Embed Size (px)
DESCRIPTION
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 - PowerPoint PPT Presentation
Citation preview
ALTERNATING HEMIPLEGIA OF ALTERNATING HEMIPLEGIA OF CHILDHOOD: TREATMENTCHILDHOOD: TREATMENT
Kenneth Silver MD Kenneth Silver MD University of Chicago University of Chicago
Comer Childrens HospitalComer Childrens Hospital
AHC: TreatmentAHC: Treatment
Pathophysiology unknownPathophysiology unknown Medication TrialsMedication Trials Anti-epilepticAnti-epileptic Anti-migraineAnti-migraine Movement DisordersMovement Disorders Flunarizine most effective med Flunarizine most effective med
but not sufficient but not sufficient
FLUNARIZINEFLUNARIZINE
Non selective blocker of voltage Non selective blocker of voltage dependant Calcium and Sodium dependant Calcium and Sodium ChannelsChannels
Attenuates amplitude of spontaneous Attenuates amplitude of spontaneous post-synaptic currents in cortical post-synaptic currents in cortical pyramidal cellspyramidal cells
Reduces firing frequency in high extra-Reduces firing frequency in high extra-cellular Potassiumcellular Potassium
Alternating Hemiplegia of Alternating Hemiplegia of Childhood: TreatmentChildhood: Treatment
M. Mikati et al Pediatric Neurology (2000) 23M. Mikati et al Pediatric Neurology (2000) 23 27/44 patients on FLU27/44 patients on FLU 21 Favorable response (78 %)21 Favorable response (78 %) 100% decrease duration100% decrease duration 86% decrease frequency86% decrease frequency One patient attack freeOne patient attack free Two patients exacerbation after D/CTwo patients exacerbation after D/C 2/7 responded to Verapamil2/7 responded to Verapamil Use or effectivness of FLU not correlated Use or effectivness of FLU not correlated
with developmental outcomewith developmental outcome
Alternating Hemiplegia of Alternating Hemiplegia of Childhood: TreatmentChildhood: Treatment
M. Sasaki, N. Sakuagawa, M. Osawa Brain M. Sasaki, N. Sakuagawa, M. Osawa Brain & Development (2001) 23 & Development (2001) 23
106 of 201 Japanese Child Neurologist responded to 106 of 201 Japanese Child Neurologist responded to questionnaire 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 response18 showed positive response 7 decrease duration, 5 decrease frequency7 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 31Subsequent report K. Sone Neuropediatrics 2000 31 Improvement with Amantadine not sustainedImprovement with Amantadine not sustained
AHC: Treatment N=103 AHC: Treatment N=103
Pediatrics 2009;123:e534–e541
AHC: Flunarizine Treatment AHC: Flunarizine Treatment N=80N=80
60
2.5
37.5
0
10
20
30
40
50
60
%
positive
% no
change
% positive
% negative
% no change
BenzodiazepinesN= 55
38
3
59
0
10
20
30
40
50
60
%
positive
% no
change
% positive
% negative
% no change
Diazepam N=34Diazepam N=34
26
-9
65
-10
010
20
30
4050
60
70
%
positive
% no
change
% positive
% negative
% no change18
-4
78
-20
0
20
40
60
80
%
positive
% no
change
% positive
% negative
% no change
Clonazepam N=28
Lorazepam N=25
12
-8
80
-20
0
20
40
60
80
%
positive
% no
change
% positive
% negative
% no change
Benzodiazepines
Valproic Acid N=42Valproic Acid N=42
10
-7
83
-20
0
20
40
60
80
100
%
positive
% no
change
% positive
% negative
% no change
Phenobarbital N=42
12
-10
78
-20
0
20
40
60
80
%
positive
% no
change
% positive
% negative
% no change
Carbamazepine N=39
3
-10
87
-20
0
20
40
60
80
100
%
positive
% no
change
% positive
% negative
% no change
Phenytoin N=29
10
-7
83
-20
0
20
40
60
80
100
%
positive
% no
change
% positive
% negative
% no change
AHC: Other Anticonvulsant AHC: Other Anticonvulsant Treatment N=81 Treatment N=81
6
-20
74
-20
0
20
40
60
80
%
positive
% no
change
% positive
% negative
% no change
Chloral Hydrate N=19Chloral Hydrate N=19
11
-5
84
-20
0
20
40
60
80
100
%
positive
% no
change
% positive
% negative
% no change
90
91
0
20
40
60
80
100
%
positive
% no
change
% positive
% negative
% no change
10
-6
84
-20
0
20
40
60
80
100
%
positive
% no
change
% positive
% negative
% no change
Anti-migraine N=23Anti-migraine N=23
Extra-pyramidalExtra-pyramidal Med N=31Med N=31 Psychotropic Med N=36Psychotropic Med N=36
19
-14
67
-20
0
20
40
60
80
%
positive
% no
change
% positive
% negative
% no change
AHC: TreatmentAHC: Treatment Pathophysiology unknownPathophysiology unknown Medication TrialsMedication Trials Anti-epilepticAnti-epileptic Anti-migraineAnti-migraine Movement Disorder: Movement Disorder:
Paroxysmal Dyskinesia Paroxysmal Dyskinesia Channelopathy Channelopathy
Flunarizine most effective med Flunarizine most effective med but not sufficient but not sufficient
2
1
Ca2+ channel structure
THE P/Q GENE PRODUCTTHE P/Q GENE PRODUCT
Ophoff RA, et al. Cell. 1996.
Familial Hemiplegic Migraine FHM1
Ca2+ channel structureFamilial hemiplegic migraine:
Severe, autosomal dominant, associated with reversible weaknessOther associations: progressive cerebellar ataxia, coma, neuromuscular junction defect
Molecular pathogenesis: or current density left-shifted activation threshold
van den Maagdenberg et al, 2004
Familial hemiplegic migraine: mouse knock-in model
Cortical spreading depression
Alternating Hemiplegia of Childhood: Alternating Hemiplegia of Childhood: PathophysiologyPathophysiology
Channelopathy:Channelopathy: Ion channels responsible for generating signals Ion channels responsible for generating signals
between excitable membranesbetween excitable membranes Heterogeneous protein complexes with Heterogeneous protein complexes with
selective ion permeability (Na, K, Ca, Cl)selective ion permeability (Na, K, Ca, Cl) Channels are gated by changes in Channels are gated by changes in
transmembrane potential and ligandstransmembrane potential and ligands Several paroxysmal neurological disorders Several paroxysmal neurological disorders
known,eg. Periodic paralysis, episodic ataxia, known,eg. Periodic paralysis, episodic ataxia, frontal epilepsy, frontal epilepsy,
Hemiplegic migraine: FHM1:-CACNA1A,Hemiplegic migraine: FHM1:-CACNA1A, FHM2:-ATP1A2FHM2:-ATP1A2
Alternating Hemiplegia of Childhood: Alternating Hemiplegia of Childhood: PathophysiologyPathophysiology
Channelopathy:Channelopathy:
Paroxysmal features, episodic, Paroxysmal features, episodic, unpredictable from a stable baselineunpredictable from a stable baseline
Therapeutic Flunarizine is channel blockerTherapeutic Flunarizine is channel blocker
Mutations demonstrated in known channel Mutations demonstrated in known channel genes such as those seen in FHMgenes such as those seen in FHM
Alternating Hemiplegia of Childhood: Alternating Hemiplegia of Childhood: PathophysiologyPathophysiology
Cortical Speading Depression Cortical Speading Depression EEG contralateral slow wavesEEG contralateral slow waves Neuroimaging and Neuropathology do not Neuroimaging and Neuropathology do not
show any structural abnormalitiesshow any structural abnormalities Fluctuating HemiplegiaFluctuating Hemiplegia Depolarization of neuronal region stimulated Depolarization of neuronal region stimulated
by increased K or glutamateby increased K or glutamate Spread of depolarization at 2-4 mm/minSpread of depolarization at 2-4 mm/min Long lasting neuronal depression Long lasting neuronal depression Responsible for aura in migraineResponsible for aura in migraine
Alternating Hemiplegia of Childhood: Alternating Hemiplegia of Childhood: PathophysiologyPathophysiology
Cortical Spreading Depression:Cortical Spreading Depression: FHM1 mutant presynaptic voltage gated Ca FHM1 mutant presynaptic voltage gated Ca
channels open to small membrane channels open to small membrane depolarizationsdepolarizations
Neuronal excitability is increased with more Neuronal excitability is increased with more influx of Ca, release of glutamate and Kinflux of Ca, release of glutamate and K
FHM2: extracellular K builds up because FHM2: extracellular K builds up because mutant Na/K ATPase cannot bind K and mutant Na/K ATPase cannot bind K and exchange for Na results in increase exchange for Na results in increase glutamateglutamate
ATP required to maintain neuronal ATP required to maintain neuronal membrane potential and used up to quicklymembrane potential and used up to quickly
ALTERNATING HEMIPLEGIA OF CHILDHOOD From peas to pores
