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.

The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC derived Cortical Organoid of Alpers' Disease.

Alpers' syndrome is an early-onset neurodegenerative disorder usually caused by biallelic pathogenic variants in the gene encoding the catalytic subunit of polymerase-gamma (POLG), which is essential for mitochondrial DNA (mtDNA) replication. The disease is progressive, incurable, and inevitably it leads to death from drug-resistant status epilepticus. The neurological features of Alpers' syndrome are intractable epilepsy and developmental regression, with no effective treatment; the underlying mechanisms are still elusive, partially due to lack of good experimental models. Here, we generated the patient derived induced pluripotent stem cells (iPSCs) from one Alpers' patient carrying the compound heterozygous mutations of A467T (c.1399G>A) and P589L (c.1766C>T), and further differentiated them into cortical organoids and neural stem cells (NSCs) for mechanistic studies of neural dysfunction in Alpers' syndrome. Patient cortical organoids exhibited a phenotype that faithfully replicated the molecular changes found in patient postmortem brain tissue, as evidenced by cortical neuronal loss and depletion of mtDNA and complex I (CI). Patient NSCs showed mitochondrial dysfunction leading to ROS overproduction and downregulation of the NADH pathway. More importantly, the NAD+ precursor nicotinamide riboside (NR) significantly ameliorated mitochondrial defects in patient brain organoids. Our findings demonstrate that the iPSC model and brain organoids are good in vitro models of Alpers' disease; this first-in-its-kind stem cell platform for Alpers' syndrome enables therapeutic exploration and has identified NR as a viable drug candidate for Alpers' disease and, potentially, other mitochondrial diseases with similar causes.

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.

Astrocytic pathology in Alpers' syndrome.

Refractory epilepsy is the main neurological manifestation of Alpers' syndrome, a severe childhood-onset mitochondrial disease caused by bi-allelic pathogenic variants in the mitochondrial DNA (mtDNA) polymerase gamma gene (POLG). The pathophysiological mechanisms underpinning neuronal hyperexcitabilty leading to seizures in Alpers' syndrome remain unknown. However, pathological changes to reactive astrocytes are hypothesised to exacerbate neural dysfunction and seizure-associated cortical activity in POLG-related disease. Therefore, we sought to phenotypically characterise astrocytic pathology in Alpers' syndrome. We performed a detailed quantitative investigation of reactive astrocytes in post-mortem neocortical tissues from thirteen patients with Alpers' syndrome, eight neurologically normal controls and five sudden unexpected death in epilepsy (SUDEP) patients, to control for generalised epilepsy-associated astrocytic pathology. Immunohistochemistry to identify glial fibrillary acidic protein (GFAP)-reactive astrocytes revealed striking reactive astrogliosis localised to the primary visual cortex of Alpers' syndrome tissues, characterised by abnormal-appearing hypertrophic astrocytes. Phenotypic characterisation of individual GFAP-reactive astrocytes demonstrated decreased abundance of mitochondrial oxidative phosphorylation (OXPHOS) proteins and altered expression of key astrocytic proteins including Kir4.1 (subunit of the inwardly rectifying K+ ion channel), AQP4 (astrocytic water channel) and glutamine synthetase (enzyme that metabolises glutamate). These phenotypic astrocytic changes were typically different from the pathology observed in SUDEP tissues, suggesting alternative mechanisms of astrocytic dysfunction between these epilepsies. Crucially, our findings provide further evidence of occipital lobe involvement in Alpers' syndrome and support the involvement of reactive astrocytes in the pathogenesis of POLG-related disease.

The effects of nuclear DNA mutations on mitochondrial function.

ABSTRACT: The multiple functions of mitochondria, including adenosine triphosphate synthesis, are controlled by the coordination of both the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA) genomes. Mitochondrial disorders manifest because of impairment of energy metabolism. This article focuses on mutations in two nuclear genes and their effect on mitochondrial function. Mutations in the polymerase gamma, or POLG, gene are associated with multisystemic disease processes, including Alpers Syndrome, a severe childhood-onset syndrome. Mutations in the OPA1 gene are associated with autosomal dominant optic atrophy and other neurologic, musculoskeletal, and ophthalmologic symptoms. When assessing for disorders affecting energy metabolism, sequencing of both the mtDNA genome and the nDNA whole exome sequencing is necessary.

Pediatric tumefactive multiple sclerosis case (with baló-like lesions), diagnostic and treatment challenges.

BACKGROUND: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, rare during childhood. MS variations, like tumefactive MS and Balo concentric sclerosis, constitute puzzling to treat diagnostic dilemmas for pediatric patients. Differential diagnosis, mainly from brain tumors, is an absolute necessity. In addition, apart from treating acute attacks, immunomodulatory alternatives are limited. CASE: We present a 12.5-year-old boy diagnosed, 5 years ago, with tumefactive relapsing-remitting MS, with severe recurrent clinical attacks. Definite diagnosis of demyelination was achieved via combined brain imaging including magnetic resonance (MR) imaging, MR spectroscopy and computed tomography, avoiding brain biopsy. Acute attacks showed satisfactory response to aggressive treatment choices, like plasmapheresis and cyclophosphamide, but age-appropriate immunomodulating treatment was available, only 2 years later. Finally, after a last radiological relapse, when he was 10 years old, fingolimod was initiated. He has been clinically and radiologically stable since, presenting an excellent treatment tolerance.

Delineating selective vulnerability of inhibitory interneurons in Alpers' syndrome.

AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Clinical and molecular spectrum associated with Polymerase-γ related disorders.

BACKGROUND: POLG pathogenic variants are the commonest single-gene cause of inherited mitochondrial disease. However, the data on clinicogenetic associations in POLG-related disorders are sparse. This study maps the clinicogenetic spectrum of POLG-related disorders in the pediatric population. METHODS: Individuals were recruited across 6 centers in India. Children diagnosed between January 2015 and August 2020 with pathogenic or likely pathogenic POLG variants and age of onset <15 years were eligible. Phenotypically, patients were categorized into Alpers-Huttenlocher syndrome; myocerebrohepatopathy syndrome; myoclonic epilepsy, myopathy, and sensory ataxia; ataxia-neuropathy spectrum; Leigh disease; and autosomal dominant / recessive progressive external ophthalmoplegia. RESULTS: A total of 3729 genetic reports and 4256 hospital records were screened. Twenty-two patients with pathogenic variants were included. Phenotypically, patients were classifiable into Alpers-Huttenlocher syndrome (8/22; 36.4%), progressive external ophthalmoplegia (8/22; 36.4%), Leigh disease (2/22; 9.1%), ataxia-neuropathy spectrum (2/22; 9.1%), and unclassified (2/22; 9.1%). The prominent clinical manifestations included developmental delay (n = 14; 63.7%), neuroregression (n = 14; 63.7%), encephalopathy (n = 11; 50%), epilepsy (n = 11; 50%), ophthalmoplegia (n = 8; 36.4%), and liver dysfunction (n = 8; 36.4%). Forty-four pathogenic variants were identified at 13 loci, and these were clustered at exonuclease (18/44; 40.9%), linker (13/44; 29.5%), polymerase (10/44; 22.7%), and N-terminal domains (3/44; 6.8%). Genotype-phenotype analysis suggested that serious outcomes including neuroregression (odds ratio [OR] 11, 95% CI 2.5, 41), epilepsy (OR 9, 95% CI 2.4, 39), encephalopathy (OR 5.7, 95% CI 1.4, 19), and hepatic dysfunction (OR 4.6, 95% CI 21.3, 15) were associated with at least 1 variant involving linker or polymerase domain. CONCLUSIONS: We describe the clinical subgroups and their associations with different POLG domains. These can aid in the development of follow-up and management strategies of presymptomatic individuals.

Baló's concentric sclerosis - A rare entity within the spectrum of demyelinating diseases.

Baló'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 Baló-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.

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.