Tumefactive Demyelination Lesions: Report on three cases.

PURPOSE: Tumefactive demyelination (TD) lesion and its subtype Balo's concentric sclerosis (BCS), are rare manifestations of central nervous system demyelinating disease. Because of its rarity, physicians might hesitate in reaching a diagnosis or initiating steroid pulse therapy. This study aims at pinpointing the key neuroimaging features to distinguish TD lesions from surgical conditions, and illustrating the clinical outcomes of patients with TD lesions. CASE REPORT: Two of the three patients had solitary TD lesions, one 47-year-old man presenting with newly onset seizure and another 54-year-old women suffering from progressive hemiparesis. The male patient underwent craniotomy for mass excision without further steroid therapy, while the female patient received methylprednisolone pulse therapy only. Both patients remained free of clinical and radiological relapses over the past 6-7 years, leading to the diagnosis of clinically isolated syndrome. The third case is a 30-year-old woman with subacute onset of dysarthria and hemiparesis. She had two BCS lesions along with other demyelinating lesions in the juxtacortical and periventricular regions, cerebellar peduncles, and spinal cord, fulfilling dissemination in time and space. Her neurological deficits resolved after pulse therapy, and she received long-term disease modifying therapy for multiple sclerosis. CONCLUSION: This study underscores the diverse neuroimaging and clinical presentations of patients with TD lesions, and emphasizes the importance of clinical vigilance regarding this rare condition.

[TUMOR-LIKE EFFECT AS INITIAL PRESENTATION OF PEDIATRIC MULTIPLE SCLEROSIS].

INTRODUCTION: In both children and adults, magnetic resonance imaging of the brain in cases of multiple sclerosis (MS) has typical indications, where one of the key points for differentiating between demyelinating processes and place-taking processes is the fact that most of the lesions that appear in multiple sclerosis do not cause a mass effect or much edema around them. There are several uncommon subtypes of multiple sclerosis that can appear specifically in adolescents, presenting with a stormy clinical course and accompanied by brain lesions that resemble space-occupying lesions. These include Marburg disease, Balò's concentric sclerosis, and tumefactive MS. These unusual presentations raise the question regarding the ability to distinguish between neoplastic and demyelinating processes. In this article we present two case studies that illustrate this diagnostic dilemma and an accompanying literature review.

Antibody signatures in patients with histopathologically defined multiple sclerosis patterns.

Early active multiple sclerosis (MS) lesions can be classified histologically into three main immunopathological patterns of demyelination (patterns I-III), which suggest pathogenic heterogeneity and may predict therapy response. Patterns I and II show signs of immune-mediated demyelination, but only pattern II is associated with antibody/complement deposition. In pattern III lesions, which include Baló's concentric sclerosis, primary oligodendrocyte damage was proposed. Serum antibody reactivities could reflect disease pathogenesis and thus distinguish histopathologically defined MS patterns. We established a customized microarray with more than 700 peptides that represent human and viral antigens potentially relevant for inflammatory demyelinating CNS diseases, and tested sera from 66 patients (pattern I n = 12; II n = 29; III n = 25, including 8 with Baló's), healthy controls, patients with Sjögren's syndrome and stroke patients. Cell-based assays were performed for aquaporin 1 (AQP1) and AQP4 antibody detection. No single peptide showed differential binding among study cohorts. Because antibodies can react with different peptides from one protein, we also analyzed groups of peptides. Patients with pattern II showed significantly higher reactivities to Nogo-A peptides as compared to patterns I (p = 0.02) and III (p = 0.02). Pattern III patients showed higher reactivities to AQP1 (compared to pattern I p = 0.002, pattern II p = 0.001) and varicella zoster virus (VZV, compared to pattern II p = 0.05). In patients with Baló's, AQP1 reactivity was also significantly higher compared to patients without Baló's (p = 0.04), and the former revealed distinct antibody signatures. Histologically, Baló's patients showed loss of AQP1 and AQP4 in demyelinating lesions, but no antibodies binding conformational AQP1 or AQP4 were detected. In summary, higher reactivities to Nogo-A peptides in pattern II patients could be relevant for enhanced axonal repair and remyelination. Higher reactivities to AQP1 peptides in pattern III patients and its subgroup of Baló's patients possibly reflect astrocytic damage. Finally, latent VZV infection may cause peripheral immune activation.

Heterogeneity of Baló's concentric sclerosis: a study of eight cases with different therapeutic concepts.

BACKGROUND: Baló's Concentric Sclerosis (BCS) is a rare heterogeneous demyelinating disease with a variety of phenotypes on Magnetic Resonance Imaging (MRI). Existing literature lacks data especially on the therapeutic approach of the disease which we intended to elucidate by means of suggesting a new possible BCS classification and introducing different therapeutic concepts based on each BCS-subgroup characteristics. METHODS: We present a retrospective study of eight treated patients with BCS-type lesions, emphasizing on MRI characteristics and differences on therapeutic maneuvers. RESULTS: Data analysis showed: at disease onset the BCS-type lesion was tumefactive (size ≥2 cm) in 6 patients, with a mean size of 2.7 cm (± 0.80 SD); a coexistence of MS-like plaques on brain MRI was identified in 7 patients of our cohort. The mean age was 26.3 years (±7.3 SD) at disease onset and the mean follow-up period was 56.8 months (range 9-132 months). According to radiological characteristics and response to therapies, we further categorized them into 3 subgroups: a) Group-1; BCS with or without coexisting nonspecific white matter lesions; poor response to intravenous methylprednisolone (IVMP); treated with high doses of immunosuppressive agents (4 patients), b) Group-2; BCS with typical MS lesions; good response to IVMP; treated with MS-disease modifying therapies (2 patients), c) Group-3; BCS with typical MS lesions; poor response to IVMP; treated with rituximab (2 patients). CONCLUSIONS: Our study introduces a new insight regarding the categorization of BCS into three subgroups depending on radiological features at onset and during the course of the disease, in combination with the response to different immunotherapies. Immunosuppressive agents such as cyclophosphamide are usually effective in BCS. However, therapeutic alternatives like anti-CD20 monoclonal antibodies or more classical disease-modifying MS therapies can be considered when BCS has also mixed lesions similar to MS. Future studies with a larger sample size are necessary to further establish these findings, thus leading to better treatment algorithms and improved clinical outcomes.

[First description of Schilder's disease : Paul Ferdinand Schilder and his struggle for the delimitation of a new entity]. / Die Erstbeschreibung der Schilder-Krankheit : Paul Ferdinand Schilder und sein Ringen um die Abgrenzung einer neuen Entität.

Paul Ferdinand Schilder was born in Vienna in 1886 and died in New York in 1940. He is nowadays remembered predominantly for his contributions to modern psychiatry and psychotherapy; however, he was also a neurologist and neuroscientist and in particular in his early years, he researched and published on neuropathological topics. This paper focuses on his scientific work during his years in Middle Germany (1909-1914), where he worked with Gabriel Anton in Halle and Paul Flechsig in Leipzig. During those years, he laid the foundations for his definition, clinical classification and differentiation of encephalitis periaxialis diffusa. Today, this inflammatory brain disease is known as Schilder's disease and is of some importance as a rare differential diagnosis of multiple sclerosis (MS), especially in children. Schilder's reflections and findings were based on his scrupulous and detailed analysis of only a few medical histories, which also comprised histological neuropathological examinations, as well as on his extensive and critical review of the relevant literature of the time. His aim was to differentiate encephalitis periaxialis diffusa from brain tumors, MS and Heubner's diffuse sclerosis. Schilder's scientific achievement, made in relatively young years, is still impressive even to the present day due do its thoroughness and accuracy as well as the enormous workload and ambition it required. Even though ambitious, Schilder was always prepared to critically review his own ideas.

Exploring the overlap between multiple sclerosis, tumefactive demyelination and Baló's concentric sclerosis.

The availability of magnetic resonance imaging (MRI) has led to increasing recognition that multiple sclerosis (MS), tumefactive demyelination (TD) and Baló's concentric sclerosis (BCS) share many overlapping features. Baló-like lesions, which exhibit limited features of BCS, may represent an intermediate between BCS and typical MS demyelination. Lesions labeled as tumefactive are typically larger, but otherwise have much in common with conventional MS lesions, and TD and BCS lesions can also overlap. In this article, we explore the similarities between typical MS, TD and BCS cases, and reflect on the potential insights that intermediate or overlapping phenotypes may contribute towards an understanding of MS immunopathogenesis, and question whether these atypical forms of demyelination should be classified as separate demyelinating diseases, as different lesional manifestations of demyelination of any cause or as part of a spectrum with conventional MS.

"Clues on Balo's concentric sclerosis evolution from serial analysis of ADC values".

Balò's sclerosis is considered a rare variant of multiple sclerosis characterized by demyelination with concentric rings. Advanced magnetic resonance studies allow nowadays early diagnosis and prompt treatment. However, the pathophysiology of lesion evolution is still matter of debate, as detailed in our literature review. Based on a clear-cut Balò's lesion analysis, we describe early changes in DWI and ADC values within the different layers, favoring the concept of a centrifugal growth.

Peripheral late reactivation of a previously typical monofocal Baló's concentric sclerosis lesion.

We report a 41-year-old woman with rapidly progressive left hemiparesis, revealing an inflammatory reactivation of a previously known parietal Baló's concentric sclerosis lesion. The first attack occurred five years before. After a slow recovery following high-dose steroid infusions the patient stabilized. Because of recurrent ataxia and left hemiparesis a new magnetic resonance imaging was performed showing an extension of the initial lesion with a peripheral gadolinium enhancement on T1-weighted images. Such a reactivation pattern of an isolated Baló's concentric sclerosis lesion, occurring some years later, is described for the first time.

Early disruption of glial communication via connexin gap junction in multiple sclerosis, Baló's disease and neuromyelitis optica.

Multiple sclerosis (MS), neuromyelitis optica (NMO), and Baló's disease (BD) are inflammatory demyelinating diseases of the CNS. We previously reported anti-aquaporin-4 (anti-AQP4) antibody-dependent AQP4 loss occurs in some NMO patients, while antibody-independent AQP4 astrocytopathy can occur in heterogeneous demyelinating conditions, including MS, NMO and BD. To investigate the relationship between astrocytopathy and demyelination, we focused on connexins (Cxs), which form gap junctions (GJs) between astrocytes and oligodendrocytes and maintain homeostasis in the CNS. We evaluated expression of astrocytic Cx43/Cx30 and oligodendrocytic Cx47/Cx32 in autopsied materials from MS, NMO and BD patients. Astrocytic Cx43 and oligodendrocytic Cx32/Cx47 expressions were significantly diminished in both demyelinated and preserved myelin layers in all BD samples. In the leading edge of BD lesions, Cx43 and AQP4 loss preceded Cx32/Cx47 loss. Half of the NMO and MS samples showed preferential loss of astrocytic Cx43 expression in actively demyelinating and chronic active lesions, where heterotypic Cx43/Cx47 astrocyte-oligodendrocyte GJs were lost. Cases with Cx43 loss were significantly associated with rapid disease progression, regardless of the disease phenotype. Pathologically, Cx43 loss was frequently accompanied by distal oligodendrogliopathy. Our findings suggest that Cx43 astrocytopathy can occur in MS, BD and NMO. Moreover, astrocytic Cx43 loss may be associated with disease aggressiveness and distal oligodendrogliopathy in demyelinating conditions. Early disruption of glial communications via GJs may cause loss of glia syncytium, thereby inducing oligodendroglial damage and myelin loss. Inhibition of Cx hemichannels and restoration of GJs may be a possible therapeutic target for demyelinating disorders.

Baló concentric sclerosis: Literature review and report of two cases.

BACKGROUND: Baló's concentric sclerosis (BCS) is a rare variant of multiple sclerosis characterized by unique pathological features of alternating demyelination and preserved myelin. OBJECTIVES: To describe two cases of BCS, radiological and pathological findings and its clinical course. RESULTS: We report two distinct cases of BCS that presented with unique MRI findings suggestive of BCS, but with different clinical courses and responses to treatment. The first case demonstrated substantial recovery following corticosteroid therapy, while the second case, initially suspected to be a malignant tumour, showed improvement after surgical intervention and immunoglobulin therapy. CONCLUSION: These cases highlight the variability in presentation and course of BCS, underscoring the challenges in diagnosis and the importance of considering BCS in the differential diagnosis of demyelinating and tumefactive lesions. The cases also emphasize the potential for favourable outcomes with appropriate management, challenging the traditional view of BCS as uniformly severe.

7 Tesla MRI demonstrates vascular pathology in Balo's concentric sclerosis.

Baló's concentric sclerosis (BCS) is an inflammatory demyelinating disease related to multiple sclerosis; its underlying pathology remains unclear. At 7 T MRI in a 19-year-old female BCS patient, microhaemorrhages and ectatic veins were found in T2 hyperintense regions, features which have not been previously reported in conjunction with BCS, and these findings may support the view that vascular pathology plays a role in BCS. MRS data suggest that neuron loss and lipid turnover still took place months after a remission. Plasma exchange was effective in treating a relapse with severe motor deficits, and the off-label use of natalizumab was successful in maintaining remission in this patient.

First use of alemtuzumab in Balo's concentric sclerosis: a case report.

Balo's concentric sclerosis (BCS) is a rare demyelinating disorder of the central nervous system. The humanised monoclonal antibody alemtuzumab has shown efficacy in another demyelinating disorder, relapsing-remitting multiple sclerosis. We aimed to explore its efficacy in treatment-refractory BCS. A 52-year-old male with radiologically confirmed progressive BCS resistant to steroids, plasmapharesis and cyclophosphamide was administered a standard protocol of alemtuzumab. Treatment failed to slow his decline; he died 6 months after administration. Why alemtuzumab induced no clinical or radiological impact may be multifactorial. We review the evidence directing BCS therapy and propose the next steps for exploring this potentially fatal condition.

Early muscle and brain ultrastructural changes in polymerase gamma 1-related encephalomyopathy.

Mutations affecting the mitochondrial DNA-polymerase gamma 1 (POLG1) gene have been shown to cause Alpers-Huttenlocher disease. Ultrastructural data on brain and muscle tissue are rare. We report on ultrastructural changes in brain and muscle tissue of two sisters who were compound heterozygous for the c.2243G>C and c.1879C>T POLG1 mutations. Patient 1 (16 years) presented with epilepsia partialis continua that did not respond to antiepileptic treatment. Neuroimaging showed right occipital and bithalamic changes. Light microscopy from a brain biopsy performed after 3 weeks suggested chronic encephalitis showing astro- and microgliosis as well as perivascular CD8-positive T-cells. However, immunosuppressive therapy failed to improve her condition. When her 17-year-old sister (patient 2) also developed epilepsy, an intensified search for metabolic diseases led to the diagnosis. On electron microscopy mitochondrial abnormalities mainly affecting neurons were detected in the brain biopsy of patient 1, including an increase in number and size, structural changes and globoid inclusions. In patient 2, light and electron microscopy on a muscle biopsy confirmed a mitochondrial myopathy, also revealing an increase in mitochondrial size and number, as well as globoid inclusions. Neurons may be the primary target of mitochondrial dysfunction in brains of patients with Alpers disease related to POLG1 mutations. During early disease stages, brain histopathology may be misleading, showing reactive inflammatory changes.

POLG mutations cause decreased mitochondrial DNA repopulation rates following induced depletion in human fibroblasts.

Disorders of mitochondrial DNA (mtDNA) maintenance have emerged as an important cause of human genetic disease, but demonstrating the functional consequences of de novo mutations remains a major challenge. We studied the rate of depletion and repopulation of mtDNA in human fibroblasts exposed to ethidium bromide in patients with heterozygous POLG mutations, POLG2 and TK2 mutations. Ethidium bromide induced mtDNA depletion occurred at the same rate in human fibroblasts from patients and healthy controls. By contrast, the restoration of mtDNA levels was markedly delayed in fibroblasts from patients with compound heterozygous POLG mutations. Specific POLG2 and TK2 mutations did not delay mtDNA repopulation rates. These observations are consistent with the hypothesis that mutations in POLG impair mtDNA repopulation within intact cells, and provide a potential method of demonstrating the functional consequences of putative pathogenic alleles causing a defect of mtDNA synthesis.

Texture analysis of high resolution MRI allows discrimination between febrile and afebrile initial precipitating injury in mesial temporal sclerosis.

A computational pipeline combining texture analysis and pattern classification algorithms was developed for investigating associations between high-resolution MRI features and histological data. This methodology was tested in the study of dentate gyrus images of sclerotic hippocampi resected from refractory epilepsy patients. Images were acquired using a simple surface coil in a 3.0T MRI scanner. All specimens were subsequently submitted to histological semiquantitative evaluation. The computational pipeline was applied for classifying pixels according to: a) dentate gyrus histological parameters and b) patients' febrile or afebrile initial precipitating insult history. The pipeline results for febrile and afebrile patients achieved 70% classification accuracy, with 78% sensitivity and 80% specificity [area under the reader observer characteristics (ROC) curve: 0.89]. The analysis of the histological data alone was not sufficient to achieve significant power to separate febrile and afebrile groups. Interesting enough, the results from our approach did not show significant correlation with histological parameters (which per se were not enough to classify patient groups). These results showed the potential of adding computational texture analysis together with classification methods for detecting subtle MRI signal differences, a method sufficient to provide good clinical classification. A wide range of applications of this pipeline can also be used in other areas of medical imaging.

Extensive loss of connexins in Baló's disease: evidence for an auto-antibody-independent astrocytopathy via impaired astrocyte-oligodendrocyte/myelin interaction.

Extensive aquaporin-4 (AQP4) loss without perivascular deposition of either activated complement or immunoglobulins is a characteristic of Baló's disease. Our aim in this study was to investigate the relationship between astrocytopathy and demyelination in Baló's disease, focusing on connexins (Cx), which form gap junctions among glial cells and myelin. Autopsied specimens from four cases that provided seven actively demyelinating concentric lesions infiltrated with numerous CD68(+) macrophages were immunohistochemically examined for the astrocyte markers glial fibrillary acidic protein (GFAP), AQP4, Cx43, Cx30 and megalencephalic leukoencephalopathy with subcortical cyst 1 (MLC1). Specimens were also stained for oligodendrocyte/myelin markers, namely Cx32, Cx47, myelin-associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein (OSP) and Nogo-A. Serum samples from six patients that had undergone magnetic resonance imaging, confirming a diagnosis of Baló's disease, were assayed for the presence of anti-Cx43, -Cx32 and -AQP4 antibodies. Despite the presence of numerous GFAP- and MLC1-positive astrocytes, there was a marked decrease in the levels of Cx43, Cx32 and Cx47. At the leading edges, Cx43 and AQP4 were mostly absent despite positive GFAP, MLC1, Cx32, Cx47, MOG, MAG, and OSP immunoreactivity. Of the six Baló's disease patients, none were positive for anti-Cxs or -AQP4 antibodies. Baló's disease is characterized by extensive loss of Cxs and AQP4, and a lack of auto-antibodies to Cxs and AQP4. Loss of Cx43 and AQP4 in the presence of other oligodendrocyte/myelin proteins at the leading edges suggests the possibility that auto-antibody-independent astrocytopathy may contribute to disease pathology via the disruption of astrocyte-oligodendrocyte/myelin interactions.

Astrocytopathy in Balo's disease.

Baló's disease is characterized by alternating rings of demyelination and preserved myelin. As additional multiple sclerosis (MS)-like lesions often coexist in Baló's cases, Baló's disease is regarded as a variant of MS. In demyelinated areas, many hypertrophic astrocytes are present in close contact with oligodendrocytes, which often show apoptotic features. In the outermost layer of preserved myelin, stress proteins involved in tissue preconditioning are abundant in oligodendrocytes. The peri-plaque perimeter is thus assumed resistant to subsequent attack, thereby leaving a layer of preserved myelin. In some cases, Baló's concentric rings develop step by step in a centrifugal direction, whereas many other cases show simultaneous enhancement of multiple rings. Therefore tissue preconditioning and successive ring formation does not fully describe the mechanism of the disease. We recently reported that in four Filipino Baló's patients, aquaporin-4 (AQP4) was extensively lost in glial fibrillary acidic protein-positive hypertrophic astrocytes, both in demyelinated and myelinated layers of all actively demyelinating lesions. None of six further patients with MRI-confirmed Baló's disease were seropositive for anti-AQP4 antibody. I propose that AQP4 astrocytopathy, in the absence of anti-AQP4 antibody, is characteristic of Baló's disease. This hypothesis should be tested in future experimental studies.

Drug-resistant epilepsia and fulminant valproate liver toxicity. Alpers-Huttenlocher syndrome in two children confirmed post mortem by identification of p.W748S mutation in POLG gene.

BACKGROUND: POLG (polymerase gamma) gene mutations lead to a variety of neurological disorders, including Alpers-Huttenlocher syndrome (AHS). The diagnostic triad of AHS is: resistant epilepsy, liver impairment triggered by sodium valproate (VA), and mitochondrial DNA depletion. MATERIAL/METHODS: A cohort of 28 children with mitochondrial encephalopathy and liver failure was qualified for retrospective study of mitochondrial DNA depletion and POLG mutations. RESULTS: The p.W748S POLG gene mutation was revealed in 2 children, the only ones in the cohort who fulfilled the AHS criteria. Depletion of mtDNA (16% of control value) was confirmed post mortem in available liver tissue and was not detected in the muscle. The disease started with drug-resistant seizures, failure to thrive and developmental regression at the ages of 7 and 18 months, respectively. Irreversible liver failure developed after VA administration. Co-existence of epilepsy, VA liver toxicity, lactic acidemia and muscle respiratory chain dysfunction led finally to the diagnosis of mitochondrial disorder (and AHS suspicion). CONCLUSIONS: Our results confirm, for the first time, the occurrence of a pathology caused by POLG gene mutation(s) in the Polish population. POLG mutation screening and mtDNA depletion assessment should be included in differential diagnosis of drug-resistant epilepsy associated with a hepatopathy.

Balo's concentric sclerosis involving bilateral thalami.

Balo's concentric sclerosis (BCS) is a rare inflammatory demyelinating disease of central nervous system, pathologically characterized by alternate bands of demyelination and preserved myelin tissue. Before the era of magnetic resonance imaging (MRI), most cases of BCS were diagnosed on postmortem examination. MRI allows for noninvasive diagnosis by demonstrating characteristic changes which closely parallels the histopathological features of BCS. We report a case of 26-year-old female with BCS involving bilateral thalami, with typical MRI appearance.

Magnetic Resonance Characteristics of Baló Concentric Sclerosis in Children.

BACKGROUND: Baló concentric sclerosis is a rare demyelinating disease with characteristic magnetic resonance appearance of multilayered ringlike lesions of demyelination. This disease is extremely rare in children. We present the clinical data, radiological appearance, and development of lesions in eight children. METHODS: We analyzed the clinical information of eight patients diagnosed between 2012 and 2020. Magnetic resonance brain and spinal cord examinations with contrast medium administration were performed using a 1.5-T scanner. RESULTS: All patients presented at least one typical Baló lesion on brain imaging. Four patients additionally had typical multiple sclerosis plaques. All primary Baló lesions had a characteristic appearance of concentric hyperintense rings on T2-weighted imaging and were round or ovoid. Cerebrospinal fluid analysis was performed in all patients. Oligoclonal bands were present in seven patients, and four of them had multiple sclerosis plaques on baseline brain magnetic resonance imaging. CONCLUSION: Baló concentric sclerosis in children is characterized by acute and severe onset with hemiparesis as a predominant symptom. The size, contrast enhancement, and restricted diffusion depend on the phase of the disease.