Actualización en el diagnóstico de la encefalitis / Update on the diagnosis of encephalitis

Las encefalitis autoinmunes son procesos inflamatorios cerebrales que se clasifican en dos grandes grupos según el mecanismo patogénico subyacente: las mediadas por anticuerpos vs. antígenos intracelulares (paraneoplásicas) y las mediadas por anticuerpos frente a los antígenos extracelulares o de superficie neuronal. Las manifestaciones clínicas son muy variadas y poco específicas. Las pruebas complementarias incluidas en el diagnóstico clínico de la encefalitis autoinmune incluyen, entre otras, la determinación de anticuerpos en suero o en líquido cefalorraquídeo y la resonancia magnética (RM). La RM puede presentar patrones característicos como la afectación mesial del temporal, aunque en determinados casos puede ser normal. La imagen de tomografía por emisión de positrones (PET/TC) con 18F-Fluorodeoxiglucosa (18F-FDG PET/TC) puede ser de gran utilidad en los casos de encefalitis autoinmunes paraneoplásicas para encontrar el tumor primario. En los casos de encefalitis autoinmunes mediadas por anticuerpos frente a los antígenos extracelulares, la 18F-FDG PET/TC presenta unos patrones que pueden ayudar al diagnóstico clínico. Esta colaboración especial pretende presentar de forma clara y de fácil comprensión las características clínicas de la encefalitis autoinmune, las dificultades en el diagnóstico clínico y los patrones observados en la RM y en la 18F-FDG PET/TC (AU)

Autoimmune encephalitis are brain inflammatory processes that are classified into two main groups according to the underlying pathogenic mechanism: antibodies to intracellular antigens (paraneoplastic) and antibodies to extracellular or neuronal surface antigens. The clinical manifestations of autoimmune encephalitis are very varied and non-specific. Complementary tests included in its clinical diagnosis include determination of antibodies in serum or cerebrospinal fluid and magnetic resonance imaging (MRI). MRI may show characteristic patterns such as mesial temporal involvement, although in some cases it may be normal or non-specific. 18F-Fluorodeoxyglucose PET/CT (18F-FDG PET/CT) imaging may be helpful in cases of paraneoplastic autoimmune encephalitis to find the primary tumor. In autoimmune encephalitis mediated by antibodies to extracellular antigens, 18F-FDG PET/CT shows distinctive patterns that can aid clinical diagnosis. This special collaboration aims to present in a clear and easy-to-understand way, the clinical features of autoimmune encephalitis, the difficulties in clinical diagnosis and the patterns seen on MRI and 18F-FDG PET/CT (AU)

Recognition of seizure semiology and semiquantitative FDG-PET analysis of anti-LGI1 encephalitis.

AIMS: Anti-leucine-rich glioma-inactivated 1 (LGI1) autoimmune encephalitis (AE) is characterized by complex manifestations of seizures. Here, we report a new seizure semiology, attempt to classify the disease by semiology type, and explore the metabolic pattern of each group. METHODS: Anti-LGI1 AE patients were retrospectively screened between May 2014 and September 2019 in our tertiary epilepsy center. All enrolled patients had seizures during long-range video electroencephalogram (EEG) recordings, and all patients (except one) underwent [18 F] fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) scans. Voxel-based metabolic analysis and z-distribution analysis were carried out to determine the metabolic pattern. RESULTS: Thirty-three patients were enrolled. According to the patients' seizure semiology, we divided the patients into four groups: focal impaired awareness seizures (FIAS, n = 17), faciobrachial dystonic seizures (FBDS)-only (n = 6), FBDS-plus (n = 8), and focal aware motor seizures (FAMS) (n = 2). No significant differences were found in the clinical manifestations or accessory tests except for the onset age (FIAS < FBDS-plus) and seizure semiology. This was the first study to extensively describe the clinical manifestations and EEG of FAMS in anti-LGI1 AE patients. In addition, we found that the patients with different semiologies all showed a wide range of abnormal metabolism, which is not limited to the temporal regions and basal ganglia, and extends far beyond our previous interpretation of FDG-PET data. CONCLUSION: Our results showed that FAMS can serve as a rare indicative seizure semiology of anti-LGI1 AE and that individuals with this disease exhibited widespread functional network alterations.

Clinical Presentation and Outcomes of Severe Acute Respiratory Syndrome Coronavirus 2-Related Encephalitis: The ENCOVID Multicenter Study.

BACKGROUND: Several preclinical and clinical investigations have argued for nervous system involvement in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some sparse case reports have described various forms of encephalitis in coronavirus disease 2019 (COVID-19) disease, but very few data have focused on clinical presentations, clinical course, response to treatment, and outcomes. METHODS: The SARS-CoV-2 related encephalopaties (ENCOVID) multicenter study included patients with encephalitis with full infectious screening, cerebrospinal fluid (CSF), electroencephalography (EEG), and magnetic resonance imaging (MRI) data and confirmed SARS-CoV-2 infection recruited from 13 centers in northern Italy. Clinical presentation and laboratory markers, severity of COVID-19 disease, response to treatment, and outcomes were recorded. RESULTS: Twenty-five cases of encephalitis positive for SARS-CoV-2 infection were included. CSF showed hyperproteinorrachia and/or pleocytosis in 68% of cases whereas SARS-CoV-2 RNA by reverse-transcription polymerase chain reaction resulted negative. Based on MRI, cases were classified as acute demyelinating encephalomyelitis (ADEM; n = 3), limbic encephalitis (LE; n = 2), encephalitis with normal imaging (n = 13), and encephalitis with MRI alterations (n = 7). ADEM and LE cases showed a delayed onset compared to the other encephalitis cases (P = .001) and were associated with previous, more severe COVID-19 respiratory involvement. Patients with MRI alterations exhibited worse response to treatment and final outcomes compared to those with other encephalitis. CONCLUSIONS: SARS-CoV-2 infection is associated with a wide spectrum of encephalitis characterized by different clinical presentation, response to treatment, and outcomes.

Differences and diversity of autoimmune encephalitis in 77 cases from a single tertiary care center.

BACKGROUND: The incidence of autoimmune encephalitis has risen globally. There are two general categories of disease-associated antibodies that can be tested for: neuronal surface and intracellular. However, testing both groups of autoantibodies are costly. This study aims to identify differences between groups by comparing clinical presentations, radiological findings and CSF profile of patients, and determine if any parameters are indicative of one group of autoantibodies over another. Additionally, we aim to report the local incidence of less common groups of disease-associated antibodies as well. METHODS: Seventy-seven records of autoimmune encephalitis/encephalomyelitis patients admitted to King Chulalongkorn Memorial Hospital, Bangkok, Thailand, between October 2010 and February 2017 were reviewed. Patients with infections or those with classic central nervous system demyelinating features were excluded. RESULTS: Of 77 patients, 40% presented with neuronal surface antibodies and 33% had intracellular antibodies. The most common autoantibody detected in each group was anti-NMDAr antibody (25/31, 81%) and anti-Ri antibody (7/25, 28%) respectively. In the neuronal surface antibody group, behavioral change was the most common complaint (45%), followed by seizures (39%) and abnormal movements (29%). In the latter group, seizure was the most common presenting symptom (32%), followed by motor weakness (20%), behavioural change (16%) and abnormal movements (16%). Patients with neuronal surface antibodies were younger (35 vs 48 years old, p = 0.04) and more likely to present with behavioral change (45% vs 16%, p = 0.02). Mortality rate was higher in the intracellular group (16% vs 3.2%, p = 0.09). No differences were detected in magnetic resonance imaging (MRI) and CSF profile. CONCLUSIONS: In the early stages of the disease, both groups have comparable clinical outcomes. Although there were significant differences in age and percentage of patients with behavioral change, both groups of autoimmune encephalitis still shared many clinical features and could not be distinguished based on MRI and CSF profiles. Therefore, we recommend that patients with features of autoimmune encephalitis should be screened for both the neuronal surface and intracellular antibodies regardless of clinical presentation.

[Autoimmune encephalitis. Anti-NMDA receptor and new immunophenotypes]. / Encefalitis autoinmunes. Receptor anti-NMDA y nuevos inmunofenotipos.

Autoimmune encephalitis (AE) is defined as neurological syndromes of subacute installation of compromise of consciousness, alteration of working memory and psychiatric disorders associated with abnormal movements and epileptic seizures and that are produced by the action of anti-neuronal antibodies. They bind to neurotransmitter receptors or membrane proteins. Antibody to NMDAR is the origin of the majority of cases of AD in children and young adults, followed by anti-LGI1 antibody for presentation in adults. The AE has increased in the last decade, with a large number of new agents described that produce mostly neurological syndromes that involve the central nervous system, with predominance of psychiatric signaling, except in children and the predominant abnormal movements, epileptic seizures and compromise of conscience. They are frequently associated with tumors in adults but in children this association is more infrecuent. All AEs respond to immunomodulatory therapy although in different measures depending on the type of antibody involved. In general, the evolution to improvement is slow and can be completed in months or even in one year or more. In this review, the main EA clinical pictures related to specific antibodies are highlighted, also mentioning recently discovered immunophenotypes.

Las encefalitis autoinmunes (EA) se definen como síndromes neurológicos de instalación subaguda de compromiso de conciencia, alteración de la memoria de trabajo y trastornos psiquiátricos frecuentemente asociados a movimientos anormales y crisis epilépticas y que se producen por la acción de anticuerpos anti neuronales específicos que se fijan a receptores de neurotransmisores o proteínas de membrana. El anticuerpo anti NMDAR es el que origina la mayoría de los casos de EA en niños y adultos jóvenes, seguido por el anticuerpo anti LGI1 de presentación en el adulto. Las EA han aumentado en la última década, en la que se ha descrito un gran número de nuevos anticuerpos que producen en su mayoría síndromes neurológicos que involucran al sistema nervioso central, con predominio de signología psiquiátrica, excepto en niños en los que predominan movimientos anormales, crisis epilépticas y compromiso de conciencia. Se asocian frecuentemente a tumores en el adulto pero en los niños esta asociación es más rara. Todas las EA responden a terapia inmunomoduladora aunque en diferente medida según el tipo de anticuerpo involucrado. Generalmente la evolución a la mejoría es lenta y puede completarse en meses o incluso en un año o más. En esta revisión se destaca los principales cuadros de EA relacionados con anticuerpos específicos mencionando también los inmunofenotipos descubiertos recientemente.

Encefalitis autoinmunes: Receptor anti-NMDA y nuevos inmunofenotipos / Autoimmune encephalitis. Anti-NMDA receptor and new immunophenotypes

Las encefalitis autoinmunes (EA) se definen como síndromes neurológicos de instalación subaguda de compromiso de conciencia, alteración de la memoria de trabajo y trastornos psiquiátricos frecuentemente asociados a movimientos anormales y crisis epilépticas y que se producen por la acción de anticuerpos anti neuronales específicos que se fijan a receptores de neurotransmisores o proteínas de membrana. El anticuerpo anti NMDAR es el que origina la mayoría de los casos de EA en niños y adultos jóvenes, seguido por el anticuerpo anti LGI1 de presentación en el adulto. Las EA han aumentado en la última década, en la que se ha descrito un gran número de nuevos anticuerpos que producen en su mayoría síndromes neurológicos que involucran al sistema nervioso central, con predominio de signología psiquiátrica, excepto en niños en los que predominan movimientos anormales, crisis epilépticas y compromiso de conciencia. Se asocian frecuentemente a tumores en el adulto pero en los niños esta asociación es más rara. Todas las EA responden a terapia inmunomoduladora aunque en diferente medida según el tipo de anticuerpo involucrado. Generalmente la evolución a la mejoría es lenta y puede completarse en meses o incluso en un año o más. En esta revisión se destaca los principales cuadros de EA relacionados con anticuerpos específicos mencionando también los inmunofenotipos descubiertos recientemente.

Autoimmune encephalitis (AE) is defined as neurological syndromes of subacute installation of compromise of consciousness, alteration of working memory and psychiatric disorders associated with abnormal movements and epileptic seizures and that are produced by the action of anti-neuronal antibodies. They bind to neurotransmitter receptors or membrane proteins. Antibody to NMDAR is the origin of the majority of cases of AD in children and young adults, followed by anti-LGI1 antibody for presentation in adults. The AE has increased in the last decade, with a large number of new agents described that produce mostly neurological syndromes that involve the central nervous system, with predominance of psychiatric signaling, except in children and the predominant abnormal movements, epileptic seizures and compromise of conscience. They are frequently associated with tumors in adults but in children this association is more infrecuent. All AEs respond to immunomodulatory therapy although in different measures depending on the type of antibody involved. In general, the evolution to improvement is slow and can be completed in months or even in one year or more. In this review, the main EA clinical pictures related to specific antibodies are highlighted, also mentioning recently discovered immunophenotypes.

[Autoimmune encephalitis. New diagnosis for an old condition]. / Autoimmune encephalitis. New diagnosis for an old condition.

Autoimmune encephalitis is a new group of diseases of great clinical and therapeutic importance due to the good response in most cases to the immunomodulatory therapy indicated, with a large percentage of healing without significant neurological effects (cognitive, motor, seizures or involuntary movements). Since 2007, the presence of neuronal autoantibodies in the pathogenesis of this group of diseases has been demonstrated, with psychotic symptoms and involuntary movements as clinical markers of the disease. The present review emphasizes the crucial leap and change of paradigms arising after the discovery of these encephalitis associated with antibodies.

[Autoimmune encephalitis. A review]. / Encefalitis autoinmunes: criterios diagnósticos y pautas terapéuticas.

Autoimmune encephalitis are one of the emergent causes of subacute changes in the level of consciousness, behavior, cognitive impairment and seizures, mainly in young people. They are a consequence of inflammation or dysfunction of parts of the brain caused by antibodies against specific brain antigens, usually located in the limbic system, resulting in clinical presentation as a limbic encephalitis. The objectives of this article are to show the clinical presentation, complementary studies and treatment of this entity, considering that the patient's prognostic depends on a high level of clinical suspicion, and on an early initiation of immunosuppressive therapy. We did a nonsystematic review of the literature on autoimmune encephalitis between 2005 and 2017. We conclude that the prevalence of autoimmune encephalitis is increasing, even surpassing infectious causes of encephalitis in developed countries. Clinical presentation includes sub-acute cognitive and behavioral impairment, with or without alterations in consciousness and seizures. Fever and inflammation of the cerebrospinal fluid are less common than in the infectious causes but psychiatric symptoms are more frequent. There are specific clinical presentations according to the particular type of antigen/antibody present, which also determines the association with cancer, constituting a paraneoplastic syndrome only in some cases. Immunosuppressive therapy has been standardized in steps, and should be initiated early to improve prognosis.

Encefalitis autoinmunes: criterios diagnósticos y pautas terapéuticas / Autoimmune encephalitis. a review

Autoimmune encephalitis are one of the emergent causes of subacute changes in the level of consciousness, behavior, cognitive impairment and seizures, mainly in young people. They are a consequence of inflammation or dysfunction of parts of the brain caused by antibodies against specific brain antigens, usually located in the limbic system, resulting in clinical presentation as a limbic encephalitis. The objectives of this article are to show the clinical presentation, complementary studies and treatment of this entity, considering that the patient's prognostic depends on a high level of clinical suspicion, and on an early initiation of immunosuppressive therapy. We did a nonsystematic review of the literature on autoimmune encephalitis between 2005 and 2017. We conclude that the prevalence of autoimmune encephalitis is increasing, even surpassing infectious causes of encephalitis in developed countries. Clinical presentation includes sub-acute cognitive and behavioral impairment, with or without alterations in consciousness and seizures. Fever and inflammation of the cerebrospinal fluid are less common than in the infectious causes but psychiatric symptoms are more frequent. There are specific clinical presentations according to the particular type of antigen/antibody present, which also determines the association with cancer, constituting a paraneoplastic syndrome only in some cases. Immunosuppressive therapy has been standardized in steps, and should be initiated early to improve prognosis.

The expanding spectrum of clinically-distinctive, immunotherapy-responsive autoimmune encephalopathies.

The autoimmune encephalopathies are a group of conditions that are associated with autoantibodies against surface neuronal proteins, which are likely to mediate the disease. They are established as a frequent cause of encephalitis. Characteristic clinical features in individual patients often allow the specificity of the underlying antibody to be confidently predicted. Antibodies against the VGKC-complex, mainly LGI1(leucine-rich glioma-inactivated 1), CASPR2 (contactin-associated protein 2), and contactin-2, and NMDA (N-methyl, D-aspartate) -receptor are the most frequently established serological associations. In the minority of cases, an underlying tumour can be responsible. Early administration of immunotherapies, and tumour removal, where it is relevant, offer the greatest chance of improvement. Prolonged courses of immunotherapies may be required, and clinical improvements often correlate well with the antibody levels. In the present article, we have summarised recent developments in the clinical and laboratory findings within this rapidly expanding field.

The expanding spectrum of clinically-distinctive, immunotherapy-responsive autoimmune encephalopathies / O espectro em expansão das encefalopatias autoimunes clinicamente distintas e que respondem à imunoterapia

The autoimmune encephalopathies are a group of conditions that are associated with autoantibodies against surface neuronal proteins, which are likely to mediate the disease. They are established as a frequent cause of encephalitis. Characteristic clinical features in individual patients often allow the specificity of the underlying antibody to be confidently predicted. Antibodies against the VGKC-complex, mainly LGI1(leucine-rich glioma-inactivated 1), CASPR2 (contactin-associated protein 2), and contactin-2, and NMDA (N-methyl, D-aspartate) -receptor are the most frequently established serological associations. In the minority of cases, an underlying tumour can be responsible. Early administration of immunotherapies, and tumour removal, where it is relevant, offer the greatest chance of improvement. Prolonged courses of immunotherapies may be required, and clinical improvements often correlate well with the antibody levels. In the present article, we have summarised recent developments in the clinical and laboratory findings within this rapidly expanding field.

As encefalopatias autoimunes constituem um grupo de condições associadas à presença, no soro, de anticorpos contra proteínas de superfície neuronais. Acredita-se que esses anticorpos sejam mediadores da ocorrência da doença, sendo reconhecidos atualmente como causas frequentes de encefalite. Apresentações clínicas características permitem, muitas vezes, predizer o grupo específico de anticorpos subjacentes. Anticorpos contra o complexo VGKF, especialmente LGI1 (leucine-rich glioma-inactivated1), CASPR2 (contactin-associated protein 2) e contactina-2, e contra o receptor NMDA(N-methyl, D-aspartate) são as associações sorológicas mais frequentemente estabelecidas. Na minoria dos casos, pode ser detectado um tumor subjacente. As maiores chances de melhora estão relacionadas à administração precoce de imunoterapia e à remoção do tumor, quando presente. A duração da imunoterapia pode se prolongada e a melhora se correlaciona, muitas vezes, com os níveis séricos de anticorpos. Neste artigo, estão resumidos os avanços recentes nos achados clínicos e laboratoriais neste campo que está em tão rápida expansão.

[Pathogenesis of acute encephalitis and acute encephalopathy].

Many aspects of the pathogenesis of acute encephalitis and acute encephalopathy have been clarified in this decade, although many unknown mechanisms remain to be elucidated. According to progress of MRI and neuroimmunological analysis and the observation of clinical findings, many new syndromes were found, which enhanced our understanding of acute encephalitis and acute encephalopathy. The pathogenesis of encephalitis is divided into infection and immune mediated mechanisms. The antibodies to neuronal surface antigens(NSA) such as NMDA receptors, leucin-rich glioma inactivated 1 (LGI1) and aquaporin 4 were demonstrated in specific encephalitis, limbic encephalitis and neuromyelitis optica. Anti-NSA antibody encephalitis should be treated by immunotherapy such as corticosteroid and plasmapheresis. Acute encephalitis with refractory repetitive partial seizures (AERRPS) is a devastating postinfectious disease in children and adults, although the pathogenesis of AERRPS is poorly understood. Influenza associated encephalopathy(IAE) is characterized by it's high incidence in Japanese children between 1 year and 5 years of age, its onset in the first or the second day of illness and its high mortality (15-30%) and morbidity (25-40%). We proposed the classification of IAE with poor prognosis from the neuroradiological findings. Four types of encephalopathy seem to be differentiated from each other, acute necrotizing encephalopathy (ANE) type, hemorrhagic shock and encephalopathy syndrome (HSES) type, acute brain swelling (ABS) type, febrile convulsive status epilepticus (FCSE) type. The notable radiological features are thalamic lesions in ANE, diffuse cerebral cortical cytotoxic edema in HSES, reversible cerebral swelling in ABS which sometimes reaches lethal brain herniation, and in FCSE type, dendritic high signal in subcortical white matter by DWI ("bright tree appearance") appears simultaneously with the later onset of repetitive focal seizure. These four types are not specific to IAE but are noticed in another encephalopathies caused by HHV6, rotavirus, etc.

Comparison of oral administration of lomustine and prednisolone or prednisolone alone as treatment for granulomatous meningoencephalomyelitis or necrotizing encephalitis in dogs.

OBJECTIVE: To compare oral administration of lomustine and prednisolone with oral administration of prednisolone alone as treatment for granulomatous meningoencephalomyelitis (GME) or necrotizing encephalitis (NE) in dogs. DESIGN: Retrospective cohort study. ANIMALS: 25 dogs with GME and 18 dogs with NE (diagnosis confirmed in 8 and 5 dogs, respectively). PROCEDURES: Records of dogs with GME or NE were reviewed for results of initial neurologic assessments and clinicopathologic findings, treatment, follow-up clinicopathologic findings (for lomustine-treated dogs), and survival time. Dogs with GME or NE treated with lomustine and prednisolone were assigned to groups 1 (n = 14) and 3 (10), respectively; those treated with prednisolone alone were assigned to groups 2 (11) and 4 (8), respectively. RESULTS: Prednisolone was administered orally every 12 hours to all dogs. In groups 1 and 3, mean lomustine dosage was 60.3 mg/m², PO, every 6 weeks. Median survival times in groups 1 through 4 were 457, 329, 323, and 91 days, respectively (no significant difference between groups 1 and 2 or between groups 3 and 4). Within the initial 12 months of treatment, median prednisolone dosage was reduced in all groups; dosage reduction in group 1 was significantly larger than that in group 2 at 6, 9, and 12 months. Combination treatment most frequently caused leukopenia, but had no significant effect on liver enzyme activities. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs with GME and NE, oral administration of lomustine and prednisolone or prednisolone alone had similar efficacy. Inclusion of lomustine in the treatment regimen was generally tolerated well.

Epidemiological study of acute encephalitis in Tottori Prefecture, Japan.

BACKGROUND AND PURPOSE: To conduct an epidemiological survey of acute encephalitis focusing on non-herpetic acute limbic encephalitis (NHALE) in Tottori Prefecture, western area of Japan. METHODS: A questionnaire survey on the annual number of patients aged 16 years or more with acute encephalitis from 2001 to 2005 was undertaken in 2006. RESULTS: During the study period, 49 patients were diagnosed with acute encephalitis. The subtype of acute encephalitis was as follows: 10 patients with herpes simplex encephalitis (HSE), 12 patients with NHALE, 4 patients with paraneoplastic encephalitis, 2 patients with encephalitis associated with collagen disease, one patient with viral encephalitis other than HSE, 20 patients with encephalitis with unknown causes. The service-based incidence rate of acute encephalitis was 19.0 per million person-years. The incidence rate of NHALE subtype was 4.7 per million person-years. CONCLUSIONS: Our epidemiological survey indicated an estimated 550 patients would develop NHALE per year in Japan, suggesting that NHALE may not be a rare disorder.

[Bickerstaff's brainstem encephalitis with positive findings on head MRI--case report].

We report a case of Bickerstaff's brainstem encephalitis (BBE) with positive findings on head MRI. Abnormal lesions on head MRI were detected in approximately 30% cases of BBE. An 81-year-old female presented with disturbance of consciousness (Japan Coma Scale 200), ophthalmoplegia (downward deviation) and tetraplegia. Cerebrospinal fluid examination revealed mild pleocytosis 244 cells in 3 microl of CSF with normal glycorrhachia. Head MRI showed high-intensity abnormalities extending over the brain stem. The patient was diagnosed with BBE. It was thought that her symptoms were believed to arise from the lesion in reticular formation, rostral interstitial nucleus of the medial longitudinal fasciculus, and the pyramidal tract. At discharged after 1 month, she had no sequela.

MRI characteristics of atypical idiopathic inflammatory demyelinating lesions of the brain : A review of reported findings.

BACKGROUND: Idiopathic inflammatory demyelinating lesions (IIDL) of the brain usually present with a morphologic pattern characteristic of multiple sclerosis (MS). Atypical appearances of IIDLs also exist, however, and can pose significant diagnostic problems and uncertainty regarding prognosis and adequate therapy. We attempted to improve upon this situation by reviewing the literature. METHODS: We performed a PubMed search from January 1984 through December 2004 for articles in English reporting on IIDLs which had been considered as morphologically atypical (66 articles; 270 cases reported). From these publications 69 individual patient reports allowed the extraction of adequate information on magnetic resonance imaging (MRI) and associated disease characteristics. RESULTS: Reported atypical IIDLs most frequently manifested as large ring-like lesions (n = 27) which are now considered quite suggestive of an antibodymediated form of MS. Truly atypical IIDLs were less common and exhibited appearances which we termed megacystic (n = 8), Balolike (n = 11) and diffusely infiltrating (n = 11). Despite limitations imposed by the absence of original data the inter-rater agreement in defining these subtypes of atypical IIDLs was moderate to substantial (kappa 0.48-0.68) and we noted trends for their association with certain demographic, clinical and paraclinical variables. INTERPRETATION: We suggest that IIDLs reported as atypical in the literature can be segregated into several distinct subtypes based on their MRI appearance. The recognition of these patterns may be useful for the differential diagnosis and for a future classification. Because of the limitations inherent in our review this will have to be confirmed by a prospective registry.