deep$brain$stimulation$in$children$ - … anesthetic release, involuntary movements are much less...

DEEP BRAIN STIMULATION IN CHILDREN

Unité des Pathologies Cérébrales Rés is tantes

Unité de Recherche sur les Comportements et Mouvements Anormaux

CHRU Montpell ier ; Univers ité Montpe ll ier ; France

08/07/2017 MDS-‐ES 1ST SUMMER SCHOOL ON NEUROMODULATION FOR MOVEMENT DISORDERS GRENOBLE, FRANCE ·∙ JULY 6-‐8, 2017

Laura Cif, Montpellier, France

PHENOMENOLOGIC CLASSIFICATION OF PEDIATRIC MOVEMENT DISORDERS


Schlaggar, Mink 2003

DIAGNOSIS


Koy, 2016

PEDIATRIC MOVEMENT DISORDERS


oTransient/Permanent

oAge-‐dependent

oAge at onset, phenomenologyand extent orientate towards etiology

oComplexe dystonia rather in acquired and progressive disorders

oOften unremitting (most frequent lasting movement disorder in children)

oEarly spread of symptoms (generalized)

oÌncreasingdisability

oEventually life-‐threatening conditions

oNo efficient pharmacological therapy

oSide effects of medication/cognitive impact insufficiently assessed

DYSTONIA


MEDICAL TREATMENToLittle evidence from controlled trials on the best therapeuticstrategies (Trihexyphenidyl, Fahn , 1983)

oHeterogeneity in the pharmacological management of pediatricdystonia

oMostly related to personal experience, drugs availability, …

oThe higher number of treatment -‐proxy measure for nonresponsiveness and severity of the movement disorder

oL-‐dopa trial mainly for isolated dystonia and patients with symptomfluctuations not to miss a DRD


MEDICAL TREATMENT


Koy, 2016


o Baclofene 42,5%o Trihexyphenidyl 35,3%o L-‐DOPA 20,5%

MEDICAL TREATMENT

DYSTONIA CLASSIFICATIONAXIS I :CLINICAL CARACTERISTICS

Associated featuresBody

distribution Age of onset Temporal patternIsolated /combined withother movement disorders

Focal Infancy (0-‐2) Disease course

Combined dystonia

Segmental Childhood (3-‐12)

ProgressiveMultifocal Adolescence (13-‐20)

Occurrence of otherneurological or systemicmanifestations

Hemi dystonia Early adulthood (21-‐ 40)Temporal variability

Generalized Late adulthood (>40)

PersistentAction-‐specificDiurnalParoxysmal

Isolated dystonia Static

Albanese, 2013

MDS-‐ES 1ST SUMMER SCHOOL ON NEUROMODULATION FOR MOVEMENT DISORDERS GRENOBLE, FRANCE ·∙ JULY 6-‐8, 201708/07/2017

CLASSIFICATION AXIS II-‐ETIOLOGY

A. Nervous system pathologyoEvidence of degenerationoEvidence structural (often static) lesionsoNo degeneration or structural lesion

B. Inherited or acquiredInheritedoAutosomal dominantoAutosomal recessiveo X-‐linked recessiveoMitochondrial

Acquiredo Perinatal brain injuryo Infectiono Drugo Toxico Vascularo Neoplastico Brain injuryo Psychogenic

C. Idiopathico Sporadico Familial


DEEP BRAIN STIMULATION IN DYSTONIAoFollowing ablative surgeries (thalamotomy, pallidotomy)

oFollowing DBS in adults for PD (suppression of dyskinesia in the GPi)and ET

o1996: 1st child with isolated generalized dystonia receiving GPi DBS inMontpellier (Coubes, 1999 Neurochirurgie)

oSimultaneously, DBS proposed for other forms of dystonia in adultsKumar, Neurology, 1999, and Krauss, Lancet, 1999


THE CASE OF SOPHIE-‐first patient with DBS treated childhood onset generalized dystonia

Coubes, Neurochirurgie, 1999

« Although her future remains uncertain, we believe thatchronic bilateral pallidal stimulation may prove to be thetreatment of choice for early onset generalized dystonia,especially in children.Electrical stimulation is a conservative, adaptable,reversible neurosurgical procedure, and seemsparticularly worthwhile in children because of theirongoing brain development »


21 years of follow-‐up with DBS

oAt anesthetic release, involuntary movements are much less severe, no pain,breathing is autonomous

oRecovery is very progressive

oOral feeding is again possible and PEG tube is removed one month after DBSonset.

oIPG early depleted, with recurrence of symptoms, controlled within one weekafter IPG replacement

oNo immediate effect on dystonic symptoms

oIt could be possible to propose this therapy also to severe forms of secondarydystonias


Coubes, Neurochirurgie, 1999

08/07/2017MDS-‐ES 1ST SUMMER SCHOOL ON NEUROMODULATION FOR MOVEMENT DISORDERS GRENOBLE,

FRANCE ·∙ JULY 6-‐8, 2017

SUPERIOR INITIAL RESULTS IN PEDIATRIC ISOLATED DYSTONIA VERSUS ADULTS (AGE AT DBS ADMINISTRATION)

Coubes et al, JNS 2004

TARGETS

Starr, JNS, 2006

ALTERNATIVE TARGETS FOR DBS IN DYSTONIAPOSTERO-‐LATERAL AND VENTRAL PART OF THE GPI

STNWhen GPi structurally impairedPKAN, Ge, 2011To avoid side effects related to GPi DBS; Kleiner Fisman, 2007; Ostrem, 2011; Blahak, 2011; Ostrem 2017

Thalamic motor nuclei+VimDystonic tremor Carvalho, 2013Myoclonus dystonia Grüber, 2010

DYT6 dystonia Mure H, 2014+Ventral lateral anterior (VLa) nucleus


INDICATIONSoMedical therapy refractoriness

oSymptoms severe enough to producedisability

oPain Moro et al., 2013

oBetter response in the hyperkinetic forms (but not always)

oBetter response in children (in isolated cases) Vidailhet, 2013

But most frequently dystonia in children is acquired/degenerative (and complexe…)


INDICATIONS

oNo validated criteria for DBS in children (severity, refractoriness to conventional therapy…)

oNo cut-‐off related to symptom severity

oNo predictor such as levodopa challenge in PD

oChalenging task especially in acquired /progressive dystonias


INDICATIONS

ISOLATED (PRIMARY) DYSTONIA

opositive outcome in pediatric and adult populations

oDYT1 dystonia (TOR1A gene)

o DYT6 (THAP1 gene)

oOther forms of idiopathic dystonia

COMBINED DYSTONIA

o DYT11 (epsilon sarcoglycan gene) myoclonus dystonia


THAP1 GENE RELATED DYT6 DYSTONIA


oGeneralized dystonia and dyskinesia

oSevere axial symptoms (neck, trunk)

oDysarthria, oromandibular dystonia

oSpread of the symptoms Cranial –caudal

Decrease of dystonia a at early FU (32%; p = 0.046) and 42/ at late follow-up.

The rate of responders considerably lower in DYT6 vs DYT1(57% vs >90%; p = 0.017)

Brüggemann, 2015

COMBINED DYSTONIA DYT11 MYOCLONUS DYSTONIAoEpsilon sarcoglycane gene related

Myoclonus-‐dystonia

Myoclonusand dystonia improvement>80%

Pediatric cases


Cif L, 2004, Kühn A, 2014

ACQUIRED DYSTONIA

oDyskinetic/dystonic cerebral palsy ; Hemidystonia (post traumatic, vascular )Two different phenotypes of HIE related CPFirst-‐delayed onset dystonic/dyskinetic CP-‐very good outcomeSecond case-‐dyskinetic CP; axial decreased tone; mild response to DBS


PROGRESSIVE FORMS (EVIDENCE FOR DEGENERATION)

oPantothenate kinase associatedneurodegeneration, PANK2 gene mutations Castelnau, 2005; Krause M, 2006

o Atypical PLA2G6-‐neurodegeneration (PLAN)

MDS-‐ES 1ST SUMMER SCHOOL ON NEUROMODULATION FOR MOVEMENT DISORDERS GRENOBLE, FRANCE ·∙ JULY 6-‐8, 2017

08/07/2017

Cif, 2014

EMERGENCIESo GNAO1 gene related dystonia/choreaWaak, M, 2017


08/07/2017

SPECIFICITIES OF PROGRAMMING IN CHILDREN WITH DYSTONIA

oClinical improvement not immediate (vs tremor)

oMonotonic time course of improvement (days, weeks, months)

oOften monopolar stimulation (in our experiencemost frequentlydouble monopolar)

oHigh frequency stimulation (almost exclusively)

oBut settings no different from adults


oMore often generalized anesthaesia suitable/requested

oHigher risk for clinical worseningdespite ongoing efficient DBS

oWithout efficient treatment, higher risk of life threateningconditions

oPossible influence on growth and development

oRechargeable systems suitable

MANAGEMENT OF PEDIATRIC VS. ADULT DYSTONIA POPULATIONS


08/07/2017

PROGNOSISoRelated to the underlying disorder

oUsual good maintain of the clinical benefit on long term in isolated and combined dystonias

oHowever some variability (initial and long term clinical benefit)

oBradykinesia/gait impairment induced versus control of dystonia/dysphagia

oRebound at DBS interruption in some patients

oDisease progression

oTolerance in some patients Miyagi, 2013-‐Two DYT1 cases


RISK RELATED TO DBS: OPERATE LATE


o Status Dystonicus in a case of fast progression of dystonic symptoms (delayed DBS indication)

o Spontaneous femoral fracture because of dystonic spasms


RISK RELATED TO DBS: DISCONTINUE TREATMENT BECAUSE OF NON AVAIALBILITY

o Severeworsening of dystonia because of IPG depletion in a patient coming from abroad(no possibility of IPG to be replaced in the Country and no financial support for doing it)

o Disease can become an emergency

RISK RELATED TO DBS: NOT CONTROLLING ALL THE TARGETED SYMPTOMS: DYSPHONIA


THAP1 gene related (DYT6) dystonia: excellent control of cervicaland trunk dystoniabut no improvement of laryngeal dystonia

COMPLICATIONSosurgical site infections 10.3% for new implants and revisionsomalfunction in 7.7% N= 129 patients; mean FU =3.3yoshort extension 3.8% oelectrode migration in 2.3%oskin erosions (2.3%)obleeding (1 patient)o unexpected switching off in 18.7% of Soletra/Kinetra and3.4% of Activa RC, otransient seroma at IPG site in postoperative period (8%)

Kaminska, 2017


WHEN TO OPERATE?


o Childhood onset TOR1A gene related DYT1 dystoniao Surgery in adulthood; excellent control of dystonia but severe scoliosis requesting arthrodesis

RELATIONSHIP BETWEEN ETIOLOGY, SYMPTOM DURATION AND PROGRESSION OF MUSCULOSKELETAL DEFORMITY


RUNNING FAST INTO STATUS DYSTONICUSoDystonic storm (independentlyof the etiology)

oTOR1A gene related DYT1 dystonia

oDBS scheduled; Status Dystonicus two day previous to planned DBS


o Monitor evolution and ANTICIPATE when needed

FREQUENT FAILURESo Complexe forms (dystonia associated with pyramidal signs, ataxia, …)

o Mitochondrial encephalopathy (frequently but not always)

o Other Progessive disorders (glutaric aciduria type 1…)

o Static forms with severe structural alterations (thalamic, motor cortex)

o DYT12 rapid onset dystonia parkinsonismMDS-‐ES 1ST SUMMER SCHOOL ON NEUROMODULATION FOR MOVEMENT DISORDERS GRENOBLE,

FRANCE ·∙ JULY 6-‐8, 201708/07/2017

FACTORS OF GOOD PROGNOSISophasic component of dystonia

o short disease duration

o absence of skeletal deformities

oDYT1 genemutation in isolated dystonia

o no associated weakness and spasticity in acquired forms

Isaias, 2008, Vasques, 2009, Cif, 2017


CONCLUSIONSoDBS in pediatric movement disorders refers mainly to dystonia

oObjective depends on the type of dystonia (etiology and phenotype)

oObjective must be defined and validated together with the childand his family

oComplications are related mainly to DBS system and treatmentinterruption

oDBS is a life time treatment dealing sometimes with progressivedisorders (inform patient and family)


CONCLUSION DBS administration in pediatrics requires a multidisciplinary team to

o select candidates

o identify reasonable target symptoms

o perform the procedure

o cope with complications related to therapy and devices

ooptimize DBS administration

o support the patients and families over the changing life


University Hospital in MontpellierOver the last 20 years…

Neurology/PediatricNeurologyL. Cif, V Gonzalez, I de Antonio, M Azais, B Biolsi, A Roubertie, B Echenne, F Rivier

Neurosurgery

P Coubes, S Gil Robles, H Elfertit, T Roujeau, S James, E Chan Seng

ICU: A Boularan, F Gréco, G Cambonie, C Milési

Psychiatry: A Seychelle, A Ionita, D Capdevielle, F Cyprien

Neuropsychology: E Sanrey

Genetics: C Coubes, G Collod-‐Beroud, M Claustres

Rehabilitation: I Laffont, F Coroian, V Carre, C Jourdan


deep$brain$stimulation$in$children$ - … anesthetic release, involuntary movements are much less...

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