Choreas and paroxysmal disorders. Bedside examination. Chorea

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1 Focus on: Characteristic of the disorders (clues) Phenomenology -> syndrome Etiologies (diagnostic approach (clues/ tests) Treatment (s) Choreas and paroxysmal disorders Pr. Marie Vidailhet Department of Neurology and ICM UPMC/ Inserm UMR-1127 University Pierre Marie Curie Paris-6 Salpêtrière Hospital, Paris, France Bedside examination Definition Chorea Clinical clues Erratic involuntary brief purposeless movements Non repetitive, randomly distributed, irregularly timed, Age at onset Acute/ progressive Familial history Associated clues Streptococal Infection Pregnancy Hypotonia APL, polyglobulia, etc. Drugs Associated signs: dementia, behavior, eye movements, neuropathy, ataxia Distribution (focal lesions) Progressive onset, 40 years-old, behavioral disorders, cognitive decline Facial chorea Huntington s disease CAG repeat (huntingtin) 1

2 Akinetic presentation Dementia in HD dysexecutive syndrome, reduced verbal fluency, apathy, bradyphrenia, relative preservation of language and memory, dementia of HD patients Family history Dystonia Rigidity akinesia Juvenile form (large number of CAG repeats, paternal transmission) Caudate atrophy Focal dystonia, may be also the first symptom in autosomal dominant ataxia (SCA1, SCA 2, SCA3, SCA6, SCA7, SCA17, DRPLA) or recessive EAO1 (aprataxin) Not a treatment yet, but some hope GPi-DBS attenuated chorea Long term beneficial effect on chorea despite progression of other symptoms Kang GA et al JNNP 2011,Gruber et al J Neural Transmission 2014, Gonzales V et al J Neurosurg 2014 dietary anaplerotic therapy: triheptanoin replenishing the pool of metabolic intermediates in the Krebs cycle Neurology 2015;84: Other types of hereditary chorea DRPLA Huntington like syndromes HDL-1/ PRNP (a few families) HDL-2/ JPH-3 junctophilin3 (Africa) HDL-3, SCA 17 Rare: C9orf72 mutation, SCA2 Neuro-acanthocytosis Inorganic phosphate (Pi)/phosphocreatine (PCr) ratio: an outcome measure of brain metabolic dysfunction in patients with HD visual activation with 6-Hz red/black checkerboard flashes Occipital cortex metabolism «benin» hereditary chorea DRPLA Dentatorubral-pallidoluysian atrophy Other types of chorea : Clues Variable age at onset Chorea, myoclonus, dystonia, parkinsonism Ataxia Dementia, psychosis Epilepsy (may be severe i.e. progressive myoclonus epilepsy) Patients with progressive myoclonus epilepsy (PME) phenotype: larger expansions (62-79 repeats) earlier ages of onset (onset before age 20). autosomal dominant CAG repeat (CTG-B37 triplet repeat expansion) Atrophin-1 gene clinically overlaps with Huntington's disease combination of chorea, myoclonus, seizures, ataxia, and dementia. 2

3 Other types of chorea : Clues Neuroacanthocytosis Young adult onset Chorea, myoclonus, dystonia, parkinsonism Ataxia Oromandibular dystonia Areflexia Dementia, psychosis Other types of chorea : Clues Young onset (childhood) Some improvement in adulthood Chorea, myoclonus, dystonia, Ataxia (that may be early in life and disappears) No Dementia chorea-acanthocytosis (ChAc), autosomal recessive rare autosomal recessive disorder, VPS13A gene, encoding chorein wide spectrum of symptoms that may vary over time Dystonia lower face and tongue precipitated by eating, speech and swallowing difficulties neck ( head drops ) and truncal flexion/extension movements gait can appear bizarre and rubbery, with buckling at the knees and hips bradykinesia usually develops later Areflexia Psychiatric symptoms, cognitive decline seizures are seen in approximately 40% of patients with ChAc Acanthocytes, increased CPK Mac Leod similar features with neuropathy and myopathy X linked: XK gene Walker RH, Tremor Other Hyperkinet Mov 2015 Benign hereditary chorea NKX2-1 gene (previously called TITF1), essential for organogenesis of the basal ganglia, thyroid lung rare autosomal dominant disorder childhood onset that tends to improve in adulthood. Hypotonia and chorea in early infancy, with delayed walking ability dystonia, myoclonus, tics, ADHD may be associated over time Learning difficulties in some, mental retardation may be present Various combinations of, thyroid (67%) and lung (46%) features beneficial effect of tetrabenazine (even in children) Gras D, et al JNNP

4 Bedside examination Definition Erratic involuntary brief purposeless movements Non repetitive, randomly distributed, irregularly timed, Hypotonia Clinical clues Age at onset Acute/ progressive Familial history Associated clues Streptococal Infection Pregnancy APL, polyglobulia, etc. Drugs Associated signs: dementia, behavior, eye movements, neuropathy, ataxia Distribution (focal lesions) 20 Antiphospholipid syndrome (Lupus erythematosus) Sydenham chorea frequency ranges from 1% to 2% age at onset of chorea 20.6 years (9 62) may be the initial symptom or early in the course of LED female predominance (84%), high prevalence of antiphospholipid antibodies (91%) heart valvulopathy during follow-up Arterial thrombosis Spontaneous abortions importance of prophylactic treatment of the ALP syndrome (pregrancy) beneficial effect of steroids (may also improve spontaneously) Symptomatic treatment of chorea Reiner P, et al Mov Disord 2011 may have concomitant hyperactivity and OCD symptoms Post-stroke Paroxysmal disorders 23 4

5 - Triggering factors - paroxysmal kinesigenic dyskinesia (PKD) PRRT2 Age of onset > 20y No family history Variable duration of attacks and triggering factors Abnormal interictal clinical exam Abnormal laboratory/mri findings Méneret and Roze, 2016 Consider secondary causes Yes No paroxysmal exercise-induced dyskinesia (PED) SLC2A1 (Glut1 deficiency) Paroxysmal Dyskinesia Triggering factor/dura>on of a?acks and paroxysmal non-kinesigenic dyskinesia (PNKD) Rare troubles Alternating hemiplegia ATP1A2 ( and CACNA1A, SCN1A) Episodic ataxia (EA1: KCNA1 mutations, EA2: CACNA1A mutations) Kinesigenic/ < 1 min Exercice/ Min to hours PKD PED PNKD PRRT2 SLC2A1 GCH1, PARK2 PNKD Becoming more complex over time: expanding spectrum Episodic Ataxia Triggering factor/dura>on of a?acks/interictal manifesta>ons Non kinesigenic/ Min to hours Kinesigenic/ Seconds to min /Myokymia Stress/ Hours/ Nystagmus, Progressive ataxia EA1 KCNA1 EA2 CACNA1A PKD Paroxysmal Dyskinesia Triggering factor/dura>on of a?acks Kinesigenic/ < 1 min Exercice/ Min to hours PED PKD PRRT2 ADCY5 (SCN8A) SLC16A2 Non kinesigenic/ Min to hours SLC2A1 GCH1 ADCY5 PRRT2 PARK2 ATP1A3 PDHA1, PDHX PNKD PNKD PRRT2 ADCY5 SLC2A1 ATP1A3 KCNMA1 BCKD complex onset in childhood Triggering factor : sdden movement after rest (standing up) Duration < 1 min. No pain, no loss of consciousness, interictal examination normal Frequent (up to 100 /day), variable, often peaking in puberty, improvement in adulthood Past history of benign infantile convulsions (before 1 year-old) Low doses Carbamazepine, Oxcarbazepine Phénytoine, Lamotrigine Topiramate, Clobazam Decreases the frequency of attacks Méneret & Roze, 2016 PRRT2 mutations and Kinesigenic paroxysmal Dyskinesias (PKD) Nat Genet. 2011, Meneret et al, Neurology 2012, Gardiner et al Brain

6 Clinical spectrum of PRRT2 mutations PKD: paroxysmal kinesigenic dyskinesias ICCA : infantile convulsions with choreoathetosis syndrome BFIS: benign familial infantile seizures PED: paroxysmal exercice induced dyskinesias HM : hemiplegic migraine EA: episodic ataxia, FS: febrile seizures, CAE: childhood-absence epilepsy Vidéo d Emmmanuel Roze PKD PED The most frequent among paroxysmal dyskinesia Exercice induced onset in childhood Triggering factor : prolonged exercice Duration 5-30 minutes (variable frequency) No pain, no loss of consciousness, interictal examination normal No beneficial effect of antiepileptic drugs Onset childhood between 1 and 20 years-old Premonitory sensation* (aura) Triggering factor : initiation of movement after a period of rest Duration < 1 min. No improvement by anti-epileptic drugs Main cause : mutations SLC2A1 (GLUT 1 deficiency) Main cause : mutations SLC2A1 Courtesy E Roze Variable phenotype Microcephaly, mental retardation Complex movement disorders, ataxia, pyramidal signs Paroxysmal disorders (epileptic and non epileptic episodes) PED may be isolated Mongin et al., Tremor and Other Hyperkinet Disord,

7 Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1 deficiency ATP1A3 mutations Large spectrum: but less on movement disorders. ketone bodies to the brain and compensate for the lack of glucose - Early infantile epileptic encephalopathy paroxysmal episodes Ketogenic diets, standard of care in GLUT1 efficient on seizures control severe encephalopathy with ataxia and dystonia following a regression episode during a febrile episode during infancy. - Alternating hemiplegia of childhood (AHC) - CAPOS ( paroxysmal cerebellar ataxia /pes cavus/ optic neuropathy / SN deafness) CAPOS syndrome and hemiplegic migraine Significant reduction of non-epileptic paroxysmal manifestations when patients were treated with triheptanoin for 2 months (*p<0.05) - Rapid-Onset Dystonia-Parkinsonism (RDP) - Relapsing encephalopathy with cerebellar ataxia Mochel F et al JNNP 2016 Alternating hemiplegia childhood Age at onset before 18 months Triggering factor : temperature, bath-induced paroxysmal events physical exercice Duration : minutes to days. All patients experience hemiplegic attacks; 86.5% episodes of bilateral weakness, 88% dystonic attacks, 53% epileptic seizures, 72% developed chorea and/or dystonia and 92% mental retardation other: hemiplegia or quadriplegia, seizures, nystagmus, autonomic disturbances, dyspnea,altered consciousness, seiszures Paroxysmal eye movements by the age of 3 months in 80% Hemiplegic episodes appeared by 6 months of age in 56% of infants. Ataxia (96%), cognitive impairment (100%) frequent nonepisodic symptoms Lancet Neurol 2012 Dopa-reponsive dystonia (DRD) Due to heterozygous mutation (+++) or deletion GTP cyclohydrolase gene, GCH1, in 70% cases AD, incomplete penetrance, female predominance (3:1) Typical form : - onset first decade, initial involvement of one limb, Diurnal fluctuations (70%), exercise-related worsening, excellent response to L-Dopa Dopa-responsive dystonia GCH1 mutations Atypical forms Adult-onset generalized dystonia Dystonia that remains focal over decades Exercise-induced dystonia Task-specific dystonia Myoclonus-dystonia Isolated parkinsonism Spastic paraparesis Additional signs: cerebellar features, axial hypotonia, oculogyric crisis Payed football all day with his friends dystonia when walking +/ akinesia A$er treatment Trender-Gerhardt I et al., JNNP,

8 ADCY5 Onset in childhood Hyperkinetic movement disorders (mixed chorea/ dystonia), some fluctuations Axial hypotonia Orofacial myokimia / myoclonus No ataxiia, no marked cognitive deficiency, Slow progression Paroxysmal nocturnal movement disorders at night Friedman, Méneret et al., Mov Disord, 2016 Episodic Ataxia Episodic Ataxia Triggering factor/dura>on of a?acks/interictal manifesta>ons Kinesigenic/ Seconds to min /Myokymia EA1 KCNA1 Stress/ Hours/ Nystagmus, Progressive ataxia EA2 CACNA1A (CACNB4) Others SLC1A3 (EA6) CACNB4 (EA5) SNC2A PRRT2 ATP1A3 PDHA1, PDHX SLC2A1 FGF14 BCKD complx Episodic ataxias Recurrent ataxia +/- dysathria, tremor, diziness and vertigo, diplopia, Duration : Seconds to several days No loss of consciousness Sometimes improvement by acetazolamide Episodic ataxia type 1: EA1 Mutation on the KCNA1 gene Onset in childhood or adolescence Duration : brief, seconds to minutes Triggering factor: movement, starttle Myokimia (facial) +/- mental retardation, epilepsia, myotonia May be improved by acetazolamide or anti-epileptic drugs 8

9 Paroxysmal episode Episodic ataxia type 2: EA2 Mutation on the CACNA1A gene Onset in childhood or adolescence Duration :a few hours to a few days Triggering factor: stress, exercice, coffee, alcohol Between episodes : persistence of ataxia, nystagmus, epilepsy, migraine.. May be improved by acetazolamide or 4-aminopyridine Started at the age of 25 Duration : 3 sec to 5 min Variable frequency: 3/day à 1/ month Triggered by a movement or when he is surprised Courtesy Pr V Navarro Ataxie épisodique de type 2 (EA2) Mutations htz du gène CACNA1A Début dans l enfance ou à l adolescence Durée des attaques: qq heures à qq jours Facteurs déclenchants: stress, exercice, caféine, alcool En interictal: ataxie + nystagmus +/- épilepsie, migraine, dystonie Ttt: acetazolamide, 4-aminopyridine ictal Inter-ictal ictal Inter-ictal Symptomatic episodic ataxia Episodic ataxia 1 Episodic ataxia 2 Onset (years) Adulthood Childhood (2-15) Childhood (2-20) Usual attack duration Seconds Minutes Hours to days Attack signs Ataxia, dysarthria, vertigo Ataxia, dysarthria, diffuse tremor, myokimias Ataxia, vertigo, nystagmus Possible interictal signs Signs related to the underlying disorder Myokimias Nystagmus, progressive ataxia Brain MRI Brainstem lesions Vermian atrophy Thank you for your attention Response to acetazolamide Response to carbamazepine +/- +/ Unknown Inheritance Sporadic AD AD 9

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