Alternating Hemiplegia of Childhood: Treatment

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
(No Transcript)
4
(No Transcript)
5
(No Transcript)
6
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

7
(No Transcript)
8
(No Transcript)
9
(No Transcript)
10
(No Transcript)
11
(No Transcript)
12
(No Transcript)
13
(No Transcript)
14
(No Transcript)
15
(No Transcript)
16
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

17
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

18
AHC Treatment N103
Pediatrics 2009123e534e541
19
AHC Flunarizine Treatment N80
20
BenzodiazepinesN 55
21
Diazepam N34
Clonazepam N28
Lorazepam N25
Benzodiazepines
22
Valproic Acid N42
Phenobarbital N42
Carbamazepine N39
Phenytoin N29
23
AHC Other Anticonvulsant Treatment N81
24
Chloral Hydrate N19
Anti-migraine N23
Extra-pyramidal Med N31
Psychotropic Med N36
25
AHC Treatment

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

26
(No Transcript)
27
Familial Hemiplegic Migraine FHM1
Ca2 channel structure
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
Familial hemiplegic migraine mouse knock-in
model Cortical spreading depression ?
van den Maagdenberg et al, 2004
30
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

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
• 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

33
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

34
ALTERNATING HEMIPLEGIA OF CHILDHOOD
From peas to pores