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Mohamad Mikati MDWilburt C. Davison Professor of Pediatrics,
Professor of Neurobiology, Chief of Pediatric Neurology, Duke
University Medical Center.
Satio, Y. et al., 2010
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OrganizationEuropean DataJapanese DataConclusions and
Implications
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EUROPEAN DATA
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Small Vessel AbnormalitiesFour AHC patientsElectron Microscopy
of Muscle and skin small vesselsEndothelium: Vacuoles Smooth
muscles in the tunica media there were small and unevenly shaped,
contained intracytoplasmic vacuoles and, occasionally, apoptotic
nuclei. Implications: etiology of AHC
Auvin et al Neurology. 2006 Feb 28;66(4):499-504
Auvin et al Neurology. 2006 Feb 28;66(4):499-504
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European Registry Report157 cases all fulfilling the Aicardi
criteriaOnset 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. Panagiotakaki E et al., Brain
2010: 133; 3598-3610
Panagiotakaki E et al., Brain 2010: 133; 3598-3610
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DemographicsPanagiotakaki E et al., Brain 2010: 133;
3598-3610
Age GroupNumber of Patients0 -2 y1572 6 y1446 -12 y10712 18
y7018 24 y37>24 y 14
PercentilesNumber of Patients (at the end of
follow-up)HeightWeight< 2nd Percentile6142-10th
Percentile201910-25th Percentile232425-50th Percentile272750-75th
Percentile231475-90th Percentile3790-98th Percentile14
Panagiotakaki E et al., Brain 2010: 133; 3598-3610
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(A) all patients, (B) a subset of 14 patients each with at least
24 years follow-up periodParoxysmal features of AHC at different
agesPanagiotakaki E et al., Brain 2010: 133; 3598-3610
Panagiotakaki E et al., Brain 2010: 133; 3598-3610
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(A) all patients, (B) a subset of 14 patients each with at least
24 years follow-up periodNon-paroxysmal features of AHC at
different agesPanagiotakaki E et al., Brain 2010: 133;
3598-3610
Panagiotakaki E et al., Brain 2010: 133; 3598-3610
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Neonatal Onsets12.5% of patients (n=20) 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 hypotoniaPanagiotakaki E et al., Brain 2010: 133;
3598-3610
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Autonomic Dysfunction65% of patients (n=102) 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
casesPanagiotakaki E et al., Brain 2010: 133; 3598-3610
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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
patientPanagiotakaki E et al., Brain 2010: 133; 3598-3610
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AurasSeen in 41% of patients (n=64) 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 patientPanagiotakaki E et al., Brain 2010: 133;
3598-3610
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Sudden Death7 patients
Sometimes associated with severe plegic attacks and epileptic
seizures
Patients who experienced sudden death:Similar severity of
plegic/dystonic attacks than other patientsHigher 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
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Patient DeathsPanagiotakaki E et al., Brain 2010: 133;
3598-3610
Age in years at DeathSexCause of Death28 MProlonged plegic
attack25 FCardiorespiratory Failure12 MSevere and prolonged
quadriplegia12 MEpileptic seizure complicated by cardiorespiratory
arrest3.5 FN/A2 FStatus epilepticus2 FStatus epilepticus
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Panagiotakaki E et al., Brain 2010: 133; 3598-3610Comparisons of
mean paroxysmal and non-paroxysmal index values and final
non-paroxysmal index values between deceased and non-deceased
patients
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Panagiotakaki E et al., Brain 2010: 133; 3598-3610Paroxysmal (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
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Median disability indices of all patients as a function of
timePanagiotakaki E et al., Brain 2010: 133; 3598-3610
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Small vessel abnormalities in ACHInvestigated 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 AHCSasaki, M. et al.,
Brain and Development 2011: 33; 390-393
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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
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Epileptic seizures in AHCRetrospective 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
Saito, Y. et al., Epilepsy Research 2010: 90; 248-258
Saito, Y. et al., Epilepsy Research 2010: 90; 248-258
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MRI in Patients with StatusSaito et al., Epilepsy Research 2010:
90; 248-258
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Increased MMP-9 and decreased substance-PTo 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
Inui. T. et al., Brain and Development 2011: ePub ahead of
print
Inui. T. et al., Brain and Development 2011: ePub ahead of
print
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Increased MMP-9 and decreased substance-PInui. T. et al., Brain
and Development 2011: ePub ahead of printIncreased 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
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Abnormal cerebral glucose metabolism in ACHBrain 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
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Abnormal cerebral glucose metabolism in ACHSasaki, M. et al.,
Brain and Development 2010: 31; 20-26
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Abnormal cerebral glucose metabolism in ACHSasaki, M. et al.,
Brain and Development 2010: 31; 20-26Interictal 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
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European ExperienceWhen 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
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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
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Our increasing knowledge is improving our ability to help AHC
patients and increasing our hopes for major discoveries in the
future.
Conclusions
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Satio, Y. et al., 2010
**Paroxysmal features of AHC at different ages in (A) all
patients and (B) a subset of 14 patients each with at least 24
years follow-up period.Non-paroxysmal features of AHC at different
ages in (A) all patients and (B) a subset of 14 patients each with
at least 24 years follow-up period.**Comparisons of mean paroxysmal
and non-paroxysmal index values and final non-paroxysmal index
values between deceased and non-deceased patients.Paroxysmal (A)
and non-paroxysmal (B) disability index values as a function of
time for individual patients with available clinical information up
to adulthood (at least 18 years of age, n=37).Median disability
indices of all patients as a function of time. (A) Median values of
paroxysmal disability index. (B) Median values of non-paroxysmal
disability index. Bars depict standard deviation (1 or 2
SD).****
