Arzimanoglou - EURORDIS

Patient driven research:Alternating Hemiplegia

Alexis Arzimanoglou

Hôpital Robert DebréService de neurologie pédiatrique et de maladies

métaboliques

CENTRE THEMATIQUE DE RECHERCHE ET DE SOINS

I.D.E.E.Institute for children and adolescents

with epilepsyHOSPICES CIVILS DE LYON

ALTERNATING HEMIPLEGIA:A rare and strange neurological disorder

Major Clinical Features:

• Onset in infancy (< 18 months)

• Repeated episodes of hemiplegia on either side

• Episodes of bilateral paralysis

• Associated paroxysmal events (dystonic, chorea, …)

• Abnormal ocular movements

• Epileptic seizures

• Appearance of fixed chronic features• Sleep interrupts paralytic attacks (that may last several hours)

Differential diagnosis:

1.Epilepsy2.Migraine : hemiplegic, basilar

3.Paroxysmal dyskinesias4.Vascular disorders:,malformations; multiple emboli; Osler-

Weber-Rendu disease; cutis marmorata5.Hematologic disorders: homocystinuria; thrombophilia

6.Metabolic diseases: MELAS and other mitochondrial diseases; urea cycle diseases

7.Others: including paroxysmal torticollis of infancy, demyelinating diseases, relapsing encephalitides

In summary:

A rare and difficult to diagnose disorder of early childhood;

It is the association of signs and symptoms that allows diagnosis of Alternating Hemiplegia;

No biological marker

All investigations normal

The absolute need for a multicenter - multicountrycollaboration

The European Network for The European Network for Research on AHC (ENRAH)Research on AHC (ENRAH)

Network of Centers of ExpertiseNetwork of Centers of ExpertiseResearch GroupsResearch GroupsPatient OrganisationsPatient Organisations

Coordination, Vienna, ACoordination, Vienna, A

Facilitate exchange of ideas & development of new ideas between experts from several European countries

The benefits

Participants

Alexis Arzimanoglou, MD, Paris, France Andreas Moser, MES, MBA,Vienna, Austria

Arn M.J.M. van den Maagdenberg, PhD, Leden, NL

Brian G R Neville, Prof., London, UKCarme Fons , MD, Barcelona, SpainClaudio Zucca , M.D.,Bosisio Parini , ItalyDilsad Türkdogan, M.D., Istanbul, TurkeyDominique Ponceline , St. G. Arpajon, FranceEmilio Fernandez-Alvarez, Prof , Barcelona, SpainFrancis P. Crawley, Prof. , Brussels, BelgiumFriedrich Ebinger, Dr., Heidelberg, GermanyGeorg Spiel, Univ. Doz. Dr. , Klagenfurt, AustriaGiuseppe Gobbi , Dr. , Bologna, ItalyInês Carrilho, MD, Porto, PortugalLaura A.E.M. Laan, MD, PhD, Leden, The NetherlandsM. Valeriani , Dr. Rome, ItalyMelania Gianotta, MD, Bologna, ItalyMirjana Toullec ,Saint Germain En Laye , FrancePaul Casaer, Prof., Leuven, BelgiumPhilip Hirst , Dr., Warfield Bracknell Berks , UKRosaria Vavassori , Verderio Superiore , ItalySona Nevsimalova, Dr., Prague, Czech RepublicTsveta Schyns, PhD , Vienna, Austria

The creation of an impressive database:a web-based European registry

The benefits Financial support for young researchers;

Work closer with the patient associations

People with AHC and their Families, GPs, Following neurologists

Patients Data Files and Human Samples at the National Clinical CentersConfidential

European Registryon AHC cases

Restricted

Coded standardized data

Information www.enrah.netPublic

INTERNATIONAL REGISTRY OF AHC PATIENTSINTERNATIONAL REGISTRY OF AHC PATIENTS-- EUROPEEUROPE

e n r a hEUROPEAN NETWORK FOR RESEARCH ONALTERNATING HEMIPLEGIA

THE QUESTIONNAIREGeneral information

*at least with grand parents

Any history of comorbidity in the family* (0=no; 1=yes; 88=unknown)Any history of mortality in childhood in the family* (0=no; 1=yes; 88=unknown)Any history of other neurological disease in the family* (0=no; 1=yes; 88=unknown)Any history of other paroxysmal disease in the family* (0=no; 1=yes; 88=unknown)Any history of epilepsy in the family* (0=no; 1=yes; 88=unknown)Any history of migraine in the family* (0=no; 1=yes; 88=unknown)First or second degree consanguineity (0=no; 1=yes; 88=unknown)Delivery (0=eutocic; 1= dystocic. 88=unknown) (or 0=vaginal delivery 1= section caesarea ?)

Pregnancy (O= normal; 1= abnormal; 88=unknown)Patient Birth Date Patient CODEDiagnosis dateRecruitment date



Disappearance of symptoms with sleep (0=no 1=yes; 88=unknown)

Pain (0=no 1=yes; 88=unknown)

Breathing difficulties (0=no 1=yes; 88=unknown)

Neurovegetative disorders (0=no 1=yes; 88=unknown) ( orautonomic disturbances)

Headache (0=no 1=yes; 88=unknown)

Status epilepticus (0=no 1=yes; 88=unknown)

Epilepsy (0=no 1=yes; 88=unknown)

Abnormal ocular movement (0=no 1=yes; 88=unknown)

Plegic attack (0=no 1=yes; 88=unknown)

Tonic/dystonic attack (0=no 1=yes; 88=unknown)

Premonitory signs (0=no 1=yes; 88=unknown)

Onset<18 mths (0=no 1=yes; 88=unknown)

PAROXYSMAL EVENTS (0=no 1=yes; 88=unknown)



Working employment (0=no; 1=autonomous ; 2=with assistance; 88=unknown)

School attendance (0=normal without help; 1=normal with help; 2=special course)

Behavioural disorders (0=no; 1=mild; 2=moderate; 3=severe 88=unknown)

Language disorder (0=no; 1=mild; 2=moderate; 3=severe 88=unknown)

Cognitive impairment (0=no; 1=mild; 2=moderate; 3=severe 88=unknown)

Muscle Tone (0=normal; 1= hypertonia; 2= hypotonia)

Complex Movement Disorder (0=no; 1=mild; 2=moderate; 3=severe 88=unknown)

Tremor (0=no; 1=mild; 2=moderate;3=severe 88=unknown)

Chorea (0=no; 1=mild; 2=moderate; 3=severe 88=unknown)

Myoclonus (0=no; 1=mild; 2=moderate; 3=severe 88=unknown)

Dystonia (0=no; 1=mild; 2=moderate; 3=severe 88=unknown)

Pyramidal signs (0=no; 1=mild; 2=moderate; 3=severe 88=unknown)

Fine motor problems (0=no; 1=mild; 2=moderate; 3=severe 88=unknown)

Gross Motor problems (0=no; 1=mild; 2=moderate; 3=severe 88=unknown)

NON PAROXYSMAL FEATURES (0=no; 1=mild; 2=moderate; 3=severe 88=unknown)


FOLLOW UP AT 2 YRS(from 0 yrs to 2 yrs)

date:

Other effective measures (0=no; 1=yes)*link to the open windowMost effective drugs to prevent the attack (0=no; 1=yes) ( or any effective drug…?)Most effective drugs for acute attack (0=no; 1=yes) ( or any effective drug…?)Trigger events (0=no; 1= yes)Length (0=<1hour; 1=1-6 hours; 2=6-12 hours; 3=12-24 hours, 4=>24 hours)Frequency (0=<1/year; 1=monthly; 2=weekly; 3=daily)Consciousness (0= normal; 1= altered)Limb involvement (0=one; 1= >1 same side; 2=>1 different side)Semeiology (0=simple; 1= mixed)TONIC OR DYSTONIC ATTACKS (0=no; 1=yes )

PAROXYSMAL features



OTHER INFORMATION:

A huge amount of clinical data collected

Direct benefits

• Better define the severity spectrum of the disorder, atypical forms, co-morbidities, …;• Have some hints on global natural evolution;• Be prepared for genotype-phenotype correlations …

Fluoxetine

Flunarizine

Felbamate

Ethosuximide

Ergotamine

Dihydroergotamine

Diazepam

Clonidine

Clonazepam

Clobazam

Ciproterone-ethinylestradiol

Chloral Hidrate

Carbamazepine

Buspirone

Bromocriptine

Biperiden

Barbexaclone

Baclofen

Alprazolam

Acetazolamide

Sumatriptan

Sulthiame

Sertraline

Propanolol

Primidone

Pregabaline

Piracetam

Pimozide

Phenobarbital

Phenitoine

Oxcarbazepine

Nitrazepam

Nimodipine

Niaprazine

Methysergide

Methoclopramide

Lorazepam

Levetiracetam

L-dopa + carbidopa

Lamotrigine

Haloperidol

Gabapentin

Valproate

Tript-OH

Triexyphenidyl

Trazodone

Topiramate

Tiagabine

Olygosaccarid

Skin Biopsy

Mitochondrial chain analysis

Muscle Biopsy

LCR amino acids

LCR lactate

LCR pyruvate

LCR neurotrasmitter

Liquor (standard examination)

Ana

Antiphospholipid

Purine, pirimidyne

CDG

VLFA

Organic acids

Amino acids

lysosomal enzyme

Ammonium

CPK

Pyruvate

Lactate

Base screening *

LABORATORY INVESTIGATION(0=normal; 1=not normal; 99=not

done)

Echocardiogram

ECG

Angiogram

ENG

SEP

EMG

Blink reflex

ABR

VEP

interictal EEG

ictal EEG (during motor attack)

Ictal EEG (during epileptic seizure)

MRI spectroscopy

ictal SPECT

interictal SPECT

fMRI scan

MRI scan

CT scan

(0=normal;1=not normal; 99=not done)

NEURORADIOLOGICAL AND NEUROPHYSIOLOGICAL INVESTIGATION



OTHER INFORMATION:

A huge amount of data to collect on drugs and investigations already performed

Indirect benefits

• Eventually identify the most pertinent investigations to perform;• Identify what drugs have been used by others, eventually build-up a controlled trials• Reduce costs;

1.The creation of a database for rare disorders is an unavoidable step for the development of new projects but not a research project proper;

2. This would be possible in parallel but a substantial funding would be necessary.

The difficulties and limits

A critique !!

Although it is easy to understand some of the reasons … obtaining funding for such projects on rare (but they are many) disorders remains a very complex procedure both at a European and at a local level.

MERCI !!!!

1. Projects like ENRAH enormously facilitate close collaboration between clinicians, geneticists, basic scientists … at a European level.

2. Such a collaboration represents the unique pathway for a competent collaboration with US centers, for the benefit of the patients.

Arzimanoglou - EURORDIS

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