Magnetic resonance metrics for identification of cuprizone-induced demyelination in the mouse model of neurodegeneration: a review.

Neurodegenerative disorders, including Multiple Sclerosis (MS), are heterogenous disorders which affect the myelin sheath of the central nervous system (CNS). Magnetic Resonance Imaging (MRI) provides a non-invasive method for studying, diagnosing, and monitoring disease progression. As an emerging research area, many studies have attempted to connect MR metrics to underlying pathophysiological presentations of heterogenous neurodegeneration. Most commonly, small animal models are used, including Experimental Autoimmune Encephalomyelitis (EAE), Theiler's Murine Encephalomyelitis (TMEV), and toxin models including cuprizone (CPZ), lysolecithin, and ethidium bromide (EtBr). A contrast and comparison of these models is presented, with focus on the cuprizone model, followed by a review of literature studying neurodegeneration using MRI and the cuprizone model. Conventional MRI methods including T1 Weighted (T1W) and T2 Weighted (T2W) Imaging are mentioned. Quantitative MRI methods which are sensitive to diffusion, magnetization transfer, susceptibility, relaxation, and chemical composition are discussed in relation to studying the CPZ model. Overall, additional studies are needed to improve both the sensitivity and specificity of MRI metrics for underlying pathophysiology of neurodegeneration and the relationships in attempts to clear the clinico-radiological paradox. We therefore propose a multiparametric approach for the investigation of MR metrics for underlying pathophysiology.

The use of optical coherence tomography in neurology: a review.

Optical coherence tomography is a non-invasive, cost-efficient technique that provides high-resolution in vivo imaging of retinal tissue. The peripapillary retinal nerve fibre layer and macular ganglion cell complex are surrogate markers of neuroaxonal integrity in not only the eye, but also the CNS. Retinal atrophy may occur in tandem with CNS pathologies as a result of injury to ganglion cells, direct degeneration of the pregeniculate pathway, or retrograde trans-synaptic degeneration secondary to postgeniculate lesions. In this review, we outline the basic principles of optical coherence tomography and discuss its application to managing patients with demyelinating disorders, idiopathic intracranial hypertension, stroke, neurodegenerative conditions, and mitochondrial disorders. We demonstrate that measurements of peripapillary retinal nerve fibre layer and macular ganglion cell complex thickness are paramount in diagnosing and monitoring neurological disorders, including those with subclinical disease progression.

Neurology of cancer immunotherapy.

BACKGROUND: Immunotherapy is nowadays considered a mainstay of cancer treatment, dramatically affecting the disease-free survival rate in several aggressive malignancies. Unfortunately, cancer immunotherapy can also trigger life-threatening autoimmune neurological complications named "neurological adverse effects" (NAEs). NAEs can affect both the central nervous system (CNS), as in ipilimumab-related aseptic meningitis, and the peripheral nervous system (PNS), as in nivolumab-induced myasthenia gravis. CURRENT EVIDENCE: The incidence of NAEs is highly variable, ranging from 2 to 4% using checkpoint inhibitors to 50% using blinatumomab. Looking at these numbers, it appears clear that neurologists will soon be called more and more frequently to decide upon the best therapeutic strategy for a patient receiving immunotherapy and experiencing a NAE. Most of them can be treated or reverted withholding the offending drug and adding IVIg, plasmapheresis, or steroids to the therapy. Sometimes, however, for oncological reasons, immunotherapy cannot be stopped so the neurologist needs to know what countermeasures have proven most effective. Moreover, patients with a pre-existing autoimmune neurological disease (AID), such as myasthenia gravis or multiple sclerosis, might need immunotherapy during their life, risking a severe worsening of their symptoms. In that setting, the neurologist needs to properly counsel patients about the risk of a therapy-related relapse. CONCLUSION: In this article, we describe the most frequently reported NAEs and aim to give neurologists a practical overview on how to deal with them.

Characteristics and management of Susac syndrome in an emergent country: a multi-center case series from Brazil.

BACKGROUND: Susac syndrome (SS) is a rare endotheliopathy with an estimated prevalence of 0.14-0.024 per 100,000. It is an important differential diagnosis in demyelinating disorders. There are few case series and no large randomized controlled trials, and most reports come from developed countries. We report six cases of SS in three centers in Brazil and discuss management challenges in emergent countries. METHODS: This is a retrospective case series of patients diagnosed with SS in three medical centers in Brazil between April 2018 and July 2021. The European Susac consortium (EuSaC) criteria were used for diagnosis of SS. Demographic data and clinical interventions were described and outcomes were assessed subjectively and by applying the modified Rankin Scale (mRS) on last follow-up. RESULTS: Six patients were diagnosed with SS (3 males, 3 females). Mean age at presentation was 36 years (range 17 to 54). The most common initial symptom was confusion, followed by visual impairment and hearing loss. Characteristic snowball lesions on magnetic resonance imaging (MRI) were present in four patients (66%). Retinal artery abnormalities were present in half (3/6) of patients, and sensorineural hearing loss was present in four patients (66%). Outcome was favorable (mRS ≤ 2) in five patients (86%). Patients treated early had a more favorable outcome. CONCLUSION: Emergent countries face challenges in the diagnosis and management of patients with SS, such as access to advanced tests (fluorescein angiography, serial MRI) and treatment drugs (rituximab, mycophenolate). Further research should consider particularities of patients with SS in emergent countries.

Inflammatory activity following motor progression due to critical CNS demyelinating lesions.

BACKGROUND: New inflammatory activity is of unclear frequency and clinical significance in progressive multiple sclerosis (MS); it is uncertain in patient cohorts with motor progression due to critical demyelinating lesions. OBJECTIVES: The aim of this study is to determine the likelihood of central nervous system (CNS) inflammatory activity, assessed by new clinical relapses or active magnetic resonance imaging (MRI) lesions, following onset of motor progression due to critical demyelinating lesions. METHODS: Patients with progressive upper motor neuron impairment for ⩾1 year attributable to critical demyelinating lesions with single CNS lesion (progressive solitary sclerosis (PSS)), 2 to 5 total CNS demyelinating lesions (progressive "pauci-sclerosis" (PPS)), or >5 CNS demyelinating lesions and progressive exclusively unilateral monoparesis or hemiparesis (PUHMS) were identified. Clinical data were reviewed for acute MS relapses, and subsequent MRI was reviewed for active T1-gadolinium-enhancing or T2-demyelinating lesions. RESULTS: None of the 91 patients (22 PSS, 40 PPS, 29 PUHMS) identified experienced clinical relapses over a median clinical follow-up of 93 months (range: 12-518 months). Nine patients (10%) developed active lesions over median 84 months radiologic follow-up (range: 12-518 months). Active lesions occurred in 24% PUHMS, 5% PSS, and 3% PPS cohorts. CONCLUSION: New inflammatory activity, defined by active lesions and clinical relapses following motor progression in patients with critical demyelinating lesions, is low. Disease-modifying therapies that reduce demyelinating relapses and active MRI lesions are of uncertain benefit in these cohorts.

Serum α-synuclein and IL-1ß are increased and correlated with measures of disease severity in children with epilepsy: potential prognostic biomarkers?

BACKGROUND: The search for noninvasive biomarkers of neuroinflammation and neurodegeneration has focused on various neurological disorders, including epilepsy. We sought to determine whether α-synuclein and cytokines are correlated with the degree of neuroinflammation and/or neurodegeneration in children with epilepsy and with acquired demyelinating disorders of the central nervous system (CNS), as a prototype of autoimmune neuroinflammatory disorders. METHODS: We analyzed serum and exosome levels of α-synuclein and serum proinflammatory and anti-inflammatory cytokines among 115 children with epilepsy and 10 acquired demyelinating disorders of the CNS and compared to 146 controls. Patients were enrolled prospectively and blood was obtained from patients within 48 h after acute afebrile seizure attacks or relapse of neurological symptoms. Acquired demyelinating disorders of the CNS include acute disseminated encephalomyelitis, multiple sclerosis, neuromyelitis optica spectrum disorders, and transverse myelitis. The controls were healthy age-matched children. The serum exosomes were extracted with ExoQuick exosome precipitation solution. Serum α-synuclein levels and serum levels of cytokines including IFN-ß, IFN-γ, IL-1ß, IL-6, IL-10 and TNF-α were measured using single and multiplex ELISA kits. Data were analyzed and compared with measures of disease severity, such as age at disease onset, duration of disease, and numbers of antiepileptic drug in use. RESULTS: Serum α-synuclein levels were significantly increased in patients with epilepsy and acquired demyelinating disorders of the CNS compared to controls (both, p < 0.05) and showed correlation with measures of disease severity both in epilepsy (p < 0.05, r = 0.2132) and in acquired demyelinating disorders of the CNS (p < 0.05, r = 0.5892). Exosome α-synuclein showed a significant correlation with serum α-synuclein (p < 0.0001, r = 0.5915). Serum IL-1ß levels were correlated only with the numbers of antiepileptic drug used in children with epilepsy (p < 0.001, r = 0.3428), suggesting drug resistant epilepsy. CONCLUSIONS: This is the first study in children demonstrating that serum α-synuclein levels were significantly increased in children with epilepsy and with acquired demyelinating disorders of the CNS and correlated with measures of disease severity. Serum IL-1ß levels showed significant correlation only with drug resistance in children with epilepsy. Thus, these data support that serum levels of α-synuclein and IL-1ß are potential prognostic biomarkers for disease severity in children with epilepsy. CNS, central nervous system.

Donepezil, a drug for Alzheimer's disease, promotes oligodendrocyte generation and remyelination.

Myelin sheaths play important roles in neuronal functions. In the central nervous system (CNS), the myelin is formed by oligodendrocytes (OLs), which are differentiated from oligodendrocyte precursor cells (OPCs). In CNS demyelinating disorders such as multiple sclerosis (MS), the myelin sheaths are damaged and the remyelination process is hindered. Small molecule drugs that promote OPC to OL differentiation and remyelination may provide a new way to treat these demyelinating diseases. Here we report that donepezil, an acetylcholinesterase inhibitor (AChEI) developed for the treatment of Alzheimer's disease (AD), significantly promotes OPC to OL differentiation. Interestingly, other AChEIs, including huperzine A, rivastigmine, and tacrine, have no such effect, indicating that donepezil's effect in promoting OPC differentiation is not dependent on the inhibition of AChE. Donepezil also facilitates the formation of myelin sheaths in OPC-DRG neuron co-culture. More interestingly, donepezil also promotes the repair of the myelin sheaths in vivo and provides significant therapeutic effect in a cuprizone-mediated demyelination animal model. Donepezil is a drug that has been used to treat AD safely for many years; our findings suggest that it might be repurposed to treat CNS demyelinating diseases such as MS by promoting OPC to OL differentiation and remyelination.

Reprint of "Hypomyelinating disorders: An MRI approach.

In recent years, the concept of hypomyelinating disorders has been proposed as a group of disorders with varying systemic manifestations that are identified by MR findings of absence or near absence of the T2 hypointensity that develops in white matter as a result of myelination. Initially proposed as a separate group because they were the largest single category of undiagnosed leukodystrophies, their separation as a distinct group that can be recognized by looking for a specific MRI feature has resulted in a marked increase in their diagnosis and a better understanding of the different causes of hypomyelination. This review will discuss the clinical presentations, imaging findings on standard MRI, and new MRI-related techniques that allow a better understanding of these disorders and proposed methods for quantifying the myelination as a potential means of assessing disease course and the effects of proposed treatments. Disorders with hypomyelination of white matter, or hypomyelinating disorders (HMDs), represent the single largest category among undiagnosed genetic leukoencephalopathies (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010). This group of inborn errors of metabolism is characterized by a magnetic resonance imaging (MRI) appearance of reduced or absent myelin development: delay in the development of T2 hypointensity and, often, T1 hyperintensity in the white matter of the brain. The concept of hypomyelination was first conceptualized by (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010; Schiffmann et al., 1994) in a series of papers that showed that these MRI characteristics were easily recognized, were different from the MRI characteristics of dysmyelinating and demyelinating disorders, and that the combination of these imaging findings with specific other clinical and imaging features could be used to make diagnoses with some confidence. In this manuscript, we will discuss the physiologic and genetic bases of hypomyelinating disorders, as well as their classification, clinical manifestations and imaging characteristics.

Hypomyelinating disorders: An MRI approach.

In recent years, the concept of hypomyelinating disorders has been proposed as a group of disorders with varying systemic manifestations that are identified by MR findings of absence or near absence of the T2 hypointensity that develops in white matter as a result of myelination. Initially proposed as a separate group because they were the largest single category of undiagnosed leukodystrophies, their separation as a distinct group that can be recognized by looking for a specific MRI feature has resulted in a marked increase in their diagnosis and a better understanding of the different causes of hypomyelination. This review will discuss the clinical presentations, imaging findings on standard MRI, and new MRI-related techniques that allow a better understanding of these disorders and proposed methods for quantifying the myelination as a potential means of assessing disease course and the effects of proposed treatments. Disorders with hypomyelination of white matter, or hypomyelinating disorders (HMDs), represent the single largest category among undiagnosed genetic leukoencephalopathies (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010). This group of inborn errors of metabolism is characterized by a magnetic resonance imaging (MRI) appearance of reduced or absent myelin development: delay in the development of T2 hypointensity and, often, T1 hyperintensity in the white matter of the brain. The concept of hypomyelination was first conceptualized by (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010; Schiffmann et al., 1994) in a series of papers that showed that these MRI characteristics were easily recognized, were different from the MRI characteristics of dysmyelinating and demyelinating disorders, and that the combination of these imaging findings with specific other clinical and imaging features could be used to make diagnoses with some confidence. In this manuscript, we will discuss the physiologic and genetic bases of hypomyelinating disorders, as well as their classification, clinical manifestations and imaging characteristics.

Prevalence and patterns of demyelinating central nervous system disorders in urban Mangalore, South India.

There is a dearth of epidemiological data about multiple sclerosis (MS) and related demyelinating disorders in India. In this study, a registry method was used for collecting data from secure sources and the index cases were verified Seventy nine patients were identified . A crude prevalence of 8.3/100,000 was obtained for MS and 6.2/100,000 for clinically-isolated syndrome (CIS). Age-standardized prevalence of MS relative to the world population was 7.8/100,000. Neuromyelitis optica (NMO) and spectrum disorders (NMOS) constituted 13.9% of all demyelinating disorders, with a prevalence of 2.6/100,000. Larger studies with more refined survey methodologies are required to understand the true prevalence of demyelinating disorders in India.

Hidden hearing loss in a Charcot-Marie-Tooth type 1A mouse model.

Hidden hearing loss (HHL), a recently described auditory neuropathy characterized by normal audiometric thresholds but reduced sound-evoked cochlear compound action potentials, has been proposed to contribute to hearing difficulty in noisy environments in people with normal hearing thresholds, a widespread complaint. While most studies on HHL pathogenesis have focused on inner hair cell (IHC) synaptopathy, we recently showed that transient auditory nerve (AN) demyelination also causes HHL in mice. To test the impact of myelinopathy on hearing in a clinically relevant model, we studied a mouse model of Charcot-Marie-Tooth type 1A (CMT1A), the most prevalent hereditary peripheral neuropathy in humans. CMT1A mice exhibit the functional hallmarks of HHL together with disorganization of AN heminodes near the IHCs with minor loss of AN fibers. These results support the hypothesis that mild disruptions of AN myelination can cause HHL, and that heminodal defects contribute to the alterations in the sound-evoked cochlear compound action potentials seen in this mouse model. Also, these findings suggest that patients with CMT1A or other mild peripheral neuropathies are likely to suffer from HHL. Furthermore, these results suggest that studies of hearing in CMT1A patients might help develop robust clinical tests for HHL, which are currently lacking.

Loss of microRNA-15a/16-1 function promotes neuropathological and functional recovery in experimental traumatic brain injury.

The diffuse axonal damage in white matter and neuronal loss, along with excessive neuroinflammation, hinder long-term functional recovery after traumatic brain injury (TBI). MicroRNAs (miRs) are small noncoding RNAs that negatively regulate protein-coding target genes in a posttranscriptional manner. Recent studies have shown that loss of function of the miR-15a/16-1 cluster reduced neurovascular damage and improved functional recovery in ischemic stroke and vascular dementia. However, the role of the miR-15a/16-1 cluster in neurotrauma is poorly explored. Here, we report that genetic deletion of the miR-15a/16-1 cluster facilitated the recovery of sensorimotor and cognitive functions, alleviated white matter/gray matter lesions, reduced cerebral glial cell activation, and inhibited infiltration of peripheral blood immune cells to brain parenchyma in a murine model of TBI when compared with WT controls. Moreover, intranasal delivery of the miR-15a/16-1 antagomir provided similar brain-protective effects conferred by genetic deletion of the miR-15a/16-1 cluster after experimental TBI, as evidenced by showing improved sensorimotor and cognitive outcomes, better white/gray matter integrity, and less inflammatory responses than the control antagomir-treated mice after brain trauma. miR-15a/16-1 genetic deficiency and miR-15a/16-1 antagomir also significantly suppressed inflammatory mediators in posttrauma brains. These results suggest miR-15a/16-1 as a potential therapeutic target for TBI.

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.

New-Onset Vision Impairment in Children: Magnetic Resonance Imaging Findings by Age Groups.

INTRODUCTION: Non-traumatic visual impairment is rare in the pediatric population, but early diagnosis and treatment of the cause is crucial to prevent long-term consequences affecting children's neurocognitive development. The authors aim to determine the most common causes of non-traumatic visual impairment in pediatric patients according to age groups by magnetic resonance imaging (MRI). METHODS: Images of patients who underwent contrast-enhanced cranial and orbital MRI for new-onset visual impairment between June 2019 and June 2022 were retrospectively reviewed. MRI findings were categorized as tumors, idiopathic intracranial hypertension, demyelinating disorders, infections, isolated optic neuritis, and others. The patients were grouped according to age as preschoolers, schoolchildren, and adolescents. Demographic features of patients and MRI findings were collected and compared among age groups. RESULTS: One hundred seventeen of the 238 patients had pathologic MRI findings. The most common pathologies were tumors (26.4%), idiopathic intracranial hypertension (24.7%), demyelinating disorders (18.8%), infections (11.1%), and isolated optic neuritis (7.6%). Tumors (69.2%) in preschool children, idiopathic intracranial hypertension (36.3%) in schoolchildren, and demyelinating disorders (32.7%) in adolescents were the most common cause of vision impairment by age group. CONCLUSION: Children with acute vision impairment could have severe pathologies. Tumors in preschool children, idiopathic intracranial hypertension in schoolchildren, and demyelinating disorders in adolescents were the most common causes of new-onset vision impairment detected with MRI. Because of the difficulty of performing optimal ophthalmologic and neurologic examinations, especially in young children, cranial and orbital MRI should be considered to detect life-threatening pathologies.

Leukodystrophy Imaging: Insights for Diagnostic Dilemmas.

Leukodystrophies, a group of rare demyelinating disorders, mainly affect the CNS. Clinical presentation of different types of leukodystrophies can be nonspecific, and thus, imaging techniques like MRI can be used for a more definitive diagnosis. These diseases are characterized as cerebral lesions with characteristic demyelinating patterns which can be used as differentiating tools. In this review, we talk about these MRI study findings for each leukodystrophy, associated genetics, blood work that can help in differentiation, emerging diagnostics, and a follow-up imaging strategy. The leukodystrophies discussed in this paper include X-linked adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe's disease, Pelizaeus-Merzbacher disease, Alexander's disease, Canavan disease, and Aicardi-Goutières Syndrome.

A Case of Balo Concentric Sclerosis: A Multiple Sclerosis Mimic.

Balo Concentric Sclerosis (BCS) is a rare neurological demyelinating disorder similar to Multiple Sclerosis. Both present with progressive neurological debility but differences on brain imaging help with distinction. The lack of prevalence and general diagnostic information about BCS makes it an underdiagnosed disease which can sometimes delay treatment. This case of BCS was initially treated as an infectious brain mass, leading to unnecessary interventions. Early recognition and differentiation from other neurological conditions are crucial for appropriate management and prognosis. We hope that by presenting this case, we can aid in creating diagnostic criteria and promote awareness of this chronic debilitating disease.

Tumefactive Demyelinating Lesions: An Illustrative Pediatric Case With an Atypical Presentation and Literature Review.

Tumefactive demyelinating lesions remain a rare entity and a source of diagnostic difficulty. Here, we report the case of a teenage girl who presented with a one-month history of progressive quadriparesis and symptoms of intracranial hypertension. Brain MRI showed multiple large subcortical white matter lesions with both open- and closed-rim enhancement on gadolinium injection. The patient subsequently underwent a brain biopsy which showed an inflammatory infiltrate and no signs of malignancy. She was treated with pulse intravenous methylprednisolone at a dose of 500mg per day for five days and had rapid improvement. Her symptoms fully resolved after three months. This case highlights the need for better recognition and diagnosis of tumefactive demyelination, potentially avoiding unnecessary invasive diagnostic procedures such as brain biopsies.

A rare case of Balo's disease in a young adult: A clinical presentation and management.

Key Clinical Message: Accurate diagnosis of rare neurological conditions like Balo's concentric sclerosis (BCS) is challenging but crucial for tailored treatment. Interdisciplinary collaboration and further research are essential to advance our understanding. Abstract: This case report presents a 32-year-old female patient with a puzzling neurological condition characterized by feverish feelings, joint pain, unclear speech, and an unsteady gait. Initial management did not lead to improvement, and further examination revealed neurological involvement and joint tenderness without signs of inflammatory arthritis. Laboratory investigations ruled out infectious and autoimmune causes. Magnetic resonance imaging (MRI) showed well-defined lesions with concentric rings, leading to a diagnosis of Balo' concentric sclerosis. Treatment with intravenous methylprednisolone resulted in limited improvement. This case highlights the importance of thorough evaluation and collaboration in diagnosing rare neurological conditions. Further research is needed to enhance the understanding and treatment of rare neurological disorders.

The Clinical Spectrum of Adrenoleukodystrophy at a Portuguese Tertiary Hospital: Case Series and Review of Literature.

Adrenoleukodystrophy, a rare genetic disease associated with the X chromosome (X-ALD - X-linked adrenoleukodystrophy), predominantly affects males and stems from mutations in the ABCD1 gene, responsible for transporting very long chain fatty acids (VLCFA) into peroxisomes. It leads to adrenal insufficiency (AI) and axonal demyelination. In males, the phenotype varies from isolated adrenocortical insufficiency and progressive myelopathy to cerebral adrenoleukodystrophy (CALD). The aim of this case series is to characterize patients with different clinical presentations of X-ALD with follow-up at a tertiary Portuguese hospital. All four patients were males, and the median age at the diagnosis was 5 years. Three patients were diagnosed through family screening, with the oldest already displaying hyperpigmentation. Two distinct forms were identified: adolescent CALD (25%) and isolated primary adrenal insufficiency (75%). Analytical studies revealed elevated plasma VLCFA levels in all cases, and genetic analysis demonstrated two different mutations in the ABCD1 gene. This disorder requires early diagnosis for improved prognosis. Screening male children with primary AIfor X-ALD using a VLCFA panel should be considered, particularly after ruling out the most common causes or when learning difficulties are evident. Genetic confirmation of the diagnosis is essential, enabling genetic counseling, family planning, and preimplantation genetic diagnosis.