19/07/2013. Motor and vocal tics

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1 Aims of workshop What to do if AED s are not working? Managing Intractability Christin Eltze Consultant Paediatric Neurologist, Great Ormond Street Hospital for Children, London Recognising / Predicting Intractability Setting Goals of therapeutic interventions Management beyond seizures Non-pharmacologic approaches and when to consider these Kate Pregnancy and Birth: uncomplicated Early development: age appropriate mile stones, no concerns First seizure at 5 y: Generalised tonic clonic (< 5min) EEG: after hyperventilation burst of generalised S/W discharges associated with staring and mouthing movements, some evidence of photosensitivity Seizure free for 2 years without AEDs Age 7y: paroxysmal headaches episodes of facial twitching (bilateral involvement), later associated with vocalising noise, EEG: single spikes over central and occipital regions Kate Age y: seizure in the morning in shower (found half sitting, unresponsive, jerking all over, < 5 min) Further similar seizures, often early morning after waking initially every 2-3 months, than 1-2 seizures/month Unable to attend school for 2-3 days following seizure AEDs: 1. Carbamazepine: episodes of starring + abnormal mouth movements 2. Topiramate: numbness in both legs, tiredness, headaches 3. Lamotrigine: increased jerks both arms + vocalisation 4. Levetiracetam: no improvement 5. Valproate: jerks improved and seizures less frequent (6 weeks seizure free, school attendance improved) EEG: no epileptiform activities, no photosensitivity MRI (age 13.5 y) reported normal Motor and vocal tics Mother: Questions Which type of epilepsy has she got? Will she always have to take AEDs? What is intractability? Intractable epilepsy How common is it? Adults (>15 y): 16% approx 1:1000 Picolet et al, 2008 Childhood epilepsy cohorts: Netherlands: DSEC: 8.5 % (Geerts et al 2010) USA: Connecticut cohort 14% (Berg AT et al, 2006) 23% failed at least 2 AEDs Temporal lobe epilepsy: 37 % (Dlugos et al, 2001) 69% (Spooner et al 2006) 1

2 Symptomatic aetiology Predictors Neuroimaging abnormality Abnormal Neurology Early age at onset History of neonatal seizures and status epilepticus Epilepsy Syndrome Berg et al 2001 Supporting information Table A. Significant variables for active epilepsy (TR E < 5 year) and final intractability, and odds ratios for intractability (OR) for each value as compared with the reference value of that variable. Number Active epilepsy Overall [29.1%] Intractable in final year 35 [8.5%] OR for intractability (95% CI) Type of epilepsy *** *** ** - generalized idiopathic 176 (42.6%) 41 [23.3%] 5 [2.8%] ref - generalized symptomatic 29 (7.0%) 8 [27.6%] 2 [6.9%] 2.5 (0.5, 13.7) - generalized cryptogenic or symptomatic (incl. LGS, West Synd) 32 (7.7%) 15 [53.1%] 10 [31.2%] 15.5 (4.9, 49.7) - localization-related idiopathic 23 (5.6%) localization-related symptomatic 59 (14.3%) 27 [45.8%] 8 [13.6%] 5.4 (1.7, 17.1) - localization-related cryptogenic 78 (18.9%) 26 [33.3%] 10 [12.8%] 5.0 (1.7, 15.3) - unclassifiable 16 (3.9%) 1 [6.2%] 0.00 Aetiology at enrolment *** *** *** - idiopathic 210 (50.8%) 43 [20.5%] 6 [2.9%] ref - remote symptomatic 115 (27.8%) 48 [41.7%] 17 [14.8%] 5.9 (2.3, 15.4) - cryptogenic 88 (21.3%) 29 [33.0%] 12 [13.6%] 5.4 (1.9, 14.8) From Geerts et al Epilepsia 2010, 51(7): year follow up Dutch Study of Epilepsy in Childhood New-onset temporal lobe epilepsy in children Connecticut childhood epilepsy cohort Berg AT et al, 2006: n=613, median follow up 9.7 y ~14% intractable (stringent criterium) ~ 23% failure of 2 AEDs 1/3 reached these criteria after > 3 years Mean duration of preceding remission: 2 years (range 1-8years) after becoming intractable (17/83) 20% experienced periods of remission and of these 11 (13%) in remission after last contact Relapsing remitting course Spooner, C. G. et al. Neurology 2006;67: Kate Drug resistant epilepsy may be defined as failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. Drug responsiveness: seizure-free for a minimum of three times the longest pretreatment interseizure interval, or 12 months, whichever is longer. Age 15: Nocturnal seizures 1-3 per month Parents alerted by noise find her in bed unresponsive neck hyperextended body jerking, usually < 5 minutes, 1-2 days unwell after seizure, tired feels washed out, unable to attend school Mainstream school academically keeping up with difficulties Waking and sleep EEG reported no unequivocal epileptiform activities 2

3 Question Should other differential diagnoses be considered? How can school attendance be improved? Next steps in management Several events: Home video In bed head extended backwards into pillow, appears unresponsive, body appears stiff with generalised rhythmic jerking movements 3-4 minutes Interictal discharges stage 1 sleep Video-telemetry age 15.5 y 2 nights Nocturnal seizure 1 Video clip 3

4 Nocturnal seizure 2 Conclusion: ictal onset no consistent lateralisation, seizures appear to have frontal lobe origin Kate Age 16 y: 4 months seizure free on VAL + LEV Worsening of paroxysmal headaches, tiredness during day time (AEDs adjusted) Investigations: Optimised MR imaging (Epilepsy protocol, 3T MRI) No cortical abnormalities Age 16.5 y Worsening of seizures, now 2-3 per months, nocturnal incontinence Parents: Question What is the chance that her seizures respond to the next AED (Zonisamide suggested)? Quantifying the response to AEDs: Effect of past treatment history Schiller, Y. et al. Neurology 2008;70:54-65 Information from 429 consecutive patients > 12 years maximal sz free ~ 62% For every 1.5 failed AED decrease of sz free rate by 50% After 2-5 AEDs 16.6% sz free > 50% sz reduction max 85% Decrease by 50% for every 2 AEDs tried After 6-7 AEDs.>50% sz reduction in 1/3 No effect on response of any specific AED or EEG findings Remission on medical treatment 67% that started on AEDs > 5 y sz remission Greets et al, Epilepsia 2010, 51(7): Success of AED s in 470 untreated patients (9-93y) 93y) [Kwan P, Brodie M, NEJM, 2000] 47 % response to 1rst drug 13% response to 2 nd drug 9% seizure-free on mono-therapy with 2 nd drug 4% response to 3rd or multiple drugs 1 % seizure-free on monotherapy with 3 rd drug 3% seizure-free on 2 drugs Chance of seizure freedom declines with successive drug regimes Cumulative probability of being seizure-free by time from start of treatment and number of antiepileptic drug regimens Brodie M et al. Neurology 2012;78:

5 Question Parents: Are there any other treatment options? Epilepsy surgery Long-term sz outcome after epilepsy surgery Téllez-Zenteno et al 2005, Brain: 128: Systematic literature review (>= 5 years follow up, 40 studies, children and adults) Seizure free outcome Temporal lobe surgery: 66% Temporal lobe and extra temporal surgery: 48% Epilepsy surgery in Children Seizure outcomes UK (London): D Argenzio et al, 2012: n=80, 3 m-18 y, median 9.1 y Extra-temporal temporal lobe epilepsy Follow up: 8m-10years, median 3 y 50% sz free USA (Los Angeles)Hauptman et al 2012 n=257/338 (76%), 5 year follow up data, 53% continuously sz free 18% late sz recurrence 25% never sz free Epilepsy surgery? Worth exploring if MRI lesion negative Téllez-Zenteno et al 2010, Epilepsy Res 89, systematic literature review: 40 papers, 697 patients non-lesional, 2860 patients lesional >= 1 year follow up Paediatric subgroup: Meta analysis of extra-temporal epilepsy surgery 13 studies adults and children n= 350 lesional epilepsy, n=156 non lesional Lesion present vs no lesion (MRI or pathology) Odds of seizure freedom 2.5 higher in lesional epilepsy (OR 2.9, 95% CI , p < 0.001) Presurgical Evaluation Presurgical Evaluation Identification of epileptogenic zone Ictal onset zone (video telemetry, SPECT) Eloquent cortex (cortical stimulation, fmri) Functional deficit zone (FDG-PET) generation of focal seizures removal necessary for seizure freedom Lesion (MRI) Irritative zone (interictal EEG) Slide Courtesy of Ronit Pressler 5

6 Multi-modality pre-surgical work up Core investigations: Scalp video EEG (video-telemetry) Optimised MRI Neuropsychology + Neuropsychiatry Extended work up step1: Radioisotope imaging FDG-PET, ictal SPECT FMRI language, motor (eloquent cortex) spike activated (irritative zone) MEG Specialised MRI (DTI) Extended work up step 2 Invasive EEG recording Subdural grids, depth electrodes Stereo tactic EEG (stereotactic depth electrode implantation) Question Is timing of referral and epilepsy surgery important? Long-term intellectual outcome after temporal lobe surgery in childhood Skirrow C et al. Neurology 2011;76: Longitudinal profile of IQ changes Preoperative to postoperative full-scale IQ changes across time after surgery, shown for subsequent 2-year periods (positive values denote IQ gains). Surgical group: N=42 Follow up 5-15 years (mean 9 years) Seizure free 86%, off AEDs 57% Control group: N=11 Underwent presurgical evaluation At follow up seizure free 36%, off AEDs 27% Full-scale IQ (FSIQ) changes from baseline to long-term follow-up (A) FSIQ distribution of the surgical group at baseline (white bars) and at long-term follow-up (black bars) by Lippincott Williams & Wilkins 2011 by Lippincott Williams & Wilkins Skirrow C et al. Neurology 2011;76: Difficulties Potential delay in entering pre-surgical evaluation at time care is transitioned to adult services Clear transition of care arrangements are important which service can carry out which elements of work up Joint paediatric/adult multidisciplinary team meetings Question: Are there alternatives? 6

7 Ketogenic Diet High fat, low carbohydrates (Glucose) Classical Ketogenic Diet 4:1 ratio (LCT) Normal Diet MCT Ketogenic Diet Modified Atkins Diet (1:1 ratio) Hartman et al, Ped Neurol, 2007 E. Neal, 2012 Dietary Treatment of Epilepsy, Wiley-Blackell Classical Diet: Types of the KD Composition of meals : 3:1 or 4:1 fat : (carbohydrate + protein ratio) 90% of total calories from fat Strict meal/snack recipes, all in correct ratio MCT Diet: 40-60% of daily calorie intake as MCT oil / MCT liquigen (overall 75% fat) Greater choice of foods less carbohydrate restricted (15-20% of total calories) Modified Atkins Diet: High fat, carbohydrate restricted (10-30gm/d), unlimited protein Indications Drug resistant epilepsy? Poor tolerance to AEDs (Rare) metabolic disorders affecting transport of glucose from blood into brain Glut 1 transporter deficiency syndrome Metabolism of glucose Pyruvate dehydrogenase deficiency When would be the KD be contraindicated? Metabolic conditions Beta-Fatty oxidation defects Familial hyperlipidaemia Organic acidurias Pyruvate carboxylase deficiency (lactic acidosis) Relative contraindications Feeding difficulties (food refusal) Dysphagia (alternative feeding route: NG tube or PEG) Severe gastro-oesophageal oesophageal reflux (frequent vomiting) Adverse effects? Keene D, Pediatr Neurology, 2006; 35, 1-5 7

8 Side Effects Gastro-intestian symptoms (nausea, vomiting, constipation) Hypoglycamia (initiation phase) Excess ketosis acidosis (initiation phase) Pancreatitis Renal stones (3-6%) Risk factors: young age, hypercalciuria, (tx with carbonic anhydrase inhibitors: Topiramate, Zonisamide) Prevention potassium citrate (alkalinisation of urine) reduction from 6.7 to 0.9 % (McNally et al, Pediatrics, 2009) Bruising easily Hyperlipidaemia Weight loss, Inadequate growth Decreased bone density fractures (Long-term treatment) Cardiomyopathy, cardiac arrhythmias Efficacy D Keene Ped Neurol 2006;35:1-5 Systematic review 26 studies; 14 met criteria for inclusion Total collective population N=972 After 6 months on the diet 16 % (CI 10-21) seizure free 33 % (CI 24-42) 42) >50% reduction Keene D, Pediatr Neurology, 2006; 35, 1-5 Response rates percentages based on initial sample size Keene D, Pediatr Neurology, 2006; 35, 1-5 Efficacy - longterm Freeman et al 1998, Hemingway et al 2001 Seizure improvement continued after coming off the diet? KD disease modifying effect or? Natural progress of epilepsy (relapsing and remitting) Lancet Neurology, 2008;7(6): pp RCT seizure control in children (2-16 years) on the KD against control group (delayed start on diet ) the classical type and MCT type Results: After 3 months: significantly lower seizures in diet group than control (75% decrease, 95%CI %) > 50% sz reduction 38% diet group vs 6% in control (p < ) MCT and classical diet comparable in efficiency and tolerability (Neal et al, Epilepsia 50 (5): , 1117, 2009) 8

9 Mechanisms hypotheses Bough &Rho Epilepsia 48 (1):43-58, 2007 Rho & Stafstrom Epilepsy Research 2011 Anti-epileptic effect not only mediated by ketone bodies but by adaptive metabolic processes induced by ketosis Effects mediated by polyunsaturated fatty acids Ketosis induces shifts in brain amino acid handling favouring GABA production Suppression of seizures mediated by adenosine acting on adenosine A1 receptors Neuroprotective effects of KD Maalouf et al 2009, Brain Research Reviews Potential role of KD following brain trauma and in neurodegenerative conditions Improvement of mitochondrial function Decrease of reactive oxygen species reduction of oxidative stress Increased ATP production Inhibition of apoptosis Anti-inflammatory inflammatory effects Efficacy MAD Miranda et al, Seizure 20:151 Seizure 20: , 155, 2011 Prospective, n=33, y (mean 8 y) Chen, Kossoff; J Child Efficacy MAD J Child Neurol 2012, 27(6): follow up data on 56/87 patients 54 on MAD > 6 months (mean age 8.1 y, SD 4.2) 34/87 (39%) on MAD at 12 months At 6 months (n=54) 36 (64%) > 50% sz reduction, incl 24 (43%) > 90 reduction 12 months (n=35) 28 (50%) > 50% sz reduction, incl 22 (44%) > 90 sz reduction KD in adolescents/adults Lack of data in the literature High attrition rate in some studies Open label studies suggestive of response in proportion of patients Lack of service provision in adult services possible exception Glut1 transporter defciency 9

10 VNS Therapy Pulse generator device is implanted surgically in the left chest/axilla Electrodes are tunneled beneath the skin from the pulse generator to the left vagus nerve in the neck. The vagus nerve is stimulated periodically at the site of the neck. Surgical scars left axilla and left neck VNS Therapy: the components Pulse generator Lead Electrodes Slide courtesy of Sophia Varadkar Programming System Components Handheld Computer Platform for Programming Software Programming Wand Accessory to programming handheld computer Communication tool between Programming Software and Pulse Generator Vagus Nerve Stimulation Therapy Non-pharmacological therapy for epilepsy Repeated electrical stimulation of the left vagus nerve by the pulse generator device 3 areas of benefit for seizures Acute abortive Acute prophylactic Chronic progressive Other benefits? Quality of life Mood, behaviour, alertness, memory, school Slide courtesy of Sophia Varadkar Potential mechanisms of action Animal models Early neurophysiological studies indicated desynchronisation in cats Locus coeruleus mediates anti-seizure effect of VNS Human studies Changes in cerebral blood flow; Changes in CSF neurotransmitters UCL - Institute of Child Health Average VNS Therapy Response:Real-World 1 Post-approval Responder Rate % Patients 1. De Herdt V, et al. Eur J Paediatr Neurol 2007;11: Labar DR. Seizure 2004;13: Renfroe JB and Wheless JW. Neurology 2002;59(suppl 4):S26-S Vonck K, et al. J Clin Neurophysiol 2004;21: Elliot RE et al.epilepsia BeBehavior 2011: 20(1):57-63 Slide courtesy of Sophia Varadkar Slide courtesy of Sophia Varadkar 10

11 UCL - Institute of Child Health VNS Effectiveness Over Time UCL - Institute of Child Health VNS Therapy Seizure-Free Rates Morris GL, Mueller WM. Neurology. 1999;53(7): Slide courtesy of Sophia Varadkar 1. Renfroe JB and Wheless JW. Neurology 2002;59(suppl 4):S26-S Helmers SL, et al. Neurologist 2003;9: De Herdt V, et al. Eur J Paediatr Neurol 2007;11: Amar AP, et al. Neurosurgery 2004;55: Labar DR, et al. Neurology 2002;59:S Labar DR. Seizure 2004;13: Amar AP, et al. Stereotact Funct Neurosurg 1999;73: Ghaemi K et al. Seizure,2010;19: (6.9%). Slide courtesy of Sophia Varadkar Efficacy Meta-analysis: analysis: Englot et al J Neurosurg clinical studies, 3321 patients, incl 3 blinded RCT, 2 non blinded RCT, 10 prospective studies > 1 year after implant 51% sz reduction, at last follow up seizure reduction of at least 50% in 50% Predictors of favorable outcome - post traumatic epilepsy and TS VNS in Children Elliot et al 2011J J Neurosurg Pediatrics N =141, mean follow up 5.3 years (25 days-11.4 years) Mean reduction of sz 59%, > 50 sz reduction in 64% Consider VNS Therapy if drug resistant epilepsy and resective surgery not an option multifocal seizures generalised seizures in epilepsy with bilateral structural/ metabolic or genetic aetiology idiopathic generalised epilepsies Deep Brain Stimulation (Not evaluated in children!) SANTE study, Fisher et al Epilepsia 2010 Bilateral anterior thalamic nucleus stimulation for medically refractory epilepsy in adults 3 months blinded phase stimulation vs no stimulation, followed by unblended phase At end of 3 months blinded phase median sz reduction control group 14 % vs 40 % in stimulated group, by 2 years 56% reduction in sz frequency, Adverse events: 5 haemorrhages (incidentally identified), 2 transient stimulation related sz exacerbations, depression and memory problems 11

12 Trigeminal Nerve Stimulation DeGiorgio et al Neurology 2013 Trigeminal Nerve Stimulation DeGiorgio et al, Neurology 2013 Applied for a minimum of 12 hours per day Double-blind blind randomised active control trial n=50 (adults) High stimulation (120Hz) vs low stimulation (2 Hz) Baseline 6 weeks, evaluation at 6,12, 18 weeks At 18 weeks : > 50% sz reduction 30% tx group vs 21% control (p=0.31) Potential role: response to peripheral nerve neurostimulation prior to implantation of VNS device Conclusion Intractability can be difficult to recognise (relapsing and remitting course) Consider non-pharmacological treatment options early in the course and set goals appropriately Clear transition of care arrangements are important to avoid delays in provision of care and negative impact on outcomes 12