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A previously healthy 40-year-old man developed acute left-sided weakness and numbness that progressed over 2 weeks. Physical examination revealed decreased sensation to pinprick in the left arm and leg and left leg weakness. MRI supported a diagnosis of Balo concentric sclerosis (BCS), a rare demyelinating disease (figure). The concentric bands of differing intensities on MRI are due to alternating layers of normal and demyelinated tissue that is classically observed with BCS.1,2 Patients with BCS commonly present with acute neurologic symptoms, which can be due to a solitary lesion. The clinical course can be fulminant and progressive or benign. In the case presented, the patient's symptoms improved within 1 week of starting high-dose glucocorticoids.

ObjectiveTo describe clinical, radiologic, and pathologic features of Baló concentric sclerosis (BCS) and assess overlap between BCS and other CNS inflammatory demyelinating diseases.MethodsRetrospective review of BCS cases from US and Australian tertiary care centers.ResultsWe identified 40 BCS cases with 38 available MRIs. Solitary MRI lesions were present in 26% (10/38). We saw >1 active concurrent BCS lesion in 45% (17/38). A third (13/38) had multiple sclerosis–suggestive lesions on the index MRI, of which 10 fulfilled Barkhof criteria. In patients with serial MRI performed within 1 month of the index MRI, lesions expanded radially with sequentially increased numbers of T2 hyperintense rings 52% (14/27). Initially nonenhancing or centrally enhancing lesions subsequently developed single or multiple enhancing rings (41%; 9/22) and incomplete enhancing rings (14%; 3/22). Discordance between rings as they appear on apparent diffusion coefficient, diffusion-weighted imaging, and gadolinium-enhanced imaging was observed in 67% (22/33). Aquaporin-4 immunoglobulin G (n = 26) and myelin oligodendrocyte glycoprotein immunoglobulin G (n = 21) were negative in all patients with serum available. Clinical response to steroid treatment was seen in 46% (13/28). A monophasic clinical course was present in 56% (18/32) at last follow-up (median 27.5 months; range 3–100 months). The initial attack was fatal in 10% (4/40). Median time from symptom onset to death was 23 days (range 19–49 days). All 17 patients with pathology available demonstrated typical findings of multiple sclerosis. Patients with active demyelinating lesions all demonstrated oligodendrocytopathy (pattern III).ConclusionsBCS may be a distinct subtype of multiple sclerosis characterized by pattern III immunopathology.

Alpers' syndrome is a severe neurodegenerative disease typically caused by bi-allelic variants in the mitochondrial DNA (mtDNA) polymerase gene, POLG, leading to mtDNA depletion. Intractable epilepsy, often with an occipital focus, and extensive neurodegeneration are prominent features of Alpers' syndrome. Mitochondrial oxidative phosphorylation (OXPHOS) is severely impaired with mtDNA depletion and is likely to be a major contributor to the epilepsy and neurodegeneration in Alpers' syndrome. We hypothesised that parvalbumin-positive(+) interneurons, a neuronal class critical for inhibitory regulation of physiological cortical rhythms, would be particularly vulnerable in Alpers' syndrome due to the excessive energy demands necessary to sustain their fast-spiking activity.We performed a quantitative neuropathological investigation of inhibitory interneuron subtypes (parvalbumin+, calretinin+, calbindin+, somatostatin interneurons+) in postmortem neocortex from 14 Alpers' syndrome patients, five sudden unexpected death in epilepsy (SUDEP) patients (to control for effects of epilepsy) and nine controls.We identified a severe loss of parvalbumin+ interneurons and clear evidence of OXPHOS impairment in those that remained. Comparison of regional abundance of interneuron subtypes in control tissues demonstrated enrichment of parvalbumin+ interneurons in the occipital cortex, while other subtypes did not exhibit such topographic specificity.These findings suggest that the vulnerability of parvalbumin+ interneurons to OXPHOS deficits coupled with the high abundance of parvalbumin+ interneurons in the occipital cortex is a key factor in the aetiology of the occipital-predominant epilepsy that characterises Alpers' syndrome. These findings provide novel insights into Alpers' syndrome neuropathology, with important implications for the development of preclinical models and disease-modifying therapeutics.

TMEM119 and purinergic receptor P2Y12 (P2RY12), which are not expressed by recruited peripheral blood macrophages, are proposed to discriminate microglia from macrophages. Therefore, we investigated the distribution patterns of microglia and macrophages in 10 concentric lesions from four autopsied Baló's disease cases and one neuromyelitis optica spectrum disorder (NMOSD) case, using quantitative immunohistochemistry for the markers TMEM119, P2RY12, CD68, CD163 and GLUT5. Three cases with Baló's disease had distal oligodendrogliopathy (DO) showing preferential loss of myelin-associated glycoprotein and early active demyelination in the outermost demyelinating layer (termed DMY-MO). In DMY-MO with DO, TMEM119-positive activated microglia expressing upregulated GLUT5 but markedly downregulated P2RY12 were significantly increased. These activated microglia expressed inducible nitric oxide synthase. Oligodendrocytes and their precursors showed apoptotic-like nuclear condensation in DMY-MO. TMEM119-negative and CD68/CD163-positive macrophages were distributed throughout the lesion center of DMY-MO with DO and these cells demonstrated foamy morphology only in the inner portion but not in the outer portion. In concentric demyelinating lesions from another Baló's case and lamellar demyelinating lesions in an NMOSD case, which had late active demyelination without DO, the densities of TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology were significantly increased in myelinated layers but not in demyelinating layers. In particular, in the NMOSD case, TMEM119-positive microglia were confined to the outer portion of the myelinated layers. CD68-positive macrophages with foamy morphology also expressing CD163 accumulated in myelinated as well as in demyelinated layers. These findings suggest that activated microglia expressing TMEM119 and GLUT5, but not P2RY12, are associated with apoptosis of oligodendrocytes in the leading edge of Baló's concentric lesions with DO, whereas TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology are associated with myelin preservation in concentric lesions without DO in Baló's disease and NMOSD. These two types of microglia appear to play distinct roles in the formation of concentric lesions.

Balo's concentric sclerosis (BCS) is a rare, inflammatory demyelinating disease of the central nervous system (CNS). Historically, BCS was thought to be uniformly fatal and diagnosis was based on postmortem findings. With advances in modern neuroimaging, BCS is currently defined by the presence of concentric layered patterns composed of alternating rings of varying intensity. They are best appreciated on gadolinium-enhanced T1-weighted sequences and predominantly occur in the supratentorial cerebral white matter with sparing of cortical U-fibers. The lamellar pattern of the lesions likely reflects bands of demyelination and relative myelin preservation with minimal axonal loss. While BCS falls within the spectrum of atypical demyelinating diseases, there is ongoing debate over whether BCS is a phenotypical variant of multiple sclerosis (MS) or a separate entity. Corticosteroids comprise first-line therapy but there is ongoing controversy regarding appropriate maintenance therapy. First-line MS disease-modifying therapies such as interferon beta-1a are appropriate for patients who fulfill diagnostic criteria for relapsing-remitting MS. Fingolimod should likely be avoided as Balo-like lesions have been reported during its administration or after withdrawal. Monoclonal antibodies such as natalizumab and rituximab are potentially effective at reducing BCS relapses, but alemtuzumab may be relatively ineffective because humoral immunity does not play a central role in BCS pathogenesis.

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.

Baló's concentric sclerosis (BCS) is considered a variant of inflammatory demyelinating disease closely related to multiple sclerosis characterized by a discrete concentrically layered lesion in the cerebal white matter. Khonsari and Calvez (Plos ONE. 2(2007)) proposed a parabolic-elliptic-ODE chemotaxis model for BCS which describes the evolution of the densities of activated macrophages, cytokine and apoptotic oligodendrocytes. Because "classically activated" M1 microglia can produce cytotoxicity, we introduce a linear production term from the activated microglia in the ODE for pro-inflammatory cytotoxic. For the new BCS chemotaxis model, we first investigate the uniform boundedness and global existence of classical solutions, and then get a range of the chemosensitive rate χ where the unique positive equilibrium point is exponentially asymptotically stable.

The differential diagnosis of the central nervous system (CNS) demyelinating diseases can be greatly facilitated by visualization and appreciation of pathognomonic radiological signs, visualized on magnetic resonance imaging (MRI) sequences. Given the distinct therapeutic approaches for each of these diseases, a decisive and reliable diagnosis in patients presenting with demyelination-associated symptoms is of crucial value. Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are major examples of such conditions, each possessing a number of MRI signs, closely associated with the disorder. This pictorial review aims to describe seventeen pathognomonic MRI signs associated with several CNS demyelinating disorders including MS, NMOSD, myelin oligodendrocyte glycoprotein-associated disease, Balo's concentric sclerosis, metachromatic leukodystrophy, progressive multifocal leukoencephalopathy, and neurosarcoidosis.

PET targeting the translocator protein (TSPO) expression is an interesting approach to detect neuroinflammation, as TSPO is upregulated in activated macrophages and microglia. Considering the variable pathophysiology of multiple sclerosis (MS) variants, we compare TSPO PET using F-GE-180 in 3 different demyelinating diseases of the central nervous system: relapsing-remitting MS, tumefactive MS, and Balo's concentric sclerosis. Visualization of neuroinflammation and its PET patterns in addition to MRI may contribute to accurate distinction and monitoring of central nervous system demyelination.

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.

Objective To examine whether rhythmic high-amplitude delta with superimposed (poly)spikes (RHADS) in EEG allow a reliable early diagnosis of Alpers-Huttenlocher syndrome (AHS) and contribute to recognition of this disease. Methods EEGs of nine patients with DNA-proven AHS and fifty age-matched patients with status epilepticus were retrospectively examined by experts for the presence of RHADS and for accompanying clinical signs and high-frequency ripples. Reproducibility of RHADS identification was tested in a blinded panel. Results Expert defined RHADS were found in at least one EEG of all AHS patients and none of the control group. RHADS were present at first status epilepticus in six AHS patients (67%). Sometimes they appeared 5–10 weeks later and disappeared over time. RHADS were symptomatic in three AHS patients and five AHS patients showed distinct ripples on the (poly)spikes of RHADS. Independent RHADS identification by the blinded panel resulted in a sensitivity of 87.5% (95% CI 47–100) and a specificity of 87.5% (95% CI 77–94) as compared to the experts’ reporting. Conclusion RHADS are a highly specific EEG phenomenon for diagnosis of AHS and can be reliably recognized. Clinical expression and EEG ripples suggest that they signify an epileptic phenomenon. Significance RHADS provide a specific tool for AHS diagnosis.

Mutations in nucleus-encoded mitochondrial aminoacyl-tRNA synthetases (mitaaRSs) lead to defects in mitochondrial translation affecting the expression and function of 13 subunits of the respiratory chain complex leading to diverse pathological conditions. Mutations in the FARS2 gene encoding human mitochondrial phenylalanyl-tRNA synthetase (HsmitPheRS) have been found to be associated with two different clinical representations, infantile Alpers encephalopathy and spastic paraplegia. Here we have studied three pathogenic mutants (Tyr144Cys, Ile329Thr, and Asp391Val) associated with Alpers encephalopathy to understand how these variants affect the biophysical properties of the enzyme. These mutants have already been reported to have reduced aminoacylation activity. Our study established that the mutants are significantly more thermolabile compared to the wild-type enzyme with reduced solubility in vitro. The presence of aggregation-prone insoluble HsmitPheRS variants could have a detrimental impact on organellar translation, and potentially impact normal mitochondrial function. © 2019 IUBMB Life, 71(8): 1141-1149, 2019 © 2019 IUBMB Life, 71(8):1141-1149, 2019.

Background: Myelinoclastic diffuse sclerosis (MDS; also termed Schilder’s disease) is a rare inflammatory demyelinating disorder of the central nervous system characterised by demyelination of vast areas of the white matter. It is unclear whether MDS is a variant of multiple sclerosis (MS) or a disease entity in its own right. Objective: To compare the cerebrospinal fluid (CSF) features of MDS with those of MS. Methods: Retrospective analysis of the CSF profile of all patients with MDS reported in the medical literature between 1960 and 2018. Results: The most striking finding was a substantial lack of oligoclonal bands (OCBs) in MDS, which were absent in at least 77% (30/39) of all lumbar punctures (LP) in the total cohort and in 86% in the subgroup of patients with normal very long-chain fatty acid serum ratios (VLCFA). Almost all cases published in the past 15 years were negative for OCBs. These findings are in contrast to MS, in which OCBs are present in up to 98% of cases (p 100 mg/dL in 13/22; up to 220 mg/dL). EBV serum antibodies, which are present in virtually all patients with MS, and the so-called MRZ (measles/rubella/zoster) reaction, a highly specific marker of MS, were absent in all of the few patients tested. In addition, we discuss further differences between MS and MDS, taking into account also Schilder’s original comprehensive case description from 1912. Conclusion: In the majority of patients diagnosed with MDS, CSF features differ significantly from those typically found in MS and are more similar to those previously reported in patients with myelin oligodendrocyte glycoprotein-immunoglobulin G (IgG)-positive encephalomyelitis, aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders or Baló’s concentric sclerosis. Our data suggest that MDS and MS are immunopathologically distinct entities in the majority of cases.

Diseases related to DNA polymerase gamma dysfunction comprise of heterogeneous clinical presentations with variable severity and age of onset. Molecular screening for the common POLG variants: p.Ala467Thr, p.Trp748Ser, p.Gly848Ser, and p.Tre251Ile has been conducted in a large population cohort (n = 3123) and in a clinically heterogeneous group of 1289 patients. Recessive pathogenic variants, including six novel ones were revealed in 22/26 patients. Infantile Alpers-Huttenlocher syndrome and adulthood ataxia spectrum were the most common found in our group. Distinct molecular profile identified in the Polish patients with significant predominance of p.Trp748Ser variant (50% of mutant alleles) reflected strikingly low population frequency of the three remaining variants and slightly higher p.Trp748Ser allele frequency in the general Polish population as compared to the non-Finish European population.

Introduction Balo’s concentric sclerosis (BCS) is a rare CNS disorder characterized by alternating bands of demyelination on MRI. One of the main issues is its relationship with multiple sclerosis (MS). Objectives To describe 6 BCS patients. To review the risk of developing MS in BCS patients. Methods We retrospectively recorded clinical and radiological findings of 6 BCS patients and performed a review of the literature. Results Six patients (5 women) with a mean age of 25 years old were included. Main symptoms were hemiparesis/hemihypoesthesia. On MRI, two patients had a single BCS lesion and four had additional MS-like lesions. Alternating bands were usually more visible on DWI. A patient had reduced central perfusion and SWI hypointensity suggestive of a central vein. Oligoclonal bands were identified in 5/6 patients. After 7 years of follow-up, all patients achieved MS criteria with mild disability (mean EDSS 1.75; 0–4). Our literature review included 65 BCS patients from 30 studies: although CSF oligoclonal bands and the presence of additional MS lesions were associated with subsequent relapses, this was not significant. Discussion/conclusion Our series allows a detailed MRI description in BCS and gives a new insight into BCS evolution and its strong relationship with MS.

Tumefactive demyelinating lesions of the central nervous system can be the initial presentation in various pathological entities [multiple sclerosis (the most common), Balo’s concentric sclerosis, Schilder’s disease and acute disseminated encephalomyelitis] with overlapping clinical presentation. The aim of our study was to better characterize these patients. Eighty-seven patients (62 women and 25 men) from different MS centers in France were studied retrospectively. Inclusion criteria were (1) a first clinical event (2) MRI showing one or more large demyelinating lesions (20 mm or more in diameter) with mass-like features. Patients with a previous demyelinating event (i.e. confirmed multiple sclerosis) were excluded. Mean age at onset was 26 years. The most common initial symptoms (67% of the patients) were hemiparesis or hemiplegia. Aphasia, headache and cognitive disturbances (i.e. atypical symptoms for demyelinating diseases) were observed in 15, 18 and 15% of patients, respectively. The mean largest diameter of the tumefactive lesions was 26.9 mm, with gadolinium enhancement in 66 patients (81%). Twenty-one patients (24%) had a single tumefactive lesion. During follow-up (median time 5.7 years) 4 patients died, 70 patients improved or remained stable and 12 worsened. 86% of patients received initial corticosteroid treatment, and 73% received disease-modifying therapy subsequently. EDSS at the end of the follow-up was 2.4 ± 2.6 (mean ± SD). This study provides further evidence that the clinical course of MS presenting with large focal tumor-like lesions does not differ from that of classical relapsing-remitting MS, once the noisy first relapsing occurred.

Schilder's disease is a rare and aggressive central nervous system demyelinating disorder that is typically monophasic and steroid responsive. Here, we present an unusual case of a teenager with Schilder's disease who was treated with corticosteroids and had a clinical and radiographic recurrence nearly one year after the initial presentation.

A 23-year-old man presented to our clinic with acute left-sided numbness for one week. He had been given a diagnosis of lymphoma as a child and had been in remission for more than 10 years. The neurologic examination showed decreased sensation to pinprick over the left side of the patient’s face

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.

Alpers’ syndrome is an early‐onset neurodegenerative disorder often caused by biallelic pathogenic variants in the gene encoding the catalytic subunit of polymerase‐gamma (POLG) which is essential for mitochondrial DNA (mtDNA) replication. Alpers’ syndrome is characterized by intractable epilepsy, developmental regression and liver failure which typically affects children aged 6 months–3 years. Although later onset variants are now recognized, they differ in that they are primarily an epileptic encephalopathy with ataxia. The disorder is progressive, without cure and inevitably leads to death from drug‐resistant status epilepticus, often with concomitant liver failure. Since our understanding of the mechanisms contributing the neurological features in Alpers’ syndrome is rudimentary, we performed a detailed and quantitative neuropathological study on 13 patients with clinically and histologically‐defined Alpers’ syndrome with ages ranging from 2 months to 18 years. Quantitative immunofluorescence showed severe respiratory chain deficiencies involving mitochondrial respiratory chain subunits of complex I and, to a lesser extent, complex IV in inhibitory interneurons and pyramidal neurons in the occipital cortex and in Purkinje cells of the cerebellum. Diminished densities of these neuronal populations were also observed. This study represents the largest cohort of post‐mortem brains from patients with clinically defined Alpers’ syndrome where we provide quantitative evidence of extensive complex I defects affecting interneurons and Purkinje cells for the first time. We believe interneuron and Purkinje cell pathology underpins the clinical development of seizures and ataxia seen in Alpers’ syndrome. This study also further highlights the extensive involvement of GABAergic neurons in mitochondrial disease.

International audience; Atypical idiopathic inflammatory demyelinating disorders (IIDDs) of the brain have long been known to be disorders closely related to multiple sclerosis (MS), despite having distinctive clinical and radiological characteristics. Originally, they mostly corresponded to acute-onset variants of MS that classically had poor prognoses, such as Baló's concentric sclerosis, Marburg variant of MS and Schilder's disease, and their relationship with MS was based on their shared pathological findings and the co-occurrence of these variants in patients with typical MS. More recently, other atypical disorders, such as solitary sclerosis, have also been described as belonging to the MS spectrum, raising the question of their links with MS. Meanwhile, multiple MS mimics have been described and need to be considered in the differential diagnosis of MS. In addition, thorough characterization of these atypical entities, including advanced MRI and biological studies, is now warranted to further improve their management.

Balo’s concentric sclerosis (BCS) is considered a variant of multiple sclerosis characterized by concentric lamella of alternating demyelinated and partially myelinated tissues. It is a rare and a relatively acute condition. Attacks may proceed rapidly over weeks or months, typically without remission, like Marburg’s variant, resulting in death or severe disability. However, the majority of cases have a more benign, self-limiting course with spontaneous remission. Magnetic resonance imaging is a primary imaging modality in the diagnosis of BCS. Treatment with intense immunosuppression may be indicated in patients with more aggressive form. New reports reveal more evidence regarding the pathophysiology and treatment strategies.

Balò's concentric sclerosis (BCS) is considered a rare demyelinating disease and regarded as an aggressive variant of multiple sclerosis (MS). We describe three cases (one male and two females) with neuroimaging features suggestive of BCS and heterogeneous symptoms, with benign long-term clinical course upon treatment with natalizumab and fingolimod. Neurological examination, blood and cerebrospinal fluid analyses, brain and spinal cord magnetic resonance imaging (MRI) and brain proton magnetic resonance spectroscopy were performed. At onset, patient #1 showed predominant cognitive impairment with consciousness disturbances; patient #2 presented with left hemiparesis; patient #3 demonstrated hesitance in speech and in written word production, along with right central facial palsy. All patients showed the typical MRI changes associated with BCS, such as concentric rings or a whorled appearance on T2-weighted and contrast-enhanced T1-weighted images. They were treated with high dosage i.v. steroid with clinical improvement and followed-up for 3 years with different clinical course. Two patients fulfilled the revised McDonald criteria for MS and received preventive therapy, natalizumab and fingolimod, respectively, whereas the third patient is still stable without clinical and radiological evolution. All of them did not have new exacerbations or MRI lesions over 2-4 year follow-up. Our descriptions demonstrate the heterogeneity of clinical presentation of BCS. Moreover, these case reports suggest that BCS may neither be rapidly progressive nor fatal and may be considered part of the MS spectrum. In line with this hypothesis, current treatments for MS were effective in our patients.

Cocaine abuse may cause stroke, metabolic or multifocal inflammatory leukoencephalopathy. We described a patient with cocaine abuse who presented with Balo's type acute multifocal leukoencephalopathy. Magnetic Resonance Imaging (MRI) of the brain showed onion like patchy concentric ring enhancement on T1-weighted MRI with gadolinium. Balo's Concentric Sclerosis like radiological findings related to cocaine has not been reported. Levamisole is now frequently used as an ingredient in cocaine and may cause leukoencephalopathy. It is recommended to check urine levamisole levels in patients with cocaine-induced leukoencephalopathy with or without mimicking Balo's Concentric Sclerosis. On the other hand, it is also possible that the cocaine use was coincidental and this was a demyelinating case arising de novo in patient who uses cocaine.

Introduction We came across 3 cases of Balo’s concentric sclerosis (BCS). The first of these patients presented to an outside hospital and was transferred to our institution due to complications resulting from a biopsy. The other 2 patients, despite having a characteristic imaging appearance and despite insistence on our part on the diagnosis of BCS, underwent a surgical procedure, which could have been prevented. This led us to review the available literature on BCS. Material and Methods A total of 68 patients diagnosed with BCS between 1995 and 2015 were studied and the data collected for the clinical presentation and course, imaging, spinal fluid analysis, treatment, and clinical and imaging outcome. Conclusions A 25% surgery rate (biopsy or resection) was found in the study. We concluded that this relatively high surgery rate in this auntminnie nonsurgical disease is multifactorial; and includes factors like nonfamiliarity with the disease, anxiety on the part of patients and physicians, due to a sometimes rapidly deteriorating clinical picture; and resemblance of the disease with other entities such as tumor and infection. However, characteristic imaging appearance combined with acute or subacute presentation and dramatic improvement in clinical status after high-dose steroid chemotherapy; are highly suggestive of the disease, and can prevent unnecessary surgery.

Background Mitochondria play an important role in iron metabolism and haematopoietic cell homeostasis. Recent studies in mice showed that a mutation in the catalytic subunit of polymerase gamma (POLG) was associated with haematopoietic dysfunction including anaemia. The aim of this study was to analyse the frequency of anaemia in a large cohort of patients with POLG related disease. Methods We conducted a multi-national, retrospective study of 61 patients with confirmed, pathogenic biallelic POLG mutations from six centres, four in Norway and two in the United Kingdom. Clinical, laboratory and genetic data were collected using a structured questionnaire. Anaemia was defined as an abnormally low haemoglobin value adjusted for age and sex. Univariate survival analysis was performed using log-rank test to compare differences in survival time between categories. Results Anaemia occurred in 67% (41/61) of patients and in 23% (14/61) it was already present at clinical presentation. The frequency of anaemia in patients with early onset disease including Alpers syndrome and myocerebrohepatopathy spectrum (MCHS) was high (72%) and 35% (8/23) of these had anaemia at presentation. Survival analysis showed that the presence of anaemia was associated with a significantly worse survival (P = 0.004). Conclusion Our study reveals that anaemia can be a feature of POLG-related disease. Further, we show that its presence is associated with significantly worse prognosis either because anaemia itself is impacting survival or because it reflects the presence of more serious disease. In either case, our data suggests anaemia is a marker for negative prognosis.

Mutations in the mitochondrial aminoacyl‐tRNA synthetases (mtaaRSs) can cause profound clinical presentations, and have manifested as diseases with very selective tissue specificity. To date most of the mtaaRS mutations could be phenotypically recognized, such that clinicians could identify the affected mtaaRS from the symptoms alone. Among the recently reported pathogenic variants are point mutations in FARS2 gene, encoding the human mitochondrial PheRS. Patient symptoms range from spastic paraplegia to fatal infantile Alpers encephalopathy. How clinical manifestations of these mutations relate to the changes in three‐dimensional structures and kinetic characteristics remains unclear, although impaired aminoacylation has been proposed as possible etiology of diseases. Here, we report four crystal structures of HsmtPheRS mutants, and extensive MD simulations for wild‐type and nine mutants to reveal the structural changes on dynamic trajectories of HsmtPheRS. Using steady‐state kinetic measurements of phenylalanine activation and tRNAPhe aminoacylation, we gained insight into the structural and kinetic effects of mitochondrial disease‐related mutations in FARS2 gene.

The concentricity of BCS has captured wide attention; the findings of the current study may provide useful information on the centrifugal pathogenesis of BCS.This study aims to evaluate the performance of MRI, DWI and MRS in elucidating the pathogenesis of Balo's lesions expanding.Six clinically diagnosed BCS cases were reviewed, and the findings obtained by MRI, DWI and MRS were analyzed. DWI data were available for six patients, with the DWI and ADC imaging locations being central and peripheral layers of the index lesion. At TE 144ms, we calculated metabolite ratios of MRS at different depths of the demyelinating lesions and compared with the lesion on the opposite normal side for two patients.The ADC values of 18 typical concentric lesions revealed that the central lesion had the highest ADC value, followed by the internal ring, and the outermost layer had the lowest ADC value. The reduction in NAA/Cr and the increase in Cho/Cr were more evident in the central lesion than in the internal and outermost ring.The findings of DWI and MRS indicate Balo's concentric rings develop gradually and centrifugally. Of course, this hypothesis remains to be proved by further experimental studies.

Summary Balo's concentric sclerosis is often regarded as a rare variant of multiple sclerosis. Patients with this disorder present with acute or subacute neurological deterioration, with MRI showing one or more concentrically multilayered ring-like lesions usually in the cerebral white matter. Historically, Balo's concentric sclerosis was thought fatal in all cases. However, the availability of MRI has led to a better appreciation of the variable natural history of patients presenting with radiologically evident Balo lesions and the clinical association with multiple sclerosis and, less often, with other neurological disorders. Important advances have increased understanding of the immunopathogenic mechanisms associated with the formation of Balo lesions. However, how to treat an acute lesion and when or whether to start treatment are less well understood, although for patients with Balo lesions who also fulfil standard diagnostic criteria for multiple sclerosis, our opinion is that treatment with multiple sclerosis disease-modifying therapy would seem reasonable.

Mutations in the human mitochondrial polymerase (polymerase-γ (Pol-γ)) are associated with various mitochondrial disorders, including mitochondrial DNA (mtDNA) depletion syndrome, Alpers syndrome, and progressive external opthamalplegia. To correlate biochemically quantifiable defects resulting from point mutations in Pol-γ with their physiological consequences, we created "humanized" yeast, replacing the yeast mtDNA polymerase (MIP1) with human Pol-γ. Despite differences in the replication and repair mechanism, we show that the human polymerase efficiently complements the yeast mip1 knockouts, suggesting common fundamental mechanisms of replication and conserved interactions between the human polymerase and other components of the replisome. We also examined the effects of four disease-related point mutations (S305R, H932Y, Y951N, and Y955C) and an exonuclease-deficient mutant (D198A/E200A). In haploid cells, each mutant results in rapid mtDNA depletion, increased mutation frequency, and mitochondrial dysfunction. Mutation frequencies measured in vivo equal those measured with purified enzyme in vitro. In heterozygous diploid cells, wild-type Pol-γ suppresses mutation-associated growth defects, but continuous growth eventually leads to aerobic respiration defects, reduced mtDNA content, and depolarized mitochondrial membranes. The severity of the Pol-γ mutant phenotype in heterozygous diploid humanized yeast correlates with the approximate age of disease onset and the severity of symptoms observed in humans.

Background Schilder's disease is a rare, subacute, or chronic demyelinating disorder that mainly affects children and generally shows a monophasic course. Case Here, we present three boys diagnosed with Schilder's disease, age at onset 10–14 years, and followed up for 4–8 years. All of them presented with headache, two with encephalopathy and vomiting, and one with diplopia and vertigo. Cranial magnetic resonance imaging (MRI) showed two large demyelinating lesions, asymmetric in two patients and symmetric in the other. They were treated with steroid therapy. There were no radiologic relapses after discontinuation of corticosteroid therapy in all patients, but clinical attack without objective clinical findings was observed in one patient. Mild memory deficits and decline in school performance were the only neurologic sequelae in two patients. Cranial MRI findings showed significant shrinkage, but persistent T2-weighted hyperintensity of white matter lesions and loss of ring contrast enhancement at the end of the steroid therapy. There were no differences between the radiologic findings at the end of the steroid therapy and subsequent follow-ups. Conclusion Although Schilder's disease is considered to be a variant of MS, it behaves more like ADEM with its monophasic course, and low recurrence rates. Radiologic features include shrinkage of mass lesions after steroid therapy, but sequel lesions remain same at the subacute and chronic stage.

Schilder disease, also termed diffuse myelinoclastic sclerosis, is characterized by a large demyelinating lesion involving 1 or both sides of the centrum semiovale of the cerebral hemispheres. It often presents with tumorlike features and poses a diagnostic challenge. Schilder disease can be monophasic or relapsing, and disease-modifying therapy for the latter scenario is largely empirical. Here, we report a 14-year-old girl with relapsing Schilder disease within 1 year after disease onset. She has been followed-up for nearly 10 years and remains in sustained remission ever since interferon-β therapy was prescribed after the second attack. In this case study, it is suggested that interferon-β may induce long-term remission in relapsing Schilder disease and is therefore worth considering in this regard.

Balo's concentric sclerosis (BCS) is a rare demyelinating disease, first described by Hungarian neurologist Josef Balo in 1928. BCS occurs predominantly in young adults, the average age of onset of the disease - 34 years (range from 3 to 62 years). Our case report describes a 27-year woman with acute onset progressive right-side pyramidal weakness, MRI results showed a variant of demyelination as Balo's concentric sclerosis.Концентрический склероз Бало представляет собой редкое демиелинизирующее заболевание, которое впервые было описано венгерским невропатологом J. Balo в 1928 г. Концентрический склероз Бало возникает преимущественно у лиц молодого возраста, средний возраст дебюта заболевания - 34 года (от 3 до 62 лет). В нашем клиническом случае описывается молодая женщина 27 лет с остро возникшей прогрессирующей правосторонней пирамидной недостаточностью, у пациентки по данным магнитно-резонансной томографии был диагностирован вариант демиелинизации в виде концентрического склероза Бало.

To study the clinical and biochemical features of atypical variants of multiple sclerosis (MS) (tumefactive demyelination (TD), Balo's concentric sclerosis (BCS)) and acute disseminated encephalomyelitis (ADEM)).Forty-two patients were studied, including 32 patients with atypical variants of MS (6 patients with BCS and 26 patients with TD) and 10 patients with ADEM. The control group included 20 healthy volunteers. Clinical characteristics and EDSS scores were evaluated. Antibodies to aquaporin 1 (AQP1-IgG), aquaporin 4 (AQP4-IgG), antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) and aquaporin 1 (AQP1) in serum and cerebrospinal fluid (CSF) were detected using ELISA.BCS and TD occurred both in isolation and comorbid with MS (in 50% of cases with BCS, 50% of cases with TD). Atypical symptoms of MS were detected in 50% of cases of CFS, 15.4% of cases of PD. The levels of CSF cytosis and CSF protein were not significantly different between the groups. The levels of AQP1-IgG, AQP4-IgG, AQP1, MOG-IgG in serum with BCS, TD and ADEM were significantly higher than in the control group. No significant differences were found between atypical variants of MS. A correlation between a high level of MOG-IgG and the EDSS score in BCS was shown. MOG-IgG may have a pathogenetic significance in BCS. Further studies of AQP1-IgG, AQP4-IgG and MOG-IgG in patients with atypical variants of MS are needed.Цель исследования. Изучить клинические и биохимические особенности атипичных вариантов рассеянного склероза (РС) (псевдотуморозная демиелинизация - ПД; концентрический склероз Бало - КСБ) и острого рассеянного энцефаломиелита (ОРЭМ). Материал и методы. Обследованы 42 пациента: 32 - с атипичными вариантами РС (6 - с КСБ и 26 - с ПД), 10 - с ОРЭМ. В контрольную группу вошли 20 здоровых. Обследование включало анализ клинических данных, оценку по шкале EDSS, определение антител к аквапорину-1 (AQP1-IgG), к аквапорину-4 (AQP4-IgG), к миелин-олигодендроцитарному гликопротеину (MOG-IgG) и уровня аквапорина-1 (AQP1) в сыворотке крови и ЦСЖ с помощью метода иммуноферментного анализа. Результаты и заключение. Развитие КСБ и ПД встречалось как изолированно, так и на фоне РС (в 50% случаев при КСБ, 50% случаев при ПД). Атипичные проявления РС выявлены в 50% случаев КСБ, 15,4% случаев ПД. Уровень цитоза и белка между группами статистически значимо различался. Выявлено, что уровни AQP1-IgG, AQP4-IgG, MOG-IgG, AQP1 в сыворотке крови при КСБ, ПД и ОРЭМ были статистически значимо выше, чем в контрольной группе. Не было определено достоверных различий между атипичными вариантами РС по этим маркерам. Обнаружена положительная корреляция между высоким уровнем MOG-IgG и выраженностью степени инвалидизации при КСБ. Таким образом, MOG-IgG может иметь патогенетическое значение при КСБ. Целесообразно проведение дальнейших исследований AQP1-IgG, AQP4-IgG и MOG-IgG у пациентов с атипичными вариантами РС.

Aim Mitochondrial diseases affect about 1/5000-1/10000 in the population. Twenty percent of patients with mitochondrial disease show liver involvement. In contrast to current belief among most internists, these diseases do not only present in childhood. Methods We present four cases of adults (three with Alpers-Huttenlocher syndrome and one with mitochondrial neurogastrointestinal encephalomyopathy), diagnosed between 2005 and 2010, in our university referral center. Result We focus on the broad clinical spectrum of liver involvement in mitochondrial diseases and their diagnosis. Biochemical investigations are often found to be inconclusive, and genetic confirmation cannot always be obtained, leaving many patients without a final diagnosis. Evidence-based causal therapy is unavailable for most mitochondrial diseases and liver transplantation for this indication remains a controversial issue. Conclusion For clinicians, it is important to consider the possibility of an underlying mitochondrial disorder when there is systemic involvement (more than one organ affected), a suggestive family history, or an elevated level of lactic acid in the blood or cerebrospinal fluid.

Item does not contain fulltext Polymerase-gamma (POLG) is a major human disease gene and may account for up to 25% of all mitochondrial diseases in the UK and in Italy. To date, >150 different pathogenic mutations have been described in POLG. Some mutations behave as both dominant and recessive alleles, but an autosomal recessive inheritance pattern is much more common. The most frequently detected pathogenic POLG mutation in the Caucasian population is c.1399G>A leading to a p.Ala467Thr missense mutation in the linker domain of the protein. Although many patients are homozygous for this mutation, clinical presentation is highly variable, ranging from childhood-onset Alpers-Huttenlocher syndrome to adult-onset sensory ataxic neuropathy dysarthria and ophthalmoparesis. The reasons for this are not clear, but familial clustering of phenotypes suggests that modifying factors may influence the clinical manifestation. In this study, we collected clinical, histological and biochemical data from 68 patients carrying the homozygous p.Ala467Thr mutation from eight diagnostic centres in Europe and the USA. We performed DNA analysis in 44 of these patients to search for a genetic modifier within POLG and flanking regions potentially involved in the regulation of gene expression, and extended our analysis to other genes affecting mitochondrial DNA maintenance (POLG2, PEO1 and ANT1). The clinical presentation included almost the entire phenotypic spectrum of all known POLG mutations. Interestingly, the clinical presentation was similar in siblings, implying a genetic basis for the phenotypic variability amongst homozygotes. However, the p.Ala467Thr allele was present on a shared haplotype in each affected individual, and there was no correlation between the clinical presentation and genetic variants in any of the analysed nuclear genes. Patients with mitochondrial DNA haplogroup U developed epilepsy significantly less frequently than patients with any other mitochondrial DNA haplotype. Epilepsy was reported significantly more frequently in females than in males, and also showed an association with one of the chromosomal markers defining the POLG haplotype. In conclusion, our clinical results show that the homozygous p.Ala467Thr POLG mutation does not cause discrete phenotypes, as previously suggested, but rather there is a continuum of clinical symptoms. Our results suggest that the mitochondrial DNA background plays an important role in modifying the disease phenotype but nuclear modifiers, epigenetic and environmental factors may also influence the severity of disease.