Pathologies de la substance blanche chez l’enfant

1. Pathologies de la substance blanche chez l’enfant Dr. Kalthoum TLILI-GRAIESS Master Neuroradiologie FMS Avril 2008

2. Children WM Disorders • Genetic disorders affecting WM in pediatric age • Acquired pathologies : inflammatory, auto-immune, tumoral or vascular diseases. Although uncommon, aware of their occurence and able to recognize MR appearances. • MR imaging is highly sensitive in the detection of WM lesions • Limited specificity with regards to the pathologic conditions underlying WM signal abnormalities • Correct diagnosis need multidisciplinar approach : • clinical history Data • Findings laboratory Data

3. Herpetic meningo-encephalitis Cerebral Abscess

4. Childhood WM Disorders : MR approach • Variable pathologic changes may underlie WM signal abnormalities • Hypomyelination • dysmyelination • Demyelination • Gliosis • Interstitial edema • Myelin vacuolation • Cystic WM degeneration • Diffuse infitration by tumors cells (Gliomatosis) • All types : lead to a non specifically • increase signal intensity T2 WI, • discrease signal intensity T1 WI

5. Childhood WM Disorders : MRI • « Morphological » sequences • « Functional » or parametric sequences and techniques: • Evaluation WM biochemistry: MRS • Evaluation WM tissue microstructure: diffusion and Magnetization transfer sequences May provide new insights.

6. Children WM Disorders • Demyelinating lesions • Primary disorders : ADEM, MS • Secondary disorders : Toxic, Viral…. • Hyo and dysmyelinating lesions: more common primary disordersClassified according to causative enzyme defect • Lysosomal storage diseases: metachromatic leucodystrophy, Krabbe disease… • Peroxisomal disorders: Zellweger syndrome, ADL X.. • Mitochondrial syndromes : leigh syndrome, Kearns – Sayre syndrome, MELAS…

7. Genetic WM Disorders • Well defined leucoencephalopathies • Hypomyelinating disorders • Dysmyelinating disorders • Leucodystrophies • Disorders related to cystic degeneration of myelin • Disorders secondary to axonal damage • Undefined leucoencephalopathies • Up to 50 % of leucoencephalopathies in childhood • Requiring multidisciplinar approach in order to define novel homogenious subgroups of patients and therefore « new genetic disorders » Megalencephaly-leucoencephalopathy with sub cortical cysts (1995), CACH Sydrome or Vanishing WM disease (1997) Van der Knaap Leucoencephalopathy with high brain lactate.

8. Genetic WM Disorders • Characteristic MR pattern : Metachromatic leucodystrohy, ALDX, Canavan disorder… • Role of MR techniques in the discrimination of differents WM disorders: Parametic imaging.

9. Krabbe disease Metachromatic leukodystrophy Classic: Sparing of the subcortical U fibers and periventricular WM. Tigroid pattern Frequent involvement: CC,IC, corticospinal tracts Early-onset form: pyramidal tract, periventricular WM, cerebellar WM, and deep gray matter , The most often affected

10. Adrenoleucodystrophy, X linked ALD Symmetric WM demyelination in peri-trigonal regions Extendion across the corpus callosum splenium Spread outward and cephalad Symmetric abnormal signal internal capsule, deep cerebelar WM and descending pyramidal tract (1) Cheon JE et al, Radiographics 2002;22:461

11. TE 35 TE 144 TE 35 TE 144 Pelizaeus-Merzbacher Disease

12. Megalencephaly and abnormal WM • Canavan disease • L -2-hydroxyglutaric Aciduria • Megalencephaly-leucoencephalopathy with sub cortical cysts • Alexander disease Diagnosis relay on neuroimaging and biochemical findings

13. TE 35 TE 144 Canavan disease Predominant subcortical WM and dentate nuclei lesions Variable basal ganglia involvement Typical brainstem involvement

14. L -2-hydroxyglutaric Aciduria • Similarities with Canavan except brainstem involvement • SRM

15. Megalencephaly-leucoencephalopathy with sub cortical cysts. Van der Knaap 1995

16. Mehdi 11years-old and 3SD Naim 13 years-old and 4 SD Syrine 7 years-old and 2.5 SD Mutation MLC1 gene although variable phenotype Megalencephaly-leucoencephalopathy with sub cortical cysts

17. Cerebral WM involvement in Mitochondrial disorders • Major findings : Alteration of basal ganglia and Brainstem • Demonstrated that severe WM involvement is possible (1,2) and even the only abnormal neurologic features (3) : 3 unrelated families / 5 • Suggestive findings of mitochondria disease : • Multiples small cyst-like lesions in the abnormal WM • Involvement of cerebral and cereberal WM • Combination of Leucoencephalopathy and bilateral basal ganglia lesions • MRS : may demonstrate lactate or succinate peak (1) Valannel et al AJNR 1998 ; 19 : 369 (2) Nakai A et al Lancet 1994; 343 : 1397 (3) de Lonlay – Debeney P et al J Pediatric 2000 ; 136 : 209

18. Leigh disease 13 months-old. Complexe II deficiency

19. 8 month-old child, Axial hypotonia Mitochondrial disease

20. 16 months-old girl with one week respiratory distress • At the age of 9 months progressive loss of normal developmental and motor acquisitions with sudden alopecia and global hypotonia • Mild optic atrophy • Brain stem acoustic-evoked potentials were deteriorated. • lactic acidosis with high concentration of lactate and pyruvate in CSF and blood Biotin responsive encephalopathy

21. 5 month MRI follow-up Pharmacologic doses of biotin normal pattern of the spectrum from right caudate et putamen and no lactate is detected Progression of myelination with resolution of WM and GM abnormalities except for the genu of the corpus callosum which remains in high signal T2, low signal T1 and high ADC level, stigmate of cystic degeneration.

22. Childhood WM Disorders and MR parametric approach • Prospective Study (1) of 41 patients with WM disorders of known cause : • 12 hypomyelinating, • 14 Demyelinating (10 Metachromatic and 4 Krabb), • 5 disorders with myelin vacuolation • 10 disorders with cystic degeneration • Using MR parameters : MTR, ADC, FA and MRS • Discrimination between different types of pathologic conditions thar underlie signal intensity abnormatities in the WM • Linear discimination analysis showed • The combination of tCr, Cho, MTR and ADC mesurements results in only 2 misclassification • 95 % of patients were correctly classified. (1) Van der Voorn JP et al , Radiology 2006; 241 : 510.

23. T2WI ADC FA MRS MTR Healthy 5-year-old boy 2-year-old boy with hypomyelination 6-year-old boy with demyelination 11-year-old girl with myelin vacuolation 3-year-old girl with cystic degeneration

24. Oumaima, 8 years-old. Fever, Sudden onset Upper Limbs paresthesia Treated as viral encephalitis CT Day 7 MRI Day 8

25. 3 Weeks later: Fever, headache and seizures. Cerebellar ataxia, facial and brachial motor deficit 4 months

26. Acute disseminated Encephalomyelitis ADEM • CNS demyelinating disease more frequently diagnosed (1) : 0,4 / 100000/year with incidence quadruple (98 – 2000 v/s 91-98) >>> MRI and Flair in acute encephalopathy • Usually following benign infection or vaccination in healthy young person • Acute neurologic symptoms with imaging evidence of demyelination: MRI required, CT usually normal. • Dilemna >> distinguish ADEM from MS: 4/42 (9.5%) initially diagnosed with ADEM were MS cases after episodes of demyelination (1). (1) Leake JA et al Pediatr Infect Dis J 2004, 23 : 756.

27. ADEM • Clinical impairement faster than neuroradiological deterioration • Usually complete regression of clinical and neuroradiological symptoms • Remaining deficit 10 – 20 % J4 1 Week Later 3 Weeks Later

28. ADEM Heterogenous disease with variable course and development • Monophasic form • RDEM : Relapses with sterotype symptoms and without new MRI lesions • MDEM : reccurent pattern in long lengths of time (years) with new symptoms and corresponding new MRI lesions • AHEM : rare, hyperacute onset , monophasic course with fever and severe neurologic dysfunction. Fulminant and often mortel outcome. Spectrum of pathologies still imprecisely known Most important pronostic factor for differential diagnosis with MS : FOLLOW-UP

29. ADEM Differential diagnosis • Lyme’s disease • Subacute Sclerosing Panencephalitis • Progressive multifocal leucoencephalopathy • Blood coagualtion diseases • Vasculitis • Leucodystrophies • Mitochondrial diseases • Haematologie disorders • Optic neuromyelitis – subform of ADEM • Schilder and Balo diseases (variant of MS) • MS ++

30. 5 Y 11 Y Blindness and paraplegia

31. Pediatric MS • 4 reviews concerning MS in childhood and summarizing published literature between 2005 – 2007. • 2 Focusing on MRI features • All reviews state that children • are more likely to have monosymptomatic illness • Have typically fewer lesions than adults • with lower propensity for lesions to enhance with gadolinium. (1) Banwell B et al Neurology 2007; 68: 546 (2) Chabas D et al NeuroRX 2006; 3: 264 (3) Pena JA et al Invest Clin 2006; 47: 413 (4) Waldman A et al Ment Retard Dev Disabil Res Rev 2006; 12: 147

32. 3 years-old, right hemiparesis with rapidly progressive onset IRM J8 Corticotherapy: complete regression of the symptoms and considerable decrease in cerebral lesion IRM at 6 years Sequellea: R hemiparesis Extensive WM hypodensities : relapse immediatly after TTT arrest

33. Pediatric MS • MRI criteria specific for pediatric onset MS and criteria predictive of MS outcome in children with first demyelinating event : challenged by the over lap in MRI features between MS and ADEM • Most important differentiel criteria : Follow-up.

34. 13 Y Pediatric MS • Rare in childhood : less than 1 % of MS cases begin in the first decade (1) • Symptoms usually less severe • MRI lesions multiple • Mainly in periventricular areas • Middle cerebellar peduncle • Sharper margins • Small with variable enhancement : Active lesion coexisting with silent lesions • Tumefaction lesions > 20 mm. (1) Dale RC et al, Brain 2000; 123 : 2047 5 Y

35. Pediatric MS • demonstrate several differences • Initial presentation : frequently simulates ADEM or acute metabolic encephalopathy. • 5 : 1 female predominance in adolescence v/s 1.4 to 1.9 : 1 in adults • Cerebellar and brainstem plaques more frequent : 70 – 80 % • Tumoral form : even if uncommon, mostly seen in children. Size and enhancement >>> DD with abscess and tumor. MRS : indistinguishable from tumor spectra. • Incomplete rim enhancement and mild edema and mass effect.

36. 10 years-old boy with intense headache and 01 week before:seizures CT 2 years later Resolutive multiple relapses: visual loss, seizures, paraparesis Follow-up MRI 5 years later Sudden visual loss

37. 17-year-old female, with tetraplegia , ataxia and urinary disturbance. • Balo’s concentric sclerosis (BCS) • Rare demyelinating disease: Balo in 1928 (post mortem) • variant of MS • typical concentric mass patterns on MRI • characteristic alternating rings of demyelination • and spared myelin

38. Glomerulonephritis CRF . Seizures and coma. Hypertension SevereGNA hemodialysis

39. Posterior Reversible Encephalopathy syndrom: PRES • 20 cases, most with severe alterations in consciousness and seizures • Age 1.9 to 18.3 years • 10 (177) kidney transplant recipients: 6 cyclosporine and 4 Tacrolimus • 5 (87) nephrotic syndrome (cyclosporine) • 5 acute post streptococcal glomerulonephritis, diffuse mesangial sclerosis… Ishikura K et al, AJ Kidney disesases 2006, 48 : 235 • Relatively new clinical-radiological entity : 1996 in adults with renal insufficiency, hypertension, immunosuppression • Usually benign and reversible • Hypertension and Calcineurin inhibitor administration: chief risk factors. Characteristics of PRES in pediatric patients remain obscure. • AWARENESS of this syndrome possibly traitable • Clinically : • Generalized TC seizures: 60 % • Hypertensive crises: 60 %

40. PRES in children • Diagnosis improved with MRI – Flair > CT Combination MRI – CT recommanded • Abnormalities : edema in posterior WM regions, bilateral in parieto-occipital • 17/20 abnormalities (1) extented • GM • Frontal and temporal • cerebellum (16/20). • Lower ADC value indicate cystotoxic edema with ischemic infarct • Differential diagnosis: • Ischemic stroke • Cerebral venous thrombosis • Vascularitis • Progressive multifocal leucoencephalopathy • Adrenaleucodystrohy… (1) Ishikura K et al, AJ Kidney disesases 2006, 48 : 235

41. PRES in children • Key points • Should be suspected with any sudden episode of neuroradiological symptoms in patients with Kidney diseases • Should be considered event when imaging findings are not restricted to subcortical WM in parieto occipital regions • Significant effect of early management on prognosis : rigourous and meticulous control of BP is Mandatory (antihypertensive therapy, hemodialysis). Reversible is inaccurate >>> Importance of DWI for differentiation cytotoxic v/s non cytotoxic edema.

42. CNS Manifestations in 49 Patients with • Oncohematologic Disease • CNS Manifestation No. Of Patients • Manifestations of primary disease(n 11) • Hemorrhage 1 • CNS involvement • Meningeal infiltration 2 • Parenchymal infiltration 1 • Bone marrow infiltration 2 • Orbital infiltration 3 • Spinal infiltration 2 • Effects of therapeutic methods(n 38) • Effects of radiation therapy • White matter disease 3 • Mineralizing microangiopathy 3 • Parenchymal volume loss 12 • Radiation-induced cryptic • Malformations 2 • Second neoplasms 2 • Effects of chemotherapy and bone • marrow transplantation • Hemorrhage 3 • Dural venous thrombosis 3 • White matter disease 2 • Reversible posterior encephalopathy 4 • Effects of immunosuppressive states • Infectious processes 4 10-year-old girl with ALL who presented with posterior headaches and seizures Reversible posterior leukoencephalopathy Dural Venous Thrombosis V’azquez E et al,RadioGraphics 2002; 22:1411–1428

43. Phacomatosis NF1 • Hyperintense lesions are highly prevalent and characteristic in patients with NF1 • MRI contributed to a definitive diagnosis of NF1 in 53 % of suspected cases • Follow up studies are necessary in the evaluation of suspected NF1 even if the 1st examination is negative(1,2) (1) Menor F e al, Eur J Radiol 1998, 26 : 121 (2) Balestri P, Child Nerr syst 1993, 9 : 448

44. Phacomatosis • Neurofibromatosis type1 NF1 • 72 NF1 in recent review with follow-up(1) • T2 high signal lesions UBOS dectected in : • Basal ganglia, cerebellum • Globus pallidus • 45 follow up with 3 years mean interval • WM lesions cerebellum and brainstem • Decreased in size 40 % • Involutional tendency occured in children older > 10 years. (1) Menor F e al, Eur J Radiol 1998, 26 : 121

45. WM lesions in TS : • Noted in all cases • Supratentorial localization. • Most commonly: • Isointense or hypointense to normal WM on T1 SE • Hyperintense on T2 SE and FLAIR. • Superiority of MT-T1WI over Flair is demonstrated. • MR pattern • linear and radial • nodular • Cyst-like: 8/18 patients (1) iso intense to CSF (1) Van Tassel P et al, AJNR 1997 ; 18 : 1367

46. Conclusion • MR Imaging highly sensitive in the detection of WM lesions • Integrated description of clinical, neuroimaging and pathophysiological features is crucial for categorizing myelin disorders. • MR, primary imaging modality in patients with leukodystrophy: important role in the identification, localization, and characterization of underlying WM abnormalities. • MR serve to redefine and broaden the disease spectrum of reported WM abnormalities in children • Quantitative MR techniques : may HELP to CLASSIFY unknown WM lesions in subgroups