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Inherited Neurological Diseases and Disorders of Myelin

ly with diffusion tensor (DT) imaging. DT imaging Introduction characterizes the 3D spatial distribution of water dif- fusion in each MRI voxel. The history of clinical description of genetically in- The first DT imaging studies in human brain mat- herited white matter diseases is long. More than uration were performed on preterm and term 100years ago the pathological description of neonates and revealed that the isotropic diffusion co- Pelizaeus-Merzbacher disease started the history of efficient decreases and the diffusion anisotropy in- leukodystrophies, followed by a description of creases with increasing gestational age. This tech- metachromatic leukodystrophy and Krabbe disease. nique was later applied to normal brain development The original term of leukodystrophy has been in children. From normal brain development the use changed to leukoencephalopathy to better cover the of DT imaging has been expanded in pathological group of diseases. This term better describes the CNS conditions.DT imaging has been used as an ear- group of diseases that not only include loss of previ- ly indicator of white matter demyelination and to ously formed myelin, but also hypomyelination (de- monitor the severity of the white matter change be- lay in normal myelination process) and failure to fore it is seen in conventional MR sequences. Use of myelinate at all or failure to maintain normal myeli- more sophisticated techniques will generate new op- nation, such as destruction of myelin. In the past portunities to provide clinically useful information 10years our understanding of the diseases has in- early in the disease process and detect CNS dysfunc- creased and simultaneously new leukoencephalopa- tion that have been previously been considered be- thy syndromes have been defined. In spite of all the yond the capabilities of routine imaging techniques. genetic,biochemical marker and imaging advances,a significant number of white matter leukoencephalo- pathy syndromes remain without specific diagnosis. Suggested Reading Our prospective has broadened with the new discov- eries associated with CNS involvement, such as de- Engelbrecht V, Scherer A, Rassek M, Witsack HJ, Modder U fects in genes coding for protein that are not typical- (2002) Diffusion-weighted MR imaging in the brain in children: findings in the normal brain and in the brain ly associated with myelin sheath that can cause with white matter diseases. Radiology 222:410–418 myelin disorders. Holland BA, Haas DK, Norman D, Brant-Zawadzki M, Newton CT and later MR imaging markedly changed our TH (1986) MRI of normal brain maturation. AJNR Am J concept of white matter abnormalities. New imaging Neuroradiol 7:201–208 techniques such as DW imaging,ADC maps and pro- Kreis R, Hofmann L, Kuhlmann B, Boesch C, Bossi E, Huppi PS (2002) Brain metabolite composition during early human ton and phosphorus MRS have helped further to brain development as measured by quantitative in vivo 1H characterize the leukoencephalopathies. magnetic resonance spectroscopy. Magn Reson Med 48: MRI imaging has become a routine clinical tool for 949–958 the evaluation of brain maturation and myelination Mukherjee P,Miller JH, Shimony JS, et al (2002) Diffusion-ten- in young children. The maturation and decrease in sor MR imaging of gray and white matter development during normal human brain maturation. AJNR Am J Neu- brain water content and increase in macromolecules roradiol 23:1445–1456 such as myelin reflects signal intensity changes in Schneider JF, Il’yasov KA, Boltshauser E, Hennig J, Martin E standard T1- and T2-weighted images. The matura- (2003) Diffusion tensor imaging in cases of adrenoleuko- tion process can also cause alterations in brain water dystrophy: preliminary experience as a marker for early diffusion that can be seen and analyzed quantitative- demyelination? AJNR Am J Neuroradiol 24:819–824 03_Westesson_Inherited 25.10.2004 16:57 Uhr Seite 70

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Figure3.1 Krabbe’s disease, infantile type with progression over time and cerebellar involvement

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B. T2-weighted image at the age of 13months de- Hereditary Myelin Disorders monstrates increased low signal in the globus pal- lidi and thalami (arrows). The corpus callosum Krabbe’s Disease and frontal white matter myelination have pro- (Globoid Cell Leukodystrophy) gressed at the same time with increase in hyperin- tensity at the posterior limb of the internal capsule Infantile Type with Progression Over Time C. T2-weighted image at the age of 22months. There and Cerebellar Involvement is severe loss of hemispheric white matter with ab- normal hyperintensity and deep sulci. An abnor- Clinical Presentation mal high signal is seen in both pulvinar regions, the posterior limb of internal capsules and insular A floppy female infant with irritability and hyperacu- cortices. Hyperintensity in the anterior thalamic sis. She had also feeding difficulties. and lentiform nucleus have progressed with de- creased volume of the gray nuclei. At the same time the patient stopped interacting with her envi- Images (Fig.3.1) ronment D. Coronal T2-weighted image at the age of 32months. A. T2-weighted (conventional SE) image at the age The white matter hyperintensity has progressed of 12months shows nonspecific hyperintensity significantly and now also the cerebellar white around the frontal horns, atria and putamen. Al- matter is hyperintense. There is diffuse volume though CT at the age of 11months did not demon- loss strate calcification, the globus pallidus low signal can be related to mineral accumulation 03_Westesson_Inherited 25.10.2004 16:57 Uhr Seite 71

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Figure3.2 Krabbe’s disease, infantile type with delayed myelination

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Infantile Type with Delayed Myelination Images (Fig.3.2)

Clinical Presentation A. Axial T2-weighted image at the age of 3months shows prominence of sylvian fissures and cortical A 3-month-old male with irritability. sulci B. Coronal T2-weighted image at the age of 3months reveals mild prominence of cortical CSF spaces 03_Westesson_Inherited 25.10.2004 16:57 Uhr Seite 72

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C. Axial T2-weighted image through the centrum semiovale shows nonmyelinated white matter D. Axial T2-weighted image at the age of 6months re- veals hyperintensity on the posterior limb of inter- nal capsules that normally are myelinated at this age (arrows). Abnormal white matter hyperinten- sity is also seen behind the trigones. Diffuse vol- ume loss has progressed E. Coronal T2 image at the age of 6months shows progression of the periventricular white matter hyperintensity. Diffuse atrophy has progressed with dilated ventricles and sulci. Hippocampi are atrophic F. Coronal T2-weighted image posterior to the image shown in E reveals progression of the periventric- ular and internal capsule white matter hyperinten- sity.The diffuse atrophy is well seen by progressive Figure3.3 ventricular dilatation Krabbe’s disease, infantile type with caudate calcifica- G. At the age of 6months the global volume loss has tion progressed. White matter volume has decreased and hyperintensity has also progressed

Infantile Type with Caudate Calcification presents with progressive irritability, vision loss, hy- peracusis and rapid motor or mental decline and Clinical Presentation death usually occurs by 2years of age. The late onset type presents after 10years of age and mimics a pe- A 6-month-old female infant with irritability,spastic- ripheral neuropathy. ity and blindness MR imaging demonstrates diffuse abnormalities of the white matter, which may be difficult to appre- ciate at the very early stage, when the nonmyelinated Image (Fig.3.3) white matter is still normally hyperintense on T2- weighted images. CT imaging may be more helpful in A. Noncontrast CT scan shows thalamic and caudate the initial stages and shows symmetrically increased body calcification (arrow). Mild periventricular attenuation within the basal ganglia, thalami, and hypodensity is seen centrum semiovale.Progressive cerebral and cerebel- lar atrophy are seen in the late stage of the disease. Pyramidal tract involvement is the characteristic fea- Discussion ture of the disease. In late onset disease, a hyperin- tense signal may be seen in the white matter, mostly Krabbe’s disease is a neurodegenerative disease char- in the posterior regions,with frequent involvement of acterized by severe destruction of myelin and the the splenium of the corpus callosum. presence of globoid bodies in the white matter. The MR spectroscopy reveals prominent peaks from biochemical defect is marked by deficiency of lysoso- choline-containing areas with high creatine and in- mal enzyme, galactosylceramidase, resulting in accu- ositol peaks. The NAA peak is markedly reduced and mulation of galactocerebroside. It is an autosomal re- the choline to NAA ratio is abnormally high. The lac- cessive childhood disorder with the gene localized at tic acid peak may be seen in some cases. This constel- chromosome 14. Krabbe’s disease is classically divid- lation MR spectroscopy finding is seen of extensive ed into three groups: early infantile, late infantile and demyelination, gliosis, and loss of axons in the in- juvenile forms. Others have simplified the classifica- volved white matter. The latter two events occur in tion into “infantile” and “late onset”. The infantile the later stages of Krabbe’s disease. form is the most common subtype and generally 03_Westesson_Inherited 25.10.2004 16:57 Uhr Seite 73

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Figure3.4 Hurler-Scheie syndrome with prominent Virchow-Robin spaces

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Suggested Reading Mucopolysaccharidoses (MPS)

Farina L, Bizzi A, Finocchiro G, et al (2000) MR imaging and Hurler-Scheie Syndrome with Prominent proton MR spectroscopy in adult Krabbe disease. AJNR Virchow-Robin Spaces (MPS I H/S) Am J Neuroradiol 21:1478–1482 Farley TJ, Ketonen LM, Bodensteiner JB, Wang DD (1992) Ser- ial MRI and CT findings in infantile Krabbe disease. Pedi- Clinical Presentation atr Neurol 6:455–458 Given CA 2nd, Santos CC, Durden DD (2001) Intracranial and A 5-year-old male with known MPS I presents for spinal MR imaging findings associated with Krabbe’s dis- MRI with headaches. ease. ANJR Am J Neuroradiol 22:1782–1785 Zarifi MK, Tzika AA, Astrakas LG, Poussaint TY, Anthony DC, Darras BT (2001) Magnetic resonance spectroscopy and magnetic resonance imaging findings in Krabbe’s disease. Images (Fig.3.4) J Child Neurol 16:522–526 A. T2-weighted image shows characteristic dilated Virchow-Robin perivascular spaces, where mu- copolysaccharides accumulate in phagocytic cells. They are characteristically seen in the peritrigonal region and corpus callosum (arrows) 03_Westesson_Inherited 25.10.2004 16:57 Uhr Seite 74

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B. The dilated perivascular spaces are hypointense on T1-weighted image (arrows) C. The perivascular spaces on the corpus callosum follow the CSF signal on FLAIR image. The per- itrigonal perivascular spaces range from low to isointense to CSF D. The wide perivascular spaces on the corpus callo- sum are hypointense on DW image (arrow) E. On ADC map the perivascular spaces are hyperin- tense

Hurler-Scheie Syndrome with Atrophy (MPS I H/S)

Clinical Presentation

A 22-year-old female who presents with cord com- A pression symptoms. She has normal intelligence (see also Chapter 10). Figure3.5A Images (Fig.3.5) Hurler-Scheie syndrome with atrophy

A. Sagittal T1-weighted image shows dilated ventri- cles. Note the significantly narrowed upper spinal canal and cord compression. For more details see Chapter 10 (Spine) F. Contrast-enhanced T1-weighted image fails to B. T2-weighted image shows honeycomb appearance demonstrate enhancement in the thalamic cribri- of the thalami (arrows). Ventriculomegaly is pres- form lesions ent with prominent sylvian fissures. Dilated per- G. DW image shows hypointensity in the thalami itrigonal Virchow-Robin spaces are also present. consistent with increased diffusibility Both frontal lobes show fine network of signal ab- H. The fine white matter changes and prominent normality perivascular space in the frontoparietal area are C. T2-weighted image.Prominent perivascular spaces difficult to appreciate on DW image are seen throughout the white matter, the frontal I. On ADC map the thalami show hyperintensity; lobes being the least involved there is no restricted diffusion D. FLAIR image demonstrates better the thalamic ab- J. Exponential image reveals hypointensity in the normalities thalami, consistent with increased diffusion E. FLAIR image shows periventricular white matter hyperintensities 03_Westesson_Inherited 25.10.2004 16:57 Uhr Seite 75

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Figure3.6 Sanfilippo syndrome

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Sanfilippo Syndrome (MPS III) Images (Fig.3.6)

Clinical Presentation A. Axial T2-weighted image through the cerebellum is normal A 6-year-old female with Sanfilippo syndrome has B. T2 image through the basal ganglia shows lack of been stable and interacting until 5months ago, when myelination in the anterior limb of the internal she experienced a rapid downhill course. Now she is capsule with poor myelination of the posterior in a vegetative state with posturing. limb. Normal basal ganglia structures are not identified as separate structures. There is diffuse periventricular and subcortical white matter T2 hyperintensity, and also there is low volume of white matter, thin corpus callosum and cortical volume loss with deep gyri C and D.No abnormality is seen in the DW images 03_Westesson_Inherited 25.10.2004 16:57 Uhr Seite 77

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Discussion Hunter’s Syndrome (MPS II) Hunter’s syndrome is due to deficiency of iduronate 2-sulfatase enzyme. MPS are inherited metabolic disorders due to defi- These children tend to have severe mental retarda- ciency of lysosomal enzymes involved in the degen- tion and deafness. Communicating hydrocephalus is eration of glycosaminoglycans. Undegraded gly- common. MR studies typically demonstrate thick- cosaminoglycans accumulate in lysosomes and affect ened dura, cortical atrophy, and perivascular “pits”, tissue function. MPS have been divided into seven seen as low and high signal cystic foci on T1- and T2- major types. The classification is based on the defi- weighted images. cient enzyme responsible for the disease. They share many clinical features, including multiple system in- Sanfilippo Syndrome (MPS III) Sanfilippo syndrome volvement, organomegaly, dysostosis multiplex, fa- (MPS III), is characterized by lysosomal accumula- cial abnormalities (“gargoylism”, coarse faces), hear- tion of the glycosaminoglycan (GAG) heparan sulfate ing and vision loss, joint involvement, cardiac in- (HS). In humans, the disease manifests in early child- volvement and central nervous system involvement. hood with severe developmental retardation, and is Profound mental retardation may be found in Hurler, characterized by a combination of progressive men- Hunter’s and Sanfilippo syndromes (MPS types I, II, tal deterioration from the third year of life, he- and III), but normal intellect may be retained in oth- patosplenomegaly and a typical facial appearance er MPS. All MPS have autosomal recessive inheri- (mild ‘Hurler’ phenotype), leading to death in the tance, except of MPS II which is X-linked. second decade. MR imaging shows white matter ab- Imaging findings of the brain in the MPS include normalities,cortical atrophy and ventricular enlarge- delayed myelination, atrophy, varying degrees of hy- ment, while other findings may include thickening of drocephalus, and white matter changes. The white the diploë, callosal atrophy, and basal ganglia in- matter and corpus callosum show a cribriform ap- volvement. Cerebellar changes have also been de- pearance due to dilated perivascular spaces filled scribed. Atrophy and abnormal or delayed myelina- with glycosaminoglycans (mucopolysaccharides) tion have been described to precede the onset of overt neurological symptoms. Hurler Syndrome (MPS I) Hurler syndrome is char- acterized by deficiency of alpha-iduronidase leading Sly Disease (MPS VII) Sly disease is caused by defi- to the storage and massive excretion of dermatan sul- ciency of beta-glucuronidase enzyme. Progressive fate and heparin sulfate. In addition to the imaging hearing loss leading to early deafness is a prominent findings of brain parenchyma mentioned above, pro- feature of this disease. On imaging, odontoid hy- gressive white matter involvement may be seen in poplasia is the distinct feature. Hurler syndrome. It may be differentiated into three different subtypes based on age at onset and severity of the clinical symptoms.The natural history of white Suggested Reading matter abnormalities in patients with MPS is still un- clear. It has been suggested that the degree of MR Barone R, Nigro F, Triulzi F, Masumeci S, Fiumara A, Pavone L changes in patients with MPS does not always reflect (1999) Clinical and neuroradiological follow-up in mu- copolysaccharidosis type III (Sanfilippo syndrome). Neu- their neurological impairment. ropediatrics 5:270–274 Barone R, Parano E, Trifiletti RR, Fiumara A, Pavone P (2002) Hurler-Scheie Syndrome (MPS I H/S) Hurler-Scheie White matter changes mimicking a leukodystrophy in a syndrome represents an intermediate variant of the patient with mucopolysaccharidosis: characterization by previous MPS type I syndrome with clinical symp- MRI. J Neurol Sci 195:171–175 Lee C, Dineen TE, Brack M, Kirsch JE, Runge VM (1993) The toms manifesting between 3 and 8years of age. Most mucopolysaccharidoses: characterization by cranial MR patients have normal or near-normal intelligence. imaging. AJNR Am J Neuroradiol 14:1285–1292 Cervical spinal cord compression is a typical feature. Parsons VJ, Hughes DG, Wraith JE (1996) Magnetic resonance Most patients survive to adulthood. imaging of the brain, neck and cervical spine in mild Hunter’s syndrome (mucopolysaccharidoses type II). Clin Radiol 51:719–723 Zafeiriou DI, Augoustidou-Savvopoulou P, Papadopoulou FA, et al (1998) MRI findings in mild mucopolysaccharidosis II (Hunter’s syndrome). Eur J Paediatr Neurol 2:153–156 03_Westesson_Inherited 25.10.2004 16:57 Uhr Seite 78

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Figure3.7 Zellweger syndrome

Zellweger Syndrome Images (Fig.3.7)

Clinical Presentation A. Sagittal T1-weighted image reveals underdevelop- ment of the rostrum and genu of the corpus callo- A 4-week old female infant presents with hypotonia sum (arrow) and seizures. She also has pulmonary hypertension B. T2-weighted image shows paucity of cortical gyri and multiple cysts in the kidneys. that appear broad as seen in pachygyria. The cor- tex is thick, especially in the frontal and temporal regions. No myelination is seen in the corti- cospinal tracts 03_Westesson_Inherited 25.10.2004 16:57 Uhr Seite 79

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C. T2-weighted image. Polymicrogyria are seen in the poorly developed sylvian fissure regions (ar- rows). There are no germinolytic cysts D. The cortex reveals also broad and shallow gyri on T2-weighted image. Low volume of white matter is seen in the centrum semiovale. There is lack of myelination in the motor cortex that is usually myelinated at birth E. No signal abnormality is seen on DW image

Discussion

Zellweger (cerebrohepatorenal) syndrome is a rare, congenital disorder characterized by the reduction or absence of peroxisomes that presents in the neonatal period. Patients are characterized by multiple distur- Figure3.8 bances of lipid metabolism, profound hypotonia and neonatal seizures, and distinct facial dysmorphism Adrenoleukodystrophy and malformations in the brain. Additional features include mental retardation, liver dysfunction and re- nal cysts. The disorder is always fatal and most pa- tients die within the first year. MR imaging is the neuroimaging study of choice. Adrenoleukodystrophy MR imaging demonstrates the unusual combination of abnormalities of neuronal migration disorders Clinical Presentation with heterotopic gray matter, pachygyria, polymicro- gyria, with hypomyelination. Abnormal gyration is A 21-month-old male with a history of myopathy. most commonly seen in the perisylvian and periro- landic regions. Some authors consider the cortical changes as cortical dysplasia rather than true migra- Image (Fig.3.8) tion anomaly. Nonspecific subependymal germi- nolytic cysts may be seen as a result of hemorrhage. A. T2-weighted image shows extensive peritrigonal The presence of hypomyelination helps in differenti- demyelination with lesser areas of demyelination ating Zellweger syndrome from neonatal adreno- in the deep white matter anteriorly and around the leukodystrophy. Congenital muscular dystrophies frontal horns can be differentiating from Zellweger syndrome by absence of facial deformities, seizures and lack of hy- potonia. Discussion

Adrenoleukodystrophy is a rare genetic metabolic Suggested Reading disorder characterized by progressive demyelination of nerve cells in the brain, dysfunction of adrenal Barkovich AJ, Peck WW (1997) MR of Zellweger syndrome. glands and testes due to impaired peroxisomal func- AJNR Am J Neuroradiol 18:1163–1170 tion. Adrenoleukodystrophy comprises three sub- Pueschel SM, Oyer CE (1995) Cerebrohepatorenal (Zellweger) syndrome: clinical, neuropathological, and biochemical types: X-linked recessive disorder, and neonatal and findings. Childs Nerv Syst 11:639–642 childhood forms. In adrenoleukodystrophy, there is accumulation of high levels of very long-chain fatty acids in various organs due to the absence of peroxi- somes. This accumulation is most severe in the brain and adrenal glands resulting in neurological prob- lems and endocrine dysfunction. Neonatal adreno- 03_Westesson_Inherited 25.10.2004 16:57 Uhr Seite 80

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Figure3.9 Juvenile neuronal ceroid lipofus- cinosis with mild radiographic changes

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leukodystrophy presents with mental retardation, fa- Neuronal Ceroid Lipofuscinosis (NCL) cial abnormalities, retinal degeneration, weak muscle tone, enlarged liver, and adrenal dysfunction. This Juvenile NCL with Mild Radiographic Changes form usually progresses rapidly. Neonatal adreno- leukodystrophy is similar to Zellweger syndrome and Clinical Presentation may actually represent a milder variant of Zellweger syndrome. Neonatal adrenoleukodystrophy has de- A 14-year-old male with juvenile NCL (Spielmeyer- myelinating with inflammatory cells and foamy mi- Vogt subtype) with seizures, developmental delay crophages whereas Zellweger syndrome patients and progressive mental deterioration. He has also have hypomyelination. von Willebrand’s disease. On T2-weighted MR images, bilateral symmetrical diffuse deep white matter high signal foci are seen in the occipital lobes. A bilateral occipital pattern with Images (Fig.3.9) involvement of pontomedullary corticospinal tracts is an extremely helpful finding in the diagnosis of A. T2-weighted image at the age of 14years shows adrenoleukodystrophy. Contrast enhancement may only mild volume loss. The thalami show hy- be seen and is attributed to the inflammatory pointensity, except the posterior, medial aspect. process. The putamen also shows hypointensity and is isointense with the globus pallidus’ normal low signal Suggested Reading B. CT scan at the age of 19years shows significant progression of the global atrophy with dilated ven- Barkovich AJ, Ferriero DM, Bass N, Boyer R (1997) Involve- tricles and cortical sulci. Note traumatic changes ment of the pontomedullary corticospinal tracts: a useful in the subcutaneous tissue on the left finding in the diagnosis of X-linked adrenoleukodystro- phy. AJNR Am J Neuroradiol 18:95–100 Chen X, DeLellis RA, Hoda SA (2003) Adrenoleukodystrophy. Arch Pathol Lab Med 127:119–120 Melhem ER, Gotwald TF,Itoh R, Zinreich SJ, Moser HW (2001) T2 relaxation measurements in X-linked adrenoleukodys- trophy performed using dual-echo fast fluid-attenuated inversion recovery MR imaging. AJNR Am J Neuroradiol 22:773–776 03_Westesson_Inherited 25.10.2004 16:57 Uhr Seite 81

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Juvenile NCL with Atrophy In the infantile type the typical MR imaging find- ings can be seen even before the clinical signs. In the Clinical Presentation classic late infantile type, MR imaging is less inform- ative in the early phase. When the disease progresses A 15-year-old female with seizures, progressive visu- MR imaging demonstrates global cerebral and cere- al loss and developmental delay. She has juvenile or bellar atrophy, T2-hyperintensity of the lobar white Spielmeyer-Vogt subtype of NCL. matter and thinning of the cerebral cortex. Hy- pointensity is seen in the thalami. MR spectroscopy shows reduction of NAA consistent with neuronal Images (Fig.3.10) damage. An increase of myoinositol and glutamine/ glutamate is seen. No lactate is seen, helping in MR A. Sagittal T1-weighted image shows severe cerebel- imaging differentiation between this disease and the lar atrophy mitochondrial group. The infantile type shows early B. T2-weighted image confirms the presence of cere- atrophy and decreased signal in the thalami. A bellar atrophy periventricular high-signal rim on T2-weighted MR C. T2-weighted image through the superior cerebel- images is a typical finding. Hypointensity is seen in lar peduncles shows significant atrophy addition to the thalami also in the corpus striatum. D. T2-weighted image through the basal ganglia Atrophy, most prominent in the cerebellum, is espe- shows hypointensity in the putamen with a thin cially marked in the infantile and late infantile sub- linear hypointensity in both thalami.External cap- types. Demyelination and gliosis may be seen initial- sule shows hyperintensity consistent with de- ly in the external capsules, but later in the cerebral myelination or gliosis white matter. An autopsy MR imaging correlation E. Cortical brain atrophy is present on T2-weighted study has shown that periventricular changes detect- image ed in vivo on MRI are due to severe loss of myelin F. MRS (TE=35ms) shows decreased NAA peak with and gliosis. MR spectroscopy shows reduced levels of increased myoinositol peak. Cho and Cr peaks are NAA. normal

Suggested Reading Discussion Autti T, Raininko R, Santavuori P,Vanhanen SL, Poutanen VP, NCL represent a group of inherited neurodegenera- Haltia M (1997) MRI of neuronal ceroid lipofuscinosis. II. Postmortem MRI and histopathological study of the brain tive disorders with an autosomal recessive inheri- in 16 cases of neuronal ceroid lipofuscinosis of juvenile or tance. They are caused by the accumulation of late infantile type. Neuroradiology 5:371–377 lipopigment within the lysosomes of neurons and D’Incerti L (2000) MRI in neuronal ceroid lipofuscinosis. Neu- other tissues. Several main types have been de- rol Sci 21:71–73 scribed: infantile onset (Haltia-Santavuori subtype), Santavuori P,Vanhanen SL, Autti T (2001) Clinical and neuro- radiological diagnostic aspects of neuronal ceroid lipofus- late infantile (Jansky-Bielschowsky subtype), and ju- cinosis disorders. Eur J Paediatr Neurol [Suppl A]:157–161 venile (Spielmeyer-Vogt or Batten subtype), to adult Vanhanen SL, Raininko R, Santavuori P (1994) Early differen- onset (Kufs subtype) forms, and early juvenile and tial diagnosis of infantile neuronal ceroid lipofuscinosis, heterogeneous group atypical forms. The most com- Rett syndrome, and Krabbe disease by CT and MR. AJNR mon types are the infantile and classic juvenile Am J Neuroradiol 15:1443–1453 Vanhanen SL, Raininko R, Autti T, Santavuori P (1995) MRI forms. Infantile NCL is progressive and uniformly fa- evaluation of the brain in infantile neuronal ceroid-lipo- tal. The common clinical presentation is seizures, de- fuscinosis, part 2. MRI findings in 21 patients. J Child Neu- layed milestones leading to dementia, involuntary rol 10:444–450 movements, ataxia, visual loss and abnormal behav- ior. 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 82

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Figure3.10 Juvenile neuronal ceroid lipofuscinosis with atrophy

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Figure3.11 MELAS at 6days of age

Mitochondrial Disorders Images (Fig.3.11)

MELAS at Six Days of Age A. T2-weighted image is unremarkable B. MRS (TE=135ms) shows reversed lactate peak at Clinical Presentation 1.3ppm. The low NAA and high Cho peaks are normal for a 6-day-old infant A 6-day-old female infant with lactic acidosis. 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 84

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Figure3.12 MELAS at 20months of age

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MELAS at Twenty Months of Age Images (Fig.3.12)

Clinical Presentation A. There is increased signal on T2-weighted images diffusely within the cortex of both cerebral hemi- A 20-month-old female with lactic acidosis, develop- spheres, within the subcortical white matter bilat- mental delay and seizures. erally and also within the basal ganglia, cingular gyrus and thalami bilaterally. Diffuse mass effect upon the sulci is present B. Coronal FLAIR shows hyperintensity involving both hemispheres and thalami compared to the darker (normal) signal in the cerebellum C. DW image reveals increased signal in both cere- bral hemispheres (arrows), cingular gyri and on both thalami D. MR spectroscopy (TE=135ms). Single voxel was placed over the subcortical and deep white matter in the right parietal region. There is an inverted lactate peak at 1.3ppm consistent with increased anaerobic glycolysis. The NAA peak is significant- ly decreased with normal Cr and Cho peaks 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 85

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Figure3.13 Kearns-Sayre syndrome

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Kearns-Sayre Syndrome Images (Fig.3.13)

Clinical Presentation A. T2-weighted image through basal ganglia shows subcortical white matter hyperintensity sparing A young adult who has profound deafness since late the corpus callosum and optic radiation. The teens, dementia, ataxia, and ophthalmoplegia. globus pallidi show round hyperintensity bilater- ally (arrows) B. T2-weighted image through the centrum semio- vale shows the peripheral “new” subcortical white matter involvement sparing the central “older” white matter 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 86

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Figure3.14 Leigh’s disease, classic presenta- tion

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Leigh’s Disease, Classic Presentation Images (Fig.3.14)

Clinical Presentation A. Noncontrast CT image shows low densities in the caudate and lentiform nuclei (arrows) A 2-year-old female with failure to thrive. B. T2-weighted image demonstrates increased signal within the lentiform nucleus and caudate nuclei bilaterally (arrows) C. T1-weighted image shows low signal in the cau- date and lentiform nucleus (arrows) D. Contrast-enhanced T1-weighted image shows no abnormal contrast enhancement 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 87

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Figure3.15 Leigh’s disease, classic presentation with cerebellar involvement

Leigh’s Disease, Classic Presentation Leigh’s Disease, Peripheral Involvement with Cerebellar Involvement Clinical Presentation Clinical Presentation An 18-year-old female college student with new onset A 3-year-old male with arrested development, trun- of seizures. She had repeatedly high lactate in the cal ataxia and nystagmus since the age of 19months. CSF.Brain biopsy was obtained. He presents with respiratory failure.

Images (Fig.3.16) Images (Fig.3.15) A. T2-weighted image shows hyperintense lesion in A. T2-weighted image shows increased signal within the left posterior temporal and parietal region (ar- the caudate nuclei and putamen bilaterally (ar- row). Another T2 hyperintensity is seen in the pe- rows) riaqueductal gray matter (arrowhead) B. The hyperintense areas are better seen on axial B. DW image shows hyperintensity in the same le- FLAIR image (arrows) sions C. Coronal FLAIR image reveals hyperintense lesions C. ADC map shows increased signal in the left poste- symmetrically and diffusely also within the cere- rior temporoparietal and periaqueductal areas bellar hemispheres (arrows) D. There was no enhancement in the abnormal areas E. MR spectroscopy (TE=35ms) from left temporal lesion. Although the image is noisy, it demon- strates the presence of lactate at 1.33ppm F. MR spectroscopy (TE=144ms) from the same area as in E demonstrates an inverted lactate doublet at 1.33ppm 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 88

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Figure3.16 Leigh’s disease, peripheral involvement

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Discussion images, non-enhancing hypodense areas are seen in the putamen and caudate nuclei. In the classic form Mitochondrial disorders are a clinically heteroge- T2-weighted MR images show symmetric hyperin- neous group of diseases caused by defects in mito- tense foci in the globus pallidus, putamen, and cau- chondrial function and oxidative phosphorylation. date nuclei. Putaminal involvement is not a pathog- The most common disorder is MELAS (mitochon- nomonic radiological finding. The brain stem drial encephalopathy, lactic acidosis, and stroke-like tegmentum, particularly the mesencephalon, is char- events) which is a multisystem disease associated acteristically involved on MR imaging in the early with specific maternally inherited point mutations of and late phases of the illness.Patients who harbor ap- mitochondrial DNA (mtDNA). The most common of proximately 70–90% mutant mtDNA in their tissues these is an A-to-G transition at nucleotide 3243 of the have highly variable manifestations. Patients with tRNA Leu (UUR) gene.This point mutation is hetero- over 90% mutations have severe disease, such as plasmic, i.e. both normal and mutant mtDNA coexist Leigh’s disease. in the tissues of the patient and the clinical symptoms Kearns-Sayre syndrome is an autosomal domi- are often related to the proportion of mutant and nant mitochondrial encephalopathy caused by dele- normal mtDNA in different tissues. The high energy tion in muscle mtDNA with elevated serum pyruvate. demand of brain and muscle makes them particular- Clinical features include progressive ophthalmople- ly vulnerable to deficient energy production. MELAS gia, pigmentary degeneration of the retina, ataxia, is characterized by stroke-like episodes often preced- myopathy, and cardiac conduction defects. On MR ed by treatment-resistant partial seizures. Short imaging,T2-weighted images show high signal inten- stature, diabetes mellitus, and slowly progressive sity areas in the brain stem,globus pallidus,thalamus, mental impairment leading to dementia are common and white matter of the cerebrum and cerebellum. features. Exercise intolerance is common. Histologi- The peripheral (“new”) white matter is involved spar- cal examination and muscle biopsy reveals accumu- ing the deep (“old”) white matter. The imaging find- lation of abnormal mitochondria and ragged red ings may be similar to those seen in Leigh’s disease. fibers. During stroke-like episodes, CT and MR imaging reveal multifocal infarct-like, mainly gray matter le- Suggested Reading sions,not confined to the vascular territories.MR im- aging classically demonstrate signal changes involv- Abe K, Yoshimura H, Tanaka H, Fujita N, Hikita T, Sakoda S ing both grey and white matter predominantly in the (2004) Comparison of conventional and diffusion-weight- ed MRI and proton MR spectroscopy in patients with mi- occipital and parietal lobes that strongly mimic tochondrial encephalomyopathy, lactic acidosis, and stroke lesions. DW imaging shows increased ADC stroke-like events. Neuroradiology 46:113–117 values consistent with predominant extracellular Arii J,Tanabe Y (2000) Leigh syndrome: serial MR imaging and edema in acute lesions in MELAS thereby indicating clinical follow-up. AJNR Am J Neuroradiol 21:1502–1509 a nonischemic cause of the strokes seen in MELAS. Heckmann JM, Eastman R, Handler L, Wright M, Owen P (1993) Leigh disease (subacute necrotizing encephalo- MR spectroscopy may show lactate peaks suggestive myelopathy): MR documentation of the evolution of an of metabolic damage associated with this disease. acute attack. AJNR Am J Neuroradiol 14:1157–1159 Leigh’s syndrome, also known as subacute necro- Phillips CI, Gosden CM (1991) Leber’s hereditary optic neu- tizing encephalomyelopathy, is included with mito- ropathy and Kearns-Sayre syndrome: mitochondrial DNA chondrial cytopathies. It is a progressive neurode- mutations. Surv Ophthalmol 35:463–472 Schoffner JM (1996) Maternal inheritance and the evaluation generative disorder associated with several enzyme of oxidative phosphorylation diseases. Lancet 348:1283– deficiencies such as pyruvate dehydrogenase com- 1288 plex, pyruvate carboxylase and defects in electron Valanne L, Ketonen L, Majander A, Suomalainen A, Pihko H transport chain. Leigh syndromes have a common (1998) Neuroradiological findings in children with mito- clinical phenotype, although genetic and biochemi- chondrial disorders. AJNR Am J Neuroradiol 19:369–377 Yonemura K, Hasegawa Y,Kimura K, Minematsu K,Yamaguchi cal abnormalities are heterogeneous. They are char- T (2001) Diffusion-weighted MR imaging in a case of mi- acterized by spongiosis, astrogliosis and capillary tochondrial myopathy,encephalopathy,lactic acidosis,and proliferation. Three clinical subtypes are identified: stroke like episodes. AJNR Am J Neuroradiol 22:269–272 infantile type with symptoms occurring in first Zeviani M, Moraes CT,DiMauro S, et al (1988) Deletions of mi- 2years of life, juvenile form and adult form. The in- tochondrial DNA in Kearns-Sayre syndrome. Neurology 38:1339–1346 fantile form presents with hypotonia, vomiting, seizures, and death from respiratory failure. On CT 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 90

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Figure3.17 Cerebellar degeneration associated with coenzyme Q10 deficiency

Cerebellar Degeneration Associated B. Sagittal T1-weighted image also shows cerebellar with Coenzyme Q10 Deficiency atrophy C. Coronal FLAIR shows significant cerebellar corti- Clinical Presentation cal hyperintensity with normal-appearing white matter (arrows) An 8-year-old male with episodic seizures and ataxia. D. Axial contrast-enhanced T1-weighted image shows no significant enhancement in the cerebellum E. Coronal contrast-enhanced gradient echo (SPGR) Images (Fig.3.17) image reveals cortical low signal intensity in the cerebellum (arrows). No abnormal enhancement A. Axial T2-weighted image through posterior fossa is present shows marked atrophy of cerebellum with abnor- F. DW image through posterior fossa shows no sig- mal hyperintensity (arrows) nificant abnormality 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 91

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Discussion

Coenzyme Q10 is an essential lipophilic component of an electron transport chain that has oxidoreduc- tase functions. It also serves as an antioxidant and membrane stabilizer and has been found to protect cultured cerebellar neurons against both sponta- neous and toxin-induced degeneration. Primary coenzyme Q10 deficiency is a mitochon- drial encephalopathy with a heterogeneous clinical presentation. It was first reported as a predominantly myopathic form in two sisters in 1989 characterized by the triad of exercise intolerance, recurrent myo- globinuria, and neurological manifestations. Howev- er, the most frequent ataxic form is dominated by ataxia and cerebellar atrophy, and is variously associ- ated with seizures, developmental delay, weakness, Figure3.18 pyramidal signs, or peripheral neuropathy. A third less-common form with fatal infantile encephalomy- Hallervorden-Spatz disease, classical presentation opathy and renal involvement has also been de- scribed. Usually the presentation is in childhood, but sometimes it may be delayed in onset until even fifth decade of life. On imaging,atrophy of the cerebellar hemispheres Hallervorden-Spatz Disease as well as the vermis is the hallmark of primary CoQ10 deficiency. MR imaging is the modality of Clinical Presentation choice to demonstrate such atrophy. Primary coen- zyme Q10 deficiency is important to diagnose, as its A 12-year-old girl with visual symptoms and pro- clinical spectrum continues to expand and more im- gressive spasticity and choreoathetosis. portantly such patients may improve with early ad- ministration of CoQ10 supplementation. Image (Fig.3.18)

Suggested Reading A. T2-weighted image shows dark signal in the globus pallidus with symmetric hyperintense foci Favit A, Nicoletti F, Scapagnini U, Canonico PL (1992) Ubi- in medial globus pallidus. This is “classical eye-of- quinone protects cultured neurons against spontaneous the-tiger” imaging appearance in this entity and excitotoxin-induced degeneration. J Cereb Blood Flow Metab 12:638–645 Gironi M, Lamperti C, Nemmi R, et al (2004) Late-onset cere- bellar ataxia with hypogonadism and muscle coenzyme Q10 deficiency. Neurology 62(5):818–820 Lamperti C, Naini A, Hirano M, et al (2003) Cerebellar ataxia and coenzyme Q10 deficiency. Neurology 60:1206–1208 Musumeci O, Naini A, Slonim AE, et al (2001) Familial cerebel- lar ataxia with muscle coenzyme Q10 deficiency. Neurolo- gy 56:849–855 Ogasahara S, Engel AG, Frens D, Mack D (1989) Muscle coen- zyme Q deficiency in familial mitochondrial encephalo- myopathy. Proc Natl Acad Sci U S A 86:2379–2386 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 92

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Figure3.19 Hallervorden-Spatz disease, asymmetric presentation

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Asymmetric Presentation Discussion

Clinical Presentation Hallervorden-Spatz disease (synonym: neurodegen- eration with brain iron accumulation, pantothenate A 15-year-old girl with visual symptoms, dysarthria kinase-associated neurodegeneration) is a rare neu- and seizures. rodegenerative disorder characterized by iron accu- mulation in the basal ganglia, progressive extrapyra- midal dysfunction and dementia. The exact patho- Images (Fig.3.19) genesis is unknown. Mutations in the pantothenate kinase 2 gene (PANK2) have been shown to lead to A. T2-weighted image shows (more than expected) pantothenate kinase-associated neurodegeneration low signal in the globus pallidi with a central high by influencing mitochondrial function.This may lead signal (arrows), the so called “eye-of-the-tiger”. to abnormal iron accumulation in the globus pallidus The high signal areas in the globus pallidi are and reticular substantia nigra and cause late-onset slightly asymmetric neurodegenerative disorders. B. MR spectroscopy (TE=35ms) reveals decreased NAA with increased myoinositol peaks.Cho is also low C. T2-weighted image demonstrates the voxel loca- tion over the left basal ganglia 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 93

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Noncontrast-enhanced CT shows bilateral low densities in the globus pallidus and substantia nigra. T2-weighted MR images demonstrate hypointense signals due to iron accumulation.Areas of gliosis, de- myelination, neuronal loss, and axonal swelling are seen as high signal intensity areas on T2-weighted MR images. Initially hyperintense areas are seen in the globus pallidi and substantia nigra. Later as the disease progresses, a hypointense rim is seen around it, due to iron deposition, causing the characteristic “eye-of-the-tiger” sign.

Suggested Reading

Johnson MA, Kuo YM, Westaway SK, Parker SM, Ching KH, Gitschier J, Hayflick SJ (2004) Mitochondrial localization of human PANK2 and hypotheses of secondary iron accu- mulation in pantothenate kinase-associated neurodegen- Figure3.20 eration. Ann N Y Acad Sci 1012:282–298 Pelizaeus-Merzbacher disease with lack of normal mye- Nuri Sener R (2003) Pantothenate kinase-associated neurode- lination generation: MR imaging,proton MR spectroscopy,and dif- fusion MR imaging findings. AJNR Am J Neuroradiol 24:1690–1693 Sethi N, Sethi PK (2003) Eye-of-the-tiger sign. J Assoc Physi- cians India 51:486 Swaiman KF (2001) Hallervorden-Spatz syndrome. Pediatr Neurol 25:102–108 Defects in Genes Encoding Trimble M (2003) Magnetic resonance imaging and Hallervor- the Myelin Proteins den-Spatz syndrome. CNS Spectr 8:420 Pelizaeus-Merzbacher Disease

Pelizaeus-Merzbacher Disease with Lack of Normal Myelination

Clinical Presentation

A 10-month-old male with nystagmus and develop- mental delay presents for MR imaging evaluation.

Image (Fig.3.20)

A. T2-weighted image demonstrates diffuse hyperin- tensity in the white matter including the corpus callosum and internal capsule. This is consistent with near-total lack of normal myelination. Severe white matter atrophy is present with normal-ap- pearing cortical ribbon 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 94

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Figure3.21 Pelizaeus-Merzbacher disease with delayed myelination

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Pelizaeus-Merzbacher Disease Pelizaeus-Merzbacher Disease with Delayed Myelination with Prominent Cerebellar Involvement

Clinical Presentation Clinical Presentation

An 11-month-old male with developmental delay, A 9-year-old male with developmental delay and hy- ataxia, visual symptoms and spasticity. He has a 3- potonia. year-old brother with similar symptoms and hy- pomyelination on MRI. Images (Fig.3.22)

Images (Fig.3.21) A. Noncontrast CT scan at the age of 1year shows sig- nificant hypodensity in the white matter tracts A. T2-weighted image fails to show myelination in B. The white matter tracts show unusual low density posterior limbs of internal capsules (arrows) usu- also in the supratentorial area on noncontrast CT ally present by 2months of age image B. Brain myelination is inappropriate for an 11- C. T2-weighted image at the age of 9years shows ab- month-old, since no myelination is present on T2- normal hyperintensity in the cerebellum weighted image D. T2-weighted image fails to show any myelination in the corticospinal fibers as expected. The cen- trum semiovale is abnormally hyperintense

Discussion

Pelizaeus-Merzbacher disease is an X-linked reces- sive leukodystrophy caused by a mutation in the pro- teolipid protein gene on chromosome Xq22.It is char- acterized by hypotonia, respiratory distress, stridor, nystagmus, and profound myelin loss. It has been di- vided into a number of subtypes. 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 95

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Figure3.22 Pelizaeus-Merzbacher disease with prominent cerebellar involvement

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On CT images, mild nonspecific cerebral and cere- p10 p9 Translocation bellar atrophy is seen. T2-weighted MR images show extensive white matter hypomyelination. Severe cas- Clinical Presentation es may show near-total lack of myelination which ex- tends peripherally to involve the arcuate fibers. The A 13-month-old female with chromosome disorder: white matter has often a “tigroid” appearance. There translocation of p10 and p9. She had abnormal pre- is no histological evidence of demyelination. The natal ultrasound and postnatal CT scan. She has car- brain stem, diencephalon, cerebellum, and subcorti- diac, visceral and skeletal abnormalities, develop- cal white matter may show preservation of myelin. mental delay and cleft palate. MR spectroscopy may show decreased choline peaks in the white matter resulting in markedly high NAA/Cho ratios, and low Cho/Cr ratios representing Images (Fig.3.23) deficient myelination. Diffusional anisotropy in the corpus callosum,internal capsule and white matter of A. Sagittal T1-weighted image demonstrates vermian the frontal lobes has been reported. hypoplasia with a prominent retrocerebellar CSF space. This CSF space communicates with the fourth ventricle (arrow). The corpus callosum is present but hypoplastic 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 96

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Figure3.23 p10 p9 translocation

B. Significant areas of the periventricular white mat- C. T2-weighted image reveals prominent extra-axial ter demonstrate an abnormal high signal on T2- CSF space bilaterally. The falx is absent. The white weighted image (arrows). Patchy areas of abnor- matter volume is low. The centrum semiovale mal high signal are seen also in the subcortical white matter is still abnormally bright (arrows) white matter (arrowheads). The internal capsules D. Coronal T2-weighted image demonstrates normal show normal myelination and the thin genu of the myelination in the anterior limb on the internal corpus callosum is myelinated capsules (arrows). The sylvian fissures are open 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 97

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Figure3.24 18q syndrome

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and the extra-axial CSF spaces are prominent. B. T2-weighted image confirms the findings in A.Ad- There is lack of maturity of subcortical white mat- ditionally prominent perivascular spaces (arrows) ter. The white matter volume is also decreased. No are better appreciated falx is visualized C. MR spectroscopy (TE=35ms) placing voxel over right centrum semiovale reveals no abnormal metabolites. Relatively low NAA reflects patient’s 18q Syndrome age rather than abnormality

Clinical Presentation Discussion A 15-month-old male who presents with micro- cephaly, developmental delay and hypotonia. Leukodystrophies are a heterogeneous group of dis- orders that affect the central and sometimes the pe- ripheral nervous systems and predominantly involve Images (Fig.3.24) the white matter.A typical feature is abnormal myelin formation and/or maintenance of normal formed A. T1-weighted image shows microcephaly,low white myelin. Although destruction is seen typically in de- matter volume, abnormal gyration and lack of myelinating diseases, this may also be seen in the normal operculum formation (arrow) leukodystrophies. 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 98

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Very little has been described in the literature re- Ono J, Harada K, Hasegawa T,et al (1994) Central nervous sys- garding the CNS imaging findings in patients with tem abnormalities in chromosome deletion at 11q23. Clin Genet 6:325–329 10p,9p syndrome.A case of an 18-week fetus with tri- Ono J, Harada K,Yamamoto T,Onoe S, Okada S (1994) Delayed somy 9p and 10p has been reported. Ultrasound of myelination in a patient with 18q-syndrome. Pediatr Neu- the brain and fetus at that time showed cleft rol 1:64–67 lip/palate, club feet, structural anomalies of the cere- Plecko B, Stockler-Ipsiroglu S, Gruber S, et al (2003) Degree of bellum and cystic kidneys. No brain MR imaging hypomyelination and magnetic resonance spectroscopy findings in patients with Pelizaeus Merzbacher phenotype. findings were reported. Neuropediatrics 34:127–136 White matter alterations in chromosomal disor- Sener RN (2004) Pelizaeus-Merzbacher disease: diffusion MR ders have been reported mainly in 18q syndrome. imaging and proton MR spectroscopy findings. J Neurora- This syndrome is a prototype of hypomyelination. diol 31:138–141 Chromosome analysis reveals partial deletion of the long arm of chromosome 18 including myelin basic protein genes. Typical imaging findings show small Disorders in Amino Acid brain volume and poor delineation of gray/white and Organic Acid Metabolism matter. In a case report of 18q syndrome three serial magnetic resonance images demonstrated that Phenylketonuria (PKU) myelination in the central nervous system was de- layed except for the corpus callosum and brainstem. Clinical Presentation MR spectroscopy has been reported to be normal. A small series of patients with sex chromosomal A 22-year-old male presented with mental retarda- and autosomal chromosomal disorders has been re- tion. Serum phenylalanine was 11mg/dl. ported to have white matter changes in the periven- tricular and subcortical region seen in T2-weighted and FLAIR images. These lesions were isolated or Images (Fig.3.25) confluent hyperintensities. Normal myelination pro- gresses in an orderly fashion and usually by 2years of A. T2-weighted image shows hyperintense lesion in age the pattern of myelination is similar to that of an bilateral periventricular white matter. The white adult. Alterations of the cerebral white matter due to matter abnormalities involve the regions around specific genes directly involved in the central nervous the frontal horns, bodies and atria and occipital system myelination process have recently been pub- horns of the lateral ventricles lished.The prevalence of white matter changes in dif- B. Contrast-enhanced T1-weighted image shows no ferent chromosomal abnormalities appears to be significant enhancement high,even though they have not been well reported in C. DW image shows marked hyperintense periven- the literature. Some authors hypothesize that un- tricular lesions known factors related to the myelination processes D. ADC map shows hypointensity indicating cyto- may be localized in different chromosomes. toxic edema and restricted diffusion as seen in in- tramyelinic edema

Suggested Reading Discussion Garcia-Cazorla A,Sans A,Baquero M,et al (2004) White matter alterations associated with chromosomal disorders. Dev PKU is the most common congenital disorder of Med Child Neurol 3:148–153 Hengstschlager M, Bettelheim D, Repa C, Lang S, Deutinger J, amino acid metabolism due to deficiency of the en- Bernaschek G (2002) A fetus with trisomy 9p and trisomy zyme phenylalanine hydroxylase. Untreated patients 10p originating from unbalanced segregation of a mater- typically develop a characteristic clinical picture that nal complex chromosome rearrangement t(4;10;9). Fetal may include mental retardation, seizures, growth re- Diagn Ther 4:243–246 tardation, hyperreflexia, eczematous dermatitis, and Koeppen AH, Robitaille Y (2002) Pelizaeus-Merzbacher dis- ease. Neuropathol Exp Neurol 61:747–759 hypopigmentation. Treatment consists of dietary Loevner LA,Shapiro RM,Grossman RI,Overhauser J,Kamholz control with restricted intake of phenylalanine. J.(1996) White matter changes associated with deletions of the long arm of chromosome 18 (18q-syndrome): a dys- myelinating disorder? AJNR Am J Neuroradiol 10:1843– 1848 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 99

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Figure3.25 Phenylketonuria

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With elevated phenylalanine levels (>600mmol/l), Suggested Reading patients with PKU generally demonstrate symmetric patchy and/or band-like areas of enhanced signal Brismar J, Aqeel A, Gascon G, Ozand P (1990) Malignant hy- intensity on T2-weighted MR images. The changes perphenylalaninemia: CT and MR of the brain.AJNR Am J Neuroradiol 11:135–138 predominantly affect the posterior/periventricular Moller HE,Weglage J,Bick U,Wiedermann D,Feldmann R,Ull- white matter. In more severely affected patients, the rich K (2003) Brain imaging and proton magnetic reso- lesions extend to the frontal and subcortical white nance spectroscopy in patients with phenylketonuria. matter, including corpus callosum and the area of the Pediatrics 112:1580–1583 association fibers. The etiology of T2 hyperintensity Pearsen KD, Gean-Marton AD, Levy HL, Davis KR (1990) Phenylketonuria: MR imaging of the brain with clinical is thought to be due to increased water content due to correlation. Radiology 177:437–440 edema associated with myelination or gliosis.On DW Phillips MD, McGraw P, Lowe MJ, Mathews VP, Hainline BE images, these increased signal intensity areas show (2001) Diffusion-weighted imaging of white matter abnor- restricted diffusion indicating cytotoxic edema, such malities in patients with phenylketonuria. AJNR Am J as that seen in intramyelinic edema. Neuroradiol 22:1583–1586 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 100

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Figure3.26 Propionic acidemia

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Propionic Acidemia Discussion

Clinical Presentation Propionic acidemia is an autosomal recessive disor- der of organic acid metabolism caused by a genetic A 9-week-old with propionic acidemia now with re- deficiency of mitochondrial propionyl-CoA carboxy- current seizures. lase.Patients with propionic acidemia usually present in the neonatal period with life-threatening ketoaci- dosis, failure to thrive, and developmental delay. Images (Fig.3.26) CT and MR imaging show white matter changes in the form of low attenuation areas (CT) and T2 hyper- A. CT at the age of 8weeks following a seizure. There intensity with predominant symmetric involvement are patchy hypodensities of the peripheral white of the basal ganglia region and subcortical white matter in the frontal regions matter. With progression of the disease, widening of B. T2-weighted image shows patchy and confluent sulci and fissures may be seen. Rarely, fatal rapid white matter hyperintense signal changes in the necrosis of the caudate, globus pallidus and putamen subcortical white matter of the frontal lobes (ar- may also be seen. rows) and to the lesser degree in the parietal and occipital lobes Suggested Reading

Brismar J, Ozand PT (1994) CT and MR of the brain in disor- ders of the propionate and methylmalonate metabolism. AJNR Am J Neuroradiol 15:1459–1473 Gebarski SS, Gabrielsen TO, Knake JE, Latack JT (1983) Cerebral CT findings in methylmalonic acid propionic acidemias. AJNR Am J Neuroradiol 4:955–957 Haas RH,Marsden DL,Capistrano-Estrada S,et al (1995) Acute basal ganglia infarction in propionic acidemia. J Child Neurol 10:18–22 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 101

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A B

Figure3.27 Maple syrup urine disease

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Maple Syrup Urine Disease (MSUD) Images (Fig.3.27)

Clinical Presentation A. Sagittal T2-weighted image demonstrates “full posterior fossa”with poorly visualized fourth ven- A 12-day-old girl with clinical suspicion of infection tricle and prepontine cistern presents for MR imaging with fever, poor feeding, B. Axial T2-weighted image demonstrates diffuse and lethargy. cerebellar white matter (arrows) and brainstem edema.Atypically this case shows both ventral and dorsal pons edema (arrowhead) C. Midbrain edema is seen on the T2-weighted image (arrow) D. Edema extends to the posterior limb of internal capsules and thalami, but spares the pulvinar area 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 102

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Discussion Suggested Reading

MSUD is a heterogeneous disorder with four differ- Brismar J, Aqeel A, Brismar G, Coates R, Gascon G, Ozand P ent phenotypes. All forms have an autosomal reces- (1990) Maple syrup urine disease: findings on CT and MR scans of the brain in 10 infants. ANJR Am J Neuroradiol sive mode of inheritance. It is caused by a defect in 11:1219–1228 the oxidative decarboxylation of the branched-chain Cavalleri F, Berardi A, Burlina AB, Ferrari F, Mavilla L (2002) ketoacids. As a result of the enzymatic defect, Diffusion-weighted MRI of maple syrup urine disease en- branched-chain amino acids, leucine, isoleucine and cephalopathy. Neuroradiology 44:499–502 valine, accumulate in serum, CSF, and urine. The Jan W, Zimmerman RA, Wang ZJ, Berry GT, Kaplan PB, Kaye EM (2003) MR diffusion imaging and MR spectroscopy of characteristic odor of the urine of the affected child maple syrup urine disease during acute metabolic decom- resembles maple syrup, thus the name maple syrup pensation. Neuroradiology 45:393–399 urine disease. In the classic form children born with Parmar H, Sitoh YY, Ho L (2004) Maple syrup urine disease: this disease appear normal at birth but start mani- diffusion-weighted and diffusion-tensor magnetic reso- festing the symptoms by the end of the first week of nance imaging findings. J Comput Assist Tomogr 28:93–97 life. The symptoms include lethargy, poor feeding, sometimes vomiting, and coma. Early treatment may halt or reverse neurological abnormalities, but men- Galactosemia tal and neurological residua are common even in treated patients. In the intermittent form symptoms Clinical Presentation are seen between 2months and 40years of age, and are triggered by stress, such as vaccination, infection, A 6-month-old female with refusal to feed, vomiting operation and the like. and hypotonia. In the classic form CT and MR imaging show signs of diffuse edema seen as areas of hypodensity on CT and hyperintensity on T2-weighted images. The Images (Fig.3.28) characteristic intense local edema (called MSUD ede- ma) involves the deep cerebellar white matter, poste- A. Hyperintense white matter lesions are difficult to rior brain stem, cerebral peduncles, thalami, posteri- appreciate at this age, since normal myelin is still or limb of internal capsules and posterior centrum immature and high signal; however, foci of more semiovale. All these areas are myelinated at this age, hyperintense white matter lesions in the bilateral and show hyperintensity. Edema may be difficult to frontal and temporal lobes are seen (arrows) on recognize in the T2 weighted image as immature, this T2-weighted image. Mild prominence of the nonmyelinated brain is also bright. DWI shows these cortical CSF spaces is present abnormalities more extensively with a markedly re- B. Coronal T2-weighted image shows bilateral hyper- duced ADC value thereby suggesting cytotoxic ede- intense foci in the bilateral periventricular white ma. Fractional anisotropy maps may reveal de- matter and temporal lobes creased values in the affected areas, indicating fiber destruction and/or demyelination. 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 103

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Figure3.28 Galactosemia

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Discussion CT may show diffuse cerebral edema. On T2- weighted MR images, abnormal hyperintense white Three major types of galactosemia can be seen,based matter foci suggestive of deficient myelination are on three different enzyme deficiencies. Classical seen in cerebral white matter. This high signal inten- galactosemia is an autosomal recessive disorder of sity is thought to be due to increase in the amount of galactose metabolism caused by deficiency of galac- water in the cerebral white matter. The signal intensi- tose-1-phosphate uridyltransferase. The gene encod- ty from the internal capsule and corpus callosum is ing this enzyme deficiency has been mapped to chro- not affected, since the axon bundles are coherent and mosome 9.Affected infants are normal at birth. Signs tightly packed together. Mild cerebral and cerebellar of toxicity usually occur after the initiation of milk atrophy may also be seen. feedings; presenting symptoms, however, may vary with age and in severity. In the neonatal age, clinical manifestations include lethargy, jaundice, vomiting, Suggested Reading failure to thrive, and frequently E. coli sepsis. In later infancy or early childhood, cataracts, cirrhosis of the Belman AL, Moshe SL, Zimmerman RD (1986) Computed to- liver, and mental deficiency are the classical features. mographic demonstration of cerebral edema in a child with galactosemia. Pediatrics 78:606–609 Pathologically, as the concentration of galactitol in- Marano GD, Sheils WS Jr, Gabriele OF, Klingberg WG (1987) creases, cerebral edema occurs due to osmosis. Cranial CT in galactosemia. AJNR Am J Neuroradiol Raised intracranial pressure may be the presenting 8:1150–1151 symptom in some patients. If milk is not withdrawn, Nelson MD Jr, Wolff JA, Cross CA, Donnell GN, Kaufman FR the infant may die. A galactose-free diet causes strik- (1992) Galactosemia: evaluation with MR imaging.Radiol- ogy 184:255–261 ing disappearance of symptoms. However, the long- term prognosis is less favorable. Many patients have subnormal intelligence and at the end of first decade develop tremor and ataxia. Many children have speech problems. On neuropathology diffuse white matter gliosis can be seen. The findings are mainly seen in the periventricular area. 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 104

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Late-Onset Type of Ornithine hood. The late-onset form appears usually in women Transcarbamylase (OTCD) Deficiency who have a mutation at one of their X-chromosomes. with a Recent Occipital Infarct The late-onset form of OTCD resembles an ischemic stroke. Laboratory investigations show hyperam- Clinical Presentation monemia. It is possible to establish a diagnosis ante- natally from the amniotic fluid. Pathologically sym- A now young adult female has suffered for years with metric cystic lesions at the gray/white matter junc- episodic symptoms: headache, irritability,bizarre be- tion are seen. The same cystic lesions are seen in the havior, lethargy and seizures. Now she presents with MR image and they follow the CSF signal. new visual symptoms for MR imaging. MRspectroscopy is a clinically useful diagnostic tool, since alterations in brain metabolites can beseen. The appearance of the MR spectroscopy Images (Fig.3.29) varies depending on the patient’s clinical presenta- tion and accumulation of various metabolites. NAA A. FLAIR image shows asymmetric abnormal high and creatine concentrations have been reported to be signal intensity in the cortex with minimal signal normal in all patients. The glutamine and glutamate abnormality in the periventricular white matter peak has been reported to be increased in proportion and forceps minor. Multiple cystic lesions that fol- to the clinical disease stage. Myoinositol is decreased low the CSF signal are seen in the gray/white junc- with decreased choline concentration. It has been tion (arrows). These hyperintense cortical areas found that early brain changes are reversible, thus are consistent with old ischemic events early treatment could minimize or completely pre- B. FLAIR image shows abnormal hyperintensity in- vent neurological symptoms. volving both optic tracts (arrows) C. Coronal FLAIR shows multiple small cystic lesions at the gray/white matter junction making the cor- Suggested Reading tex appear lace-like D. DW image fails to show abnormal diffusion in the Bajaj SK, Kurlemann G, Schuierer G, Peters PE (1996) CT and cortical FLAIR abnormality MRI in a girl with late-onset ornithine transcarbamylase deficiency: case report Neuroradiology 8:796–799 E. DW image. The right occipital lobe shows an area Takanashi J, Kurihara A, Tomita M, Kanazawa M,Yamamoto S, of restricted diffusion without corresponding Morita F, Ikehira H, Tanada S, Kohno Y (2002) Distinctly FLAIR abnormality. This is consistent with acute abnormal brain metabolism in late-onset ornithine tran- infarct and is responsible for the patient’s current scarbamylase deficiency. Neurology 2:210–214 symptoms Takanashi J, Barkovich AJ, Cheng SF,Weisiger K, Zlatunich CO, Mudge C, Rosenthal P, Tuchman M, Packman S (2003) F. MR spectroscopy (TE=35ms) placing the voxel Brain MR imaging in neonatal hyperammonemic en- over the right occipital signal abnormality (in E) cephalopathy resulting from proximal urea cycle disor- reveals the lactate peak. There are low choline and ders. AJNR Am J Neuroradiol 6:1184–1187 myoinositol peaks with a mildly decreased NAA Takanashi J, Barkovich AJ, Cheng SF, Kostiner D, Baker JC, peak Packman S (2003) Brain MR imaging in acute hyperam- monemic encephalopathy arising from late-onset or- nithine transcarbamylase deficiency. AJNR Am J Neurora- diol 3:390–393 Discussion

OTCD is the most common inborn error of metabo- lism of the urea cycle. It is an X-linked disorder char- acterized by signs and episodic symptoms of en- cephalopathy that is induced by accumulation of pre- cursors of urea, principally ammonia and gluta- mine.Patients present with episodic headaches, vom- iting, irritability, bizarre behavior, tremors and seizures. The most severe clinical form is seen in newborns after an unremarkable 24–48hours.Milder forms can present any time from infancy to adult- 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 105

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Figure3.29 Late-onset type of ornithine tran- scarbamylase deficiency with a re- cent occipital infarct

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Figure3.30 Multiple sclerosis

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Images (Fig.3.30) Miscellaneous A. Sagittal T2-weighted image shows a single round- Multiple Sclerosis (MS) ed hyperintensity in the occipitoparietal region. There is marked hyperintensity in the central part, Multiple Sclerosis, Possible Schilder’s Disease surrounded by a lower signal intensity rim (ar- row) and then a second zone of less-intense hyper- Clinical Presentation intensity. The subcortical U-fibers are spared B. FLAIR image demonstrates also the different “lay- A 15-year-old female presents with seizures, rapid ers” of signal intensity in the large left white mat- onset of right-sided weakness and tingling in right ter lesion. Vague hyperintensities are also seen in extremities. the right occipitoparietal region C. Contrast-enhanced T1-weighted image demon- strates peripheral enhancement (arrow). Note the lack of mass effect for the size of the lesion. An- other tiny enhancing lesion is seen in the frontal lobe 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 107

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Figure3.31 Classic multiple sclerosis

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Classic Multiple Sclerosis Images (Fig.3.31)

Clinical Presentation A. T2-weighted image shows an oval periventricular hyperintensity (arrow) A young adult with acute onset of optic neuritis. B. Sagittal FLAIR image demonstrates the typical lo- There is a past history of transient extremity numb- cation of hyperintensity in the callososeptal inter- ness. face (arrow). Multiple ovoid hyperintense lesions are seen in the periventricular white matter. These lesions are typical MS lesions and have a perpen- dicular orientation toward the ventricular surface (“Dawson’s fingers”) C. Contrast-enhanced T1-weighted image fails to demonstrate enhancement. Only acute plaques enhance with contrast D. The MS plaque seen on A is hyperintense on DW image. This, however, does not have a low ADC value 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 108

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Figure3.32 Acute multiple sclerosis with ring-enhancing lesion

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Acute Multiple Sclerosis Images (Fig.3.32) with Ring-Enhancing Lesion A. Parasagittal T2-weighted image reveals multiple Clinical Presentation ovoid areas of T2 hyperintensity in the periven- tricular and periatrial white matter A young adult with right extremity weakness and B. Hyperintense lesions are also seen in the con- numbness. There is a past history of optic neuritis. tralateral side on sagittal T2-weighted image. Note the two signal intensities in the large parietal lesion with a more hyperintense central core C. Contrast enhanced T1-weighted image demon- strates ring-enhancing lesion. Note the lack of mass effect 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 109

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Discussion MR spectroscopy has been used as a sensitive im- aging modality for studying the biochemical behav- MS is the most common demyelinating disease of the ior of MS plaques in vivo. Relative to normal-appear- CNS. It is uncommon in childhood and the peak inci- ing brain, the MS plaques show reduction of the NAA dence is at 30years of age in adults, although 13% of peak as an indicator of axonal damage. Additionally patients present before the age of 20years. The aver- Cho and myoinositol have been found to be elevated age onset of MS in children is 11–14years, but it has within MS plaques, suggesting enhanced membrane been reported as early as at 10months of age. In turnover. Lactate may be seen in the acute phase. adults it is twice as common in females as in males and in children the ratio is even higher. MS has a strong geographical distribution: it is rare in the Suggested Reading tropics and increases in frequency at higher latitudes. A number of subtypes can be distinguished: classical Banwell BL (2004) Pediatric multiple sclerosis. Curr Neurol MS, neuromyelitis optica (Devic’s disease), concen- Neurosci Rep 4:245–252 Bitsch A, Bruhn H, Vougioukas V, et al (1999) Inflammatory tric sclerosis (Baló’s disease) and diffuse sclerosis CNS demyelination: histopathologic correlation with in (Schilder’s disease). vivo quantitative proton MR spectroscopy. AJNR Am J The diagnosis of MS is usually made on the basis Neuroradiol 20:1619–1627 of clinical,laboratory and radiological findings.MS is Castriota Scanderbeg A, Tomaiuolo F, Sabatini U, Nocentini U, distinguished from ADEM by a characteristic clinical Grasso M, Caltagirone C (2000) Demyelinating plaques in relapsing-remitting and secondary-progressive multiple history of multiple neurological deficits and a chron- sclerosis: assessment with diffusion MR imaging AJNR Am ic, relapsing course, contrary to ADEM that is a J Neuroradiol 21:862–868 monophasic disease.Schilder’s myelinoclastic diffuse Kurul S, Cakmakci H, Dirik E, Kovanlikaya A (2003) Schilder’s sclerosis is a rare sporadic demyelinating disease that disease: case study with serial neuroimaging. J Child Neu- usually affects children between 5 and 14years of age. rol 1:58–61 Schaefer PW,Grant PE, Gonzalez RG (2000) Diffusion-weight- The disease often mimics intracranial neoplasm or ed MR imaging of the brain. Radiology 217:331–345 abscess. Pathologically MS is a disease of oligoden- droglia and results in multifocal areas of demyelina- tion with little or no axonal degeneration. MR imaging is the most sensitive imaging method. CT imaging provides limited information in MS. Although MR imaging is a sensitive method, it is at the same time nonspecific.Additionally, there is poor correlation between the appearance of a plaque and clinical symptoms. T2 and FLAIR images typically show hyperintensities in the periventricular white matter and/or cervical spine. The disease usually spares the subcortical U-fibers. Because the demyeli- nation is perivenular, the hyperintensity follows the veins and radiates out from the ventricles (“Dawson’s fingers”). Schilder’s disease shows one or two large demyelinating lesions in parietooccipital region that spare the U-fibers, but are contiguous with the cor- pus callosum.MS plaques demonstrate increased dif- fusion and acute plaques have significantly higher ADCs than do chronic plaques. Mean diffusivity and fractional anisotropy histograms have been used to distinguish between plaques in different severity and stage. 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 110

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Figure3.33 Acute disseminated encephalo- myelitis with brain and spinal cord involvement

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Acute Disseminated Encephalomyelitis (ADEM) Images (Fig.3.33)

ADEM with Brain and Spinal Cord Involvement A. T2-weighted image shows a hyperintense lesion in the left internal capsule (arrow) Clinical Presentation B. FLAIR image at the same level as A. The left inter- nal capsule lesion is better appreciated (arrow) A 15-year-old female with a 2-day history of extrem- C. The left internal capsule lesion is hypointense in ity weakness and confusion. Patient has also spinal the T1-weighted image (arrow) cord involvement (see chapter 10, page 433). D. DW image shows a hyperintense lesion in the left internal capsule which may be due to T2 shine- through effect (arrow) E. Postcontrast T1-weighted image shows no con- trast enhancement 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 111

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Figure3.34 Acute disseminated encephalo- myelitis with hemispheric white matter and basal ganglia involve- ment

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ADEM with Hemispheric White Matter B. FLAIR image at the same level as A. The hyperin- and Basal Ganglia Involvement tense lesions are better appreciated on FLAIR im- age Clinical Presentation C. FLAIR image through the lateral ventricles demonstrates corpus callosum swelling and hy- A 4-year-old male presents in emergency room with perintensity (arrow). Patchy white matter changes low-grade fever and mental status change. He has a are again seen history of viral infection 3weeks earlier. D. FLAIR image also shows hyperintense lesion in the right side of the medulla

Images (Fig.3.34) Discussion A. T2-weighted image through the basal ganglia demonstrates patchy and asymmetric hyperinten- ADEM is the most common post-infectious disorder sities in the subcortical and periventricular white triggered by an inflammatory response to viral infec- matter as well as along the internal capsules. The tions or vaccinations. Children are more often affect- lesions lack mass effect ed than adults, but all ages can be affected. The dis- ease process is usually monophasic, contrary to other 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 112

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demyelinating diseases.ADEM is an immunomediat- Perisylvian Syndrome ed demyelinating condition affecting the central nervous system. It usually has an acute onset 1 to Clinical Presentation 3weeks following the viral illness or vaccination. It also may occur in the absence of an identifiable viral A 5-week-old male (ex 34-week premature infant) infection. On imaging, multifocal lesions of the white presents with hypertonicity and stridor. matter of the brain, cerebellum and brain stem are seen.Also the spinal cord may be involved (see Chap- ter 10).Microscopically perivenular lymphocytic and Images (Fig.3.35) monocytic infiltration and demyelination are seen. MR imaging shows patchy bilateral often-asymmet- A. Sagittal T1-weighted image demonstrates normal ric areas of T2 hyperintensity in the subcortical and midline structures, including corpus callosum deep white matter of the cerebral hemispheres. Cere- B. T2-weighted image reveals polymicrogyria in the bellar and brain stem lesions are also seen. Although bilateral perisylvian regions (arrows). There are it is mainly a white matter disease, deep gray matter multiple small gyri in these regions resulting in an nuclei are also seen. Following the contrast injection irregular bumpy appearance of the brain surface. variable contrast enhancement is seen. The enhance- The opercula are wide bilaterally ment can be diffuse or nodular; however, peripheral C. T2-weighted image shows cavum septum pellu- enhancement is often seen. cidum and vergae. The frontal area appears pachy- Although ADEM is a monophasic illness,not all le- gyric with polymicrogyria in the sylvian region sions will appear at the same time and also the en- D. T1 FLAIR image shows the irregular cortex, main- hancement pattern can be seen through an extensive ly on the left (arrow) period of time. Typically the lesions demonstrate rel- E. Coronal FLAIR image shows the wide opercula atively little mass effect compared to the size of the with irregular cortex, but no parenchymal signal lesion. Resolution of the lesions is often complete. changes The signal intensity on DW images is variable de- F. DW image shows normal parenchymal signal pending on the severity and phase of the lesions. De- creased NAA has been reported in ADEM. Discussion

Suggested Reading Wide use of MR imaging has increased our knowl- edge of cortical development. Recently several syn- Bernarding J, Braun J, Koennecke HC (2002) Diffusion- and dromes have been described in which patients have perfusion-weighted MR imaging in a patient with acute fairly specific symptoms associated with radiological demyelinating encephalomyelitis (ADEM). J Magn Reson Imaging 15:96–100 findings of polymicrogyria. These include congenital Bizzi A, Ulug AM, Crawford TO, et al (2001) Quantitative pro- bilateral perisylvian syndrome (CBPS), bilateral pos- ton MR spectroscopic imaging in acute disseminated en- terior parietal polymicrogyria (BPPP) and bilateral cephalomyelitis. AJNR Am J Neuroradiol 22:1125–1130 frontal polymicrogyria. Bilateral perisylvian syn- Inglese M, Salvi F, Iannucci G, Mancardi GL, Mascalchi M, Fil- drome is a homogeneous clinical- radiological entity. ippi M (2002) Magnetization transfer and diffusion tensor MR imaging of acute disseminated encephalomyelitis. It is characterized by bilateral perisylvian polymicro- AJNR Am J Neuroradiol 23:267–272 gyria. The clinical spectrum of this syndrome is Kesselring J, Miller DH, Robb SA, et al (1990) Acute dissemi- much wider than previously believed and may vary nated encephalomyelitis. MRI findings and the distinction from minor speech difficulties to severe disablement. from multiple sclerosis. Brain 113:291–302 Suprabullar paresis, mild tetraparesis, cognitive im- Kuker W, Ruff J, Gaertner S, Mehnert F, Mader I, Nagele T (2004) Modern MRI tools for the characterization of acute pairment, and epilepsy are frequently associated. Al- demyelinating lesions: value of chemical shift and diffu- though evidence in the literature suggests a vascular sion-weighted imaging. Neuroradiology 46:421–426 etiology,a number of familial cases raise the possibil- ity of a genetic cause. 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 113

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Figure3.35 Perisylvian syndrome

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Figure3.36 Merosin-deficient congenital muscular dystrophy

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The diagnosis is best made with MR imaging by Merosin-Deficient Congenital Muscular analyzing the gyral pattern, cortical thickness and ir- Dystrophy (CMD) regularity on the cortical/white matter junction. Functional mapping is useful in analyzing the func- Clinical Presentation tional areas in abnormal cortex. A 6-year-old female with known merosin-negative CMD presents with new onset of seizures. Suggested Reading

Barkovich JA, Hevner R, Guerrini R (1999) Syndromes of bilat- Images (Fig.3.36) eral symmetrical polymicrogyria.AJNR Am J Neuroradiol 20:1814–1821 Paetau R, Saraneva J, Salonen O,Valanne L,Ignatius J, Salenius A. T2-weighted image shows bilateral high signal S (2004) Electromagnetic function of polymicrogyric cor- lesions in the white matter. There is frontal pre- tex in congenital bilateral perisylvian syndrome. Neurol dominance. The ventricles are slightly prominent Neurosurg Psychiatry 5:717–722 consistent with mild volume loss. The cortex is normal 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 115

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B. Coronal FLAIR image demonstrates extensive Echenne B, Rivier F,Jellali AJ,Azais M, Mornet D, Pons F (1997) white matter involvement and mild hyperintensity Merosin positive congenital muscular dystrophy with mental deficiency, epilepsy and MRI changes in the cere- is also seen involving the corpus callosum. The bral white matter. Neuromuscul Disord 7:187–190 cerebellar white matter is intact Miyagoe-Suzuki Y, Nakagawa M, Takeda S (2000) Merosin and C. T1 FLAIR image reveals the distribution of the congenital muscular dystrophy. Microsc Res Tech 48:181– white matter changes to be limited to the periven- 191 tricular and deep white matter sparing the corpus Tan E, Topaloglu H, Sewry C, et al (1997) Late onset muscular dystrophy with cerebral white matter changes due to par- callosum and subcortical U-fibers. The occipital tial merosin deficiency. Neuromuscul Disord 7:85–89 white matter is better preserved D. DW image is unremarkable E. ADC map shows high signal lesions in the bilater- al white matter. Isointensity on DW image (D) is Vanishing White Matter (VWM) Disease due to balance between T2 prolongation and in- creased diffusibility Clinical Presentation

An 11-year-old male with decreased mental status; Discussion essentially he is comatose. He has a history of pro- gressive white matter degeneration during the previ- CMDs are a heterogeneous group of congenital my- ous 4years and he is status post epilepticus. The MR opathies that are hereditary and progressive disor- image of 3years ago showed abnormality involving ders. CMD with macrocephaly and white matter ab- the entire white matter of the cerebellar hemispheres normalities without cortical dysplasia is a well-de- as well as a cerebellum and the brainstem. Spec- fined disease. It is characterized by weakness and hy- troscopy at that time was normal. That time he had potonia at birth, joint contractures, delayed motor marked ataxia and spasticity with spared vision. development and features of dystrophy on muscle biopsy. In most children the intelligence is normal. Some children develop generalized seizures. Involve- Images (Fig.3.37) ment of the central nervous system occurs in some forms of CMD: Fukuyama type, the muscle and brain A. Coronal T2-weighted image shows extensive white eye syndrome (Santavuori type CMD), the merosin- matter hyperintensity including the cerebellum negative type with cerebral white matter abnormali- B. The white matter hyperintensity extends to the ties and cerebromuscular syndromes also called centrum semiovale and includes subcortical U- “cobblestone CMD”. fibers Merosin is an isoform of laminin that is expressed C. Coronal SPGR image shows patchy hypointensi- in the basement membrane of each muscle fiber and ties in the white matter of Schwann cells in the peripheral nervous system. D. There is diffuse low signal with cystic changes in Merosin deficiency has been documented in 40–50% the white matter seen in the coronal FLAIR image of children with classical CMD. MR imaging demon- (arrow) strates a diffuse and symmetrical increase in white E. DW image reveals diffuse low signal in the white matter T2 signal of the cerebral hemispheres. The matter precise nature of the white matter lesions is un- F. ADC map reveals diffuse increased signal with known. Increased T2 prolongation is attributed to in- foci of even higher signal in the white mater, most creased water content in the white matter owing to an likely due to cystic changes abnormal blood-brain barrier rather than to de- G. Proton MR spectroscopy (TE=144ms) of the cen- creased abnormal myelination. trum semiovale white matter reveals low NAA sig- nifying neuronal damage. There are large inverted lactate peaks Suggested Reading H. Localizer demonstrating the MR spectroscopy voxel placement Caro PA, Scavina M, Hoffman E, Pegoraro E, Marks HG (1999) MR findings in children with merosin-deficient congenital muscular dystrophy. AJNR Am J Neuroradiol 20:324–326 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 116

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Discussion Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC) Leukoencephalopathy with VWM is a newly recog- and Normal Development nized white matter disease. It is an autosomal reces- sive disorder with normal early development and, Clinical Presentation usually, childhood-onset neurological deterioration. The clinical symptoms include a slowly progressive A 22-month-old infant boy with macrocephaly and cerebellar ataxia, spasticity, variable optic atrophy, normal development. MR imaging at the age of and relatively preserved mental capacity. In addition, 10months revealed white matter hyperintensities on there are episodes of rapid and major deterioration T2-weighted images. following infections with fever and minor head trau- ma. These episodes can end in unexplained coma. Until 1999 the diagnosis of VWM disease was based Images (Fig.3.38) on clinical examination and the results of repeat MR imaging and MR spectroscopy. A. T2-weighted image reveals continuous white mat- MR imaging shows diffuse cerebral hemispheric ter abnormality with abnormal hyperintensity leukoencephalopathy with evidence of white matter throughout the supratentorial white matter spar- rarefaction. MR imaging findings suggest that over ing the brainstem and cerebellum. A cystic lesion time,there is a progressive vanishing of the abnormal is seen in the left temporal tip (arrow) that was not white matter, which is replaced by cerebrospinal flu- present in the previous study.This follows CSF sig- id. MR spectroscopy of the abnormal white matter nal in all pulse sequences. Basal ganglia signal is may reveal a profound decrease of all normal signals normal with the presence of extra signals from lactate and B. T2-weighted image slightly higher than A demon- glucose.MR spectroscopy of the white matter in a pa- strates widespread white matter abnormality, thin tient whose disease is at an early stage is much less but normal appearing cortical ribbon. A cavum abnormal. septum pellucidum (arrow) is present C. Coronal contrast-enhanced SPGR image shows bitemporal cystic appearing lesions with CSF sig- Suggested Reading nal (arrows) not present in the previous scan at the age of 10months. Cavum septum pellucidum (ar- Gallo A, Rocca MA, Falini A, et al (2004) Multiparametric MRI rowhead) is well seen in the coronal image in a patient with adult-onset leukoencephalopathy with D. Gadolinium-enhanced T1-weighted image with vanishing white matter. Neurology 27:323–326 Leegwater PA, Konst AA, Kuyt B, et al (1999) The gene for magnetization transfer shows anterior temporal leukoencephalopathy with vanishing white matter is locat- tip CSF signal lesions without enhancement ed on chromosome 3q27. Am J Hum Genet 3:728–734 E. DW image confirms the CSF-like signal in the cys- Leegwater PA, Pronk JC, van der Knaap MS (2003) Leukoen- tic lesions cephalopathy with vanishing white matter: from magnetic F. The cystic lesions follow the CSF signal in the ADC resonance imaging pattern to five genes. J Child Neurol 18:639–645 map.The white matter demonstrates also hyperin- Van der Knapp,Kamphorst W,Barth PG,Kraaijeveld CL,Gut E, tense signal Valk J (1998) Phenotypic variation in leukoencephalopa- G. Multivoxel MR spectroscopy (TE=144ms) over the thy with white matter. Neurology 51:540–547 cortical gray and white matter demonstrates lower NAA peak in the white matter than in the gray matter. No abnormal metabolites are seen H. Axial image demonstrating the voxel location for the MR spectroscopy seen in G

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Discussion Van der Knaap MS, Barth PG, Vrensen GF, Valk J (1996) Histopathology of an infantile-onset spongiform leukoen- cephalopathy with a discrepantly mild clinical course.Acta MLC is a recently described white matter condition.It Neuropathol (Berl) 2:206–212 demonstrates diffuse hemispheric swelling and typi- cal cysts in the frontoparietal subcortical white mat- ter and the tips of the temporal lobes. It has a very mild disease course. In this condition screening for Delayed Myelination inborn errors, especially those that cause either megalencephaly or white matter disease have been Clinical Presentation negative. MR spectra are described to be relatively mildly abnormal. Neurological findings are initially A 13-month-old male with large head and develop- normal or near normal, despite megalencephaly and mental delay, but progressing all the time. MR imaging evidence of severe white matter affec- tion. In affected children slowly progressive ataxia and spasticity develop, while intellectual functioning Images (Fig.3.39) is preserved for years after onset of the disorder. MR imaging characteristics include diffuse abnormality A. T2-weighted image at the age of 13months shows in signal intensity and swelling of the cerebral hemi- abnormal hyperintensity involving nearly all spheral white matter with cyst-like spaces in the fron- white matter tracts,but especially in the frontal ar- toparietal and anterior-temporal subcortical areas. eas. Normal appearing myelination is seen on the Brain biopsy in one of the patients has been per- posterior limbs of the internal capsules (arrows). formed. It revealed spongiform leukoencephalopathy Patient had only mild developmental delay com- without cortical involvement. Most vacuoles were pared to significant myelination delay covered by single five-layered membranes. The vac- B. T2-weighted image at the age of 2years. There is uoles involved the outermost lamellae of myelin significant progression of myelination. Develop- sheaths only, whereas the remainder of the myelin mentally patient had also progressed sheaths remained undisturbed. The histopathologi- cal findings place the disease among the vacuolating myelinopathies, although it is distinct from the well- Discussion known forms. MCL has been localized on two differ- ent chromosomes demonstrating genetic hetero- The human brain is not fully developed at birth. In- geneity. Temporal lobe cyst with white matter stead,the brains of children undergo an extended pe- changes have been described also in another entity: riod of postnatal maturation. The process of myeli- Two patients with leukoencephalopathy and tempo- nation is a predetermined and follows a predictable ral cysts were described, but these patients present pattern that starts during the second trimester of with microcephaly. Both patients had a nonprogres- gestation. Histologic studies reveal that white matter sive neurological disorder with mental retardation, myelination continues through adolescence into microcephaly and sensorineural deafness. adult life. During the past 15years, MR imaging has been used to monitor the myelination process in the developing brain. The assessment of whether brain Suggested Reading development is at an appropriate level for age has be- come an integral part of MR imaging reporting in pe- Gomes AL, Vieira JP, Saldanha J (2001) Non-progressive diatric practice, not only in premature babies, but leukoencephalopathy with bilateral temporal cysts. Eur J also in full-term babies and toddlers with develop- Paediatr Neurol 3:121–125 Van der Knaap MS,Barth PG,Stroink H,van Nieuwenhuizen O, mental delay. Arts WF, Hoogenraad F,Valk J (1995) Leukoencephalopa- The first descriptions with myelination seen with thy with swelling and a discrepantly mild clinical course in MR imaging emphasized T1 and T2 shortening mon- eight children. Ann Neurol 3:324–334 itoring the progression of myelination in the white Van der Knaap MS,Valk J, Barth PG, Smit LM, van Engelen BG, matter tracts. Genetic abnormalities, perinatal anox- Tortori Donati P (1995) Leukoencephalopathy with swelling in children and adolescents: MRI patterns and differential ia, inborn errors of metabolism and congenital diagnosis. Neuroradiology 8:679–686 anomalies are frequently associated with delayed or diminished myelination. No underlying cause is ap- 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 120

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Figure3.39 Delayed myelination

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parent in some children who have delayed myelina- frontal white matter has reduced NAA compared tion. Delayed myelination is rarely the only abnor- with that of the thalamus and may even have some mality in the developing brain; other lesions include detectable lactate. low volume of cerebral white matter, thin corpus cal- Although in general practice it is customary to es- losum and cortical atrophy. When delayed myelina- timate the degree of myelination by using conven- tion is suspected, MR imaging should be performed tional imaging sequences such as T1, T2 and FLAIR before the age of 24months. Eventually the white sequences, diffusion and diffusion tensor imaging matter will myelinate and the delayed myelination may provide more sensitive markers of normal brain may not be detected if not imaged early enough. Al- maturation and deviations of it. Changes in magni- though myelination can be accurately assessed using tude and anisotropy of water diffusion in myelinated the routine T1 and T2 MR imaging sequences, other fibers may provide a clinically useful developmental techniques may prove more accurate. As the white milestone marker for brain maturity. Normal neona- matter myelinates it changes from hypointense to hy- tal brain shows much higher ADC values than the perintense to gray matter on T1-weighted images and adult brain. There is a decrease in ADC during child- from hyperintense to hypointense to gray matter on hood and this may be a combination of several fac- T2-weighted images. tors: reduction of overall water content of the brain Tables of specific milestones have been generated with decrease in extracellular water, cellular matura- to help estimate the progression of myelination. As a tion, white matter myelination, and proliferation of general rule myelination proceeds from below to maturing neurons and glial cells. Also there is physi- cephalad,from posterior to anterior and from central cal restriction of water motion by the multiple layers to peripheral.From the early MR imaging studies it is of the myelin membrane. Thus, the motion of water known that there is regional variability in differences molecules becomes increasingly anisotropic. The dif- in neuronal maturity and myelination, and imaging ference in maturation between infant and adult brain shows this variability in differences in regional blood is visible with ADC, with each age group demonstrat- flow, glucose uptake, water diffusion and concentra- ing values that would be pathological in another tion of NAA, choline and creatine. It is important to group. Recognizing the baseline difference is impor- take these regional differences into consideration tant when interpreting DW images particularly in the when interpreting the imaging studies of young chil- case of global ischemia, when normal brain may not dren in order to avoid wrong judgment of maturity. be available for comparison. For example, it is well known that normal neonatal ventrolateral thalamus and prerolandic cortex have slightly reduced water diffusion compared with the rest of the brain. MR spectroscopy differences do ex- ist in the developing brain as well. Normal neonatal 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 121

Inherited Neurological Diseases Chapter 3 121

Suggested Reading Autoimmune Polyglandular Syndrome (APS)

Barkovich AJ (2000) Concepts of myelin and myelination in Clinical Presentation neuroradiology. AJNR Am J Neuroradiol 21:1099–1109 Barkovich AJ, Kjos BO (1988) Normal postnatal development of the corpus callosum as demonstrated by MR imaging. A 19-year-old female presents with acute mental sta- AJNR Am J Neuroradiol 9:487–491 tus change. She is known to have APS type I. Childs AM, Ramenghi LA, Evans DJ, et al (1998) MR features of developing periventricular white matter in preterm in- fants: evidence of glial cell migration.AJNR Am J Neurora- Images (Fig.3.40) diol 19:971–976 Holland BA, Haas DK, Norman D, Brant-Zawadzki M, Newton TH (1986) MRI of normal brain maturation. AJNR Am J A. Noncontrast CT image reveals bilateral symmetric Neuroradiol 7:201–208 lentiform nucleus and thalamic calcifications. Ad- McGraw P,Liang L, Provenzale JM (2002) Evaluation of normal ditionally scattered gray/white matter junction age-related changes in anisotropy during infancy and calcifications are seen (arrows) childhood as shown by diffusion tensor imaging. AJR Am J Roentgenol 179:1515–1522 B. Basal ganglia calcification seen on CT image is dif- Mukherjee P,Miller JH, Shimony JS, et al (2001) Normal brain ficult to appreciate on T2-weighted image since maturation during childhood: developmental trends char- normal globus pallidus iron presents as low signal acterized with diffusion-tensor MR imaging. Radiology intensity 221:349–358 C. FLAIR image reveals mild hyperintensity on the Sie LT, van der Knaap MS, van Wezel-Meijler G, Valk J (1997) MRI assessment of myelination of motor and sensory putamen and hypointensity on the globus pallidus pathways in the brain of preterm and term-born infants. (arrows), consistent with calcification seen on CT Neuropediatrics 28:97–105 image D. T1-weighted image shows bilateral hyperintense symmetric lentiform nucleus calcifications (ar- rows). Vague calcifications are also seen in the thalami (arrowhead), but not in the gray/white matter junction. These parenchymal calcifications are considered to be a manifestation of hy- poparathyroidism with metabolic calcinosis E. The heaviest calcification on the CT image is seen as dark signal (arrows) on DW image F. Contrast-enhanced T1-weighted image shows no abnormal enhancement

Discussion

APS is caused by an autoimmune process in multiple endocrine glands.Affected individuals develop prob- lems with numerous glands including the thyroid and parathyroid glands, adrenal glands, gonads, and pancreas. This usually results in endocrine gland hy- pofunction, except for the thyroid gland, in which both hyper- and hypofunction may occur. The syn- drome can be classified into two types, type I and type II. Type I PGA syndrome is characterized by hy- poparathyroidism,primary adrenal insufficiency and primary ovarian failure. Type II PGA is associated with primary adrenal insufficiency, Hashimoto’s thy- roiditis and primary ovarian failure. 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 122

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DE F

Figure3.40 Autoimmune polyglandular syndrome

Long-standing type I PGA with endocrine mani- Suggested Reading festations of hypoparathyroidism leads to extensive calcification of the basal ganglia which may result in Baumert T, Kleber G, Schwarz J, Stabler A, Lamerz R, Mann K extrapyramidal symptoms. The common differential (1993) Reversible hyperkinesia in a patient with autoim- mune polyglandular syndrome type I. Clin Invest 71: diagnosis of dense basal ganglia calcification in- 924–927 cludes idiopathic variety, metabolic causes, polyglan- Cinaz P, Bideci A, Hazendaroglu A, Ezgu FS, Agaoglu O, Kur- dular autoimmune syndrome, and Fahr’s syndrome. saklioglu S (1997) Autoimmune polyglandular syndrome Calcification may be seen in tuberculosis, acquired type I. A case report. Turk J Pediatr 39:271–275 immunodeficiency syndromes, congenital toxoplas- mosis, rubella and cytomegalovirus virus infections, but they are usually more scattered hemispheric cal- cifications rather than basal ganglia and dentate nu- cleus calcifications seen in APS type I. 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 123

Inherited Neurological Diseases Chapter 3 123

Figure3.41 Osmotic myelinolysis (extrapontine myelinolysis)

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CD

Osmotic Myelinolysis Images (Fig.3.41) (Extrapontine Myelinolysis) A and B. T1- (A) and T2-weighted (B) images show Clinical Presentation no significant abnormality C. DW image shows hyperintense lesions in A 10-year-old male with hypernatremia that was the bilateral external capsules (arrows) corrected rapidly presented with ataxia and confu- D. ADC map shows hypointensity in the le- sion. sions representing restricted diffusion (ar- rows) 03_Westesson_Inherited 25.10.2004 16:58 Uhr Seite 124

124 Chapter 3 Inherited Neurological Diseases

Discussion Suggested Reading

Osmotic myelinolysis is a disorder of unknown etiol- Brown WD, Caruso JM (1999) Extrapontine myelinolysis with ogy often related to rapid correction of hyponatrem- involvement of the hippocampus in three children with se- vere hypernatremia. J Child Neurol 14:428–433 ia and liver disease.The most common lesion is in the Cramer SC, Stegbauer KC, Schneider A, Mukai J, Maravilla KR central pons, but other locations such as thalamus, (2001) Decreased diffusion in central pontine myelinoly- basal ganglia, external capsules, and cerebellar ver- sis. AJNR Am J Neuroradiol 22:1476–1479 mis, have been also reported. Central pontine myeli- Sztencel J, Baleriaux D, Borenstein S, Brunko E, Zegers de Beyl nolysis and extrapontine myelinolysis usually occur D (1983) Central pontine myelinolysis: correlation be- tween CT and electrophysiologic data. AJNR Am J Neuro- together. radiol 4:529–530 Typically, CT scan shows hypodensity in the le- sion.MR is superior to CT imaging in detection of the lesions: it shows hypointensity on T1-weighted and hyperintensity on T2-weighted and FLAIR images. On DW imaging, the acute lesions tend to show hy- perintensity with decreased ADC representing de- creased diffusibility.