Clinical Approach to Leukoencephalopathies

Transcription

1 29 Deborah L. Renaud, M.D. 1 1 Departments of Neurology and Pediatrics, Mayo Clinic, Rochester, Minnesota Semin Neurol 2012;32: Address for correspondence and reprint requests Deborah L. Renaud, M.D., Co-Director, Mayo Clinic Peroxisomal Disorders Program; Consultant and Assistant Professor, Division of Child and Adolescent Neurology, Departments of Neurology and Pediatrics, Mayo Clinic, 200 First St. SW, Rochester, MN ( renaud.deborah@mayo.edu). Abstract Keywords leukoencephalopathy magnetic resonance imaging Leukoencephalopathies are disorders that selectively involve the white matter of the brain. Acquired causes of leukoencephalopathy include inflammatory conditions, infections, vascular disorders, neoplasia, and toxic causes. Hereditary leukoencephalopathies encompass those conditions that demonstrate progressive destruction or loss of previously acquired myelin (leukodystrophies) as well as those conditions associated with impaired formation of myelin (dysmyelination or hypomyelination). The study of clinical features, neuroimaging patterns, and biochemical and neuropathologic features of leukoencephalopathies has led to the discovery of the genetic defects responsible for many of these conditions. Variations in phenotype genotype correlation can make the prediction of the underlying condition challenging. Despite recent advances in molecular studies, 50% of patients with hereditary leukoencephalopathies remain undiagnosed. A systematic approach to guide investigations is important to lead to a diagnosis. Clinical History The temporal evolution of neurologic and nonneurologic symptoms can be helpful when attempting to categorize leukoencephalopathies. The age of onset may be neonatal (or prenatal), infantile, late-infantile, childhood, or it may occur in adulthood after a long period of normalcy. Neurologic symptoms may be static, gradually improving over time or progressively declining. The pattern of skill acquisition in children is particularly important because some conditions present with development that is delayed but where children Recent advances in biochemical and molecular genetics have led to the discovery of new leukoencephalopathies. Despite these advances, many patients with leukoencephalopathy remain undiagnosed. A systematic approach to the investigation of these patients is needed to select the most appropriate testing strategy. In this article, the author presents a clinical and magnetic resonance imaging (MRI) based approach to the evaluation of patients with leukoencephalopathy. continue to steadily gain skills at their own pace. Other conditions, particularly those associated with progressive destruction of myelin, frequently present with a period of normal development followed by a plateau in skill acquisition then a decline. It is important to note whether there is a regression of skills associated with fever, infections, or head injuries. A careful review of systems aimed at detecting neurologic and nonneurologic symptoms helps generate possible clues for pattern recognition. A family history of a similarly affected sibling, parent, or family member increases the likelihood of an inherited form of leukoencephalopathy and may suggest the inheritance pattern (autosomal dominant, autosomal recessive, X-linked, or mitochondrial). Some hereditary leukoencephalopathies have primarily been described in specific ethic groups. It is therefore important to enquire about ethnicity and consanguinity. Physical Examination A careful physical examination including general, neurologic, and ophthalmologic examinations can yield important clues to the underlying diagnosis. 1. Head circumference: Serial measurement of the head circumference is needed to determine the trajectory of head growth. Leukoencephalopathies may be associated with macrocephaly (enlarged head size)/ megalencephaly (enlarged brain size) ( Table 1). Many infants, children, and adults with leukoencephalopathy have normal or small head size (microcephaly). Issue Theme Inherited Leukoencephalopathies; Guest Editor, Deborah L. Renaud, M.D. Copyright 2012 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) DOI /s ISSN

2 30 Renaud Table 1 Leukoencephalopathies Associated with Macrocephaly (Megalencephaly) Table 3 Eye Manifestations Associated with Leukoencephalopathies Alexander's disease Childhood ataxia with central hypomyelination/ vanishing white matter disease (CACH/VWMD) Glutaric aciduria type I L2-hydroxyglutaric aciduria Megalencephalic leukoencephalopathy with subcortical cysts (MLC) Peroxisomal biogenesis defects 2. Dysmorphic features: Specific metabolic or genetic syndromes may present with typical dysmorphic features. Chromosome microdeletions or microduplications can be associated with variable dysmorphic features and static leukoencephalopathy. 3. Skin: Distinctive skin manifestations have been described in specific inherited leukoencephalopathies ( Table 2). These may be difficult to treat with standard dermatologic approaches suggesting the possibility of an underlying condition. Bronzing of the skin may be a clue to adrenal insufficiency in patients with peroxisomal disorders, including X-linked adrenoleukodystrophy and peroxisomal biogenesis defects. 4. Assessment of other organ systems: Hepatomegaly or hepatosplenomegaly may be an indication of a lysosomal storage disorder or peroxisomal disorder. Mitochondrial disorders can involve multiple organs including the liver, kidneys, or heart. 5. Ophthalmology examination: The eye has been described as the window to the brain. Ophthalmologic manifestations involving the cornea, lens, retina, and optic nerve are present in several inborn errors of metabolism associated with leukoencephalopathy. 1 Retinal vascular changes have Table 2 Skin Manifestations Associated with Leukoencephalopathies Angiokeratomas Fucosidosis Chilblain lesions Eczema-like Biotinidase deficiency Ichthyosis Multiple sulfatase deficiency Sjogren-Larsson's syndrome Tay's syndrome Xanthomas Cerebrotendinous xanthomatosis Abnormal eye movements Pelizaeus-Merzbacher-like disease Corneal abnormalities Cataracts Cerebrotendinous xanthomatosis Hypomyelination with congenital cataracts (HCC) Mitochondrial respiratory chain disorders Peroxisomal disorders Retinal degeneration / retinopathy Cobalamin C disease GM1andGM2gangliosidosis(cherryredspot) Krabbe's (late-onset) disease Mitochondrial disorders Mucolipidosis IV Peroxisomal disorders Sjogren-Larsson's syndrome Retinal vasculopathy Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts) COL4A1-associated disorders TREX1-associated retinal vasculopathy with cerebral leukodystrophy Optic neuropathy Krabbe's (globoid cell) disease Metachromatic leukodystrophy Mitochondrial disorders been described in leukoencephalopathies associated with hereditary small vessel diseases. 2 Ophthalmologic manifestations associated with leukoencephalopathies are listed in Table Neurologic features: Although progressive spasticity is one of the hallmark signs of leukodystrophy, patients may present with hypotonia or a mixed tone disorder (central hypotonia with increased tone in the extremities). Dystonia or rigidity may also be present depending on the underlying cause of the leukoencephalopathy. Peripheral neuropathy coexists in several leukoencephalopathies, which may result in decreased deep tendon reflexes despite the presence of spasticity ( Table 4). Myopathy may also be present and may be detected on electromyography (EMG) or by an elevated creatine kinase. Focal

3 Renaud 31 Table 4 Leukoencephalopathies Associated with Peripheral Neuropathy Mitochondrial disorders (especially MNGIE) Metachromatic leukodystrophy Pelizaeus-Merbacher-like disease Peroxisomal disorders (including X-linked adrenoleukodystrophy and peroxisomal biogenesis defects) Waadenburg-Hirshsprung's syndrome with peripheral neuropathy and central hypomyelination findings or stroke-like episodes may be important clues. Seizures, although not strongly associated with white matter disorders, may be present as part of the underlying cause of leukoencephalopathy. Magnetic Resonance Imaging Findings 3 6 Figure 2 T2-weighted fluid-attenuated inversion recovery axial magnetic resonance image of a patient with X-linked adrenoleukodystrophy demonstrating confluent symmetric signal abnormality in the parietooccipital regions. The term demyelination refers to the loss or damage of previously formed myelin. Acute demyelination secondary to acquired causes, such as infections or inflammatory conditions, including multiple sclerosis and acute disseminated encephalomyelitis (ADEM), is generally asymmetric and nonconfluent ( Fig. 1). Chronic demyelination associated with inherited leukoencephalopathies is more commonly bilateral, symmetric, and confluent in distribution ( Fig. 2). Regions of demyelination have increased signal intensity on magnetic resonance imaging (MRI) fluid-attenuated inversion recovery (FLAIR) imaging and may be accompanied by contrast enhancement or restricted diffusion. Defects of myelin biosynthesis and metabolism result in dysmyelination, which may coexist with demyelination or hypomyelination. Hypomyelination refers to a lack of myelin formation. Patients with delayed myelination demonstrate a gradual increase in myelin over time, which is delayed in maturity for age. Serial MRI scans at least 6 months apart are required to distinguish between hypomyelination and delayed myelination. On MRI scan, hypomyelination has the signal intensity of immature white matter and is inconspicuous on FLAIR. Conditions associated with hypomyelination are listed in Table 5. Calcifications are more clearly ascertained using computed tomography (CT) scan imaging than MRI. The differential diagnosis of central nervous system calcifications includes congenital disorders such as Sturge-Weber syndrome and Figure 1 Magnetic resonance images of a patient with multiple sclerosis demonstrating asymmetric white matter lesions with contrast enhancement (Courtesy of Dr. Jan-Mendelt Tillema and Dr. Orhun Kantarci).

4 32 Renaud Table 5 Leukoencephalopathies Associated with Hypomyelination Pelizaeus-Merzbacher disease Pelizaeus-Merbacher-like disease Allan-Herndon-Dudley's disease (MCT8) Childhood ataxia with central hypomyelination/ vanishing white matter disease (CACH/VWMD) Fucosidosis Hypomyelination with congenital cataracts (HCC) Hypomyelination with hypogonadotrophic hypogonadism and hypodentia (4H) /Tremor-ataxia with central hypomyelination (TACH) Hypomyelination with atrophy of basal ganglia and cerebellum (HABC) Oculodentodigital syndrome Salla's disease Serine synthesis defects Tay's syndrome (trichothiodystrophy with hypersensitivity to sunlight) Waadenburg-Hirshsprung's syndrome with peripheral neuropathy and central hypomyelination 18q- syndrome tuberous sclerosis; infectious causes including TORCH infections, disorders of parathyroid metabolism, and calcifications associated with neoplasms and vascular disorders. 7 Aicaridi- Goutieres syndrome is an autosomal recessive condition, associated with at least four different genes, presenting with an early encephalopathy followed by stabilization of neurologic symptoms. Neuroimaging reveals leukoencephalopathy with calcifications and cerebral atrophy. Cerebrospinal fluid analysis reveals chronic lymphocytosis, elevated INFα, and neopterin Other leukoencephalopathies associated with calcifications are listed in Table 6. Cystic changes may be characteristic of the underlying condition or may represent progressive cystic degeneration of the white matter ( Table 7). Investigations 1. First tier a. Test creatine kinase if symptoms of myopathy/muscular dystrophy are present. b. Lactate and pyruvate may be abnormal in mitochondrial and related disorders. c. Quantitative amino acids, total plasma homocysteine, folate, and vitamin B12 levels detect disorders of amino Table 6 Leukoencephalopathies Associated with Calcifications Cystic leukoencephalopathy without megalencephaly Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts) Naku-Hakola's disease RNASET2-deficient cystic leukoencephalopathy acid metabolism and homocystinuria associated with disorders of vitamin B12 and folate metabolism. d. Urine organic acids may detect elevated NAA levels characteristic of in addition to organic acid disorders associated with leukoencephalopathy, including glutaric aciduria type 1, L-2-hydroxyglutaric aciduria, 3-methylglutaconic aciduria type 1, and biotinidase deficiency. e. Very long chain fatty acids, pipecolic acid, phytanic acid, and other peroxisomal studies detect X-linked adrenoleukodystrophy, peroxisomal biogenesis defects, and single peroxisomal enzyme defects. f. Urine may be tested for mucopolysaccharides, oligosaccharides, sulfatides (for metachromatic leukodystrophy), and ceramides (for ). Table 7 Leukoencephalopathies Associated with Cysts Subcortical cysts Megalencephalic leukoencephalopathy with subcortical cysts (MLC1 and HEPACAM mutations) RNASET2-deficient cystic leukoencephalopathy Porencephalic cyst COL4A1 associated leukoencephalopathy Cystic degeneration of white matter L-2-hydroxyglutaric aciduria Mitochondrial respiratory chain defects Progressive cavitating leukoencephalopathy Vanishing white matter disease

5 Renaud 33 g. Specific lysosomal enzyme assays detect lysosomal disorders, including metachromatic leukodystrophy and Krabbe's disease. h. Specific molecular studies may be initiated based on clinical and MRI characteristics. Conclusion A systematic approach to the clinical and neuroimaging findings in patients with leukoencepholopathy helps guide investigations leading to a specific diagnosis. 2. Second tier a. Comparative genome hybridization microarray may detect a microdeletion or microduplication, particularly in patients with stable leukoencephalopathy and dysmorphic features. b. Lumbar puncture may be needed for evaluation of lactate (mitochondrial disorders), amino acids (serine biosynthesis defects), and disorders associated with cerebral folate deficiency, which may not be detected with routine blood and urine tests. c. Skin biopsy for fibroblast culture is useful for enzymatic and DNA based testing for follow-up of initial screening tests. Electron microscopy of skin may reveal inclusions suggestive of a particular underlying disorder. d. Muscle biopsy may be needed to investigate for mitochondrial disorders, although an increasing range of tests are available on white blood cells, which has decreased the need for muscle biopsy in the investigation of mitochondrial disorders. 3. Symptom-related investigations a. Nerve conduction studies and electromyography (NCV/ EMG) should be used to detect concomitant peripheral neuropathy or myopathy. b. Electroencephalography (EEG) may be useful for the evaluation of spells suggestive of seizures. c. Audiology for the detection of hearing loss can result in early detection and treatment of hearing impairment. d. Ophthalomology examination may provide clues to the underlying diagnosis and may also permit early treatment of associated vision impairment. e. Patients with conditions involving multiple organ systems should have appropriate investigations for cardiac, renal, and gastrointestinal manifestations. References 1 Poll-The BT, Maillette de Buy Wenniger-Prick CJ. The eye in metabolic diseases: clues to diagnosis. Eur J Paediatr Neurol 2011;15(3): Yamamoto Y, Craggs L, Baumann M, Kalimo H, Kalaria RN. Review: molecular genetics and pathology of hereditary small vessel diseases of the brain. Neuropathol Appl Neurobiol 2011;37 (1): Barker PB, Horská A. Neuroimaging in leukodystrophies. J Child Neurol 2004;19(8): Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 2009;72(8): Naidu S, Bibat G, Lin D. Clinical approach to identification of leukoencephalopathies. In: Raymond G, Eichler F, Fatemi A, Naidu S, eds. Leukodystrophies. LondonMac Keith Press 2011; Steenweg ME, Vanderver A, Blaser S, et al. Magnetic resonance imaging pattern recognition in hypomyelinating disorders. Brain 2010;133(10): Kıroğlu Y, Callı C, Karabulut N, Oncel C. Intracranial calcifications on CT. Diagn Interv Radiol 2010;16(4): Rice G, Patrick T, Parmar R, et al. Clinical and molecular phenotype of. Am J Hum Genet 2007;81(4): Orcesi S, La Piana R, Fazzi E.. Br Med Bull 2009;89: Uggetti C, La Piana R, Orcesi S, Egitto MG, Crow YJ, Fazzi E. Aicardi- Goutieres syndrome: neuroradiologic findings and follow-up. AJNR Am J Neuroradiol 2009;30(10): Crow YJ, Rehwinkel J. and related phenotypes: linking nucleic acid metabolism with autoimmunity. Hum Mol Genet 2009;18(R2):R130 R136