Update on Paediatric Neurology

Praccal Paediatrics, June 2017

Dr Daniel E Lumsden Consultant in Paediatric Neurology Complex Motor Disorders Service

Outline: uNeurological examinaon uMovement disorders Examples and eology Management Status Dystonicus uEpilepsy When to refer seizures/epilepsy u Autoimmune encephalis

Evelina Children’s Hospital Neurological examinaon • Observaon – Play in waing area – Walking into clinic – Facial features – Posture – Movements – Speech and cognion – Visual behaviour – Abnormal movements, events Neurological examinaon

• Fun and Games (screening) – Standing up (chair or floor) – Arms out – Eyes closed – Standing on one leg – Hopping, skipping – Walking on p toes, heels, tandem walking – Climb onto couch Neurological examinaon

• Targeted formal examinaon – Tone (trunk and limbs) – Power (full angravity = 3/5) – Reflexes – Cranial nerves (vision, eye movements, facial asymmetry, swallowing diffculty, cough) – Sensaon – Measurements • Weight, height, head circumference – Extras • Heart, abdomen, spine, hips etc

Movement disorders

Evelina Children’s Hospital Movement/Motor Disorders in Children and Young People

Hypertonic Hyperkinec Negave signs

• Spascity • Tremor uweakness • Dystonia • Myoclonus uReduced selecve motor • Rigidity • Chorea/Ballismus control • Athetosis • Dystonia uAtaxia • Tics uApraxia • Stereotypies

Sanger TD, Delgado L et al: Sanger TD, Chen D et al: Definion and Sanger TD, Chen D et al: Classificaon and definion of classificaon of hyperkinec Definions and classificaon of disorders causing hypertonia in movements in childhood; negave motor signs in childhood; Paediatrics 2003 Jan Mov Disord. 2010 Aug childhood; Paediatrics 2006

Movement disorder can be interpreted as seizures and should be carefully differenated! Evelina Children’s Hospital Spasticity “Versus” Dystonia

• Spasticity: • Velocity dependent increase in tone • Component of the UMN complex • ImpliesSpascity = Something you “feel” dysfunction of the Corticospinal tract/Descending motor pathways and loss inhibition at spinal cord level

• Dystonia: • Disorder of involuntary sustained or intermittent muscle contractions causing abnormal movements or postures • TraditionallyDystonia = Something you “see” “basal ganglia” disorder – now appreciated to be due to dysfunction across (potentially) broader motor network • CST function not involved. 2009

34 children with CP: 87% had spascity 78 % had dystonia

Spascity: •Velocity dependant increase of tone •Brisk jerks •Sustained ankle clonus •weakness Evelina Children’s Hospital Dystonia

Dystonia: involuntary connuous or intermient muscle spasms causing repeated twisng movements or postures or both. Tone not velocity dependant, jerks normal or can be absent

“Not to fast – not too slow, not to small- not too big, not too strong – not too weak” Myoclonus

myoclonus:

arrhythmic, short, shock-like movements caused by sudden muscle spasm or relaxaon Chorea

Evelina Children’s Hospital Tremor

Tremor: rhytmic movements around a joint Do these grey areas matter?

Myoclonus Chorea Athetosis Dystonia

Spectrum? Invesgaons for movement disorders – tailored to suspected aeology

• Structural brain damage – Cerebral palsies – Childhood strokes • All deserve detailed – Encephalis –infecve/autoimmune invesgaons – Tumours • Brain scans, blood and urine – Acquired brain injury (traumac, tests, genec tests hypoxic) • Metabolic and degenerave disorders • Other – Infecon, vascular malformaons, – Genec: Re syndrome, DYT1, DYT11, TITF1, other genec movement disorders

Evelina Children’s Hospital – Toxic: medicaon, CO Treat Avoid Treat Dystonia Triggering Triggers Factors

Good pressure/skin Analgesia Choice of medication care Laxatives Depends upon: Good sleep hygiene Relieve urinary retention Background meds Nutrition/varied diet Orthopaedic input Urgency of treatment Vaccination Antibiotics Other aspects of Emotional/Psychological Motor Disorder etc support

Medicaon for spascity and dystonia

Spascity Dystonia ØBaclofen Ø Baclofen ØTrihexyphenidyl Ø Benzodiazepines ØBenzodiazepines Ø Tizanidine ØL-dopa ØTetrabenazine Deep Brain Ø Dantrolene Smulaon ØTizanidine Ø Botulinum toxin ØClonidine ØChloral hydrate Intrathecal ØGabapentin baclofen pump Intrathecal ØCarbamazepine baclofen pump Selecve dorsal ØDantrolene rhizotomy ØBotulinum toxin Always think about goals for treatment! Evelina Children’s Hospital

Status dystonicus

Evelina Children’s Hospital Status dystonicus: case vignee

9y boy with quadriplegic CP, ex-prem, PEG 1 day Hx pf fever 38.5 Distressed, unseled, increased movements Increased respiratory secreons

? Chest infecon : CRP 9, WBC 11, Chest X-Ray – possible peri-bronchial changes in right lower lobe, urine clear Urea 7.4, normal electrolytes and creanine

Started treatment with co-amoxiclav

Day 3 – connues to spike fever up to 39.5 at mes, unseled Chest X-Ray reviewed – no convincing signs of chest infecon inflammatory markers low mum says – sleeps very lile, how much? Not documented

CK 60 000 urea 8.5 normal electrolytes creanine – upper normal range

Evelina Children’s Hospital Status dystonicus: definion

Life threatening movement disorder emergency Increasingly frequent or connuous severe episodes of generalized dystonic spasms (contracons)

Status dystonicus: Ø Tonic – mainly sustained contractures and postures Ø Phasic – rapid and repeve dystonic contracons

Considered rare – only 100 reported cases, but likely underreported and underrecognised

Up to 60% between ages 5 and 16 years

Cerebral palsy – most common cause of secondary dystonia in children

Allen et al 2013 Evelina Children’s Hospital Lumsden et al 2013 Adapted from Allen et al 2013 Status Dystonicus: Management Plan qConsider if increased sffness, movements, irritability, poor sleep, fever qCheck CK, electrolytes, urea, creanine, liver, Ca, Mg, P, BG qLook for contribung factors and treat– infecon, pain (os, fracture , gut), ITB or DBS malfuncon. qTalk to your paediatric neurology team

üMaintain feeding if possible üEnsure good hydraon enteral/IV– monitor urine output, fluid chart, renal funcon tests, BG as required, CK, urine dipsck for blood (myoglobinuria) üSleep chart to clearly document periods of sleep üExtreme spasms, discomfort parcularly if airway compromise – IV lorazepam/PR diazepam or buccal midazolam as temporizing measure ü“sleep abolishes dystonia” chloral hydrate 30-50mg/kg as required up to 4-6 hourly clonidine first dose 1mcg/kg and repeat 4-6-8 hourly every next dose can be increased by 1mcg/kg up tp 25mcg if response unsasfactory doses up to 2mcg/kg/hour IV or enteral. Monitor BP and HR. üConsider midazolam infusion but tolerance develops quickly.

Evelina Children’s Hospital

Epilepsy When to refer?

Evelina Children’s Hospital Case study 4/12 boy

• Term delivery, IUGR, thrombocytopenia resolved • New onset of focal seizures: eyes deviation and flickering +/- upper limb jerks • Seizures stopped after phenytoin load • Normal CT, baseline bloods and LP

• Refer to neurology? Y N • Clinic or on call service?

Evelina Children’s Hospital Neurology referral Know your service and pathway!

üInfants üAbnormal imaging üFocal onset seizures üConnuing seizures following trials of 2 AEDs (refractory epilepsy) üPossible neuro-degeneraon üUncertaines re diagnosis üOngoing ? Non-epilepc events

Evelina Children’s Hospital Case study: 18/12 girl

Ex prem 29/40 Neonatal sepsis, early seizures Developmental delay Evolving motor disorder – tone mostly increased in left UL, brisk DTR

Meds: valproate + phenobarbiton

Mum reports episodes of stiffness with glazed look

Valproate increased trihexyphenidyl started – some improvement EEG normal

Evelina Children’s Hospital 18/12 girl, ex prem - home video Medicaon: Na valproate, phenobarbiton, trihexyphenidyl

Evelina Children’s Hospital • Was it epilepc?

infant toddler Older child Normal movements Behavioural Tic disorder ‘Shuddering attacks’ Breath holding Cardiac Rigors Night terrors Vaso-vagal syncope Sleep myoclonus Gratification disorder Movement disorder Gratification disorder Stereotypies Gastro-oesophageal Day-dreaming reflux Learning Diffs Pseudo-seizures/non Movement disorder Migraine epileptic attacks (eg paroxysmal tonic Syncope upgaze) Cardiac Cardiac arrhythmia Benign paroxysmal vertigo Movement disorder Fabricated illness

Paediatric Epilepsy Training

• Standardised courses • Available in all regions • PET 1 • PET 2 • PET 3

www.bpna.org.uk/pet

Encephalis

Autoimmune encephalis

Case: 5 year old girl

• Intermient slurred speech 3 days aer minor head injury • Normal brain MRI • Within next few days: progressive episodes of confusion and behavioural change • Chorea of the le hand

Case: 5y old girl • Few focal seizures • Speech problems worsen to no speech • chorea one hand persists • EEG encephalopathic • CSF – normal cells, sugar and protein

• Viral serology and cultures negave

• Rx: anbiocs, anvirals, phenytoin Case: 5y old girl

• NMDA receptor anbody posive

• High dose steroids

• Full recovery at 12 months FU Auto-immune encephalides

• Treatable cause of encephalis • Neuropsychiatric features very common: behavioural change 63% confusion 50% hallucinaons 25% Seizures 83% and movement disorder 38% Hacohen et al 2013 • Auto-anbodies to cell surface angens, crucial for neurotransmission • VGKC, GAD, NMDA receptor anbodies . . . • >400 cases clinically relevant elevated tres in UK over last 3 years • Increasingly diagnosed in children sll under diagnosed • Paraneoplasc – much more frequent in adults NMDA encephalis

• Short history – days/weeks • Seizures/odd episodes • Behavioural change, encephalopathy • Involuntary movements

• EEG abnormal, lymphocytes in CSF, +/- imaging abnormalies • NMDA receptor anbody posive • N-methyl-D-aspartate glutamate voltage-dependent channels • Associaon with ovarian teratoma and other neoplasia (20-50% adults) VGKC encephalis

• Can present as limbic encephalis, but other presentaons possible • Subacute personality change, memory problems, seizures within first few days; temporal lobe epilepsy • MRI changes – high signal medial temporal lobe oen with contrast enhancement • Associaon with malignancy (adults; recent UK study – 39 children VGKC Ab+, none had neoplasm; presented at BPNA conference 2014) • oen monophasic illness • Anbody tres fall with treatment Auto-immune encephalis early treatment

• Byrne et al, 2014:

NMDAR encephalis, literature review, 43 cases

88% treated within 15 days had full recovery 36% treated aer 15 days had full recovery

Treatment: steroids, IVIG, plasma exchange, rituximab

Autoimmune encephalis – diagnosc criteria Zuliani et al 2012

Criteria

• Acute or subacute (<12 weeks) onset of symptoms • Evidence of CNS inflammation (at least one of): CSF (lymphocytic pleocytosis, CSF specific oligoclonal bands or elevated IgG index) MRI inflammatory changes Inflammatory neuropathology on biopsy • Exclusion of other causes (infective, trauma, toxic, metabolic, tumors, demyelinating or history of previous CNS disease

Supportive features • History of other autoimmune disorder • Preceding infectious illness or viral-disease-like prodromes

Dr Daniel E Lumsden Praccal Paediatrics, June 2017

Status epilepcus

Evelina Children’s Hospital Status epilepcus: case study 7y boy Previously fit and well, grandmother was treated for seizures as a child Few hours Hx of nausea and not feeling well GTC seizure, fever 40C on ambulance arrival, rectal diazepam given Taken to A&E lorazepam – phenytoin – phenobarbitone - midazolam infusion I/V, CT suspicion of sinus venous thrombosis (dismissed later), retrived to PICU PICU: Abnormal posturing and low GCS on aempts to wake up Inial normal MRI, on day 5 – wide spread white maer changes associated with crical condion.

negave infecon screen including LP (CRP, WBC inially mildly raised) Inially high CK, liver enzymes, mild renal and coagulaon abnormality Negave metabolic and genec invesgaons

Review of presentaon: 40 min CSE before arrival to A&E, 80 min total duraon pH 6.9, PCO2 > 20(unrecordable) on inial BG

Sequelae: wheelchair bound, quadriplegia, anarthria, PEG, seizures, intelectual impairment. Evelina Children’s Hospital

Status epilepcus

The most common paediatric neurologic emergency incidence 18-23 per 100 000 children per year

32% prolonged febrile seizures 17% Acute symptomac (most CNS infecon or acute metabolic decompensaon) 12% idiopathic (with diagnosis of idiopathic epilepsy) 7% unclasified

Chin RF, Neville BG, Peckham C, et al: Incidence, cause, and short- term outcome of convulsive status epilepcus in childhood: Prospecve populaon-based study. Lancet 368:222-229, 2006

Evelina Children’s Hospital Status epilepcus: definions

ILAE 2014: Status epilepcus: Seizure lasng more than 30 minutes or seizures without full recovery between them lasng for more than 30 minutes

Refractory status epilepcus: seizure or seizures without full recovery between them, which failed treatment with benzodiazepins and 1 AED

Prolonged seizure: lasng more than 5 minutes.

Neurocrical Care Society guideline 2012: Status epilepcus: seizure or seizures without full recovery lasng > 5min Definite control should be established within 60 min of onset

Evelina Children’s Hospital Convulsive status epilepcus: invesgaons of eology

•Blood glucose, blood gas, Na, K, Ca, Mg, P, renal funcon, liver funcon, FBC, CRP, coagulaon, blood culture, AED levels, toxicology •Virology- respiratory panel, throat and rectal swab for enterovirus, serum for HSV PCR and save sample. •CT, if normal – MRI •LP including PCR for HSV, VZV, enterovirus save sample for further test including NMDAR anbodies. •Ammonia, lactate, consider other metabolic invesgaons •An thyroid anbodies.

Abend et al 2014

Evelina Children’s Hospital Convulsive status epilepcus: mortality and morbidity

2.7-5.2% mortality in children 5-8% admied to ICU 13% adults 0-2% in unprovoked of febrile CSE 38% elderly

•< 10% or <15% children will have neurological deficit •Cause appears to be main determinant of mortality and morbidity •Some studies suggesng neurological deficit related to longer duraon of CSE •Animal models: wealth of data indicang that longer seizures are harmful and result in worse outcomes.

Novorol et al: Outcome of convulsive status epilepcus: a review. Arch Dis Child. 2007 Nov; 92(11)

Evelina Children’s Hospital Status epilepcus

Median me to administer second anconvulsant to a seizing child: 24 minutes Lewena et al 2009

23% received benzodiazepine doses outside of guidelines Tobias et al 2008

Nat Rev Neurol. 2015 Jun;11(6):310. doi: 10.1038/nrneurol.2015.93. Epub 2015 May 26.Epilepsy: Children with status epilepcus can face considerable delays before receiving effecve anseizure treatment.

Evelina Children’s Hospital Status epilepcus: APLS

Evelina Children’s Hospital Status epilepcus: APLS

Evelina Children’s Hospital Status epilepcus: Neurocrical care guideline

Unless the SE eology has been idenfied and definively corrected, all children should also receive an “urgent” category anconvulsant in addion to a benzodiazepine Intubaon by 10 min if airway and gas exchange compromised

Status epilepcus: neonates phenobarbital phenytoin midazolam ?leveracetam pirydoxine

Evelina Children’s Hospital Status epilepcus: leveracetam

•Broad spectrum anconvulsant •Increasing evidence of safety and efficacy in SE •Observaonal studies in children reported safety and efficacy in SE and acute symptomac seizures at 20-60mg/kg •No hepac metabolism •Lower risk of sedaon or cardiorespiratory depression •Clearance dependant on renal funcon – needs dose reducon for maintenance •Most common loading dose 30mg/kg

Abend et al 2014 Evelina Children’s Hospital Clonidine

ØD ystonia treatment ØSpinal and supraspinal α 2 adrenergic receptor agonist ØReduces aspartate and glutamate release in presynaptic terminals anitinocioceptive properties ØInitially used for treatment of arterial hypertension ØS ide effects : somnolence, bradycardia, low BP ØSame o ral/transdermal and IV daily dose

Clonidine - our experience

• 1 mcg /kg test dose - monitor BP • 3 – 8 doses or continuous IV infusion • Max dose used in our group:

3-4 mcg/kg/hour enteral and 48 mcg/kg/day (2mcg/kg/hour) IV

• Side effects at high doses (in combination with chloral hydrate): • Chloral hydrate

ØSedave and hypnoc through enhancing GABA receptors ØIngredient of Mickey Finn ØMetabolizes to tri-chloro-ethanol

ØDose: 30-50 mg/kg or 100mg/kg/24h in 3-4doses, max 4g/24h ØSide effects: deep sedaon, respiratory depression, low blood pressure, liver failure, tolerance, dependency, withdrawal symptoms

James Bond says, "that's...chloral hydrate" in the movie "The Living Daylights" before collapsing from it's effects

Case 2: 15y

References:

• Abend et al: Status epilepcus and refractory status epilepcus management. Semin Pediatr Neurol 21:263-274. 2014 • Lewena S, Pennington V, Acworth J, et al: Emergency management of pediatric convulsive status epilepcus: A mulcenter study of 542 paents. Pediatr Emerg Care 25:83-87, 2009 • Tobias JD, Berkenbosch JW: Management of status epilepcus in infants and children prior to pediatric ICU admission: Deviaons from the current guidelines. South Med J 101:268-272, 2008 ITB – what is it?

•Baclofen - GABA (b) agonist – laminae I-IV of spinal cord, inhibion of neurotransmiers release

•Inially discovered as an - epilepc •Poorly crosses blood-brain barrier •Intrathecal delivery much more efficient •Different modes of delivery: connuous infusion, variable infusion, boluses

Effecve, but: ØRisk of overdose including respiratory depression ØRisk of withdrawal including rhabdomyolysis

Evelina Children’s Hospital DBS: Vocabulary

Dystonia

Pallidal Deep Brain Stimulation (DBS)

Very good results in primary (genec) dystonia. Meaningful but modest results in secondary dystonia e.g. CP

Burke Fahn Marsden Dystonia Rating Scale (BFMDRS) – video based score motor score (eyes, mouth, speech/swallowing, neck, upper limbs, trunk, lower limbs) 0 -120 disability score (speech, wring, feeding, eang, hygiene, dressing, walking 0 - 30