Clinical manifesta0ons of idic15

idic15

Clinical manifesta0ons of idic15 Clinical manifestation of idic15 are mainly Neurological/Psychological Significant developmental delays (variable) gross and fine motor, speech, cognition Behavioral issues impulsivity, self- injurious, anxious, hyperactive High incidence of autism spectrum Epilepsy common Poor sleep patterns are common Low tone orthopedic issues GI dysfunction

Inters00al duplica0ons (Urraca et al. 2013)

Clinical manifesta0ons of Inters00al duplica0ons Clinical manifestations similar to idic15 but milder Subtle dysmorphic features ASD of varying degrees is most common presentation Often behavioral issues with anxiety most common issue; also can have emotional lability and hyperactivity Seizures reported but not common (<10%) Sleep dysfunction can be present GI dysfunction common

Dup15q Centers Neurology/Epilepsy Psychiatry Neuropsychology Sleep medicine GI Genetics Consults to Ortho/physiatry and Ophthalmology Consults for PT, OT, speech, Aug. Comm.

Epilepsy vs. Seizures An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition. The definition of epilepsy requires the occurrence of at least one epileptic seizure.

Seizure types Focal (Partial) Onset Seizures Arise from a small focus in one hemisphere Simple: no alteration of consciousness Complex: consciousness impaired or lost Secondarily generalized: begin as focal then spread to the rest of the brain Generalized Seizures Arise from large areas of cortex in both hemispheres ( whole brain seizures )

Seizure types

Focal Seizure

Generalized Seizure

Epilepsy in Dup15q Epilepsy appears to be multifocal MRI s show focal abnormalities Pathology shows regions of focal abnormalities Some children have focal or multifocal seizures which typically respond well to medication Some children have secondarily generalized seizures which are typically much harder to treat, including epileptic spasms

MRI Findings 11 MRI s idic(15) 9 and int dup(15) 2 8/11 children had hippocampal malformation with incomplete hippocampal inversion that was bilateral in 7 and right in 1 2/11 children had unilateral mesial temporal sclerosis (both idic(15) with refractory seizures) Hypoplasia of the corpus callosum, which is the most previous reported finding, was present in two children Boronat et al. 2014

MRI

MRI

Dup15q Seizure Survey Seizure survey performed in 2010 through the Dup15q Alliance Same survey as used by the ASF 95 responses 83/95 with idic15 63% have seizures 81% have multiple seizure types 42% with idic15 and seizures have infantile spasms Conant et al., Epilepsia 2013

Focal Seizures Occur in 40% with seizures in IDIC Arise from part of the brain symptoms depend on part of brain affected Frontal/central: shaking of one part/half of the body Temporal: fear, unusual smells, rising feeling Occipital: simple visual phenomena Parietal: more formed visual symptoms Central/parietal: sensory phenomena

Generalized Seizures Present in most with seizures in IDIC 81% with have multiple seizures types Generalized Tonic- Clonic Tonic Myoclonic Atonic Atypical Absence

Generalized Tonic- Clonic Present in 60% with IDIC Shaking of all 4 extremities with loss of consciousness Also known as grand mal seizures 3 Phases Clonic whole- body stiffening Tonic rhythmic shaking of extremities Post- ictal fatigue and confusion after event (typically lasts 2-30 minutes) Can be any length

Atonic Seizures Present in 40% with seizures in IDIC Abrupt loss of tone can be head only or whole body Also known as drop seizures Typically present in children with cognitive and learning issues

Tonic Seizures Present in 38% with seizures in IDIC Consist of whole- body stiffening with altered consciousness (without shaking of extremities) Typically present in children with cognitive and learning issues

Myoclonic Seizures Present in 40% with seizures in IDIC Very brief contraction of muscle or muscle group(s) Consciousness typically preserved Can be provoked by startle, loud noise, flashing light, or action

Absence seizures Present in 31% with seizures in IDIC Staring spells also called petite mal Abrupt onset of loss of consciousness followed by abrupt ending with resumption of activities Can be associated with blinking or automatisms (chewing, hand movements) Typical: Brief loss of consciousness, may be seen with GTC or myoclonic seizures Atypical: longer, may be partially aware, seen in mixed seizure disorders such as IDIC

Infan0le spasms Present in 42% with seizures in IDIC Present in 27% of all children with IDIC Seizures Clusters of quick spasms consisting of flexion or extension of the head and arms Onset typically between 4-8 months but can be earlier or as late as 3 years (avg: 6.5 months in IDIC) 3 types of spasms Flexor spasms (34%) Extensor spasms (25%) Mixed spasms (42%)

Infan0le spasms Spasms can occur up to hundreds per day Typically occur in clusters with variable spasms per cluster Most commonly occur on arousal; can at times be elicited by loud noises or tactile stimulation EEG: Hypsarrythmia (most common pattern) Very high voltage Multifocal spikes Disorganized background

LGS- type idic15 Multiple seizure types including spasms Spasms Tonic Atonic Generalized tonic- clonic Refractory to medications Unique EEG patterns especially in sleep

idic15 seizure types 60 50 40 30 Series1 20 10 0 GTC Spasms Atonic Myoclonic CPS Tonic Absence

Idic15 seizures Both centers Isodicentric chromosome 15q (idic15) 49 children (25M, 24F) avg. age 9.4 yrs (2-20 yrs) 89% of M with seizures; 60% F with seizures Age of onset later in F 42/49 with ASD 28/49 (57%) non- verbal 39/49 (79%) had seizures Most of the children had very refractory epilepsy with multiple seizure types (including spasms) and characteristic EEG patterns (LGS variant)

idic15 spasms

Idic15 tonic seizure

Status Epilep0cus Definition: Seizures lasting greater than 15 minutes or frequent seizures with no return to baseline between events (definitions for status range from 5-30 minutes) Status in IDIC 17/52 (33%) IDIC Of 9 that gave detailed answers, 8 had fewer than 10 episodes of status epilepticus with 2/8 having only a single episode

Non- convulsive status epilep0cus NCSE Continuous discharges on EEG, typically with no (or significantly reduced) clinical seizure activity. Results in a rapid loss of skills, mainly speech Any child with IDIC and rapid regression should be evaluated for NCSE NCSE in IDIC 33/52 reported regression with 20 (38%) clearly attributing it to seizure activity

SUDEP Sudden Unexplained Death from Epilepsy Cause not well understood More common in IDIC than in general epilepsy population 4/52 reported deaths believed to related to seizures: 1 from status epilepticus and 3 unexplained (SUDEP?)

Treatments Medications Dietary Therapy Surgery

Medica0ons - spasms Vigabatrin (Sabril) Excellent for spasms; also for partial seizures Constriction of visual fields in ~30% ACTH First line since 1950 s; exact action unknown Injections, can increase blood sugar and blood pressure and lead to increased infections and weight Ketogenic diet Clobazam very effective, recently available in US Broad spectrum agents can be helpful

Treatment - Spasms 100 90 80 70 60 50 40 ACTH vigabatrin 30 20 10 0 >90% Worse

Response to 1 st Medica0on Response to 1 st Medication (non-spasms) Worse 12% 90-100% 24% No change 31% <50% 12% 50-90% 21%

Medica0ons Broad Spectrum Valproate (Depakote) Felbamate (Felbatol) Lamotrigine (Lamictal) Zonisamide (Zonegran) Topiramate (Topamax) Levetiracetam (Keppra) Rufinamide (Banzel) Lacosamide (Vimpat) Clobazam (ONFI) Ezogabine (Potiga) Perampanel (Fycompa) Focal/GTC Phenobarbital Phenytoin (Dilantin) Carbamazapine (Tegretol) Oxcarbazepine (Trileptal) Gabapentin (Neurontin) Pregabalin (Lyrica)

Treatments non- spasms 80 70 60 50 40 30 >90% Worse 20 10 0 Tegretol (N=18) Klonopin (N=12) Keppra (N=23) Lamictal (N=19) Banzel (N=6) Topamax (N=21) Depakote (N=31) Zonegran (N=12)

Treatment Non- spasms (Tolerability) 100 90 80 70 60 50 40 Still Taking Intolerable 30 20 10 0 Tegretol (N=18) Klonopin (N=12) Keppra (N=23) Lamictal (N=19) Banzel (N=6) Topamax (N=21) Depakote (N=31) Zonegran (N=12)

Medical Marijuana (CBD) Undergoing trials for Dravet syndrome, Lennox- Gastaut Syndrome and Tuberous sclerosis. Approved in some states for use in epilepsy Benefits are not established, but empirical data are supportive Clear long term side effects described in animal and human studies No information available in Dup15q

Dietary Therapy Ketogenic Diet Low Glycemic Index Treatment Modified Atkins Diet(LGIT)

Ketogenic Diet Used since 1920 s but evidence dates back much earlier Exact mechanism of action is not known High fat diet (90%) that allows <10 gm carbs/day Typical ratio of fat to protein/carbs is 4:1 but can be less Initiate with a short hospital stay (fasting no longer used) with close laboratory monitoring Need to monitor for ketosis/acidosis and treat with poly- citrak if needed Carbonic anhydrase inhibitors (Topamax, Zonegran) can worsen acidosis and increase risk of renal stones Typically get hyperlipidemia and decreased bone density, supplement with Vitamin D, Ca and multivitamins

LGIT Based on the glycemic index of foods (how much it raises blood glucose) Allows for 40-60 gm carbohydrates per day 10% carbs; 20-30% protein; 60-70% fat No need for admission; monitoring less strict but still needed at least every 3 months Meals based on percentages above and caloric needs Compliance better than keto as less restrictive

LGIT Efficacy not quite as good as keto so can convert for better control 1/3 not effective 1/3 >50% reduction in seizures 1/3 >90% reduction in seizures or seizure free Can take 2 weeks to 2-3 months to see effects Recent study in Angelman syndrome (15q deletion) 6 children: 4 months: 4 >90%, 1 50-90%, 1<50% 1 year: 5>90%, 1 off diet Little if any data in IDIC

Surgery Resective surgery Typically not a good option for genetic disorders which tend to be generalized epilepsies Corpus callosotomy Palliative procedure to help with severe drop seizures by cutting the corpus callosum (part of the brain that connects the two sides). Vagus Nerve Stimulator (VNS)

VNS VNS generator implanted in chest wall Bipolar lead wrapped around left vagus nerve Pulse sent to vagus nerve which transmits signals to the brain though exact mechanism is unknown Generator can be reprogrammed to change current voltage, pulse width, signal frequency, on time and off time Studies have shown 25-60% have experienced >50% seizure reduction with VNS Typical side effects include altered voice, cough, paresthesia, dyspnea (but these are not common) Surgical complications and systemic effects rare Not compatible with 3T MRI

VNS

VNS in Dup15q Survey, 17 patients/families responded (10 females) Mean age: 19 years 11 with IDIC, 6 with interstitial 11/17 have generalized seizures 15 have Lennox- Gastaut Syndrome 9/17 (55%) had significant seizure reduction Well tolerated and patients were on decreased medication afterwards

Treatment Summary Broad spectrum agents are first line treatment Medications used to treat focal seizures such as Tegretol and Trileptal also effective for that type For treatment of spasms, ACTH/steroids typically much more effective than vigabatrin Benzodiazepines relatively ineffective for maintenance (still helpful as rescue medication) Dietary therapy is very promising and should be considered if >2 medications fail (start with LGIT then convert to ketogenic)

Idic15 EEG Nearly all EEG s had a common finding Excessive beta activity throughout A subset of children had very characteristic EEG patterns in sleep Bursts of high amplitude 12-16 Hz polyspikes Alpha- delta sleep Sleep activated discharges (ESES- type pattern)

Idic15 EEG

Idic15 EEG

Idic15 EEG 12-16Hz

Idic15 EEG 12-16Hz

Inters00al duplica0ons seizure survey Same survey as idic15 12 responses from families 3 reported seizures 1 had a single absence/focal seizure 1 with absence and tonic clonic 1 has spasms which resolved

Inters00al dup seizures MGH Interstitial Duplications 11 children (8M, 3F) avg. age 5.2 yrs (4 mo- 16 yrs) 9/11 with ASD Only 1/11 is non- verbal The 2 without ASD <1 year old (twins of affected sibling) 2/11 have seizures (18%) Both have focal seizures and on monotherapy None had spasms

Inters00al duplica0ons EEG Urraca et al. 2013 9/13 (69%) had excessive beta activity 1/13 had focal epileptiform discharges MGH EEG s EEG 7 children (2 with seizures, 5 without) Focal spikes in 2/7 (1 with seizures, 1 without) None with generalized discharges 3/7 had background slowing 7/7 had excessive beta activity

EEG Inters00al Duplica0ons

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