Transcript Dr Ken Silver - International Foundation for Alternating Hemiplegia

ALTERNATING HEMIPLEGIA OF
CHILDHOOD: TREATMENT
Kenneth Silver MD
University of Chicago
Comer Childrens Hospital
AHC: Treatment
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Pathophysiology unknown
Medication Trials
Anti-epileptic
Anti-migraine
Movement Disorders
Flunarizine most effective med
but not sufficient
FLUNARIZINE
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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 extracellular Potassium
Alternating Hemiplegia of
Childhood: Treatment
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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
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
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AHC: Treatment N=103
Pediatrics 2009;123:e534–e541
AHC: Flunarizine Treatment
N=80
60
60
50
40
37.5
30
% positive
% negative
20
% no change
10
2.5
0
%
positive
% no
change
Benzodiazepines
N= 55
59
60
50
40
38
% positive
30
% negative
20
% no change
10
3
0
%
positive
% no
change
Diazepam N=34
70
60
50
40
30
20
10
0
-10
78
80
65
60
40
% positive
26
% negative
% no change
20
18
0
-9
%
positive
80
Clonazepam N=28
-4
-20
% no
change
%
positive
Lorazepam N=25
% no
change
80
60
40
% positive
20
% negative
12
0
% no change
-8
-20
%
positive
% no
change
Benzodiazepines
Phenobarbital N=42
Valproic Acid N=42
78
80
100
83
80
60
40
20
% positive
40
% negative
20
% no change
10
0
60
-7
-20
%
positive
% negative
% no change
3
-20
%
positive
Phenytoin N=29
83
60
40
20
10
0
-10
-7
-20
% no
change
% no
change
80
% positive
40
0
100
87
60
20
-10
%
positive
Carbamazepine N=39
80
0
-20
% no
change
100
12
%
positive
% no
change
AHC: Other Anticonvulsant
Treatment N=81
80
74
60
40
% positive
20
% negative
0
6
-20
% no change
-20
%
positive
% no
change
Anti-migraine N=23
Chloral Hydrate N=19
100
84
80
60
% negative
11
0
% no change
-5
-20
%
positive
91
80
% positive
40
20
100
60
40
20
9
0
% no
change
0
%
% no
positive
change
Extra-pyramidal Med N=31 Psychotropic Med N=36
80
100
84
80
60
20
60
% positive
40
% negative
% no change
10
0
-6
40
20
19
0
-14
-20
-20
%
67
% no
%
positive
% no
change
AHC: Treatment
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Pathophysiology unknown
Medication Trials
Anti-epileptic
Anti-migraine
Movement Disorder:
Paroxysmal Dyskinesia
Channelopathy
Flunarizine most effective med
but not sufficient
Familial Hemiplegic Migraine FHM1
2 
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1
Ca2+ channel structure
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
Familial hemiplegic migraine:
mouse knock-in model
Cortical spreading depression 
van den Maagdenberg et al, 2004
Alternating Hemiplegia of Childhood:
Pathophysiology
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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
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
Alternating Hemiplegia of Childhood:
Pathophysiology
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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
Alternating Hemiplegia of Childhood:
Pathophysiology
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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
ALTERNATING HEMIPLEGIA
OF CHILDHOOD
From peas to pores