Review Article
Rare Inflammatory Diseases of the White Matter and Mimics of Multiple Sclerosis and Related Disorders Marc Tardieu1,2
Kumaran Deiva1,2
1 Department of Pediatric Neurology, Assistance Publique-Hôpitaux de
Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, Le Kremlin Bicêtre, France 2 National Referral Center for Neuro-Inflammatory Diseases in Children, University Paris-Sud, Le Kremlin-Bicêtre, France
Address for correspondence Marc Tardieu, MD, PhD, Neurologie pédiatrique Hôpital Bicêtre 78 rue du Général Leclerc 94275 Le Kremlin-Bicêtre Cedex, France (e-mail: [email protected]).
Neuropediatrics 2013;44:302–308.
Abstract
Keywords
► inflammatory diseases ► white matter ► multiple sclerosis ► acute disseminated encephalomyelitis ► neuroimmunology
The spectra of white matter neuroinflammatory diseases and pathological processes inducing inflammatory lesions in the white matter of the central nervous system are wider in children than in adults. The definitions of multiple sclerosis (MS) and of the related clinically isolated syndromes (CIS) and acute disseminated encephalomyelitis (ADEM) have been recently revised leading to a new consensus definition. However, other entities with similarities to these diseases may also develop with monophasic or relapsing white matter inflammation. These conditions include congenital immunogenetic diseases (such as hemophagocytic lymphohistiocytosis), vasculitis, and autoantibody-mediated encephalopathies (Hashimoto encephalopathy, encephalitis with anti-N-methyl-D -aspartate receptor antibodies and neuromyelitis optica). Moreover, infectious diseases, such as Lyme disease, tumors (oligodendroglioma and lymphoma), and even genetic or metabolic diseases should also be considered if the clinical course of the disease does not follow the typical pattern for ADEM or MS. This short review describes these different entities and provides information for the differential diagnosis of inflammatory diseases of the white matter.
Introduction In the absence of neuropathological information, white matter inflammatory diseases of the central nervous system (CNS) may be considered to widely correspond to symptoms-inducing inflammatory processes affecting the supratentorial or infratentorial white matter, spinal cord, or optic nerves. In clinical settings, these diseases are considered when a previously healthy child develops neurological symptoms over hours to days, frequently in association with fever and meningism. The neurological symptoms generally consist of alteration to the level of consciousness lasting 24 hours or more or a change in personality that cannot be explained by fever, and/or focal neurologic findings including brain stem symptoms and ataxia. Evidence for an inflammatory cause is provided by
received June 27, 2013 accepted after revision August 28, 2013 published online October 28, 2013
Issue Theme Neuroinflammation Update: New Insights and Future Directions; Guest Editor, Kevin Rostasy, MD.
cerebrospinal fluid (CSF) abnormalities and by magnetic resonance imaging (MRI) results showing lesions in the white matter. In adults, acute inflammation of the white matter often occurs with no effect on the level of consciousness, leading a diagnosis of multiple sclerosis (MS). This diagnosis may be reached after a single episode of acute inflammatory demyelination provided that specific MRI criteria are met, or after a relapse of symptoms, both these situations fulfilling the criteria of temporal and spatial dissemination.1,2 In children, the spectrum of diseases and pathological processes causing inflammatory lesions of the white matter in the CNS is broader than in adults. MS in children has been well described but is a relatively rare in this age group and may, therefore, be difficult to recognize at the time of the first event.3 The initial events may be acute disseminated encephalomyelitis
© 2013 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0033-1358599. ISSN 0174-304X.
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(ADEM), which occurs infrequently in adults, or a clinically isolated syndrome (CIS), including optic neuritis, transverse myelitis, brain stem–related symptoms, and a polysymptomatic acute syndrome without associated encephalopathy. Both ADEM and CIS may be either monophasic or relapsing. A relapse of ADEM or CIS leads to the diagnosis of MS in most of the cases.4,5 However, other entities that are more frequent in children than in adults, should also be considered as such conditions may also cause monophasic or relapsing white matter inflammatory syndromes. These conditions include congenital immunogenetic diseases, vasculitis, autoantibodymediated encephalopathies and even tumor, genetic, or metabolic diseases, and migraine (►Table 1). This review does not aim to provide an exhaustive list of these conditions but is based on our experience as the national reference center for neuroinflammatory diseases of the CNS in France: All entities listed have been referred to our center as possible MS and represent 8% of the referred cases. This short review describes several of the conditions mimicking MS and related disorders in association with other chapters of this special issue on vasculitis and autoantibodyrelated neurological diseases.
Clues to the Differential Diagnosis of White Matter Inflammatory Diseases The differential diagnosis of an acute inflammatory disease of the white matter in a given child requires great care because the
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choice of treatment differs considerably between the various diseases. The main clinical characteristics will be described for each entity, but the following features should challenge the diagnosis of ADEM (or less frequently MS): onset before the age of 1 year; a consanguineous family or the existence of another child in the family that has previously displayed severe, acute neurological symptoms; a gradual progression of clinical symptoms; any nonneurological symptoms or signs, such as liver or spleen enlargement, lymphadenopathy, cutaneous vasculitis symptoms (including livedoid vasculitis), and uveitis. The diagnosis should also be reevaluated if relapses persist despite treatment in a child previously diagnosed as MS. Similarly, the following neuroradiological symptoms on MRI are infrequent in ADEM and MS: a single lesion, high symmetric white matter lesions, an absence of lesions of the basal ganglia or brain stem, signs of arachnoiditis or lesions restricted to the brain stem and basal ganglia. A normal MRI despite frank symptoms of encephalitis is frequently observed in very young babies with familial hemophagocytic lymphohistiocytosis (HLH). Computed tomographic (CT) scan can be used to search for calcifications suggestive a more restricted group of diseases including Aicardi–Goutières syndrome and related diseases. Normal CSF results despite an “inflammatory appearance” on MRI or an associated fever are frequent in cases of HLH, whereas high concentrations of protein in the CSF ( > 1 g/L) are more frequently observed in arachnoiditis or tumors than in ADEM. However, none of these clinical or radiological symptoms is absolute, and biological markers specific of each disease are
Table 1 Major inflammatory diseases of the white matter and conditions that mimic them Multiple sclerosis and related disorders: • Multiple sclerosis. • Acute disseminated encephalomyelitis. Clinically isolated syndromes: • Optic neuritis, transverse myelitis, brain stem-related syndromes, polyfocal clinically isolated syndrome. Other inflammatory diseases of the white matter: • • • • •
Primary and secondary hemophagocytic lymphohistiocytosis. Acute encephalopathies with autoantibodies. Vasculitis. Lymphoma. Malignant lymphohistiocytosis.
Genetic, metabolic, and tumor diseases mimicking MS and related disorders: • • • • •
Mitochondrial respiratory chain deficits (Leigh, Leber diseases, OPA mutations). Other metabolic diseases (X-ALD), lysosomal diseases. Other angiopathies (e.g., Cadasil, coats þ syndrome, etc). Migraine. Some genetic diseases (e.g., Aicardi–Goutières, RANSET2 mutation).
Tumors: • Oligodendrocytoma, astrocytoma, and lymphoma. Abbreviation: X-ALD, X-linked adrenoleukodystrophy. Neuropediatrics
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required. Such markers are still lacking for MS and related disorders but have been identified in most of the other possible diagnosis. It is essential to carry out the necessary biological tests as part of the diagnostic procedure. In cases of acute demyelinating inflammatory disease for which a diagnosis of ADEM has not been established, the following determinations should be performed: complete blood formula, erythrocyte sedimentation rate, C-reactive protein, complement activity, aspartate aminotransferase/alanine aminotransferase (ALT/AST), ferritin, triglycerides, antinuclear antibodies, and in some cases, antithyroid, and antineuronal antibodies. Lactate/pyruvate ratios in blood and CSF are useful for the detection of respiratory chain dysfunction, particularly, in patients with MRI lesions restricted to the brain stem and basal ganglia.
The IPMSSG Consensus Definitions of ADEM, CIS, and MS New consensus definitions for ADEM, CIS, and MS have recently been produced by the International Pediatric Multiple Sclerosis Study Group (IPMSSG) and are shown in ►Table 2.3 Although CSF characteristics are not included in the definitions of MS and ADEM, its evaluation may have additive value in facilitating diagnosis. About 60% of the patients with ADEM have abnormal CSF findings, although the precise proportion varies between reports.4,6 In the French cohort of ADEM patients, a cell count of 10 cells/μL or more was reported in 53% of the patients and protein concentrations of 0.4 g/L or more were reported in 37% of the patients.7
Immunogenetic Diseases Mimicking MS and Related Disorders Congenital immunogenetic diseases are rare, but many of these diseases may involve the CNS. The neurological symptoms are generally not isolated and diagnosis is based principally on extraneurological symptoms. However, this is not always the case for HLH8,9 which has several different forms,
including familial HLH (FHLH), Chediak–Higashi diseases, Griscelli disease, and Purtilo disease.10 FHLH is the most frequent form of HLH and results from genetic defects impairing the cytotoxicity of CD8 T-lymphocytes. These genetic defects may remain asymptomatic until a trigger, a viral infection in most cases, induces the uncontrolled polyclonal activation of CD8þ T-lymphocytes and macrophages, resulting in the overproduction of cytokines. We recently evaluated children at the onset of the different types of HLH and compared them with children of a similar age diagnosed with ADEM.11 In HLH, the median age at onset was 2.5 months, but the range was wide (range, 0–190 months). Initial symptoms at presentation were not restricted to the CNS in most patients with fever (> 38.5°C) reported in 83% of the patients and hepatomegaly (72%), splenomegaly (63%), and lymphadenopathy (57%) also frequently reported. Neurological symptoms consisted of seizures, impaired consciousness, meningism, and focal motor deficit. Common biological signs included pancytopenia, low fibrinogen levels, high liver enzyme levels, hyperferritinemia, hypertriglyceridemia (all present in more than 90% of the patients) and hyponatremia (63% of the patients).12,13 Signs of hemophagocytosis were detected on both blood and bone marrow smears, for 66% of the patients. However, neurological symptoms were isolated in 7% of the patients in our series. Important clues that can direct the physician to the correct diagnosis include young age and consanguinity or the early death of a sibling. Moreover, in this probably inflammatory and acute encephalitis, CSF results were normal in only 50% of the patients, where a high protein titer (> 0.5 g/L) was found in 50% of the patients and high cellularity (> 10/μL), in 37% and features of hemophagocytosis in 24% of the patients. Similarly, brain MRI at onset was normal in 67% of the patients. In cases of abnormal MRI results, white matter lesions were more frequently symmetric and periventricular with hyposignal intensity on T1 sequences, in HLH than in ADEM, whereas lesions of the thalamus, basal ganglia, and brain stem were more frequent
Table 2 IPMSSG criteria for pediatric MS and ADEM MS • Two or more nonencephalopathic clinical CNS events with a presumed inflammatory cause, separated by more than 30 days and involving more than one area of the CNS. þ • One nonencephalopathic event typical of MS þ MRI findings involving more than one area and combining Gd /Gd lesions. One nonencephalopathic event with dissemination in space on MRI þ new lesions on follow-up MRI. • • One ADEM þ one nonencephalopathic event þ dissemination in space on MRI.
ADEM • • • •
A first polyfocal clinical CNS event “with a presumed inflammatory cause.” Encephalopathy that cannot be explained by fever. No new clinical and MRI findings emerging 3 months or more after onset. Brain MRI abnormal during the acute phase, typically with diffuse poorly demarcated, large lesions involving the white matter.
Abbreviations: ADEM, acute disseminated encephalomyelitis; CNS, central nervous system; IPMSSG, International Pediatric Multiple Sclerosis Study Group; MRI, magnetic resonance imaging; MS, multiple sclerosis. Neuropediatrics
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Autoantibody-Mediated Diseases Mimicking MS and Related Disorders Hashimoto Encephalopathy and Antithyroperoxydase Antibodies Hashimoto encephalopathy (HE) is a rare immune-mediated disease characterized by the presence of antithyroperoxydase antibodies (anti-TPO) in a child with acute encephalitis with predominant seizures, neuropsychiatric symptoms, and an alteration of consciousness or dystonia.14 It is also a chronic disease that relapses in some cases. It can be confused with ADEM at onset and with MS in the case of relapse. We recently reviewed all cases of acute encephalitis with compatible neurological symptoms observed at the French national reference center for inflammatory diseases of the CNS.15 The 42 selected patients included 8 children with HE (compatible clinical symptoms and median anti-TPO titer ¼ 2,838.5 IU/mL; range, 812–8,550 IU/mL) and 10 patients with a final diagnosis of acute demyelinating syndromes (6 ADEM, 2 MS, 2 CIS). For these HE cases and the small number of cases previously published, median age at onset was 12 years (range, 9–15 years) but an affected child aged 2 years and 10 months has also been reported.16 Most of the patients were girls. Most children were euthyroid and had an acute onset. The CSF was frequently abnormal, with pleocytosis (13%), high proteins titers (63%), and oligoclonal bands (43%). The EEG at onset was abnormal in some cases, but no specific pattern has been described. Similarly, brain MRI was abnormal in 50% of the children in our series, with abnormalities involving the white matter and gray matter distinctive enough for clear differential diagnosis from MS in most of the cases (►Fig. 1). Here, we routinely test for anti-TPO antibody in children with acute encephalitis without clear-cut symptoms of ADEM or presenting relapse, unless the clinical and radiological symptoms are typical of MS. HE usually responds to steroid treatment, but relapses are frequent. Immunosuppressive treatments (cyclophosphamide, mycophenolate-mofetil, or azathioprine) have been used, but there is currently no consensus concerning their efficacy, in the absence of formal results.
Acute Encephalitis with Anti-NDMA Receptor Antibody Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis can occasionally mimic ADEM or brain stem encephalitis at onset and, indeed, may have symptoms very similar to those of HE.17 Anti-NMDA receptor antibodies were detected in the serum of
Fig. 1 Various aspects of immune-mediated central nervous system demyelinating disorders on brain magnetic resonance imaging. (A) Axial T2-weighted image showing large fuzzy lesions affecting both hemisphere in a 6-year-old boy who had encephalopathy; gait difficulties at onset revealing an acute disseminated encephalomyelitis. (B) Axial T2-weighted image of a 3-year-old boy showing bilateral large and fuzzy lesions affecting right and left frontoparietal region as well as right occipital region in the context of generalized seizures with fever, associated with hemophagocytic lymphohistiocytosis. (C) Axial flair image of an 8-year-old boy showing a well-limited large right parieto occipital temporal lesion and left temporo parieto cortical lesions who presented partial seizures and hemiparesis, revealing an anaplastic large-cell lymphoma. (D) Axial T2-weighted image of a 10-year-old girl showing a lesion in the brain stem and mesencephalon. She presented relapsing gait difficulties and ataxia responding well to steroids with antithyroperoxydase antibodies confirming the diagnosis of Hashimoto encephalopathy.
1 of the 42 patients with acute encephalitis and predominantly acute cognitive and neuropsychiatric features (apart from the eight children with HE).15 In a published study of 32 children with acute encephalitis and anti-NMDA receptor antibodies, the median age at onset of the disease was 14 years (range, 23 months–18 years) and clinical symptoms included an association of fever, headache, and abnormal movements (84%), which was difficult to distinguish in some cases with partial or generalized seizures.18 Acute changes in behavior and oral dyskinesia were observed in half of the patients. CSF analysis showed pleocytosis (94%) and high protein titer (13%), and EEG was abnormal in almost all the cases, with epileptic activity reported in only 28% of the children. Brain MRI results at onset were abnormal in 30% of the cases, with hypersignal in the white matter or in cortical, cerebellar and temporal mesial areas, on T2-weighted images. Ovarian teratoma is frequently detected in adults suffering from this condition, whereas affected children are rarely found to have a tumor. The longterm course of the disease is marked by relapses despite Neuropediatrics
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in ADEM than in HLH. Gadolinium enhancement was slightly more frequent in HLH than in ADEM (33 vs. 16%) in our series but this difference was not statistically significant. Early diagnosis can be established by carrying out specific immunological tests (including analyses of perforin expression in lymphocytes, of the cytotoxic ability of the patient’s CD8 lymphocytes, before identification of the causal mutation) and is essential because treatment requires immunosuppression followed by a bone marrow transplantation. Other treatments invariably lead to relapses resulting in severe necrosis of the brain parenchyma.
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treatment in 20 to 30% of the cases.18 No formal therapeutic consensus has been established, but rituximab, plasmapheresis, and immunosuppressive drugs are the most frequently used treatment options.
Neuromyelitis Optica or Devic Disease and Antiaquaporin-4 Antibodies Neuromyelitis optica and MS are regarded as two distinct chronic relapsing white matter syndrome with recognizable differences in symptoms, detection of antiaquaporin-4 antibodies, outcome, and treatment. Neuromyelitis optica is defined by optic neuritis and/or acute myelitis which can be separated by a few weeks to months, associated with two of the following three secondary criteria: a normal brain MRI scan or brain lesions not suggestive of MS; the presence of contiguous spinal cord lesions extending over at least three vertebral segments; the presence of IgG directed against aquaporin 4.19 This condition is rare with a median age at onset of 14.5 years (range, 4.1–17.9 years), a female predominance and a median interval between the first and second attacks of 17 months (range, 7–154 months) in one series.20 In a report of 58 neuromyelitis optica (NMO)-IgG– positive children, brain symptoms were initially present in 9 (15%) children but 45% of the children went on to develop brain symptoms during the course of the disease, potentially leading to diagnostic confusion between NMO and MS.21 On brain MRI, lesions were found to be located in the periventricular areas of the third or fourth ventricle, in the midbrain, medulla, or pons. Large, extensive juxtacortical white matter lesions or lesions affecting the corpus callosum, with or without contrast enhancement, may be found, making it difficult to distinguish between this condition and ADEM or MS on the basis of radiological data. High doses of methylprednisolone are administered during the acute phase, and long-term immunosuppression is advocated although there is still some debate as to whether the most appropriate treatment is Rituximab, mycophenolate-mofetil, azathioprine, methotrexate, or more recently anticomplement C5 (eculizumab).22 It is now established that treatment with interferons can worsen NMO.23
Infectious Diseases (Lyme Disease) A few infectious diseases can mimic MS and related disorders, Lyme disease being the best known example.24 In Lyme disease, the most common neurological symptoms are observed in the second and third stages of the disease. They consist of meningitis and facial nerve palsy, but findings suggestive of parenchymal involvement may also be observed. The associated symptoms are a previous primary erythema migrans skin lesion and a tick bite, or the association with the neurological symptoms of multiple erythema migrans lesions, carditis, meningitis, and cranial nerve palsies.25 Arthritis is a sign of late Lyme disease. Brain MRI typically shows leptomeningeal enhancement or cranial or peripheral nerve root enhancement following the injection of gadolinium. White matter lesions are less common but when Neuropediatrics
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present may wrongly be considered indicative of MS. Diagnosis is usually based on the presence of typical neurological symptoms with positive results in serological tests and for polymerase chain reaction on the CSF. However, suggestive symptoms associated with CSF pleocytosis in the presence of positive serological tests for Lyme disease should be presumed to be neuro-Lyme disease. A two-step approach for serological testing is based on the use of a sensitive enzyme immunoassay or immunofluorescence assay followed by a standardized western immunoblot, to differentiate between false–positive and true–positive serological results, particularly for enzyme-linked immunosorbent assay values in the low positive range.
Tumors Mimicking Multiple Sclerosis The course of MS, with periods of relapse and remission, observed in more than 95% of the children with MS should prevent this condition being confused with tumors, but there are two exceptions. Oligodendroglioma and low-grade astrocytoma might initially yield MRI results reminiscent of white matter inflammatory diseases, leading to the incorrect diagnosis of MS if there are a few clinical symptoms. The principal clues are a gradual progression of clinical symptoms or a persistent deficit, the absence of spatial dissemination on initial MRI, and of modifications on subsequent MRI scans (or a slight extension). Spectroscopy of the pathological lesion may be useful and the diagnosis can usually be established on the basis of a biopsy.7,26 Primary cerebral lymphoma can be much more challenging to diagnose. A recent review reported 29 children with primary CNS lymphoma.27 In all these patients, disease was confined to the brain (n ¼ 26) or meninges (n ¼ 3), with no evidence of systemic lymphoma at presentation. The median age at diagnosis was 14 years, the youngest patient being 2 years old. The most frequent initial symptoms were headache/nausea, suggesting an increase in intracranial pressure, cerebellar symptoms, seizure, and hemiparesis. On MRI, 38% of the lesions were disseminated in space, with 41% of the lesions found in the basal ganglia and brain stem. CSF analysis was not informative in most cases (only 8 of the 26 patients had positive CSF cytological results for lymphoma). All the patients had primary CNS non-Hodgkin lymphoma (69% had diffuse large B-cell lymphoma, 17% had anaplastic large T-cell lymphoma, 7% had lymphoblastic lymphoma and 7% had Burkitt-like lymphoma). We observed an 8-year-old boy who initially had remitting relapsing symptoms and white matter lesions observed at different sites on successive MRI scans. As shown in ►Fig. 1, the lesion was large and welllimited with gadolinium enhancement. An initial brain biopsy indicated only “nonspecific inflammatory lesions.” The diagnosis was finally established when skin lesions appeared 4 months after the initial neurological lesions, leading after pathological evaluation of the skin lesion biopsy specimen to the diagnosis of anaplastic large-cell ALK1þ, CD30þ lymphoma, with detection of the NPM-ALK transcript. This transcript was retrospectively detected in the brain biopsy
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specimen, leading to the establishment of a diagnosis of primary CNS lymphoma.
2 Sadaka Y, Verhey LH, Shroff MM, et al; Canadian Pediatric
Other Genetic Diseases Mimicking Inflammatory White Matter Diseases
3
Leukoencephalopathies Linked to Mutations Indirectly Modifying Intracerebral Inflammation Status This is a large group of rare diseases that are progressively being discovered. Their clinical symptoms are usually sufficiently different from ADEM and MS to avoid confusion, but borderline cases can be observed. The best example is Aicardi–Goutières syndrome. This neonatal-onset encephalopathy is associated with microcephaly, brain calcifications and high interferon-α concentration in the CSF.28 However, MRI demonstrates the presence of large white matter lesions and clinical onset may occur later in childhood. This syndrome is linked to various mutations affecting RNA metabolism or to proteins that normally prevent the self-activation of innate immunity by cell-intrinsic components.29,30 Another example is provided by a mutation of the colony-stimulating factor 1 receptor gene, which has recently been demonstrated to be the cause of a dominant form of leukoencephalopathy probably resulting from microglial dysfunction.31
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Mitochondrial Respiratory Chain Deficits Mitochondrial respiratory chain deficits are the metabolic diseases most frequently misdiagnosed as optic neuritis, brain stem encephalitis or MS. These deficits can present with optic neuropathy, the most common form of which being Leber hereditary optic neuropathy.32The mutations characteristic of this disease should be sought in cases of relapsing optic neuritis or nonresolving optic neuritis. Similarly, acute brain stem encephalitis may have clinical and radiological symptoms very similar to those of mitochondrial diseases, including Leigh disease in particular. An evaluation of lactate and pyruvate concentrations in blood and CSF, spectroscopy focusing on the white matter lesions and a direct study of respiratory chain activity in lymphocytes, fibroblasts, or muscle biopsy specimens should lead to establishment of the correct diagnosis.
10 11
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Conclusion ADEM and other disease related to MS are generally easy to recognize. However, a large spectrum of rare diseases, requiring different treatments, may also occur. Special attention should be paid to diagnosis in children under the age of 3 years, children from consanguineous families, children with relapsing or progressive disease despite treatments, and children with predominantly gray matter lesions on brain MRI.
16 17
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Rare Inflammatory Diseases of the White Matter and Mimics of Multiple Sclerosis and Related Disorders Marc Tardieu1,2
Kumaran Deiva1,2
1 Department of Pediatric Neurology, Assistance Publique-Hôpitaux de
Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, Le Kremlin Bicêtre, France 2 National Referral Center for Neuro-Inflammatory Diseases in Children, University Paris-Sud, Le Kremlin-Bicêtre, France
Address for correspondence Marc Tardieu, MD, PhD, Neurologie pédiatrique Hôpital Bicêtre 78 rue du Général Leclerc 94275 Le Kremlin-Bicêtre Cedex, France (e-mail: [email protected]).
Neuropediatrics 2013;44:302–308.
Abstract
Keywords
► inflammatory diseases ► white matter ► multiple sclerosis ► acute disseminated encephalomyelitis ► neuroimmunology
The spectra of white matter neuroinflammatory diseases and pathological processes inducing inflammatory lesions in the white matter of the central nervous system are wider in children than in adults. The definitions of multiple sclerosis (MS) and of the related clinically isolated syndromes (CIS) and acute disseminated encephalomyelitis (ADEM) have been recently revised leading to a new consensus definition. However, other entities with similarities to these diseases may also develop with monophasic or relapsing white matter inflammation. These conditions include congenital immunogenetic diseases (such as hemophagocytic lymphohistiocytosis), vasculitis, and autoantibody-mediated encephalopathies (Hashimoto encephalopathy, encephalitis with anti-N-methyl-D -aspartate receptor antibodies and neuromyelitis optica). Moreover, infectious diseases, such as Lyme disease, tumors (oligodendroglioma and lymphoma), and even genetic or metabolic diseases should also be considered if the clinical course of the disease does not follow the typical pattern for ADEM or MS. This short review describes these different entities and provides information for the differential diagnosis of inflammatory diseases of the white matter.
Introduction In the absence of neuropathological information, white matter inflammatory diseases of the central nervous system (CNS) may be considered to widely correspond to symptoms-inducing inflammatory processes affecting the supratentorial or infratentorial white matter, spinal cord, or optic nerves. In clinical settings, these diseases are considered when a previously healthy child develops neurological symptoms over hours to days, frequently in association with fever and meningism. The neurological symptoms generally consist of alteration to the level of consciousness lasting 24 hours or more or a change in personality that cannot be explained by fever, and/or focal neurologic findings including brain stem symptoms and ataxia. Evidence for an inflammatory cause is provided by
received June 27, 2013 accepted after revision August 28, 2013 published online October 28, 2013
Issue Theme Neuroinflammation Update: New Insights and Future Directions; Guest Editor, Kevin Rostasy, MD.
cerebrospinal fluid (CSF) abnormalities and by magnetic resonance imaging (MRI) results showing lesions in the white matter. In adults, acute inflammation of the white matter often occurs with no effect on the level of consciousness, leading a diagnosis of multiple sclerosis (MS). This diagnosis may be reached after a single episode of acute inflammatory demyelination provided that specific MRI criteria are met, or after a relapse of symptoms, both these situations fulfilling the criteria of temporal and spatial dissemination.1,2 In children, the spectrum of diseases and pathological processes causing inflammatory lesions of the white matter in the CNS is broader than in adults. MS in children has been well described but is a relatively rare in this age group and may, therefore, be difficult to recognize at the time of the first event.3 The initial events may be acute disseminated encephalomyelitis
© 2013 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0033-1358599. ISSN 0174-304X.
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(ADEM), which occurs infrequently in adults, or a clinically isolated syndrome (CIS), including optic neuritis, transverse myelitis, brain stem–related symptoms, and a polysymptomatic acute syndrome without associated encephalopathy. Both ADEM and CIS may be either monophasic or relapsing. A relapse of ADEM or CIS leads to the diagnosis of MS in most of the cases.4,5 However, other entities that are more frequent in children than in adults, should also be considered as such conditions may also cause monophasic or relapsing white matter inflammatory syndromes. These conditions include congenital immunogenetic diseases, vasculitis, autoantibodymediated encephalopathies and even tumor, genetic, or metabolic diseases, and migraine (►Table 1). This review does not aim to provide an exhaustive list of these conditions but is based on our experience as the national reference center for neuroinflammatory diseases of the CNS in France: All entities listed have been referred to our center as possible MS and represent 8% of the referred cases. This short review describes several of the conditions mimicking MS and related disorders in association with other chapters of this special issue on vasculitis and autoantibodyrelated neurological diseases.
Clues to the Differential Diagnosis of White Matter Inflammatory Diseases The differential diagnosis of an acute inflammatory disease of the white matter in a given child requires great care because the
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choice of treatment differs considerably between the various diseases. The main clinical characteristics will be described for each entity, but the following features should challenge the diagnosis of ADEM (or less frequently MS): onset before the age of 1 year; a consanguineous family or the existence of another child in the family that has previously displayed severe, acute neurological symptoms; a gradual progression of clinical symptoms; any nonneurological symptoms or signs, such as liver or spleen enlargement, lymphadenopathy, cutaneous vasculitis symptoms (including livedoid vasculitis), and uveitis. The diagnosis should also be reevaluated if relapses persist despite treatment in a child previously diagnosed as MS. Similarly, the following neuroradiological symptoms on MRI are infrequent in ADEM and MS: a single lesion, high symmetric white matter lesions, an absence of lesions of the basal ganglia or brain stem, signs of arachnoiditis or lesions restricted to the brain stem and basal ganglia. A normal MRI despite frank symptoms of encephalitis is frequently observed in very young babies with familial hemophagocytic lymphohistiocytosis (HLH). Computed tomographic (CT) scan can be used to search for calcifications suggestive a more restricted group of diseases including Aicardi–Goutières syndrome and related diseases. Normal CSF results despite an “inflammatory appearance” on MRI or an associated fever are frequent in cases of HLH, whereas high concentrations of protein in the CSF ( > 1 g/L) are more frequently observed in arachnoiditis or tumors than in ADEM. However, none of these clinical or radiological symptoms is absolute, and biological markers specific of each disease are
Table 1 Major inflammatory diseases of the white matter and conditions that mimic them Multiple sclerosis and related disorders: • Multiple sclerosis. • Acute disseminated encephalomyelitis. Clinically isolated syndromes: • Optic neuritis, transverse myelitis, brain stem-related syndromes, polyfocal clinically isolated syndrome. Other inflammatory diseases of the white matter: • • • • •
Primary and secondary hemophagocytic lymphohistiocytosis. Acute encephalopathies with autoantibodies. Vasculitis. Lymphoma. Malignant lymphohistiocytosis.
Genetic, metabolic, and tumor diseases mimicking MS and related disorders: • • • • •
Mitochondrial respiratory chain deficits (Leigh, Leber diseases, OPA mutations). Other metabolic diseases (X-ALD), lysosomal diseases. Other angiopathies (e.g., Cadasil, coats þ syndrome, etc). Migraine. Some genetic diseases (e.g., Aicardi–Goutières, RANSET2 mutation).
Tumors: • Oligodendrocytoma, astrocytoma, and lymphoma. Abbreviation: X-ALD, X-linked adrenoleukodystrophy. Neuropediatrics
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required. Such markers are still lacking for MS and related disorders but have been identified in most of the other possible diagnosis. It is essential to carry out the necessary biological tests as part of the diagnostic procedure. In cases of acute demyelinating inflammatory disease for which a diagnosis of ADEM has not been established, the following determinations should be performed: complete blood formula, erythrocyte sedimentation rate, C-reactive protein, complement activity, aspartate aminotransferase/alanine aminotransferase (ALT/AST), ferritin, triglycerides, antinuclear antibodies, and in some cases, antithyroid, and antineuronal antibodies. Lactate/pyruvate ratios in blood and CSF are useful for the detection of respiratory chain dysfunction, particularly, in patients with MRI lesions restricted to the brain stem and basal ganglia.
The IPMSSG Consensus Definitions of ADEM, CIS, and MS New consensus definitions for ADEM, CIS, and MS have recently been produced by the International Pediatric Multiple Sclerosis Study Group (IPMSSG) and are shown in ►Table 2.3 Although CSF characteristics are not included in the definitions of MS and ADEM, its evaluation may have additive value in facilitating diagnosis. About 60% of the patients with ADEM have abnormal CSF findings, although the precise proportion varies between reports.4,6 In the French cohort of ADEM patients, a cell count of 10 cells/μL or more was reported in 53% of the patients and protein concentrations of 0.4 g/L or more were reported in 37% of the patients.7
Immunogenetic Diseases Mimicking MS and Related Disorders Congenital immunogenetic diseases are rare, but many of these diseases may involve the CNS. The neurological symptoms are generally not isolated and diagnosis is based principally on extraneurological symptoms. However, this is not always the case for HLH8,9 which has several different forms,
including familial HLH (FHLH), Chediak–Higashi diseases, Griscelli disease, and Purtilo disease.10 FHLH is the most frequent form of HLH and results from genetic defects impairing the cytotoxicity of CD8 T-lymphocytes. These genetic defects may remain asymptomatic until a trigger, a viral infection in most cases, induces the uncontrolled polyclonal activation of CD8þ T-lymphocytes and macrophages, resulting in the overproduction of cytokines. We recently evaluated children at the onset of the different types of HLH and compared them with children of a similar age diagnosed with ADEM.11 In HLH, the median age at onset was 2.5 months, but the range was wide (range, 0–190 months). Initial symptoms at presentation were not restricted to the CNS in most patients with fever (> 38.5°C) reported in 83% of the patients and hepatomegaly (72%), splenomegaly (63%), and lymphadenopathy (57%) also frequently reported. Neurological symptoms consisted of seizures, impaired consciousness, meningism, and focal motor deficit. Common biological signs included pancytopenia, low fibrinogen levels, high liver enzyme levels, hyperferritinemia, hypertriglyceridemia (all present in more than 90% of the patients) and hyponatremia (63% of the patients).12,13 Signs of hemophagocytosis were detected on both blood and bone marrow smears, for 66% of the patients. However, neurological symptoms were isolated in 7% of the patients in our series. Important clues that can direct the physician to the correct diagnosis include young age and consanguinity or the early death of a sibling. Moreover, in this probably inflammatory and acute encephalitis, CSF results were normal in only 50% of the patients, where a high protein titer (> 0.5 g/L) was found in 50% of the patients and high cellularity (> 10/μL), in 37% and features of hemophagocytosis in 24% of the patients. Similarly, brain MRI at onset was normal in 67% of the patients. In cases of abnormal MRI results, white matter lesions were more frequently symmetric and periventricular with hyposignal intensity on T1 sequences, in HLH than in ADEM, whereas lesions of the thalamus, basal ganglia, and brain stem were more frequent
Table 2 IPMSSG criteria for pediatric MS and ADEM MS • Two or more nonencephalopathic clinical CNS events with a presumed inflammatory cause, separated by more than 30 days and involving more than one area of the CNS. þ • One nonencephalopathic event typical of MS þ MRI findings involving more than one area and combining Gd /Gd lesions. One nonencephalopathic event with dissemination in space on MRI þ new lesions on follow-up MRI. • • One ADEM þ one nonencephalopathic event þ dissemination in space on MRI.
ADEM • • • •
A first polyfocal clinical CNS event “with a presumed inflammatory cause.” Encephalopathy that cannot be explained by fever. No new clinical and MRI findings emerging 3 months or more after onset. Brain MRI abnormal during the acute phase, typically with diffuse poorly demarcated, large lesions involving the white matter.
Abbreviations: ADEM, acute disseminated encephalomyelitis; CNS, central nervous system; IPMSSG, International Pediatric Multiple Sclerosis Study Group; MRI, magnetic resonance imaging; MS, multiple sclerosis. Neuropediatrics
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Autoantibody-Mediated Diseases Mimicking MS and Related Disorders Hashimoto Encephalopathy and Antithyroperoxydase Antibodies Hashimoto encephalopathy (HE) is a rare immune-mediated disease characterized by the presence of antithyroperoxydase antibodies (anti-TPO) in a child with acute encephalitis with predominant seizures, neuropsychiatric symptoms, and an alteration of consciousness or dystonia.14 It is also a chronic disease that relapses in some cases. It can be confused with ADEM at onset and with MS in the case of relapse. We recently reviewed all cases of acute encephalitis with compatible neurological symptoms observed at the French national reference center for inflammatory diseases of the CNS.15 The 42 selected patients included 8 children with HE (compatible clinical symptoms and median anti-TPO titer ¼ 2,838.5 IU/mL; range, 812–8,550 IU/mL) and 10 patients with a final diagnosis of acute demyelinating syndromes (6 ADEM, 2 MS, 2 CIS). For these HE cases and the small number of cases previously published, median age at onset was 12 years (range, 9–15 years) but an affected child aged 2 years and 10 months has also been reported.16 Most of the patients were girls. Most children were euthyroid and had an acute onset. The CSF was frequently abnormal, with pleocytosis (13%), high proteins titers (63%), and oligoclonal bands (43%). The EEG at onset was abnormal in some cases, but no specific pattern has been described. Similarly, brain MRI was abnormal in 50% of the children in our series, with abnormalities involving the white matter and gray matter distinctive enough for clear differential diagnosis from MS in most of the cases (►Fig. 1). Here, we routinely test for anti-TPO antibody in children with acute encephalitis without clear-cut symptoms of ADEM or presenting relapse, unless the clinical and radiological symptoms are typical of MS. HE usually responds to steroid treatment, but relapses are frequent. Immunosuppressive treatments (cyclophosphamide, mycophenolate-mofetil, or azathioprine) have been used, but there is currently no consensus concerning their efficacy, in the absence of formal results.
Acute Encephalitis with Anti-NDMA Receptor Antibody Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis can occasionally mimic ADEM or brain stem encephalitis at onset and, indeed, may have symptoms very similar to those of HE.17 Anti-NMDA receptor antibodies were detected in the serum of
Fig. 1 Various aspects of immune-mediated central nervous system demyelinating disorders on brain magnetic resonance imaging. (A) Axial T2-weighted image showing large fuzzy lesions affecting both hemisphere in a 6-year-old boy who had encephalopathy; gait difficulties at onset revealing an acute disseminated encephalomyelitis. (B) Axial T2-weighted image of a 3-year-old boy showing bilateral large and fuzzy lesions affecting right and left frontoparietal region as well as right occipital region in the context of generalized seizures with fever, associated with hemophagocytic lymphohistiocytosis. (C) Axial flair image of an 8-year-old boy showing a well-limited large right parieto occipital temporal lesion and left temporo parieto cortical lesions who presented partial seizures and hemiparesis, revealing an anaplastic large-cell lymphoma. (D) Axial T2-weighted image of a 10-year-old girl showing a lesion in the brain stem and mesencephalon. She presented relapsing gait difficulties and ataxia responding well to steroids with antithyroperoxydase antibodies confirming the diagnosis of Hashimoto encephalopathy.
1 of the 42 patients with acute encephalitis and predominantly acute cognitive and neuropsychiatric features (apart from the eight children with HE).15 In a published study of 32 children with acute encephalitis and anti-NMDA receptor antibodies, the median age at onset of the disease was 14 years (range, 23 months–18 years) and clinical symptoms included an association of fever, headache, and abnormal movements (84%), which was difficult to distinguish in some cases with partial or generalized seizures.18 Acute changes in behavior and oral dyskinesia were observed in half of the patients. CSF analysis showed pleocytosis (94%) and high protein titer (13%), and EEG was abnormal in almost all the cases, with epileptic activity reported in only 28% of the children. Brain MRI results at onset were abnormal in 30% of the cases, with hypersignal in the white matter or in cortical, cerebellar and temporal mesial areas, on T2-weighted images. Ovarian teratoma is frequently detected in adults suffering from this condition, whereas affected children are rarely found to have a tumor. The longterm course of the disease is marked by relapses despite Neuropediatrics
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in ADEM than in HLH. Gadolinium enhancement was slightly more frequent in HLH than in ADEM (33 vs. 16%) in our series but this difference was not statistically significant. Early diagnosis can be established by carrying out specific immunological tests (including analyses of perforin expression in lymphocytes, of the cytotoxic ability of the patient’s CD8 lymphocytes, before identification of the causal mutation) and is essential because treatment requires immunosuppression followed by a bone marrow transplantation. Other treatments invariably lead to relapses resulting in severe necrosis of the brain parenchyma.
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treatment in 20 to 30% of the cases.18 No formal therapeutic consensus has been established, but rituximab, plasmapheresis, and immunosuppressive drugs are the most frequently used treatment options.
Neuromyelitis Optica or Devic Disease and Antiaquaporin-4 Antibodies Neuromyelitis optica and MS are regarded as two distinct chronic relapsing white matter syndrome with recognizable differences in symptoms, detection of antiaquaporin-4 antibodies, outcome, and treatment. Neuromyelitis optica is defined by optic neuritis and/or acute myelitis which can be separated by a few weeks to months, associated with two of the following three secondary criteria: a normal brain MRI scan or brain lesions not suggestive of MS; the presence of contiguous spinal cord lesions extending over at least three vertebral segments; the presence of IgG directed against aquaporin 4.19 This condition is rare with a median age at onset of 14.5 years (range, 4.1–17.9 years), a female predominance and a median interval between the first and second attacks of 17 months (range, 7–154 months) in one series.20 In a report of 58 neuromyelitis optica (NMO)-IgG– positive children, brain symptoms were initially present in 9 (15%) children but 45% of the children went on to develop brain symptoms during the course of the disease, potentially leading to diagnostic confusion between NMO and MS.21 On brain MRI, lesions were found to be located in the periventricular areas of the third or fourth ventricle, in the midbrain, medulla, or pons. Large, extensive juxtacortical white matter lesions or lesions affecting the corpus callosum, with or without contrast enhancement, may be found, making it difficult to distinguish between this condition and ADEM or MS on the basis of radiological data. High doses of methylprednisolone are administered during the acute phase, and long-term immunosuppression is advocated although there is still some debate as to whether the most appropriate treatment is Rituximab, mycophenolate-mofetil, azathioprine, methotrexate, or more recently anticomplement C5 (eculizumab).22 It is now established that treatment with interferons can worsen NMO.23
Infectious Diseases (Lyme Disease) A few infectious diseases can mimic MS and related disorders, Lyme disease being the best known example.24 In Lyme disease, the most common neurological symptoms are observed in the second and third stages of the disease. They consist of meningitis and facial nerve palsy, but findings suggestive of parenchymal involvement may also be observed. The associated symptoms are a previous primary erythema migrans skin lesion and a tick bite, or the association with the neurological symptoms of multiple erythema migrans lesions, carditis, meningitis, and cranial nerve palsies.25 Arthritis is a sign of late Lyme disease. Brain MRI typically shows leptomeningeal enhancement or cranial or peripheral nerve root enhancement following the injection of gadolinium. White matter lesions are less common but when Neuropediatrics
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present may wrongly be considered indicative of MS. Diagnosis is usually based on the presence of typical neurological symptoms with positive results in serological tests and for polymerase chain reaction on the CSF. However, suggestive symptoms associated with CSF pleocytosis in the presence of positive serological tests for Lyme disease should be presumed to be neuro-Lyme disease. A two-step approach for serological testing is based on the use of a sensitive enzyme immunoassay or immunofluorescence assay followed by a standardized western immunoblot, to differentiate between false–positive and true–positive serological results, particularly for enzyme-linked immunosorbent assay values in the low positive range.
Tumors Mimicking Multiple Sclerosis The course of MS, with periods of relapse and remission, observed in more than 95% of the children with MS should prevent this condition being confused with tumors, but there are two exceptions. Oligodendroglioma and low-grade astrocytoma might initially yield MRI results reminiscent of white matter inflammatory diseases, leading to the incorrect diagnosis of MS if there are a few clinical symptoms. The principal clues are a gradual progression of clinical symptoms or a persistent deficit, the absence of spatial dissemination on initial MRI, and of modifications on subsequent MRI scans (or a slight extension). Spectroscopy of the pathological lesion may be useful and the diagnosis can usually be established on the basis of a biopsy.7,26 Primary cerebral lymphoma can be much more challenging to diagnose. A recent review reported 29 children with primary CNS lymphoma.27 In all these patients, disease was confined to the brain (n ¼ 26) or meninges (n ¼ 3), with no evidence of systemic lymphoma at presentation. The median age at diagnosis was 14 years, the youngest patient being 2 years old. The most frequent initial symptoms were headache/nausea, suggesting an increase in intracranial pressure, cerebellar symptoms, seizure, and hemiparesis. On MRI, 38% of the lesions were disseminated in space, with 41% of the lesions found in the basal ganglia and brain stem. CSF analysis was not informative in most cases (only 8 of the 26 patients had positive CSF cytological results for lymphoma). All the patients had primary CNS non-Hodgkin lymphoma (69% had diffuse large B-cell lymphoma, 17% had anaplastic large T-cell lymphoma, 7% had lymphoblastic lymphoma and 7% had Burkitt-like lymphoma). We observed an 8-year-old boy who initially had remitting relapsing symptoms and white matter lesions observed at different sites on successive MRI scans. As shown in ►Fig. 1, the lesion was large and welllimited with gadolinium enhancement. An initial brain biopsy indicated only “nonspecific inflammatory lesions.” The diagnosis was finally established when skin lesions appeared 4 months after the initial neurological lesions, leading after pathological evaluation of the skin lesion biopsy specimen to the diagnosis of anaplastic large-cell ALK1þ, CD30þ lymphoma, with detection of the NPM-ALK transcript. This transcript was retrospectively detected in the brain biopsy
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specimen, leading to the establishment of a diagnosis of primary CNS lymphoma.
2 Sadaka Y, Verhey LH, Shroff MM, et al; Canadian Pediatric
Other Genetic Diseases Mimicking Inflammatory White Matter Diseases
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Leukoencephalopathies Linked to Mutations Indirectly Modifying Intracerebral Inflammation Status This is a large group of rare diseases that are progressively being discovered. Their clinical symptoms are usually sufficiently different from ADEM and MS to avoid confusion, but borderline cases can be observed. The best example is Aicardi–Goutières syndrome. This neonatal-onset encephalopathy is associated with microcephaly, brain calcifications and high interferon-α concentration in the CSF.28 However, MRI demonstrates the presence of large white matter lesions and clinical onset may occur later in childhood. This syndrome is linked to various mutations affecting RNA metabolism or to proteins that normally prevent the self-activation of innate immunity by cell-intrinsic components.29,30 Another example is provided by a mutation of the colony-stimulating factor 1 receptor gene, which has recently been demonstrated to be the cause of a dominant form of leukoencephalopathy probably resulting from microglial dysfunction.31
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Mitochondrial Respiratory Chain Deficits Mitochondrial respiratory chain deficits are the metabolic diseases most frequently misdiagnosed as optic neuritis, brain stem encephalitis or MS. These deficits can present with optic neuropathy, the most common form of which being Leber hereditary optic neuropathy.32The mutations characteristic of this disease should be sought in cases of relapsing optic neuritis or nonresolving optic neuritis. Similarly, acute brain stem encephalitis may have clinical and radiological symptoms very similar to those of mitochondrial diseases, including Leigh disease in particular. An evaluation of lactate and pyruvate concentrations in blood and CSF, spectroscopy focusing on the white matter lesions and a direct study of respiratory chain activity in lymphocytes, fibroblasts, or muscle biopsy specimens should lead to establishment of the correct diagnosis.
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Conclusion ADEM and other disease related to MS are generally easy to recognize. However, a large spectrum of rare diseases, requiring different treatments, may also occur. Special attention should be paid to diagnosis in children under the age of 3 years, children from consanguineous families, children with relapsing or progressive disease despite treatments, and children with predominantly gray matter lesions on brain MRI.
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of Aicardi-Goutieres syndrome. Am J Hum Genet 2007;81(4): 713–725 Crow YJ, Hayward BE, Parmar R, et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat Genet 2006;38(8): 917–920 Rice GI, Bond J, Asipu A, et al. Mutations involved in AicardiGoutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet 2009;41(7):829–832 Rademakers R, Baker M, Nicholson AM, et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet 2012; 44(2):200–205 Harding AE, Sweeney MG, Miller DH, et al. Occurrence of a multiple sclerosis-like illness in women who have a Leber’s hereditary optic neuropathy mitochondrial DNA mutation. Brain 1992;115(Pt 4): 979–989
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