Alternating Hemiplegia of Childhood: Recent European Japanese and Data
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Transcript of Alternating Hemiplegia of Childhood: Recent European Japanese and Data
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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).****