Alternating Hemiplegia of Childhood: Recent European Japanese and Data

1
Alternating Hemiplegia of Childhood Recent
European Japanese and Data

• Mohamad Mikati MD
• Wilburt C. Davison Professor of Pediatrics,
• Professor of Neurobiology,
• Chief of Pediatric Neurology,
• Duke University Medical Center.

2
Organization

• European Data
• Japanese Data
• Conclusions and Implications

3
EUROPEAN DATA
4
Small Vessel Abnormalities

• Four AHC patients
• Electron Microscopy of Muscle and skin small
  vessels
• Endothelium Vacuoles
• Smooth muscles in the tunica media there were
  small and unevenly shaped, contained
  intracytoplasmic vacuoles and, occasionally,
  apoptotic nuclei.
• Implications etiology of AHC

5
European Registry Report

• 157 cases all fulfilling the Aicardi criteria
• Onset of paroxysmal events before 18 months of
  age.
• Repeated bouts of hemiplegia involving right and
  left side of the body in some attacks.
• Episodes of bilateral hemiplegia or quadriplegia
  starting either as generalization of a hemiplegic
  episode or bilateral from the start.
• Other paroxysmal disturbances including
  tonic/dystonic attacks, nystagmus, strabismus,
  dyspnoea and other autonomic phenomena occurring
  during hemiplegic bouts or in isolation.
• Immediate disappearance of all symptoms upon
  sleep, with probable recurrence of long-lasting
  bouts 10-20min after awakening.
• Evidence of developmental delay, mental
  retardation, neurologic abnormalities,
  choreoathetosis and dystonia or ataxia.
• Not attributable to other disorders.

6
Demographics
Percentiles Number of Patients (at the end of follow-up) Number of Patients (at the end of follow-up)
Percentiles Height Weight
lt 2nd Percentile 6 14
2-10th Percentile 20 19
10-25th Percentile 23 24
25-50th Percentile 27 27
50-75th Percentile 23 14
75-90th Percentile 3 7
90-98th Percentile 1 4
Age Group Number of Patients
0 -2 y 157
2 6 y 144
6 -12 y 107
12 18 y 70
18 24 y 37
gt24 y 14
7
Paroxysmal features of AHC at different ages
(A) all patients, (B) a subset of 14 patients
each with at least 24 years follow-up period
8
Non-paroxysmal features of AHC at different ages
(A) all patients, (B) a subset of 14 patients
each with at least 24 years follow-up period
9
Neonatal Onsets

• 12.5 of patients (n20) had neonatal paroxysmal
  episodes
• 5 children experienced their first episode on the
  first day of life
• Ocular movements and dystonic attacks usually
  limb stiffening with a vibratory tremor, but
  sometimes torticollis, opisthotonus or episode of
  hypotonia

Panagiotakaki E et al., Brain 2010 133 3598-3610
10
Autonomic Dysfunction

• 65 of patients (n102) had autonomic phenomena
  including reddening or pallor of the face, fever,
  tachycardia, or bradycardia and mydriasis
• Apneic spells sometimes requiring monitoring
  devices at home
• Intubation and mechanical ventilation in extreme
  cases

Panagiotakaki E et al., Brain 2010 133 3598-3610
11
Gelastic (Laughing Episodes)

• 5 children Unexplained episodes of explosive,
  violent laughter accompanied by limb movements,
  terror and ocular movements or mydriasis
  (dilation of pupil)
• Most episodes were interpreted as epileptic
  seizures
• These episodes were decreased after vagus nerve
  stimulation in 1 patient

Panagiotakaki E et al., Brain 2010 133 3598-3610
12
Auras

• Seen in 41 of patients (n64) before paroxysmal
  episodes
• Different behavior pattern, irritable
• Sensation of pinpricks, discomfort of hand or
  feet that later spread to adjacent parts of body
  in an ascending or descending manner, with a
  progression of paralysis
• Sore throat before attacks, concomitant with a
  strange sensation in the hand in one patient

Panagiotakaki E et al., Brain 2010 133 3598-3610
13
Sudden Death

• 7 patients
• Sometimes associated with severe plegic attacks
  and epileptic seizures
• Patients who experienced sudden death
• Similar severity of plegic/dystonic attacks than
  other patients
• Higher severity of global neurological impairment
• Speculation
• Increased autonomic dysfunction is a
  precipitating factor of sudden death.

Panagiotakaki E et al., Brain 2010 133 3598-3610
14
Patient Deaths
Age in years at Death Sex Cause of Death
28 M Prolonged plegic attack
25 F Cardiorespiratory Failure
12 M Severe and prolonged quadriplegia
12 M Epileptic seizure complicated by cardiorespiratory arrest
3.5 F N/A
2 F Status epilepticus
2 F Status epilepticus
Panagiotakaki E et al., Brain 2010 133 3598-3610
15
Comparisons of mean paroxysmal and non-paroxysmal
index values and final non-paroxysmal index
values between deceased and non-deceased patients
Panagiotakaki E et al., Brain 2010 133 3598-3610
16
Paroxysmal (A) and non-paroxysmal (B) disability
index as a function of time for individual
patients with available clinical information up
to adulthood (at least 18 years of age, n??37)
Deaths
Panagiotakaki E et al., Brain 2010 133 3598-3610
17
Median disability indices of all patients as a
function of time
Panagiotakaki E et al., Brain 2010 133 3598-3610
18
Japanese data
19
Small vessel abnormalities in ACH

• Investigated whether Japanese patients with AHC
  have the similar small-vessel abnormalities in
  skin reported in European patients with AHC
• Electron microscopic observation of biopsied skin
  specimens in 6 Japanese patients (5-17 years old
  boys) with AHC
• No abnormal findings in both endothelial cells
  and smooth muscle cells in skin small-vessels
• Hypothesized there might be sub-types of AHC

Sasaki, M. et al., Brain and Development 2011
33 390-393
20
Small vessel abnormalities in ACH
Electron microscopic findings of small-vessels in
4 patients with AHC. No abnormal findings were
observed. V, vascular smooth muscle cell E,
endothelial cell M, mitochondria
Sasaki, M. et al., Brain and Development 2011
33 390-393
21
Epileptic seizures in AHC

• Retrospective review of clinical information on 9
  patients (age 4-40 years)
• Presumptive epileptic seizures in 7 patients
• Multiple seizure types including GTCS, tonic,
  clonic, myoclonic or CPS accompanied by apnea and
  cyanosis
• Neonatal onset of seizures with subsequent status
  psychomotor deterioration and MRI abnormalities

22
MRI in Patients with Status
Saito et al., Epilepsy Research 2010 90 248-258
23
Increased MMP-9 and decreased substance-P

• To obtain insights into the pathophysiology of
  AHC, concentrations of substance P, matrix
  metalloproteinase-9 (MMP-9), tissue inhibitor of
  MMP-1 (TIMP-1), calcitonin gene-related peptide
  (CGRP), (SP) in the serum/plasma of 6 AHC
  patients and 11control subjects were performed by
  ELISA
• Decreased levels of serum SP which may represent
  autonomic dysfunction
• Increased levels of plasma matrix
  metalloproteinase-9 MMP-9 and increased
  MMP-9/TIMP-1 ratio which may be related to
  vascular insult

24
Increased MMP-9 and decreased substance-P
Increased MMP-9 may be related to vascular
insult Decreased SP may represent autonomic
dysfunction in AHC, for which an etiology with
progressive neuronal damage could be hypothesized
Inui. T. et al., Brain and Development 2011 ePub
ahead of print
25
Abnormal cerebral glucose metabolism in ACH

• Brain glucose metabolism by positron emission
  tomography (PET) using 2-deoxy-2 18F
  fluoro-d-glucose (FDG), performed between
  hemiplegic attacks in 5 patients (2 adults, 3
  children)
• Low glucose metabolism in the frontal lobes with
  some laterality in all
• Low glucose metabolism in the ipsilateral putamen
  in 3 patients
• Adult patients also showed low glucose metabolism
  and mild atrophy in the cerebellum

Sasaki, M. et al., Brain and Development 2010
31 20-26
26
Abnormal cerebral glucose metabolism in ACH
Sasaki, M. et al., Brain and Development 2010
31 20-26
27
Abnormal cerebral glucose metabolism in ACH
Interictal FDGPET Shows low glucose metabolism
in the bilateral frontal to parietal lobes except
for the precentral area of the right frontal
lobe. SPECT shows normal blood perfusion during
hemiplegic attack
Sasaki, M. et al., Brain and Development 2010
31 20-26
28
CONCLUSIONS IMPLICATIONS
29
European Experience

• When all patients were examined collectively the
  severity of clinical presentation and
  neurological disability remained constant with
  age suggesting that this is not necessarily a
  progressive disease
• There was change in some manifestations like
  abnormal ocular movements and hypotonia that
  appeared to decrease, but did not disappear, into
  adulthood
• When analyzed individually, highly variable
  clinical presentation
• Prospective studies needed

30
Japanese Experience

• Neonatal onset seizures, status, apnea appear
  more common
• No small vessel abnormalities in Japanese
  patients unlike European patients
• Variable clinical presentation imply multiple
  causative genes

31
Conclusions

• Our increasing knowledge is improving our ability
  to help AHC patients and increasing our hopes for
  major discoveries in the future.

32
Thank you for your attention!