Ketogenic Diet therapy in Myoclonic-Atonic Epilepsy (MAE)

Transcription

1 KD therapy in epilepsy syndromes Ketogenic Diet therapy in Myoclonic-Atonic Epilepsy (MAE) Hirokazu Oguni, MD Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan Epilepsy Center, TMG Asaka Medical Center, Saitama, Japan THE 6th Global Symposium on KETOGENIC THERAPIES FOR NEUROLOGICAL DISORDERS (KETO 2018) Jeju, Korea October 5-9, 2018.

2 Study of ketogenic diet (KD) therapy for childhood intractable epilepsy (Tajima S. No to Hattatsu 1977) N=51 (M:30/F:21) Age 2y1m ~ 11y11m Type of seizures N Fasting: 7 days Myoclonic seizures: 23 4 :1 classical KD Astatic seizures: 10 (1968 ~ 1973) Infantile spasms: 6 GTCS: 6 Result after 2 years Complex partial seizures: 3 Excellent: 8 (15.7%) Focal motor seizures: 3 Good: 3 (5.9%)

3 Effect of KD according to the seizure types at the last follow-up period N Myoclonic seizures 23 Astatic seizures 10 GTCS Infantile spasms CPS Excellent Good Ineffective focal motor seizures 3 0% 20% 40% 60% 80% 100%

4 Myoclonic-Atonic Epilepsy Normal development before the onset of epilepsy Onset of epilepsy: 18 months ~ 53 months Boys>Girls, Strong genetic predisposition Main seizure types: myoclonic-atonic, myoclonic-flexor seizures causing epileptic drop attacks (EDA) Associated seizure types: generalized (tonic-) clonic seizures, atypical absence, myoclonic status epilepticus, and tonic vibrating seizures (unfavorable type). EEG: diffuse θ rhythms that are maximal at the CP area, generalized 1.5-3Hz spike-waves or polyspikes waves. Prognosis: Favorable (70-80%) and unfavorable types (20-30%) Kaminska and Oguni, Handbook of Clinical Neurology Vol III Pediatric Neurology, Part : 2013

5 Most recent study on children with MAE in Tokyo Women s Medical University Period:1968~2017 N:85(M:63/F:22) Onset of epilepsy:13~66mo (median 34mo) Onset of MAS: 13~67mo (median 36mo) Follow-up period: 15~337mo (median 130mo) Preceding seizures: FS=8, GTCS=57 by 0~27mo (median 1mo) Last MAS: 22~151mo (N=82, median 48mo)

6 Most recent study on children with MAE Associated seizures GTCS: 76 (89%) Atypical absence seizures: 57 (67%) myoclonic status epilepticus : 27 (32%) Prognosis Remission >1y 68 (80%) Favorable: 57 (67%) Intermediate: 14 (16.5%) Unfavorable: 14 (16.5%)

7 Ictal polygraph of myoclonic-atonic seizure 1S Rt-Trap Rt-SCM Rt-Delt Rt-Biceps Lt-Delt 100μv

8 Ref A1+A2 Awake 100μv Rt-SCM Rt-Trap. Rt-Delt Lt-Delt 1S

9 Current treatment options for MAE Antiepileptic drugs VPA + ESM, LTG, CZP (in combinations) ACTH therapy Easy to introduce and most effective for MAE secondary to KD but requires 1 month admission Ketogenic diet therapy (classical 4:1) Requires strong cooperation of both patients and their family to continue KD, but most effective for MAE.

10 Ketogenic diet 4: kcal, proteins: 20g Lunch 421Kcal Prot: 6.1g; CH: 2.0g; lipids: 41.0g Breakfast 396Kcal Prot: 6.75g; CH: 2.1g; lipids: 39.4g Supper 385Kcal Prot: 6.5g; CH: 2.0g; lipids: 38.6g by courtesy of KD Dietician Yasuko Hashimoto

11 CLINICAL COURSE of 10 year-old boy with MAE Age W 2916g Referral to TWMU Development walking 2 word sentence Epilepsy diagnosis at local hospital IQ=72 IQ=79 FS CSF/Blood Glucose:0.67 Brain MRI: Normal Epilepsy Myoclonic-astatic/ myoclonic seizures Atypical absence seizures Interictal epileptic EEG 2-3Hz DSSW Background EEG activity 4-5Hz 5-6Hz 6Hz 8Hz 8Hz Treatment CBZ, PB, VPA, CZP, ZNS, TPM, ESM, LEV, LTG VPA+LTG 3:1Ketogenic Diet

12 Awake and sleep EEG immediately before KD introduction Awake sleep Rt SCM Rt Trap. Rt Delt.

13 Awake and sleep EEG at 10 days after KD introduction Awake sleep

14 % effectiveness Effectiveness of the various treatments for MAE (n=85) N=30 N=24 N=39 N=9 N=42 N=58 N=36 N=6

15 KD therapy for children with MAE Authors Journal Year KD type N 50%< 100% free Oguni H et al. Neuropediatrics 2002 KD 4: % 58% Caraballo E et al. Epileptic Disord 2006 KD 4: % 18% BergqVstA.G.C. Epilepsy Res 2012 MAD KD 9 78% 56% Simard-Tremblay E et al. Seizure 2014 MAD: 6 KD 4:1: % 78% Wiemer-Kruel A et al. Epilepsia 2017 MAD 30 83% 47%

16 Differential diagnosis of MAE Symptomatic epilepsy with epileptic spasms causing drop attacks (Late-onset infantile spasms) if patients appear neurologically normal. Patients have minor focal sign (EEG, MRI) and ES tend to occur in clusters GLUT1DS with myoclonic-atonic seizures and absence seizures associated with GSW pattern GLUT1DS has been reported as a rare cause of MAE. GLUT1DS has not only epileptic seizures but also typical neurological symptoms (i.e. movement disorders, pyramidal sign, mental retardation) Itoh Y, et al. Study of epileptic drop attacks in symptomatic epilepsy of early childhood - Differences from those in myoclonic-astatic epilepsy. Brain Dev. 2015;37: Oguni H, et al. Effect of ACTH therapy for epileptic spasms without hypsarrhythmia. Epilepsia 46(5):709-15, Ito Y, et al. Nationwide survey of glucose transporter-1 deficiency syndrome (GLUT-1DS) in Japan. Brain Dev. Brain Dev. 2015;37(8):780-9.

17 CLINICAL COURSE of 8 year-old boy with GLUT1DS associated with atonic-drop attacks Age W 3496g Diagnosis Development Sitting unsteady walking slow running No language DQ=50 CSF/Blood Glucose =0.42 SLC2A1 missense mutation DQ=31 Referral to TWMU Motor disorders Cerebellar Ataxia & Mild spastic paraplegia Paroxysmal abnormal eye movement Epilepsy GTS often occurred before meal Atonic-drop seizures & absence seizures Nocturnal myoclonic seizures Interictal epileptic EEG 2-3Hz DSSW Background EEG activity 4-5Hz 6-7Hz Treatment CBZ, PB, VPA, CZP, ZNS, TPM, ESM, LEV, LTG 2:1Ketogenic Diet Change to Modified Atkins Diet

18 Interictal EEG at 5 years and 3 months Awake Sleep Fp1-F7 F7-T3 T3-T5 T5-O1 Fp2-F8 F8-T4 T4-T6 T6-O2 Fp1-F3 F3-C3 C3-P3 P3-O1 Fp2-F4 F4-C4 C4-P4 Fz-Cz Cz-Pz ECG Fp1-A1 Fp2-A2 F7-A1 F8-A2 T3-A1 T4-A2 T5-A1 T6-A2 F3-A1 F4-A2 C3-A1 C4-A2 P3-A1 P4-A2 O1-A1 O2-A2 Fz-A1 Cz-A1 Pz-A1 ECG

19 Conclusions MAE is characterized by myoclonic-atonic drop seizures and generalized epileptiform EEG abnormalities that occur in previously normal young children. MAE is now classified into favorable and unfavorable types, the latter of which has a frequent myoclonic status epilepticus and nocturnal tonic vibrating seizures, shared in part with the clinical features of LGS. The most effective treatment for controlling MAE was found to be KD therapy (45%), followed by ACTH (33%), ESM (28%) and LTG (22%) in this decreasing order. Thus, an early introduction of KD therapy should be considered following a trial of a few recognized antiepileptic drugs for the pharmaco-resistant MAE.