Cystic Leukodystrophies M.R Ashrafi Professor of Pediatric Neurology Children’s Medical Center Tehran University of Medical Sciences

Leukodystrophies The term leukodystrophy was introduced by Bielschowsky and Henneberg in 1928 . Leukoencephalopathies comprise all inherited and acquired disorders that selectively or predominantly involve the white matter of the CNS irrespective of the underlying pathophysiologic mechanism and histopathologic basis . The term Leukodystrophy should be restricted to inherited diseases that affect myelin development and maintenance .

Leukodystrophies Powers (2004) classified leukodystrophies as disorders that are known or presumed to have : 1- A genetic causation 2- A progressive clinical course 3- A predominant and usually confluent involvement of the CNS . 4- A primary lesion of myelin or myelinating cells .

Leukodystrophies Leukodystrophies are frequently recognized on MRI, but their identification remains a challenge. Their diagnosis is important for prognostication, palliative and experimental treatment, as well as family screening. The diagnostic strategy rests upon clinical clues and MRI patterns, complemented by appropriately selected electrophysiological and laboratory testing.

Leukodystrophies The leukodystrophies may be classified according to enzymatic defect , pathology , etiology , affected organells and age of onset. Classification of WMDs according to Brain MRI findings seems to be applied and clinically oriented .

Leukoencephalopathies Pathologic Classification Hypomyelinating ( PMD ) Dysmyelinating ( ALD , MLD , Krabbe’s Disease ) Demyelinating ( ADEM , MS ) Spongiform ( Canavan , MLC ) Cystic ( MLC , RNAse T2 Deficiency )

Cystic Leukoencephalopthies prior to an emergency cesarian section.                                                                                           Cystic Leukoencephalopthies In addition to demyelination, several leukodystrophies and leukoencephalopathies present with cystic lesions. Cystic changes in white matter can be seen in many neurodegenerative disorders ,and in nonprogressive conditions such as stroke and periventricular leukomalacia after neonatal hypoxic ischemia.

Cystic Leukoencephalopthies Megalencephalic leukoencephalopathy with subcortical cysts (MLC). Cystic leukoencephalopathy without megalencephaly (RNAse T2 deficiency). Congenital CMV infection Cerebroretinal microangiopathy with calcifications and cysts. Aicardi-Goutieres syndrome Mitochondrial leukoencephalopathies COL4A1 associated disorder Alexander's disease Greatly dilated Virchow Robin or perivascular spaces.

Malegalencephy (occuring in the first year of life) Leukoencephalopathy with macrocephaly and mild clinical course (van der Knaap Disease) Megalencephalic leukoencephalopathy with subcortical cysts first described by van der Knaap in 1995 Autosomal Recessive Malegalencephy (occuring in the first year of life) Mild clinical course ( ataxia , seizures , pyramidal signs ) leukoencephalopathy ( subcortical cysts in temporal and parietal regions )

CYSTIC LEUKOENCEPHALOPATHY WITHOUT MEGALENCEPHALY Cystic leukoencephalopathy without megalencephaly also known as leukoencephalopathy with bilateral anterior temporal lobe cysts (LBATCs) was first described by Olivier et al. in 1998 and since then, fewer than 30 cases have been described . Olivier M, Lenard HG, Aksu F, GärtnerJ. A new leukoencephalopathy With bilateral anterior temporal lobe cysts. Neuropediatrics 1998;29: 225-228

CYSTIC LEUKOENCEPHALOPATHY WITHOUT MEGALENCEPHALY The distinctive findings of this rare condition are bilateral temporal lobe cysts combined with a specific pattern of multifocal white matter lesions, with an apparently nonprogressive condition characterized by normocephaly or microcephaly , severe psychomotor delay with variable degrees of tone and reflex abnormalities .

CYSTIC LEUKOENCEPHALOPATHY WITHOUT MEGALENCEPHALY There has been some controversy in the literature as to whether the recently described condition  bilateral anterior temporal lobe cysts (LBATCs)  is in fact the end result of congenital Cytomegalovirus (CMV) infection of the developing brain.

RNAse T2-Deficient Leukoencephalopathy A subset of subjects with subcortical cysts and leukoencephalopathy without megalencephaly appear to have mutations in RNase T2, encoded by RNAseT2 (Henneke et al., 2005 , 2009). This is a recently described disorder and shares clinical and neuroradiological features with congenital CMV infection. In RNAse T2-deficient leukoencephalopathy there is no evidence of CMV infection, and familial cases suggest autosomal-recessive inheritance.

RNAse T2-Deficient Leukoencephalopathy Affected subjects have normo or microcephaly, developmental delay, and epilepsy, in some cases. MRI reveals striking abnormalities, with multifocal white-matter abnormalities, and temporal lobe cystic structures similar to those seen in CMV. CT reveals scattered calcifications in some patients. The pathophysiologic mechanism eliciting a clinical and radiologic phenotype so reminiscent of congenital CMV remains unknown .

CYSTIC LEUKOENCEPHALOPATHY WITHOUT MEGALENCEPHALY

Congenital Cytomegalovirus Infection Infants with congenital CMV infection may present acutely in the neonatal period with evidence of encephalopathy, neonatal hepatitis, thrombocytopenia, and anemia, or may present chronically with progressive microcephaly, developmental delay, and sensorineural hearing loss. These subjects may pose diagnostic challenges when MRI reveals cerebral white-matter abnormalities.

Congenital Cytomegalovirus Infection These patients are often characterized as having unsolved leukoencephalopathies. CMV include multi focal cerebral white-matter lesions located in the deep white matter, predominantly in the parietal region, associated with dilated temporal horns and subcortical cysts in the temporal lobe [van der Knaap et al., 2004].

Cerebroretinal Microangiopathy With Calcifications and Cysts (CRMCC) In 1988, Tolmie and co-workers reported on two sisters with bilateral Coats disease (retinal telangiectasia and retinal exudates), intracranial calcification, sparse hair, and dystrophic nails. Subsequently Crow et al. [2003] documented skeletal defects with a tendency to fractures, a mixed cerebellar and extrapyramidal movement disorder and a leukodystrophy , termed Coats plus syndrome.

Leukoencephalopathy with extensive brain calcifications and parenchymal cysts The association of brain calcifications (basal ganglia, cerebellar grey nuclei, and white matter), leukoencephalopathy and cysts is a very uncommon disorder which was first reported in three unrelated children by Labrune et al. in 1996 . These patients also had progressive intracerebral cysts without retinal abnormalities. Leukoencephalopathy with cerebral calcifications and cysts (LCC) is a recently described and extremely rare entity of unknown origin . Labrune P, Lacroix C, Goutieıres F, et al. Extensive brain calcifications, leukodystrophy,and formation of parenchymal cysts: a new progressive disorder due to diffuse cerebral microangiopathy. Neurology 1996;46:1297–301

CRMCC / LCC / Coat’s plus syndrome CRMCC, LCC, and Coats' plus syndrome reflect a spectrum of affected patients with presumed microvascular disorders affecting the brain, eyes, liver, intestines, and bones. An underlying genetic etiology has not been identified, although reports of affected siblings, male and female probands, and children born to consanguineous families suggest an autosomal-recessive inheritance pattern.

Cerebroretinal Microangiopathy With Calcifications and Cysts (CRMCC) Visual symptoms leading to an ophthalmologic examination before or after the onset of neurologic symptoms. Ophthalmologic evaluation identifies bilateral retinal telangiectasias and retinal exudates.

Cerebroretinal Microangiopathy With Calcifications and Cysts (CRMCC) Patients may develop spontaneous fractures of the long bones or skull and have documented osteopenia. Life-threatening intestinal bleeding may occur, and many patients are found to have cirrhosis or portal hypertension. Less often, patients may have dystrophic nails, hyperpigmented skin lesions, and sparse hair with premature graying.

Cerebroretinal Microangiopathy With Calcifications and Cysts (CRMCC) The clinical presentation of this brain disorder includes progressive extrapyramidal and pyramidal signs, slowed cognitive Performances and seizures . Because of progressive neurologic symptoms varying by age and ranging from hypotonia and focal motor deficits to ataxia and extrapyramidal symptoms, neuroimaging is often performed and suggests the diagnosis.

Cerebroretinal Microangiopathy With Calcifications and Cysts (CRMCC) Neuroimaging demonstrates large progressive calcifications of cerebral white matter, basal ganglia, thalamus, cerebellar white matter, and dentate.

Cerebroretinal Microangiopathy With Calcifications and Cysts (CRMCC) Abnormally increased signal intensity can be noted in the cerebellar and cerebral peduncles and in both hemispheric white matter, whereas the cortical grey matter is spared.

Cerebroretinal Microangiopathy With Calcifications and Cysts (CRMCC) Additionally, leukoencephalopathy and parenchymal cysts are notable and often progressive findings. Ring enhancement of the cysts wall can also be observed .

Leukoencephalopathy with extensive brain calcifications and parenchymal cysts Cerebral leukoencephalopathy with calcifications and cysts operated for signs of increased intracranial pressure: case report Surgical Neurology 72 (2009) 177–181

Leukoencephalopathy with extensive brain calcifications and parenchymal cysts Patients may succumb to complications of their neurologic status, such as aspiration pneumonia, although the clinical course is variable and slow disease progression is described.

Aicardi-Goutieres Syndrome In 1984, Jean Aicardi and Francoise Goutières described eight children from five families presenting with a severe early onset encephalopathy, which was characterized by calcification of the basal ganglia, abnormalities of the cerebral white matter and diffuse brain atrophy. An excess of white cells, chiefly lymphocytes, was found in the cerebrospinal fluid (CSF), thus indicating an inflammatory condition. In 1988, Pierre Lebon and his colleagues identified the additional feature of raised levels of interferon-alpha in patient CSF in the absence of infection. This observation supported the suggestion that AGS was an inflammatory disease, as did the later finding of increased levels of the inflammatory marker neopterin in CSF . Following an original description of eight cases in 1984, the condition was first referred to as 'Aicardi–Goutières syndrome' (AGS) in 1992, and the first international meeting on AGS was held in Pavia, Italy, in 2001.

Aicardi-Goutieres Syndrome AGS is a genetically heterogeneous disease resulting from mutations in any of seven genes encoding nucleases or putative nucleases: TREX1 [Crow et aI., 2006] RNAseH2 A, B, and C [Crow et aI., 2006]. SAMHDI [Rice et aI., 2009] ADAR1 IFIH1 Approximately 83 percent of patients with characteristic AGS-related clinical findings have mutations in TREX1, RNAseH2A ,B , C [Rice et a!., 2007]. In most cases, except for IFIH1- and rare cases of TREX1- and ADAR1-related disease, these mutations follow an autosomal recessive inheritance pattern . Rarely, this condition is inherited in an autosomal dominant pattern, result from new mutations in the gene and occur in people with no history of the disorder in their family .

Aicardi-Goutieres Syndrome Aicardi-Goutieres syndrome is a disorder that mainly affects the brain, the immune system, and the skin. Most newborns with Aicardi-Goutieres syndrome do not show any signs or symptoms of the disorder at birth. However, about 20 percent are born with a combination of features that include an enlarged liver and spleen (hepatosplenomegaly), elevated transaminases, Coombs-positive hemolytic anemia , autoimmune thrombocytopenia,, microcephaly, seizures, vasculitic skin lesions, and cerebral calcifications. Often, these patients are initially suspected of having a congenital CMV, rubella, or HIV infection . For this reason, Aicardi-Goutieres syndrome is sometimes referred to as a "mimic of congenital infection."

Aicardi-Goutieres Syndrome Within the first year of life most individuals with AGS experience an episode of severe brain dysfunction (encephalopathy), typically lasting for several months. During this phase of the disorder, affected babies are usually extremely irritable and do not feed well. Sterile pyrexias Developmental regression Microcephaly They also have significant neuromuscular problems including spasticity) ,dystonia and trunk hypotonia .

Aicardi-Goutieres Syndrome Over time , up to 40 percent of people with AGS have painful, itchy skin lesions, usually on the fingers, toes, and ears ,that are usually worse in the winter . These puffy, red lesions, which are called chilblains, are caused by inflammation of small blood vessels.

AGS Diagnostic Criteria Laboratory: Normal metabolic and infectious screening. An increase in the number of white cells (particularly lymphocytes) in the CSF, and high levels of interferon-alpha activity and neopterin in the CSF are important clues , however, these features are not always present.

AGS Diagnostic Criteria Neuroradiological features : Cerebral calcifications: Calcifications on CT are seen as areas of abnormal signal, typically bilateral and located in the basal ganglia, but sometimes also extending into the white matter. Calcifications are usually better detected using CT scans and can be missed completely on MRI . White matter abnormalities: These are found in 75-100% of cases, and are best visualized on MRI. Signal changes can be particularly prominent in frontal and temporal regions , and sometimes include cystic degeneration. Cerebral atrophy: is seen frequently

Aicardi-Goutieres Syndrome

Aicardi-Goutieres Syndrome

Aicardi-Goutieres Syndrome

Progressive Cavitating Leukoencephalopathy A Novel Childhood Disease The acute phase of PCL has features of severe encephalopathy, with irritability and opisthotonic posturing, but without increased intracranial pressure or CSF evidence of infections. The essential features of progressive cavitatory leukoencephalopathy (PCL) are irregular asymmetric patchy areas of white matter abnormality that evolve to develop cystic degeneration. The cystic changes involve especially the corpus callosum, cerebral and cerebellar white matter, and spinal cord, with varying degrees of contrast enhancement. SakkuBai Naidu, December 2005 ;58:929 –938 Ann Neurol Vol 58 No 6

Progressive Cavitating Leukoencephalopathy A Novel Childhood Disease

Progressive Cavitating Leukoencephalopathy A Novel Childhood Disease SakkuBai Naidu, December 2005 ;58:929–938 Ann Neurol Vol 58 No 6

Progressive cavitating leukoencephalopathy associated with respiratory chain complex I deficiency Mitochondrial diseases are a heterogeneous, relatively common group of multisystem disorders mostly caused by the dysfunction of one or more enzyme complexes of the OXPHOS system. Complex I deficiency (OMIM #252010) is the most frequent encountered defect of the mitochondrial energy metabolism . Clinical presentation of defect of complex I is heterogeneous and includes an ample array of clinical phenotypes, such as progressive encephalocardiomyopathy, fatal lactic acidosis, leukodystrophy, and Leigh syndrome .

Progressive cavitating leukoencephalopathy associated with respiratory chain complex I deficiency The presence of a severe progressive cystic leukoencephalopathy combined with elevated lactate should prompt a thorough mitochondrial evaluation adding to the spectrum of white matter lesions in OXPHOS-related disorders . Kohlschütter A, Bley A, Brockmann K, Gärtner J, KrägelohMann I, Rolfs A, Schöls L (2010) Leukodystrophies and other genetic metabolic leukoencephalopathies in children and adults. Brain Dev 32:82–89

Progressive cavitating leukoencephalopathy associated with respiratory chain complex I deficiency

COL4A1 associated disorder COL4A1 mutations were recently identified as a monogenetic cause of weakness of the basement vascular membranes, resulting in small vessel disease and hemorrhage. The manifestations are widespread, involving the brain and eyes most commonly and other organs such as the kidneys. There is a growing spectrum of pediatric presentations of COL4A1 mutations. The earliest presentation is antenatal or perinatal cerebral hemorrhage. Porencephaly presents as infantile hemiplegia with or without recognized antenatal or perinatal events. COL4A1 mutations were first described as a cause of perinatal cerebral hemorrhage in mice and they were also identified in humans with autosomal dominant porencephaly.

COL4A1 associated disorder In patients with a history of familial intracranial hemorrhage and stroke; as well as familial intraventricular hemorrhage and porencephalic cysts in neonates, this disorder should be considered as a possible cause of cystic leukoencephalopathy [Gould et al., 2005]. The white matter change in COL4A1 when present tends to be within the cerebral small vessel distribution affecting the deep cerebral white matter and subcortical white matter but sparing the U-fibres. The distribution tends to be bilateral, anterior, and posterior in a symmetrical fashion. The porencephaly when present can be unilateral or bilateral.

COL4A1 associated disorder

COL4A1 associated disorder

Greatly dilated Virchow Robin or perivascular spaces Significantly dilated perivascular spaces can be seen in a small percentage of normal children [Boddaert et aI., 2009; Groeschelet aI., 2006; Artigas et aI.,1999] and with higher frequency in children with migraines [Lewis and Dorbad, 2000]. Autistic Spectrum Disorderes Mucopolysaccharidosis (Hurler's/Scheie's syndrome) Structural chromosomal abnormalities

Greatly dilated Virchow Robin or perivascular spaces/ MPS

Mucopolysaccharidosis 55

Cystic Periventricular Leukomalacia Cystic changes in white matter can be seen in many neurodegenerative disorders ,and in nonprogressive conditions such as stroke and periventricular leukomalacia after neonatal hypoxic ischemia.

Conclusion Approximately half of childhood leukoencephalopathies remain unclassified despite extensive laboratory, instrumental and molecular investigation [1]. Cystic leukoencephalopathies are a group of rare genetic and acquired disorders of white matter that must be considered in any unclassified leukoencephalopathies . 1- van der Knaap MS, Breiter SN, Hart AAM, Valk J. Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach. Radiology 1999;213:121– 133.

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