idic15 Clinical manifesta0ons of idic15 —  Clinical manifestation of idic15 are mainly Neurological/Psychiological —  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 MGH Dup15q Center —  Neurology/Epilepsy —  Psychiatry —  Neuropsychology —  Sleep medicine —  GI —  Genetics —  Consults to Ortho/physiatry and Ophthalmology —  Consults for PT, OT, speech, Aug. Comm. MGH Dup15q Center —  Opened in late 2009/early 2010 —  Partnered with the Dup15q Alliance since opening —  70 total families seen in clinic (~65% with idic15) —  Families from 20 states as well as Canada and South America —  Age range 3 months to 24 years —  Families seen at both MGH and Lurie Center for Autism 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”) 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
Series1
30
20
10
0
GTC
Spasms
Atonic
Myoclonic
CPS
Tonic
Absence
Idic15 seizures – MGH —  Isodicentric chromosome 15q (idic15) —  36 children (20M, 16F) – avg. age 9.9 yrs (2-­‐20 yrs) —  89% of M with seizures; 60% F with seizures —  Age of onset later in F —  32/36 with ASD —  15/36 (42%) non-­‐verbal —  29/36 (81%) had seizures —  7/29 (24%) had spasms (5M, 2F) —  7 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 (0 interstitial) —  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
ACTH
50
vigabatrin
40
30
20
10
0
>90%
Worse
Response to 1st Medica0on Response to 1st Medication (non-spasms)
Worse
12%
No change
31%
<50%
12%
90-100%
24%
50-90%
21%
Medica0ons Broad Spectrum Focal/GTC —  Valproate (Depakote) —  Felbamate (Felbatol) —  Phenobarbital —  Phenytoin (Dilantin) —  Lamotrigine (Lamictal) —  Zonisamide (Zonegran) —  Carbamazapine (Tegretol) —  Oxcarbazepine (Trileptal) —  Topiramate (Topamax) —  Gabapentin (Neurontin) —  Levetiracetam (Keppra) —  Rufinamide (Banzel) —  Pregabalin (Lyrica) —  Lacosamide (Vimpat) —  Clobazam (Frisium) Treatments – non-­‐spasms 80
70
60
50
>90%
40
Worse
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)
Treatment – Non-­‐spasms (Tolerability) 100 90 80 70 60 Still Taking 50 Intolerable 40 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) Dietary Therapy — Ketogenic Diet — Low Glycemic Index Treatment (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 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 – MGH —  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 Seizures/EEG – BP1-­‐BP2 —  BP1-­‐2 Duplications —  5 children (3F, 2M) – avg. age 7.3 years (4-­‐11) —  5/5 with ASD (4 mild, 1 more severe) —  1/5 with seizures (most severe with seizures – no spasms) —  EEG (2 EEG – children with no seizures) —  Normal, no excessive fast activity Seizures/EEG – 15q13.2-­‐3 —  15q13.2-­‐3 Duplications —  2 children (2F) – both age 5 —  2/2 with ASD —  1/2 with seizures – focal seizures and no spasms (also severe prematurity) —  EEG (1 EEG – child with seizures) —  Occasional left temporal sharp waves, no excessive beta activity MGH Dup15q Center —  Ronald Thibert DO, MsPH – Neurology/Epilepsy —  Heidi Pfeifer RD, LDN – Ketogenic dietitian —  Amy Morgan PhD -­‐ Neuropsychology —  Ken Sassower MD – Sleep Medicine —  Michelle Palumbo MD -­‐ Psychiatry —  David Sweetser – Genetics/Metabolism —  Garrett Zella MD – GI —  Susan Connors MD – Adult Developmental —  Amanda Heater RN – Nursing —  Monica Pereira – Coordinator 

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