 Genetic, clinical, and EEG characterization of EIMFS patients.
Abbreviations. DD: Developmental Delay; DQ: Developmental Quotient. EEG: MF: Multifocal, SW: Spike-wave; SSW: Slow spike-wave; PSW: Polyspike-wave. Medications: CBZ: carbamazepine; CLB: clobazam; CZP: clonazepam; KGD: ketogenic diet; FLN: folinic acid; LEV: levetiracetam; PB: phenobarbital; PHT: phenytoin; KBR: potassium bromide; B6: pyridoxine; TPM: topiramate; OXC: oxcarbazepine.
3
4
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Fig. 1. Change in seizure frequency following CBD treatment in Patient 1: Average number of seizures per week as calculated during 4-week pre-treatment period (Baseline frequency), 12-week treatment period (Treatment frequency), and 8-week period after reaching maximum dose (Post-max dose frequency).
or decreasing seizure severity rather than overall seizure frequency. Developmentally, patients 2 and 3 did not make progress while taking CBD and elected to discontinue use. Conversely, the family of patient 1 was very optimistic about the perceived therapeutic benefit of CBD. Patient 1 reportedly had improved muscle tone and attained new milestones within 6 months of CBD treatment; he currently remains on CBD. While encouraging, it is difficult to elucidate whether developmental gains were the direct result of a reduction in seizure intensity, or whether seizure frequency stabilizing at lower relative levels in his disease course may have enabled this progress. We also acknowledge that the placebo effect for this highly publicized compound may have played a role in parental reporting of developmental progress, making the CGIC scale difficult to interpret. No major adverse events were reported. Patient 2 had increased phenobarbital and bromide levels which ultimately required dose adjustment. Concomitant bromides and CBD have not been previously investigated in the literature. To our knowledge, CBD has not been previously reported to change phenobarbital levels in humans; in one animal study phenobarbital levels did not change with addition of CBD [27]. Somnolence, as experienced by patient 1, is a previously reported side effect of CBD often attributed to altered metabolism of anti-epileptic drugs such as clobazam resulting in higher levels. Because patient 1 was not on any concomitant anti-epileptic drugs, somnolence may be directly caused by CBD. A slower titration schedule may also be required to minimize side effects due to CBD. The major limitations of our study were the small number of patients, and that it was open-label and uncontrolled. However, clinical studies in orphan diseases such as EIMFS vary from those in non-rare conditions and are less likely to use randomization, blinding and active comparators [28]. In addition, the issue of the placebo response in pediatric trials of cannabidiol was especially relevant at the time of our study, prior to approval of Epidiolex®. Further investigation is warranted to evaluate for potential
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Please cite this article as: K. Poisson et al., Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: An open-label, prospective, interventional study, European Journal of Paediatric Neurology, https://doi.org/10.1016/ j.ejpn.2019.12.024