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ALTERNATING HEMIPLEGIA OF CHILDHOOD: TREATMENT

ALTERNATING HEMIPLEGIA OF CHILDHOOD: TREATMENT. Kenneth Silver MD University of Chicago Comer Childrens Hospital. AHC: Treatment. Pathophysiology unknown Medication Trials Anti-epileptic Anti-migraine Movement Disorders

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ALTERNATING HEMIPLEGIA OF CHILDHOOD: TREATMENT

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  1. ALTERNATING HEMIPLEGIA OF CHILDHOOD: TREATMENT Kenneth Silver MD University of Chicago Comer Childrens Hospital

  2. AHC: Treatment • Pathophysiology unknown • Medication Trials • Anti-epileptic • Anti-migraine • Movement Disorders • Flunarizine most effective med but not sufficient

  3. FLUNARIZINE • Non selective blocker of voltage dependant Calcium and Sodium Channels • Attenuates amplitude of spontaneous post-synaptic currents in cortical pyramidal cells • Reduces firing frequency in high extra-cellular Potassium

  4. Alternating Hemiplegia of Childhood: Treatment • M. Mikati et al Pediatric Neurology (2000) 23 • 27/44 patients on FLU • 21 Favorable response (78 %) • 100% decrease duration • 86% decrease frequency • One patient attack free • Two patients exacerbation after D/C • 2/7 responded to Verapamil • Use or effectivness of FLU not correlated with developmental outcome

  5. Alternating Hemiplegia of Childhood: Treatment • M. Sasaki, N. Sakuagawa, M. Osawa Brain & Development (2001) 23 • 106 of 201 Japanese Child Neurologist responded to questionnaire 28 AHC patients seen, All received Flunarizine Dose 5-15 mg 18 showed positive response 7 decrease duration, 5 decrease frequency 6 relapse after withdrawal 2 responded to Amantadine Subsequent report K. Sone Neuropediatrics 2000 31 Improvement with Amantadine not sustained

  6. AHC: Treatment N=103 Pediatrics 2009;123:e534–e541

  7. AHC: Flunarizine Treatment N=80

  8. BenzodiazepinesN= 55

  9. Clonazepam N=28 Diazepam N=34 Lorazepam N=25 Benzodiazepines

  10. Valproic Acid N=42 Phenobarbital N=42 Carbamazepine N=39 Phenytoin N=29

  11. AHC: Other Anticonvulsant Treatment N=81

  12. Anti-migraine N=23 Chloral Hydrate N=19 Extra-pyramidalMed N=31 Psychotropic Med N=36

  13. AHC: Treatment • Pathophysiology unknown • Medication Trials • Anti-epileptic • Anti-migraine • Movement Disorder: Paroxysmal Dyskinesia Channelopathy • Flunarizine most effective med but not sufficient

  14. 2   1 Familial Hemiplegic Migraine FHM1 Ca2+ channel structure

  15. Ca2+ channel structure Familial hemiplegic migraine: Severe, autosomal dominant, associated with reversible weakness Other associations: progressive cerebellar ataxia, coma, neuromuscular junction defect Molecular pathogenesis:  or  current density left-shifted activation threshold

  16. Familial hemiplegic migraine: mouse knock-in model Cortical spreading depression  van den Maagdenberg et al, 2004

  17. Alternating Hemiplegia of Childhood: Pathophysiology • Channelopathy: • Ion channels responsible for generating signals between excitable membranes • Heterogeneous protein complexes with selective ion permeability (Na, K, Ca, Cl) • Channels are gated by changes in transmembrane potential and ligands • Several paroxysmal neurological disorders known,eg. Periodic paralysis, episodic ataxia, frontal epilepsy, • Hemiplegic migraine: FHM1:-CACNA1A, • FHM2:-ATP1A2

  18. Alternating Hemiplegia of Childhood: Pathophysiology Channelopathy: Paroxysmal features, episodic, unpredictable from a stable baseline Therapeutic Flunarizine is channel blocker Mutations demonstrated in known channel genes such as those seen in FHM

  19. Alternating Hemiplegia of Childhood: Pathophysiology • Cortical Speading Depression • EEG contralateral slow waves • Neuroimaging and Neuropathology do not show any structural abnormalities • Fluctuating Hemiplegia • Depolarization of neuronal region stimulated by increased K or glutamate • Spread of depolarization at 2-4 mm/min • Long lasting neuronal depression • Responsible for aura in migraine

  20. Alternating Hemiplegia of Childhood: Pathophysiology • Cortical Spreading Depression: • FHM1 mutant presynaptic voltage gated Ca channels open to small membrane depolarizations • Neuronal excitability is increased with more influx of Ca, release of glutamate and K • FHM2: extracellular K builds up because mutant Na/K ATPase cannot bind K and exchange for Na results in increase glutamate • ATP required to maintain neuronal membrane potential and used up to quickly

  21. ALTERNATING HEMIPLEGIA OF CHILDHOOD From peas to pores

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