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eEdE#: eEdE196 Neonatal and early infantile epilepsy due to Inherited metabolic disorders: Clinical and neuroimaging correlation 1Prince K TLILI-GRAIESS1,2, N MAMA.2, M GAHA2, M Al ENEZI1, N Al Khuraish1, B TABARKI3 Sultan Military Medical City (PSMMC)- Neuroradiology Section Riyadh,Saudia Arabia, 2Sousse Medical School, Sousse, Tunisia, 3Prince Sultan Military Medical City (PSMMC)- Pediatric Neurology, Riyadh, Saudia Arabia Presentation eEdE#: eEdE196 Presented by: Kalthoum TLILI-GRAIESS ASNR, Washington, May 21-26, 2016 Disclosures • We have no financial disclosures or conflicts of interest to declare. Purpose We aim to: 1. Familiarize the radiologist with the clinical/EEG presentation of early onset epilepsy due to inherited metabolic disorders (IMD). 2. Recognize MRI features of the main IMD causing early onset seizures, particularly the treatable IMD. 3. Discuss the role of both conventional and advanced MRI techniques, Diffusion Weighted Imaging and MR Spectroscopy (DWI and MRS), in the diagnostic imaging work-up of IMD associated with epilepsy. Background IMD are common cause of early onset epilepsy/epileptic encephalopathy. However, seizures rarely dominate and are frequently associated with other neurological symptoms, such as hypotonia and/or cognitive disturbances. Occasionally, specific clinical signs and distinctive electroencephalographic (EEG) patterns may suggest a specific metabolic disease or certain epileptic syndromes. West's syndrome, early myoclonic encephalopathy are known to accompany particular metabolic disorder (eg. branched-chain organic acidurias, nonketotic hyperglycinemia), However seizure types are rarely specific for a particular metabolic disorder, nor are EEG findings. Neuroimaging pattern can be highly suggestive in some IMD and therefore limit the biochemical and genetics work-up and may even suggest treatable conditions . Background • The differential diagnosis of seizure disorders is extremely wide and includes: Ion channel disorders (e.g. SCN1A mutations), Malformations of cortical development, Neurocutaneous syndromes, Chromosomal disorders, Hypoxic–ischaemic encephalopathy, Congenital infection, sepsis, and tumours. Inherited metabolic disorders Background • IMD may have clinical presentation mimicking in neonates hypoxo-ischemic encephalopathy (HIE): lethargy, poor feeding, vomiting, muscular hypotonia, irritability, apnea, and/or seizures. • However, clinical history is usually different: 1. No perinatal event suggesting ischemia and/or hypoxia 2. Familial history of neonatal/early infantile death. 3. Familial history of epilepsy. 4. Refractory seizures 5. Metabolic acidosis / Hyperammonia Clinical clues: When is an inherited metabolic disorder probable? • Epilepsy • Neonatal seizures • Early onset (neonatal period, infancy) • More than 1 type of seizure: myoclonic/PME, IS, multifocal • Intractable, resistant to AED • Epileptic encephalopathy • Seizures occurring after fasting, • protein-rich meal, • Unexplained status epilepticus • Epilepsy and clear regression -That are not easily controlled with a first-line anticonvulsant - and no obvious infectious, structural, traumatic or cerebrovascular cause is not established. Interictal EEG is characterized by: - Slowing of background activity. - and progressive appearance of epileptiform abnormalities: focal and then multifocal and diffuse, forming a picture of epileptic encephalopathy. - Burst suppression Pathogenesis of epileptic seizures associated with inherited neurometabolic disorders • IMD classified by mechanism: 1. Energy production disorders 2. Intoxication disorders 3. Neurotransmitter defects 4. Disorders of the biosynthesis + breakdown of complex molecules 5. Associated brain malformations Relation type of Epilepsy and specific IMD? Often non specific as well as the electroencephalographic (EEG) findings. Refractory Epilepsy with or without mental deficiency (mitochondrial disorders, Storage diseases…). Early Myoclonic Epilepsy, West Syndrome (organic Acidurias, NonKetotic Hyperglycinemia) Epilepsy with dysmorphy (Zellweger Syndrome ), Abnormal movement (Creatine deficiency). Epilepsia partialis continua or status epilepticus may reveal mitochondrial disorders. Is there any correlation Between age of onset and type of IMD ? Neonate and infants mainly involved IMD Present with multiple seizure types, global neurodevelopmental impairment. Many are antiepileptic drug (AED) treatment resistant. N.I. Wolf. Epileptic Disord 2005 Approach/Methods We reviewed the cases of neurometabolic diseases associated with neonatal and early infantile epilepsy collected in our institutions and analyzed for clinical and EEG presentation as well as imaging features. Selected cases will be presented in a case- review format Overview CASES Neonatal Epileptic Encephalopathy • • • • • • • ISOD/Mb cofactor deficiency Glycine Encephalopathy Urea Cycle disorders Mitochondrial Disease Organic acidemias Zellweger Syndrome Pyridoxine-dependent epilepsy Although the large range of metabolic etiologies, only cases of the most frequent IMD related Neonatal Epileptic encephalopathy and L. Papetti et al. / Brain & Development 2013 with MRI slightly suggestive pattern will be presented. Some IMD mimic HIE • • • • Mitochondrial Disease Isolated Sulfite Oxidase Deficiency Molybdenum CoFactor Deficiency Some organic acidopathies # Case 1 Sibling 1, Full term girl neonate. Day 1: Jerkiness, twitching, myoclonic reactions and poor sucking. Seizures refractory to different AED. •Extensive WM swelling and T2 hyperintensity •Edematous T2 pattern of the basal ganglia; •Widespread WM and basal ganglia diffusion restriction. • Relatif sparing of thalami. Sibling 2, 2 year-old with severe development delay and frequent seizures. Extensive brain damage with: •Significant loss of WM with cystic changes. •Ex vacuo dilatation of ventricles. •Mushrom shaped gyri. •Atrophy og basal ganglia •Hyperintensity in midbrain and pontine tegmentum Molybdenum Cofactor deficiency MOCS 2 • 14 months-old male child. • 12 months-old male child. • West Syndrome with microcephaly. • Developmental delay and epilepsy. Molybdenum Cofactor deficiency Sequella of Hypoxo-ischemic Encephalopathy Differentiation from severe HHI is made by predominant thalamic involvement in HII relatively absent in MCoD Molybdenum cofactor deficiency (MoCD) • Autosomal recessive disorder, mimic ischaemic encephalopathy • Molybdenum cofactor: essential for the function of 3 enzymes: Sulfite oxydase , catalyses the oxydation of sulfite into sulfate; deficiency results in elevated levels of sulfite, extremely neurotoxic. Xanthine oxydase results in low uric acid levels and elevated xanthine levels. Aldehydedehydrogenase, catalyses the formation of xanthine from hypoxanthine. • Severe neurologic symptoms in the first days of life, the leading symptom is drug-resistant epilepsy. • The disorder should be considered in all cases of intractable seizures in the newborn period and infants with clinical and radiological features of ischemic encephalopathy. Molybdenum cofactor deficiency • MRI pattern: In the acute phase: hyperintensity on T2WI of the white matter and caudate nuclei suggestive of edema. Widespread diffusion restriction with elevated lactate and decreased NAA on MRS. In the subacute phase, the basal ganglia may show T1 and T2 shortening, similar to that of neonatal asphyxia sparing thalami. In the more chronic phase , marked volume loss of caudate and lentiform nuclei and white matter with T1 and T2 prolongation and frank cystic changes. Sparing of thalami is against HII. # Case 2 SEIZURES since birth; presented at 3 months for hypotonia, poor feed, development delay. Thinning of the cortex with zone of Presentation similar to that of MCoD. mushroom- like gyral pattern. Atrophy of the basal ganglia and cystic degeneration of WM. Ex-vacuo ventricular dilatation Sparing of the thalami Isolated sulfite oxydase Deficiency SUOX gene Isolated Sulfite oxidase deficiency Rare autosomal recessive disorder of the newborn that can be mistaken for neonatal asphyxia Gene SUOX mapped to Chr 12q13.2-13.3. Imaging: Early in the disease: edema in cerebral cortex, WM and BG with restricted diffusion in BG. Hippocampi relatively spared The presentation is similar to that of molybnenum cofactor deficiency. The latter is more common. T1 shortening at cortical – WM junction and in BG . Lens ectopia is common. MRS: decrease in NAA/ Cr ratio and a rise in the Cho/Cr. Sulfite is extremely neurotoxic Energy production disorder Biology: ↑sulfite level in urine Rapide development of BG atrophy and cystic degeneration of WM within the first month: cystic leucomalacia. # Case 3 Term neonate. Hypotonia followed by continuous seizures and deep coma. Familial history of neonatal death MRI Day 5 Ala-Lac Glx Glx Carbamyl phosphate synthase Deficiency Glu Glu ADC map ADC Swelling/edema of white matter with ↑T2 signal of basal ganglia ADC map: Reduced diffusion cortical and subcortical white matter and striatum.Ala-Lac 1H-MRS (short & longTE) Increased glutamine with Alanine-lactate triplet. Urea cycle disorders • 5 types: Citrullinemia, Ornithine carbamyl transferase deficiency, Carbamyl phosphate synthetase deficiency, Arginase deficiency and Argininosuccinate lyase deficiency. • All causing hyperammonemia and high Glutamine: Toxic to the brain. • Acute hyperammonemia rapidly leads to encephalopathy, cerebral edema, and, if untreated, death • Cerebral edema result from accumulation of glutamine in astrocytes selectively affects WM: Astrocytic swelling related To osmolar effect of intracellular Glutamine? • Neuroimaging pattern: – Reduced diffusion: cortex and subcortical WM, basal ganglia and thalami. – ↑T2 signal: globi pallidi, putamina, caudate nuclei – 1H-MRS typically: ↑glutamine/ glutamate + lactate >>> Diagnostic. – Rapid development of atrophy with severe cystic encephalomalacia Neonate admitted at 1 month of life. Since Day 2 hypotonia, poor feeding. 3 died in the family. Increased Ammonia level Glu Glu Glu Carbamyl Phosphate Synthase Deficiency CPS1 Glu 1 month later # Case 4 Term neonate with hypotonia, refractory seizures , respiratory failure and high lactic acid. Early death. 3 siblings neonatal death and same clinical presentation. Day 15 Extensive swelling and T2 hyperintensity of the WM, deep GM, midbrain and brainstem. Diffusion restriction at pallidi, corpus callosum and pericentral subcortical WM. Complex 1 MRS at frontal WM shows predominent lactate peak. Deficiency Isolated complex I deficiency The most common enzymatic defect of the oxidative phosphorylation disorders. It may cause a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Neonatal symptoms include severe respiratory distress, apnea, muscular hypotonia, weakness, seizures, cardiac hypertrophy, and/or hepatomegaly. Marked lactic acidosis with elevated blood lactate and pyruvate levels. Neuroimaging: Neonatal presentation includes WM abnormalities , involvement of the posterior columns in the lower brainstem, pontine corticospinal tracts and subcortical white matter, with an HIE-like involvement of the cortex and thalami in the absence of history of birth asphyxia Variable sites of diffusion restriction indicating acute insult. MRS: predominent Lactate peak on MRS which should lead to more extensive investigation of oxidative phosphorylation disorders. # Case 5 Term neonate, day 2 respiratory distress, continuous myoclonies followed by deep coma. MRI and EEG performed at Day 15 TE 144 Mi Gly Gly TE 35 T2 symmetrical high-signal in the tegmentum of the pons. Apart from the absence of normal hyposignal of the myelinted PLIC, supratentorial Grey and WM signal intensity within normal limits. TE 144 Mi Gly Gly high-signal lesions TE 35 DWI: in tegmentum of the pons, the pyramidal tracts, the middle cerebellar pedicles PLIC Burst-Suppression Pattern highlyand suggestif, May be noted in: • Pyridoxino-Dependant Epilepsy (PDE) • Isolated Sulfite Oxidase Deficiency (ISOD) Important Myoinositol/Glycine peak at 3.56 ppm (35ms) • Glycine NonKetotic Only (Gly) Hyperglycinemia persists at long echo time (144ms) • Mitochondrial disorders NonKetotic Hyperglycinemia (NKH) • NKH: autosomal recessive IMD due to a defect in the glycine cleavage system. • The disorder leads to the accumulation of glycine in body fluids and in the central nervous system with its subsequent neurotoxicity. • The sites of abnormal signal intensity in NKH are confined to the WM tracts that are myelinated at birth. • DWI findings reflect the histopathologic changes of the disease which consist of spongiosis of the myelinated brain tissue due to myelin vacuolation. • Microcystic changes are mostly found in the ascending tracts in the brain stem, posterior limbs of the internal capsules, the cerebellar peduncles, optic tracts and optic chiasma • MRS provide biochemical evidence of elevated cerebral glycine levels by demonstration of Glycine peaks at 3.56 ppm with a long echo time. # Case 6 3-day-old baby girl full term with refractory seizures mainly clonic and myoclonic. DAY 3 hemorrhage noted affecting the left parietal lobe and the left parasagittal region DAY 24 Bilateral and symmetrical abnomal T2 high signal In pons and midbrain along the cortico-spinal tract with mild brain atrophic changes At 3months refractory status epilepticus with burst Suppression on EEG. 3 months PDE should always be included in the differential diagnosis of neonatal seizures that are refractory to treatment with antiepileptic drugs: PDE is a treatable neurometabolic disorder. No specific imaging features. Pyridoxine Dependent Epilepsy (PDE) Reported associated abnormalities: 17 Months Mutation in LDH7A1gene Corpus callosum hypoplasia Subependymal cysts Ventriculomegaly Gray matter heterotopia White matter abnormalities including hemorrhage Gray and white matter atrophy Mega cisterna magna. Paucity of the cerebral WM with Mild diffuse brain atrophy Pyridoxine-dependent epilepsy (PDE). PDE, rare autosomal disorder caused by ALDH7A1 gene mutations. PDE described in 1954, in 1995 Folinic acid responsive seizures (FARS) described, in 2006 genetic defect identified and in 2009 FARS shown to be identical PDE is characterized by early intractable seizures not controlled with AED but responding both clinically and EEG to pyridoxine (vitamin B6) with “normal” neurodevelopmental outcome. Refractory seizures in the first week of life, mainly clonic and myoclonic. EEG: variable, Late onset seizure>1 month possible with even status epilepticus. Pyridoxine-dependent epilepsy (PDE). MRI: Non secific Neonatal period: •Ventricles normal in size and myelin pattern appropriate for age with increased incidence of mega cisterna magna. •Thinning of the posterior third of the corpus callosum •Brain hemorrhage Later and if non treated: Ventriculomegaly with atrophy of the cortex and subcortical white matter . Friedman SD et al. Dev Med Child Neurol. 2014 # Case 7 Full-term neonate, dysmorphic with seizures and history history of two death with Zellweger syndrome Small geminolytic cyst with hemorrhagic component (yellow arrow) in the left caudothalamic groove, Polymicrogyria mainly in perisylvian region (red arrow) and thin corpus callosum. Zellweger syndrome Zellweger syndrome, Peroxisomal disorder causing abnormal catabolism of very long chain fatty acids Clinical features : Neonatal hypotonia, feeding problems, hearing loss, vision loss, and seizures. Dysmorphy: flattened face, broad nasal bridge, and high forehead Life-threatening problems in other organs and tissues, such as the liver, heart, and kidneys. Possible skeletal abnormalities, including large fontanels and characteristic chondrodysplasia punctata. Imaging Key features: Unmyelinated PLIC , Frontal or opercular polymicrogyria Geminolytic cyst MRS: Low NAA and prominent lipids peaks at 0.9 and 1.3ppm Infantile metabolic epilepsy L. Papetti et al. / Brain & Development 2013 # Case 8 7 months, Developmental delay and epilepsy. Admitted for sepsis and metabolic acidosis Brain atrophic changes with abnormal signal intensity at frontal subcortical white matter and bilateral striatum. Reduced diffusion in some of the affected areas indicating metabolic crisis causing the current clinical setting. Ethylmalonic Acidemia # Case 9 2 year-old , known cas of propionic acidemia, admitted with fever and generalized tonico-clonic seizures. Hypodensity at bilateral basal ganglia and frontal subcortical WM. Mild brain volume loss, delayed myelination with T2 high signal of bilateral striatum and subcortical WM. No restricted diffusion. Propionic Acidemia Propionic and Ethylmalonic Acidemias Epilepsy is relatively rare. Usually seizures noted with metabolic decompensation. Lesions of the striatum with usually WM involvement. Volume loss, and delay in myelination are typically identified during later episodes of decompensation. MRS may demonstrated decreased NAA, and increased lactate during encephalopathic episodes when compared with MRS during metabolically stable periods. # Case 10 •16 months-old girl with one week respiratory distress •At the age of 9 months, seizures and progressive loss of developmental and motor acquisitions with sudden alopecia and global hypotonia. Hypodensity and T2 hyperintensity of frontal WM, genu of the corpus callosum and caudate nuclei. cho NAA DWI: Hypersignal demonstrating zones of restricted diffusion related to cytotoxic and myelin edema. Note the U fibers involvement and the peripheral high signal of the genu contrasting with the Acquired alopecia indicate possible Biotin more central low signal (arrow). responsive encephalopathy Likely related to lactate SRM 144 : decreased NAA biotinidase deficiency & presence of lactate 5 month MRI follow-up Pharmacologic doses of biotin Normal pattern of the spectrum Progression of myelination with resolution of WM and GM abnormalities except for the genu of the corpus callosum: high signal T2, low signal T1 and high ADC level, stigmate of cystic degeneration. Biotinidase deficiency Biotinidase deficiency is an inborn error of metabolism with autosomal recessive inheritance that usually presents in infancy with developmental delay, seizures, alopecia, and dermatitis. Episodes of acute deterioration separated with periods of apparent normality. The main imaging findings reported: White matter abnormalities, including delayed myelination and Enlargement of the ventricular system and/or the extracerebral spaces. DWI may demonstrate new lesions and MRS demonstrates the lactate peak, related to anaerobic metabolism # Case 11 12 year-old boy, progressive epileptic encephalopathy since first year of life. NA A NAA Cho Cho NGC SB Pariéto-occipitale Creatine deficiency due to guanidinoacetate methyltransferase deficiency Creatine deficiency syndromes Creatine deficiency syndromes include disorders due to: Defects in synthesis (GAMT deficiency and arginineglycine amidinotransferase (AGAT) deficiency) and Defects in the transport of creatine across the blood– brain barrier (X-linked creatine transporter defect). In GAMT deficiency :often have abnormal hyperintensity of the globi pallidi on FLAIR and T2 WI. AGAT deficiency and creatine transporter defects can only be detected by low or absent creatine peak on proton MRS of the brain. MRS is therefore the most important technique in diagnosis. MRS is also important in assessing response to therapy. # Case 12 2 year-old female child with regression milstones and myoclonic seizures since 9 months of age. • Appropriate myelination milstone for 2 Y • Prominent cerebellar atrophy • Mild hyperintensities in the deep WM Neuronal ceroid lipofuscinose Gene CLN3 •Decreased NAA peak Differential diagnosis, Cerebellar atrophy • Neurodegenerative disorders : Neuronal Ceroid Lipofuscinosis NCL Late-onset GM2 Gangliosidosis: in late disease stages with cerebral and cerebellar atrophy. • Mitochondrial disorders : Complex I, II, IV and combined complex I + III and II + III deficiencies Cenzyme Q10 Deficiency. Myoclonus epilepsy with ragged red fibers (MERRF) • Hypomyelination 4H Syndrome, POL R 3B: Cerebellar and vermis atrophy with milder hypomyelination. Neuronal ceroid lipofuscinosis. Lysomal neurodegenerative disorder caused by accumulation of lipopigments (such as lipofuscin and ceroid) in lysosomes of neurones and other tissues. Seizures and regression Possibly the most common group of neurodegenerative disorders in children. 4 types: Infantile, Late infantile, juvenile and adult. NCL should be considered in a patient with progressive epileptic encephalopathy when MRI shows such features: Cerebral atrophy, thin cortex, one of the cardinal findings regardeless of the type in both infantile and late infantile NCL. Cerebellar atrophy is a more prominent feature and shows rapid progression in late infantile NCL than in other form. Mild hyperintensities in the deep WM due to gliosis or loss of myelin as demonstrated in pathological studies/ secondary involvement. Neuronal Ceroid Lipofuscinosis MRS Progressive changes with decreased NAA and increased mI and Glx. In long standing disease, mI the most prominent and lactate absent. Reduced NAA, prominent mI and no detectable lactate seem to be more consistent with late infantile NCL: Therefore MRS help to differentiate NCL from other neurometabolic disorders such as mitochondrial or peroxisomal encephalopathies. Diagnosis of NCL has to be considered in children with cerebellar atrophy, hypointense thalami, Periventricular T2 hyperintensities with decreased NAA and increased mI and no Lactate. SUMMARY/CONCLUSION Recognition of typical neuroimaging features of some IMD causing epilepsy in neonates and infants participate in the earlier recognition and management of these disorders. DWI allows detection and characterization of regions of different diffusitivity indicating cytotoxic/myeline edema and disease activity. MRS may demonstrate specific pattern and therefore guide metabolic investigations. A specific diagnosis of metabolic disorders in epileptic patients may indicate the possibility of specific treatment that can improve seizures and allows genetic counseling. References Dublin AB. Isolated Sulfite Oxidase Deficiency: MR Imaging Features. AJNR Am J Neuroradiol 2002;23:484–485. Friedman SD. Callosal alterations in pyridoxine-dependent epilepsy. Developmental Medicine & Child Neurology 2014, 56: 1106– 1110 Gire C et al. Clinical features and neuroradiological findings of mitochondrial pathology in six neonates. Childs Nerv Syst. 2002;18:621-8. Gropman AL. ,Patterns of Brain Injury in Inborn Errors of Metabolism. Semin Pediatr Neurol. 2012; 19: 203–210 Grünewald S. Biotinidase Deficiency: a Treatable Leukoencephalopathy. Neuropediatrics 2004; 35: 211–216 Hoffmann C. Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy in Isolated Sulfite Oxidase Deficiency. Journal of Child Neurology 2007; 22:1214-1221 Jain-Ghai S. et al. 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THANKS FOR VIEWING OUR PRESENTATION Please send questions or comments to: [email protected] Professor of Radiology, Medical School of Sousse. Tunisia Consultant Pediatric Neuroradiology, PSMMC Riyadh . Saudi Arabia