Treatment of Pediatric Epilepsy

Transcription

1 Nontraditional Epilepsy Therapies: Ketogenic Diet and Other Approaches Elizabeth A., MD, PhD Director, Pediatric Epilepsy Service Director, Carol and James Herscot Center for Tuberous Sclerosis Complex Massachusetts General Hospital Associate Professor of Neurology Harvard Medical School Boston, Massachusetts Treatment of Pediatric Epilepsy Goal: Seizure control without adverse effects Appropriate therapy requires accurate diagnosis Seizure classification Epilepsy classification 1

2 Alternatives to Anticonvulsant Treatment Medically intractable seizures ( pharmacoresistant epilepsy ) Seizures that are not controlled by anticonvulsant medications, or are only controlled by medications that have significant side effects Pharmacoresistant Epilepsy Previously Untreated Epilepsy Patients (n=470) Pharmacoresistant epilepsy 36% Seizure-free with 1st drug 47% Seizure-free with 3rd or multiple drugs 4% Seizure-free with 2nd drug 13% Kwan and Brodie

3 Pharmacoresistant Epilepsy How many medications must be tried prior to declaring intractability? In the past: Every known medication Now: With nonpharmacologic treatment options and improved monitoring and surgical techniques, two or more first line medications with a consensus that earlier is better Alternatives to Anticonvulsant Treatment Dietary treatments Vagal nerve stimulator (VNS) Deep brain stimulation (DBS) Epilepsy surgery?herbal therapies?acupuncture?biofeedback 3

4 Dietary Treatments for Intractable Epilepsy Classic Ketogenic Diet History and formulation MCT Diet Ketogenic diet 2007 Variations on a theme: Modified Atkins Diet Low Glycemic Index Treatment Where do we go from here? Dietary Therapy of Epilepsy Fasting as a treatment for epilepsy was described in the Bible and in texts from the Middle Ages Hippocrates, Sacred Disease, wrote that modification of diet required to treat epilepsy Based on belief that epileptic patient s body was polluted and modification of diet allows purification Erasistratus 3 rd century BC - one inclining to epilepsy should be made to fast without mercy and be put on short rations Based on belief of a connection between epilepsy, the bowels and digestive organs St. Mark; 9:29 (The Bible, King James version) An epileptic child was brought to Jesus, who said to disciples, This kind can come forth by nothing but by prayer and fasting 4

5 Dietary Therapy of Epilepsy Galen, 2 nd century CE recommended dietary restrictions in treatment of epilepsy Arnold of Villanova, Parisian physician 13 th century, diet is the largest part of the cure of epilepsy George Cheyne, Scottish physician ( ) recommended strict and moderate diet to epileptic patients Charles Ratcliffe (1866) recommended diet high in oil and fat to treat epilepsy Dietary Therapy of Epilepsy In 1911, first modern use of diet in medical literature by French physicians Guelpa and Marie 20 patients, children and adults detoxification reduced-calorie vegetarian diet with sporadic periods of fasting and purging Overall too difficult to enforce, but a few patients had significant results Also noted diet greatly improved cognitive skills of patients 5

6 The Ketogenic Diet: History In 1921, Dr. Rawle Geylin reported to the AMA the successful treatment of epilepsy by fasting, conducted by osteopath Dr. Hugh Conklin Conklin believed epilepsy was caused by intoxication from the Peyer s patches of the intestine, so he developed program to put intestines at rest He would fast patients, with water only, for as long as tolerated, up to 25 days Cure rates of 90% in juvenile patients, 50% in adults The Ketogenic Diet: History 1925: The Ketogenic Diet was designed to mimic starvation First described by Peterman at the Mayo Clinic, with 1 g of protein per kilogram of body weight in children, g of carbohydrate per day, and the remainder of calories as fat 19/37 patients became seizure free, seizures in 13 others significant reduced Also noted an a marked change in character.. decrease in irritability and an increased interest and alertness Subsequent reports from Harvard, Univ. of Rochester 6

7 The Ketogenic Diet: History 1927: Talbot at MGH, Harvard described the protocol still used for calculating and initiating diet: hours of fasting to hasten production of ketosis gradually increasing amounts of dietary fats introduced over several days during hospitalization Maintenance on diet: Specific meal plans requiring weighing of all foods Caloric restriction to 75% Fluid restriction to 80% The Ketogenic Diet: History Because bromides and phenobarbital were the only medications available at the time, there was a flurry of clinical and research activities on the Ketogenic Diet The diet was widely used during the 1930s, but it fell out of vogue when diphenylhydantoin was introduced in Compared with DPH treatment, the diet was viewed as difficult, rigid, and expensive 7

8 The Ketogenic Diet: History Changing focus of epilepsy treatment Talbot s Treatment of Epilepsy 1930 One small chapter on medication Half of book focused on the ketogenic diet Lennox s Epilepsy and Related Disorders 1960 Single paragraph on ketogenic diet for most patients, young and old, drug therapy is the kingpin of treatment The Ketogenic Diet: Resurgence of Popularity Ketogenic diet in popular culture 1997: First do no harm (Charlie Foundation) Ketogenic diet in medical literature: Medline citations (ketogenic diet and epilepsy): in 31 years in 9 years Ketogenic diet in the kitchen: The Atkins diet? 8

9 Ketogenic Diet vs American Diet Ketogenic Diet American Diet Carbs Fats Protein Carbs Protein Fats Ketogenic Diet: Formulation Calories: Based on age, ideal body weight, and current intake Protein: RDA or above Vitamins and minerals: RDI Ketogenic Ratio Ratio (by grams) Fat : (Protein + Carbohydrate) i.e., 4:1 ratio implies 4 grams of fat to 1 gram combined of protein and carbohydrate Ratio is limited by protein requirement 9

10 Cream Fat Fruit or vegetable Protein Ketogenic Diet: Food Groups No bread, pasta, or grains No sugar No starchy fruit or vegetable Vigilant exclusion/monitoring of extra carbohydrates e.g., in medications, non-nutritive sweetener formulations, toothpastes Ketogenic Diet Efficacy in Children with Intractable Epilepsy Seizure Control Author Year # Pts >90% 90-50% <50% Peterman % 35% 5% Helmholz % 23% 46% Wilkins % 21% 50% Livingston % 34% 22% Huttenlocher % 50% et al. MCT Trauner MCT % 29% 42% Sills et al. MCT % 20% 56% Kinsman et al % 38% 33% Freeman et al % 26% 40% Katyal et al % 33% 29% Overall % 30% 33% MCT=medium-chain triglyceride 10

11 The Ketogenic Diet: Outcome by Seizure Type Seizure Type >90% Seizure Reduction Myoclonic 69% Atonic-drop 69% Absence 75% Atypical absence 75% Tonic-clonic 48% Tonic 33% Complex partial 53% Simple partial 100% Swink, et al The Ketogenic Diet: Side Effects Elevated serum lipids Constipation, possibly related to fluid restriction and decrease in bulk of food intake Deficiencies in water soluble vitamins and calcium Renal stones (5-8%) Growth inhibition (linear growth usually continues normally, as should weight gain) Acidosis and excess ketosis during illness 11

12 The Ketogenic Diet: Clinical Summary 2% incidence of epilepsy worldwide Most common neurologic disorder of childhood 1/3 of children develop medically intractable epilepsy Ketogenic diet most effective treatment available But, difficult for family and child Atkins for Seizures Modified Atkins protocol: Outpatient initiation No initial fast No caloric, fluid restriction No weighing of foods; no specific meal plans CHO limited to 10 gm/day for first month; subsequent liberalization to gm/day if too restrictive Kossoff, et al

13 Low Glycemic Index Treatment: Background Anecdotes sugary treats and seizures Remarkable glucose stability on KGD The Ketogenic Diet in Children: What Role for Glucose? Children on ketogenic diet can be VERY sensitive to extra carbohydrates, with adverse effects on seizure control Inadvertent D5 infusion M&M s Change in vanilla extract lot Varieties of grapes Certain Atkins products 13

14 The Ketogenic Diet in Children: What Role for Glucose? Blood glucose of children on the ketogenic diet is VERY stable Blood glucose levels usually low normal while on ketogenic diet (55-65 mg/dl) General anesthesia clinical series (Valencia et al. 2001) Recent epilepsy surgery patient: 5 days without caloric intake The Ketogenic Diet in Children: What Role for Glucose? Possible efficacy of low glycemic index diet 2 patients with intractable generalized epilepsy boys, ages 11 and 14 yr On 4:1 ratio ketogenic diet, seizure frequency decreased 90% Both patients had difficulty adhering to diet Baseline seizure frequency over 40/day, making it possible to appreciate correlation between seizure activity and carbohydrate ingestion Converted from KGD to a low glycemic index diet Urine ketones not consistently elevated Seizure frequency remains markedly reduced, although not at level of classic KGD 14

15 Glycemic Index (GI) The two hour blood sugar response of a high-gi food versus a low-gi food Reference food (Glucose, GI=100) Test food with equal wt carbohydrate GI=40 Blood glucose 100% Blood glucose 40% Time Time Glycemic Index (GI) Examples of foods with various glycemic index: Fruits Breads HIGH Melons Bagels MODERATE Apple Whole Grain Bread LOW Grapefruit Whole Grain Bread gms fiber 15

16 Ketogenic Diet American Diet Carbs 4% Protein 6% Fat 90% Carbs Fats Protein Carbs Carbs 50-60% Protein 10-20% Fat 30-40% Protein Fats Ketogenic Diet American Diet Carbs 4% Protein 6% Fat 90% Carbs Fats Protein Carbs Protein Carbs 50-60% Protein 10-20% Fat 30-40% Fats LGIT Low GI Carbs Protein Fat LGI Carbs 10% Protein 20-30% Fat % 16

17 MGH LGIT Protocol Compared to KGD KGD LGIT Carbohydrate 10 gm/day 40 gm/day GI < 50 Total calories Strictly calculated Roughly limited by CHO limitation Management Precise menu plan Precise weighing General guidelines Rough portion control Daily Multivitamin and Calcium supplement MGH LGIT Program: An Update 36 patients now started on LGIT with no prior dietary therapy: 25 F, 11 M Average age: 10.4 (3-19 years) 69% with numerous daily seizures 2.5 ACDs at initiation (1-7); 3 prior ACDs (0-9) 17

18 MGH LGIT Program: An Update # of Patients % 25% 25% 19% No Change <50% 50-90% >90% Percent Seizure Reduction LGIT: How Does it Work? Mechanism of KGD unknown Possible role of ketone bodies Role of glucose modulation Is seizure reduction with LGIT a direct or indirect effect, or both? i.e., does the typical American diet impose a metabolic stress?? 18

19 Low Glycemic Index Treatment Effective for partial onset and generalized seizures No dramatic change in β-hydroxybutyrate levels Better tolerated than KGD Less restrictive for child Easier to administer for family and clinic Initiation does not require hospitalization KGD, Modified Atkins and LGIT: How Do They Compare? Calculated diet compositions for: 8 year old child, 50% weight and height Calculations with Nutritionist Pro and Keto Calculator Ketogenic diet (4:1) Modified Atkins diet Low glycemic index (LGIT) gm %kcal gm %kcal gm %kcal Carbohydrate % % 50 11% Protein 31 6% % Fat % % Total calories Diet ratio 4 : : 1 19

20 Dietary Therapy in Epilepsy: Where Do We Go From Here? Classic KGD? Most effective treatment available for intractable epilepsy However, implementation and restrictions difficult for child and family Would initiation without fast, and liberalization of fluids make more doable? Current alternatives---modified Atkins and LGIT Both very promising initial observations---need broader experience. Multicenter trials comparing efficacy and tolerability But why do these diets work? MGH LGIT Program LGIT offered to children prior to initiation of classic KGD LGIT offered if classic KGD not tolerated And LGIT now offered prior to ACD changes Efficacy typically seen early Well-tolerated with minimal side effects 20

21 Vagal Nerve Stimulator (VNS): Overview Intermittent electrical stimulation of the vagal nerve Cyberonics NCP System Pacemaker generator Nerve stimulation electrode Intermittent stimulation: 30 seconds on, 5 minutes off Magnet-on-demand therapy FDA approved 1997 Indicated for partial and secondarily generalized seizures Role in treatment of Lennox-Gastaut Syndrome Vagal Nerve Stimulator: Implantation 1- to 2-hour case length General or regional/local anesthesia Does not involve the brain Chest/axillary border incision for generator Neck incision for electrode Outpatient or inpatient Minimal complications 21

22 VNS Therapy: Pulse Generator and Lead Implanted in more than 20,000 patients worldwide Pacemaker-like pulse generator New Model 102 introduced in June 2002 with single-pin lead 6.9 mm thick (33% thinner than Model 101) Weighs 25 g (34% lighter than Model 101) 6- to 11-year battery life Vagal Nerve Stimulator: Magnet-on-Demand Current Oncoming seizure Swipe magnet over generator to start current In some children can: Stop seizure Shorten seizure Decrease severity Improve post-ictal period Give sense of control 22

23 Vagus Nerve: Cranial Nerve X Left cervical vagus nerve 80% afferent fibers, mostly myelinated 20% efferent fibers, mostly unmyelinated parasympathetic fibers to viscera, with myelinated fibers to vocal muscles Henry, Animal Studies in Epilepsy Models VNS Outcomes Models Animal Seizures terminated during VNS Seizures less frequent and briefer between trains of VNS Greater effect after months of VNS Dose-response curve Prevents stage IV kindling Pentylenetetrazol Bicuculline/PTZ Strychnine/PTZ 3-MPA/PTZ Topical cobalt Topical penicillin Alumina gel Maximal electroshock Rat Cat Dog Monkey 23

24 VNS Therapy: Mechanisms Multiple actions of VNS therapy are supported by research in: Human brain anatomy Animal models of epilepsy Human electroencephalogram (EEG), cerebrospinal fluid (CSF), functional brain imaging Vagus Nerve Projects to Key Brainstem Regions Bilateral projections on nucleus tractus solitarius (NTS) STN=spinal trigeminal nucleus; NTS=nucleus tractus solitarius; DMN=dorsal motor nucleus of the vagus; AP=area postrema; NA=nucleus ambiguus; CN-X=cranial nerve X; RF=reticular formation. Henry,

25 Vagus Nerve and NTS Project to Key Brainstem Regions Parabrachial nucleus of pons has widespread cerebral projections Locus coeruleus supplies norepinephrine Raphe magnus nuclei supply serotonin KFN=Kölliker-Fuse nucleus; LC=locus coeruleus; ICH=inferior cerebellar hemisp here; RMN=raphe magnus nucleus; PBN=parabrachial nucleus; NTS=nucleus tractus solitarius Henry, Vagus Nerve - NTS - PBN Project to Key Cerebral Regions Limbic structures Amygdala Insula Autonomic structures Hypothalamus Periaqueductal gray Reticular structures Thalamus NTS=nucleus of the tractus solitarius; PBN=parabrachial nucleus; PAG=periaqueductal gray; CNA=central nucleus amygdala; PVN=periventricular nucleus of hypothalamus; VPM=ventral posteriormedial nucleus of thalamus. Henry,

26 VNS Therapy: Locus Coeruleus Lesions Suppress the Seizure-Attenuating Effects of VNS VNS demonstrated an anticonvulsant effect in rats against maximal electroshock Chronic and acute chemical lesioning of the locus coeruleus (LC) was then performed After lesioning LC, VNS was no longer effective Conclusions LC is involved in anticonvulsant effect of VNS Effect of VNS may require norepinephrine release, a neuromodulator that has anticonvulsant effects Krahl S, et al The Allure of Deep Brain Stimulation Widely used in the treatment of movement disorders such as PD, dystonia, and tremor More recently used in psychiatric disorders such as OCD Mechanism unclear but appears to result in functional inhibition Reversible and adjustable with little brain injury May be useful in treating epilepsy cases without a clear focus, with an unresectable or deep-seated focus, or with multiple foci Can be used in a continuous open loop fashion Can be also be used in a closed loop to detect and abort incipient seizures - Neuropace system 26

27 Potential Indications Bilateral or multifocal seizure disorders Unifocal seizures overlying eloquent cortex Failure to respond to resection Drop attacks Remaining Questions Best location for stimulation: Still controversial and varies based on seizure type Thalamic stimulation (CM or anterior nucleus) has the largest number of patient reports Timing of DBS surgery: Should DBS precede resection in some patients? Closed circuit DBS therapy Mechanism of action 27

28 How many medications must be tried prior to declaring intractability? In the past: Every known medication Now: With nonpharmacologic treatment options and improved monitoring and surgical techniques, two or more first line medications with a consensus that earlier is better 28