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Approach to white matter disease
- 1. Approach to WHITEMATTER DISEASES PRESENTER- DR.PALLAV JAIN DM RESIDENT(NEUROLOGY) GMC,KOTA
- 2. Introduction “White matter disease”-loosely defined term that includes practically any disease process that has pathologic changes limited to or predominantly within the WM. Pathologic point of view • Primary demyelination • Secondary demyelination • Dysmyelination • Hypomyelination
- 3. Difference between whitematter & gray matter diseases WHITE MATTER GRAY MATTER Pyramidal signs Early and prominent Late Ataxia Early and prominent Late Dementia Late Early Psychiatric symptoms Uncommon Present EPS No Present Eye involvement Primary optic atrophy may be present Retinal disease may be present Peripheral neuropathy may be associated No neuropathy MRI shows subcortical WM involvement MRI shows cortical involvement
- 4. Primary demyelinating diseases Characterizedby loss of normally formed myelin with relative preservation of axons • Multiple sclerosis • Neuromyelitis optica
- 5. Secondary demyelination Demyelination associatedwith a known etiology or a systemic disorder Preferential destruction of WM (destruction of both axons and myelin) • Infectious-ADEM,PML,HIV • Metabolic-CPM,Vitamin B12 • Vascular-Ageing,Hypertension • Trauma
- 6. Dysmyelinating/Hypomyelinating (Leukodystrophies) •Dysmyelinating diseases Defective formationor maintenance of myelin •Hypomyelinating disorders WM partially myelinates but never myelinates completely
- 7. 1. Pathologically lossof myelin 2. Inflammation 3. Asymmetrical involvement 4. Cause – idiopathic or secondary 5. Subcortical U fibres involved 1. Myelin not formed or altered 2. No inflammation 3. Symmetrical involvement 4. Cause – Metabolic or unknown 5. Subcortical fibres usually spared DEMYELINATION DYSMYELINATION
- 8. Clinical Approach- ADEMvs MS ADEM typically follows a prodromal viral illness MS may or may not ADEM may present with fever and stiff neck unusual in MS Widespread central nervous system disturbance, often with impaired consciousness and/or encephalopathy MS typically is monosymptomatic and has a relapsing-remitting course
- 9. When to suspectleukodystrophies Common: Slow/regression of mile stones B/L symmetrical signs & symptom Family H/o Mental retardation or early death Early onset of visual failure Progressive ataxia` Spasticity Behavioral changes,cognitive decline Uncommon Seizure, Myoclonus Tremor or other involuntary movements
- 10. Approach to leukodytrophies 1.Arethere any useful symptoms? Head size: Macrocephaly 2.Is the disorder primarily WM, gray matter or both? WM : spasticity, hyperreflexia, ataxia Cortical Grey matter : seizure, dementia Deep grey matter : Movement disorders, dystonia, chorea 3.Involvement of Other organs: liver, MSK, renal, eye, ear
- 11. 4. Is itprimarily SUBCORTICAL or DEEP white matter?
- 12. 5.Pattern - anterior,posterior, both? Subcortical or deep WM cysts? Thalamic /Brainstem 6. Myelination- Lack of or Delayed ? 7. MRS : Elevated NAA, lactate or other peaks
- 13. Classification Neonatal 0-3 months Infancy1-12 months Early childhood 1-4 years Late childhood 5-15 years Adult >15 years
- 14. Childhood onset disorder MLD/ALD Krabbe’s Alexander’sleukodystrophy Canavan’s disease Pelizaeus-Merzbacher disease Cerebrotendinous xanthomatosis Adult Onset MLD / ALD Krabbe’s disease (late-onset form) Alexander’s leukodystrophy CTX HDLS . CADASIL ADLD Adult Polyglucosan Body Disease LBSL Classification
- 15. Clinical Approach Neonatal orinfantile • Early: axial hypotonia • Nystagmus or seizures. • Late: spastic quadriparesis Childhood : • Delayed / regression of motor mile stones • Progressive UMN signs • Ataxia or dysarthia .
- 16. Adolescent or adult: • Cognitive regression • Psychiatric manifestation • Behavioral abnormalities • Motor manifestations are more subtle.
- 17. Head Size • Withmacrocephaly: Alexander & Canavan disease Type 1 glutaric aciduria, GM2 Gangliosidoses, Zellweger • With macrocephaly + subcortical cysts Van der Knapp disease • With macrocephaly + ataxia & decreased myelination Vanishing white matter disease
- 18. ONSET OF ILLNESS •<1YRKrabbe, Metachromatic leukodystrophy,Cannavan • 1-2yrMetachromatic leukodystrophy • 5-10yrAdreneleukodystrophy RATE OF PROGRESSION • RAPID Krabbe, Canavan • SLOWMetachromatic leukodystrophy, Pelizeus Merzbacher
- 19. Environmental precipitants (fever/trauma) Adrenoleukodystrophy Vanishing white matter disease Ethinicity • JEWSCannavan • BRONZE SKINAdrenoleukodystrophy
- 20. EXTRAPYRAMIDAL Metachromatic leukodystrophy NYSTAGMUSPelizeus Merzbacher, Metachromatic leukodystrophy EARLY CEREBELLAR Pelizeus Merzbacher EARLY HYPOTONIA Cannavan ABSENT DTR Metachromatic leukodystrophy ,Adrenomyeloneuropathy,Krabbe Seizures Krabbe disease,neonatal Adrenoleukodystrophy
- 21. Radiological approach • BrainMRI investigation in a patient with a suspected patient with white matter disease • Imaging findings interpreted a/w history, examination findings • May often be diagnostic even before these elements are known in leukodystrophies
- 22. Primary demyelinating disease Cerebrallesions in NMO • Dorsal medulla(Area prostrema) contagious with upper cervical cord lesion • Periependymal surfaces of 4th ventricle in brainstem/cerebellum • Hypothalmus,thalmus,peri ependymal surface of 3rd ventricle • Large,confluent,U/L or B/L subcortical or deep white matter lesions Cerebral lesions in MS • Periventricular • Corpus callosum • Centrum semiovale • Deep white matter structures and basal ganglia
- 23. MS VS ADEM ADEMusually has more MRI lesions than MS larger bilateral but asymmetric white matter abnormalities ADEM lesions tend to have poorly defined margins, While MS lesions tend to have better defined margins The presence of brain lesions of about the same age on MRI is most consistent with ADEM Presence of brain lesions of different ages and/or the presence of black holes (hypointense T1-weighted lesions) suggests MS Thalamic lesions are common in ADEM Rare in MS Periventricular lesions common in ADEM Less common in MS
- 24. Leukodystrophies • Sagittal T1,Axial T1, T2-weighted FLAIR sequences should be obtained. • T1 weighted imaging may be more sensitive to immature myelin than T2 weighted imaging • MR spectroscopy,Diffusion tensor imaging- sensitive indicators of involvement of certain white matter tracts or myelination but principally remain research tools.
- 25. • A singlebrain MRI(especially<1yr)-Not sufficient • Distinguish between delayed myelination, hypomyelination and the early stages of demyelination. • Serial MRI scans are often required, usually with a minimum of 6–12 months interval between studies. • Ideally, at least one scan should be obtained after the age of two years
- 26. What to lookin MRI • Presence or absence of hypomyelination Hypomyelination-unchanged pattern of deficient myelination on two MRI scans at least six months apart in a child older than one year. • Whether the white matter abnormalities are confluent or isolated and multifocal Multifocal changes-infection,vasculopathy,structural chromosomal disorders Bilateral, symmetric confluent-leukodystrophies • Predominant localization of the abnormalities • MRI features unique to disorders-cysts, contrast enhancement, calcifications
- 27.
- 28. Patterns of whitematter involvement
- 29. • Hereditary diffuse leukoencephalopathywith spherois • Alexander disease • Adrenoleukodystrophy • Metachromatic leukodystrophy
- 30. • Metachromatic leukodystrophy •Leukoencephalopathy with brainstem and spinal cord involvement and elevated white matter lactate • Krabbe disease
- 31.
- 32. • Canavan disease •Megaencephalic leukoencephalopathy • Leukoencephalopathy with brainstem and spinal cord involvement and elevated white matter lactate • Vanishing white matter disease
- 33. • Krabbe’s • Alexanderdisease • Adrenoleukodystrophy • Leukoencephalopathy with brainstem and spinal cord involvement and elevated white matter lactate • CTX
- 35. Advance MR techniques •Proton MRS, DTI-changes in metabolite levels and water diffusion parameters • Offer an opportunity to assess the degree of axonal loss and demyelination in the leukodystrophies Measurements of white matter metabolites • Help assess disease progression • Determine optimal candidates for treatment options
- 36. MRS • MRS changesprecede MRI changes, very sensitive tool for monitoring disease activity and progression • N-acetyl aspartate- evaluates axonal integrity • Choline- active demyelination • Lactate- increased in secondary LD • Myo-inositol- glial marker, early indicator of demyelination and gliosis
- 37. Alexander Disease Infantileform: myoinositol elevations in white and gray matter, decreased Nacetylaspartate Canavan Disease Highly elevated Nacetylaspartate Globoid Leukodystrophy (Krabbe Disease Choline and myoinositol elevations, decreased N-acetylaspartate Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Elevated Lactate Decreased N-acetylaspartate and increased myo-inositol, choline and lactate Megalencephalic Leukodystrophy with Cysts Decreased ratio of Nacetylaspartate to Creatine
- 40. METACHROMATIC LEUKODYSTROPHY • AR,Most common • Deficiency of enzyme arylsulfatase • Three types-late infantile, juvenile and adult forms • Age of onset 1 to 2 years
- 41. Diagnosis • NCV- markedslowing • High protein content of CSF • Sural N Bx: pathognomonic deposits of sulfatides in Schwann cells and macrophages • Diagnosis-Deficient arylsulfatase A gene (ARSA gene) activity in leukocytes or cultured skin fibroblasts. • ARSA Pseudodeficiency (1%) • Increase levels of urine sulfatides
- 45. Adrenoleukodystrophy • Defect ofperoxisomal beta-oxidation pathway • Raised level of plasma VLCFA • Mutations in the ABCD1 gene Three main phenotypes • Childhood cerebral forms • Adrenomyeloneuropathy • Adrenal insufficiency
- 46.
- 48. Megalencephalic Leukoenphalopathy withsubcortical cysts:Vander knapp disease • Remarkable for its relatively mild neurological signs and symptoms in the setting of a very abnormal imaging study • Delayed milestones, macrocephaly • Slow neurological deterioration with dysarthria and ataxia • Seizures in some • In India, predominantly seen in the Agarwal community.
- 51. • Caused bydeficiency of enzyme aspartoacylase. • Excessive accumulation of N-acetyl aspartic acid in the brain • Onset 3-6 months • Progressive macrocephaly, severe hypotonia, persistent head lag • Later hyperreflexic, hypertonic,Seizures and optic atrophy • Most patients die in first decade of life CANAVANS DISEASE
- 53. Alexander Disease • Macrocephaly,frequently associated with hydrocephalus • Frontal lobe predeliction. • Classified into 3 forms- infantile, juvenile and adult. • Mutations in GFAP • Anterior to posterior progression with generalized gray and white matter atrophy. • Treatment- supportive. AED - to control seizures
- 55. Vanishing white matterdisease • Chronic and progressive often exacerbated by infection or head trauma • Mutations- eukaryotic translation initiation factor(eIF2B) • Confluent cystic degeneration, white matter signal appears CSF-like with progressive loss of white matter over time on proton density and FLAIR images. • Lab screening: elevated glycine in the CSF,serum and urine • Prognosis: death 2nd decade
- 56. VANISHING WHITE MATTERDISEASE
- 57. KRABBE’S DISEASE (GLOBOID CELL LEUKODYSTROPHY ) • Autosomal recessive • Deficient enzyme-galactocerebroside beta galactosidase • Early onset, rapidly progressive and invariably fatal disease of infants • Raised CSF protein,Decreased motor NCV • HSCT -beneficial if performed before the onset of symptoms
- 58. Krabbe’s disease (globoid cell leukodystrophy )
- 60. Conclusion • White matterdisease are difficult to diagnose and patients with these disorders typically undergo a large number of expensive, time-consuming tests over a long time. • MRI brain is central to the differential diagnosis of white matter disease & should be interpreted in context of clinical features • Newer MRI techniques, genetic testing and advances in gene therapy and HSCT will help us in treatment of these disorders.
- 61. REFRENCES • Lynch DS,Wade C.Practical approach to the diagnosis of adult- onset leukodystrophies: an updated guide in the genomic era. J Neurol Neurosurg Psychiatry. 2019 • Scott Atlas.White matter imaging.MRI OF BARIN AND SPINE 5th edition • A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephalopathies. Mol Genet Metab. 2015 April ; 114(4): 501–515 • Deborah L. Clinical Approach to Leukoencephalopathies.2012 • Osborn brain and spine imaging 3rd edition • www.uptodate.com
- 62.