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Thomas et al. MRI of Childhood Epilepsy Pediatric Imaging Pictorial Essay

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MRI of Childhood Epilepsy Due to Inborn Errors of Metabolism

OBJECTIVE. The purpose of this pictorial essay is to classify epilepsy syndromes due to inborn errors of metabolism according to age at onset and type of seizure and to show the MRI features of many of the syndromes. CONCLUSION. Epilepsy syndromes due to inborn errors of metabolism are rare, but it is important to detect them at an early stage because some are treatable. MRI is an important tool in the assessment of these patients. eizure is a frequent symptom of metabolic diseases, but epilepsy syndromes due to inborn errors of metabolism are rather rare [1, 2]. It is important to detect these disorders at an early stage, because many are treatable and many can be worsened by inadvertent use of certain antiepileptic medications. MRI is important because many of the syndromes have specific or relatively specific imaging features, which can help in narrowing further expensive and time-consuming metabolic evaluations. Age at onset of the disease process, myelination and sulcation pattern of the brain, specific zones of demyelination and dysmyelination, structural anomalies of the brain, and the presence of diffusion or MR spectroscopic abnormalities can help in the differential diagnosis. The purpose of this pictorial essay is to review the classification of childhood epilepsy syndromes due to inborn errors of metabolism and to show the classic MRI features of many of them. Classification Epilepsy syndromes due to inborn errors of metabolism can be classified in many ways. We use a pragmatic approach based on age at onset and type of seizure disorder. Among the seizure disorders based on age at onset, neonatal disorders include nonketotic hyperglycinemia, organic aciduria, urea cycle defects, Zellweger syndrome, molybdenum cofactor deficiency, and hypoglycemia. Disorders of infancy are glucose transporter protein type 1 deficiency, creatine deficiency, biotinidase deficiency, aminoacidopathy, organic aciduria, neuronal ceroid lipofuscino-

Bejoy Thomas1 Nasser Al Dossary Elysa Widjaja

Thomas B, Al Dossary N, Widjaja E

Keywords: children, epilepsy, metabolic disorders, MRI DOI:10.2214/AJR.09.2948 Received April 22, 2009; accepted after revision June 21, 2009.
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All authors: Department of Diagnostic Imaging, The Hospital for Sick Children, 555 University Ave., Toronto, ON, M5G 1X8, Canada. Address correspondence to E. Widjaja (elysa.widjaja@sickkids.ca).

sis type 1, and hypoglycemia. Seizure disorders that occur among toddlers are neuronal ceroid lipofuscinosis type 2, mitochondrial disorders, and lysosomal disorders. Schoolage children are affected by mitochondrial disorders, neuronal ceroid lipofuscinosis type 3, and progressive myoclonic epilepsy. Disorders classified according to type of seizures are infantile spasms, such as biotinidase deficiency, Menkes syndrome, mitochondrial disorders, organic aciduria, and aminoacidopathy. Epilepsy with myoclonus includes nonketotic hyperglycinemia, mitochondrial disorders, glucose transporter protein type 1 deficiency, and lysosomal storage disorders. Progressive myoclonic epilepsy includes Lafora body disease; myoclonus epilepsy associated with ragged red fibers; mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome; and sialidosis. Epilepsy with generalized tonicclonic seizures includes glucose transporter protein type 1 deficiency, neuronal ceroid lipofuscinosis types 2 and 3, storage disorders, and mitochondrial disorders. Epilepsy with focal or multifocal seizures includes neuronal ceroid lipofuscinosis type 3 and glucose transporter protein type 1 deficiency. Epilepsia partialis continua includes Alpers disease and other mitochondrial disorders. MRI Features of Specific Disorders Nonketotic Hyperglycinemia Nonketotic hyperglycinemia is an autosomal recessive disease caused by a defect of the glycine cleavage system. Imaging findings include callosal abnormalities (hypogenesis),

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Thomas et al. delayed myelination [3], and myelin vacuolation resulting in diffusion restriction within the pyramidal tracts, middle cerebellar peduncles, and dentate nuclei [4] on diffusionweighted MR images (Figs. 1A and 1B). Diffuse loss of supratentorial white matter volume also may be present. Single-voxel proton MR spectroscopy shows elevated glycine levels in the brain. At a short TE (e.g., 31 milliseconds) (Fig. 1C), the spectral peak generated by protons of glycine may overlap with normally present myoinositol signal intensity because both glycine and myoinositol resonate at approximately 3.56 ppm. Myoinositol, however, has a much shorter T2 relaxation time than glycine. Therefore, its signal intensity decreases substantially at longer TEs (e.g., 144 milliseconds). In patients with nonketotic hyperglycinemia, an abnormal peak at 3.56 ppm (glycine) remains conspicuous at longer TEs (Fig. 1D). Brain glycine also can be measured with quantitative spectroscopic methods [5]. Methyl Malonic Aciduria Methyl malonic aciduria is a complex autosomal recessive metabolic disorder of various clinical phenotypes. In an acute metabolic crisis, T2-weighted FLAIR images show hyperintensity (Fig. 2A) within the globi pallidi associated with swelling, which can cause diffusion restriction (Fig. 2B) [6, 7]. Volume loss and gliosis occur in the chronic stage. Glutaric Aciduria Type 1 Glutaric aciduria type 1 is an autosomal recessive disorder of degradation of lysine, hydroxylysine, and tryptophan caused by deficiency of glutaryl coenzyme-A dehydrogenase. Bilateral abnormalities of the basal ganglia involving the globi pallidi, caudate nuclei, and putamina can be seen, but they usually spare the thalami [8]. The affected deep gray matter can be atrophic. Most patients have a large head with prominence of the sylvian fissures (Fig. 3). Some patients have chronic bilateral subdural hematomas [9]. L-2 Hydroxy Glutaric Aciduria L-2 hydroxy glutaric aciduria is an organic autosomal recessive disorder with an unknown cause. White matter abnormalities have a typical centripetal pattern, the subcortical U-fibers being most severely affected [10] (Fig. 4A). The central corticospinal tracts and corpus callosum usually are spared. The extreme and external capsules and the anterior limbs of the internal capsules usually are abnormal. The basal ganglia are involved but less prominently than in other types of organic acidopathy. The thalami are normal. The dentate nuclei are abnormal (Fig. 4B). Maple Syrup Urine Disease Maple syrup urine disease is an autosomal recessive disorder that manifests itself in the first few days of life as poor feeding, vomiting, ketoacidosis, hypoglycemia, lethargy, seizures, and a characteristic odor of maple syrup. MRI shows diffuse swelling of the brain due to extensive edema of the white matter. The posterior limbs of the internal capsules and optic radiations (Fig. 5A) and the central corticospinal tracts within the cerebral hemispheres (Fig. 5B) exhibit diffusion restriction, which represents myelin splitting edema and is believed to be secondary to vacuolating myelinopathy [11]. The structures in the posterior fossa exhibit prominent changes in signal intensity, swelling, and diffusion restriction of the already myelinated brain areas, such as the posterior brainstem tracks and the central cerebellar white matter (Fig. 5C). Singlevoxel proton MR spectroscopy may show the presence of branched-chain amino acids resonating at 0.91.0 ppm, especially during a metabolic crisis [11]. Zellweger Syndrome Zellweger syndrome is the most severe peroxisomal disorder, almost all peroxisomal functions being absent. This syndrome of neonatal onset is autosomal recessive in inheritance and is also called cerebrohepatorenal syndrome. MRI shows markedly delayed myelination, bilateral symmetric perisylvian polymicrogyria (Fig. 6A), periventricular germinolytic cysts, and gray matter heterotopia [12]. A large anterior fontanel, calcification within the patella (Fig. 6B), and cysts in the kidneys also may be found. Molybdenum Cofactor Deficiency Molybdenum cofactor is essential for the function of three human enzymes: sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. Molybdenum cofactor deficiency is a rare autosomal recessive disease. Disturbed development and damage to the brain can occur as a result of accumulation of toxic levels of sulfite [13]. In the acute phase, neonates may have intractable seizures, craniofacial dysmorphism, hyperexcitability, low blood uric acid levels, and MRI findings mimicking diffuse hypoxic ischemic episode (Fig. 7). In the chronic phase, multicystic encephalomalacia or diffuse brain atrophy may be present [14]. Congenital Creatine Deficiency Congenital creatine deficiency is a relatively recently identified disease of deficiency of guanidinoacetate methyltransferase, which catalyzes the conversion of guanidinoacetate to creatine. MRI of the brain may have normal findings but also may show delayed myelination. MR spectroscopic findings are relevant when the creatine peak in the brain is absent or severely attenuated at 3 ppm and the choline and N-acetylaspartate peaks are normal [15] (Fig. 8). MELAS Syndrome MELAS syndrome is a disorder of maternal inheritance. The mutation occurs on mitochondrial DNA. MRI of patients with MELAS syndrome shows recurrent strokelike lesions within the brain, usually involving the cerebral hemispheres. The most frequently affected areas are the parietal and occipital lobes, followed by the temporal and frontal regions [16] (Fig. 9). Progressive loss of volume in the brain may be detected between imaging examinations. MR spectroscopy (Fig. 9E) shows a lactate peak in the infarcted region and in normal-appearing brain. Leigh Disease Leigh disease is often referred to as subacute necrotizing encephalomyopathy. Boys are affected more frequently than are girls. MRI shows involvement of the basal ganglia (Fig. 10A). The brainstem and deep cerebellar gray matter structures, such as the dentate nuclei (Fig. 10B), also can be involved [17]. Single-voxel proton MR spectroscopy (Fig. 10C) shows a lactate peak, which is nonspecific. Neuronal Ceroid Lipofuscinosis Neuronal ceroid lipofuscinosis is a group of neurodegenerative disorders associated with various progressive symptoms, including seizures, dementia, and cerebral atrophy. Three clinical subtypes of the disease according to age at onset have been identified. MRI may show diffuse cerebellar (Fig. 11) and cerebral atrophy and white matter changes. Thalamic hypointensity on T2weighted images has been described [18]. Menkes Disease Menkes disease (also called kinky or steely hair disease and trichopoliodystrophy) is an X-linked disorder of metal metabolism. At birth, the brain often appears normal on MR images. During the course of the disease, however, rapidly developing cerebral

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MRI of Childhood Epilepsy and cerebellar atrophy and prominent white matter changes occur (Fig. 12A). T1-weighted images show hyperintensity of the basal ganglia similar to that of chronic hepatic encephalopathy. The cerebral vessels usually are tortuous and elongated on MR angiograms [19] (Fig. 12B). Chronic bilateral subdural hematomas also may be visualized. The presence of multiple wormian bones, especially along the lambdoid suture, is another feature of Menkes disease (Fig. 12C). Conclusion Many of the childhood epilepsy syndromes due to metabolic disorders have a specific or relatively specific MRI appearance. Diffusion-weighted MRI and MR spectroscopy can be useful in many cases. MRI can help in tailoring the expensive and time-consuming metabolic evaluation of patients with these syndromes. Acknowledgment We thank Susan Blaser, The Hospital for Sick Children, for her assistance in diagnosing these disorders. References
1. Wolf NI, Bast T, Surtees R. Epilepsy in inborn errors of metabolism. Epileptic Disord 2005; 7:6781 2. Sedel F, Gourfinkel-An I, Lyon-Caen O, Baulac M, Saudubray JM, Navarro V. Epilepsy and inborn errors of metabolism in adults: a diagnostic approach. J Inherit Metab Dis 2007; 30:846854 3. Press GA, Barshop BA, Haas RH, Nyhan WL, Glass RF, Hesselink JR. Abnormalities of the brain in nonketotic hyperhyperglycinemia: MR manifestations. Am J Neuroradiol 1989; 10:315321 4. Sener RN. Nonketotic hyperglycinemia: diffusion magnetic resonance imaging findings. J Comput Assist Tomogr 2003; 27:538540 5. Huisman TA, Thiel T, Steinmann B, Zeilinger G, Martin E. Proton magnetic resonance spectroscopy of the brain of a neonate with nonketotic hyperglycinemia: in vivoin vitro (ex vivo) correlation. Eur Radiol 2002; 12:858861 6. Brismar J, Ozand PT. CT and MR of the brain in disorders of the propionate and methylmalonate metabolism. Am J Neuroradiol 1994; 15:14591473 7. Trinh BC, Melhem ER, Barker PB. Multi-slice proton MR spectroscopy and diffusion-weighted imaging in methylmalonic acidemia: report of two cases and review of the literature. Am J Neuroradiol 2001; 22:831833 8. Brismar J, Ozand PT. CT and MRI of the brain in glutaric acidemia type 1: a review of 59 published cases and report of 5 new patients. Am J Neuroradiol 1995; 16:675683 9. Osaka H, Kimura S, Nezu A, Yamazaki S, Saitoh K, Yamaguchi S. Chronic subdural hematoma, as an initial manifestation of glutaric aciduria type1. Brain Dev 1993; 15:125127 10. DIncerti L, Farina L, Moroni I, Uziel G, Savoiardo M. L-2-hydroxyglutaric aciduria: MRI in seven cases. Neuroradiology 1998; 40:727733 11. Jan W, Zimmerman RA, Wang ZJ, Berry GT, Kaplan PB, Kaye EM. MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation. Neuroradiology 2003; 45:393399 12. Barkovich AJ, Peck WW. MR of Zellweger syndrome. Am J Neuroradiol 1997; 18:11631170 13. Serrano M, Lizarraga I, Reiss J, et al. Cranial ultrasound and chronological changes in molybdenum cofactor deficiency. Pediatr Radiol 2007; 37: 10431046 14. Appignani BA, Kaye EM, Wolpert SM. CT and MR appearance of the brain in two children with molybdenum cofactor deficiency. Am J Neuroradiol 1996; 17:317320 15. Stckler S, Holzbach U, Hanefeld F, et al. Creatine deficiency in the brain: a new, treatable inborn error of metabolism. Pediatr Res 1994; 36: 409413 16. Sue CM, Crimmins DS, Soo YS, et al. Neuroradiological features of six kindreds with MELAS tRNA Leu A3243G point mutation: implications for pathogenesis. J Neurol Neurosurg Psychiatry 1998; 65:233240 17. Valanne L, Ketonen L, Majander A, Suomalainen A, Pihko H. Neuroradiologic findings in children with mitochondrial disorders. Am J Neuroradiol 1998; 19:369377 18. Autti T, Joensuu R, Aberg L. Decreased T2 signal in the thalami may be a sign of lysosomal storage disease. Neuroradiology 2007; 49:571578 19. Takahashi S, Ishii K, Matsumoto K, et al. Cranial MRI and MR angiography in Menkes syndrome. Neuroradiology 1993; 35:556558

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Fig. 15-day-old boy with nonketotic hyperglycinemia. A and B, Diffusion-weighted imaging (A) and apparent diffusion coefficient (B) maps show diffusion restriction due to myelin vacuolation within pyramidal tracks (arrows), middle cerebellar peduncles, and dentate nuclei. C and D, Single-voxel proton MR spectroscopic recordings (TE, 31 milliseconds, C; TE, 144 milliseconds, D) show peak generated by glycine overlaps with normal myoinositol signal intensity. At longer TE (e.g., 144 milliseconds), abnormal peak at 3.56 ppm, which remains conspicuous in patients with nonketotic hyperglycinemia, is attributed to elevated levels of glycine (thin arrow). Thick arrow (D) indicates presence of lactate.

Fig. 218-month-old girl with methyl malonic aciduria. A, FLAIR MR image obtained during acute metabolic crisis shows area of hyperintensity within globi pallidi associated with swelling. B, Diffusion-weighted imaging map shows hyperintensity that was restricted on apparent diffusion coefficient map (not shown).

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Fig. 318-month-old boy with glutaric aciduria type 1. Axial T2-weighted MR image at level of basal ganglia shows bilateral involvement (white arrows) of basal ganglia but sparing of thalami. Black arrows indicate prominence of sylvian fissures.

Fig. 44-year-old boy with L-2 hydroxy glutaric aciduria. A, Axial T2-weighted fast spin-echo MR image shows white matter abnormalities with centripetal pattern, subcortical U-fibers (black arrows) being most severely affected. Extreme and external capsules (thin white arrows) usually are abnormal. Basal ganglia also are involved (thick white arrows) in most cases. Thalami are normal. B, Axial T2-weighted fast spin-echo MR image shows abnormal dentate nuclei (arrows), which always are abnormal in this condition.

Fig. 54-week-old boy with maple syrup urine disease. AC, Axial diffusion-weighted MR images show areas of hyperintensity restricted on apparent diffusion coefficient maps (not shown) in posterior limbs of internal capsules (arrows, A) and optic radiations, central corticospinal tracks within cerebral hemispheres (arrows, B), and brainstem (small arrows, C) and cerebellar white matter (large arrows, C). Diffusion restriction is secondary to myelin-splitting edema.

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Fig. 61-day-old boy with Zellweger syndrome. A, Axial T2-weighted MR image shows delayed myelination and bilateral symmetric perisylvian polymicrogyria (arrows). B, Knee radiograph shows calcified stippled appearance (arrow) of patella.

Fig. 75-day-old boy with molybdenum cofactor deficiency. A, Axial T2-weighted image at level of basal ganglia shows diffuse cortical swelling with white matter edema. B and C, Axial diffusion-weighted image (B) and apparent diffusion coefficient (C) maps show global diffusion restriction involving cortical gray matter.

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Fig. 86-year-old boy with creatine deficiency. A, Axial T2-weighted MR image shows no abnormality. B, MR spectroscopic recording shows severely attenuated creatine peak (arrow) in brain at 3 ppm. Cho = choline. NAA = N-acetylaspartate.

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Fig. 98-year-old girl with mitochondrial myopathy encephalopathy, lactic acidosis, and stroke-like episodes syndrome. A and B, FLAIR (A) and diffusion-weighted (B) MR images show infarct in right occipital lobe. C and D, MR images obtained 2 years after A and B when patient had acute symptoms show acute infarct in left middle cerebral artery territory. E, MR spectroscopic recording acquired from basal ganglia shows lactate peak (arrow).

Fig. 102-year-old girl with Leigh disease. A and B, MR images show involvement of deep cerebral gray matter structures (A), brainstem, and deep cerebellar gray matter (B). C, Proton MR spectroscopic recording shows lactate peak (arrow).

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Fig. 115-year-old girl with neuronal ceroid lipofuscinosis (Batten-Bielschowsky disease). Sagittal T1 shows diffuse cerebellar atrophy.

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Fig. 1211-week-old boy with Menkes disease. A, Axial T2-weighted MR image shows delay in myelination. B, MR angiogram shows tortuosity of vessels of circle of Willis. C, Three-dimensional shaded surface display of skull shows multiple wormian bones.

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