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

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

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

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

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

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

19. AHC: Flunarizine Treatment N=80

20. Benzodiazepines N= 55

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

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

23. AHC: Other Anticonvulsant Treatment N=81

24. Chloral Hydrate N=19 Chloral Hydrate N=19 Anti-migraine N=23 Extra-pyramidal Med N=31 Psychotropic Med N=36

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

27.   22 11 Ca2+ channel structure Familial Hemiplegic Migraine FHM1

28. 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

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

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

31. 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

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

33. Alternating Hemiplegia of Childhood: Pathophysiology Cortical Spreading Depression: Cortical Spreading Depression: FHM1 mutant presynaptic voltage gated Ca channels open to small membrane depolarizations 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 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 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 ATP required to maintain neuronal membrane potential and used up to quickly

34. ALTERNATING HEMIPLEGIA OF CHILDHOOD From peas to pores