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Alternating Hemiplegia of Childhood: Recent European Japanese and Data

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. Organization. European Data Japanese Data

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Alternating Hemiplegia of Childhood: Recent European Japanese and Data

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  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 Auvin et al Neurology. 2006 Feb 28;66(4):499-504

  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. Panagiotakaki E et al., Brain 2010: 133; 3598-3610

  6. Demographics Panagiotakaki E et al., Brain 2010: 133; 3598-3610

  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 Panagiotakaki E et al., Brain 2010: 133; 3598-3610

  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 Panagiotakaki E et al., Brain 2010: 133; 3598-3610

  9. Neonatal Onsets • 12.5% 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 hypotonia Panagiotakaki E et al., Brain 2010: 133; 3598-3610

  10. Autonomic Dysfunction • 65% 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 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 (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 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 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 Saito, Y. et al., Epilepsy Research 2010: 90; 248-258

  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 Inui. T. et al., Brain and Development 2011: ePub ahead of print

  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 FDG–PET: 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!

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