Radiological features in pediatric myelin oligodendrocyte glycoprotein antibody-associated disease-diagnostic criteria and lesion dynamics.

The spectrum of acquired pediatric demyelinating syndromes has been expanding over the past few years, to include myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), as a distinct neuroimmune entity, in addition to pediatric-onset multiple sclerosis (POMS) and aquaporin 4-IgG-seropositive neuromyelitis optica spectrum disorder (AQP4+NMOSD). The 2023 MOGAD diagnostic criteria require supporting clinical or magnetic resonance imaging (MRI) features in patients with low positive myelin oligodendrocyte glycoprotein IgG titers or when the titers are not available, highlighting the diagnostic role of imaging in MOGAD. In this review, we summarize the key diagnostic features in MOGAD, in comparison to POMS and AQP4+NMOSD. We describe the lesion dynamics both during attack and over time. Finally, we propose a guideline on timing of imaging in clinical practice.

Impact of autoantibodies against myelin oligodendrocyte glycoprotein in paediatric acquired demyelinating disease: Intellectual functioning and academic performance.

Paediatric acquired demyelinating syndromes (pADS) attack white matter pathways in the brain during an important period of development. Affected children can experience poor functional outcomes, including deficits in specific cognitive domains. Understanding risk factors for poor outcome will guide clinical management of these children. One clinical phenotype which may differentially impact cognitive outcomes is the presence of autoantibodies to myelin oligodendrocyte glycoprotein (MOG). Preliminary research has suggested that cognitive difficulties exist in paediatric patients who test positive for MOG antibodies or MOGAD (Myelin Oligodendrocyte Glycoprotein Associated Disease) however, they experience a less severe profile compared to seronegative counterparts. The current study assesses children diagnosed with pADS who tested positive or negative for MOG-ab using standardised assessments of both intellectual functioning and academic ability. The results show that a subset of MOGAD patients experience clinically significant sequalae in intellectual functioning and academic ability. The neuropsychological profile also differed between children with and without MOG-ab positivity, with seronegative patients more likely to show a clinically relevant difficulties at the individual patient level. Whilst no differences existed at the group-level; the current study demonstrates the relative additional risk of intellectual/academic difficulty associated with MOG-ab seronegativity. This research further supports the growing perspective that MOG-positivity confers a more favourable neuropsychological outlook than is the case for their seronegative counterparts. This broadening consensus offers reassurance for clinicians, families, and patients.

Incidence of cancer in chronic inflammatory demyelinating polyneuropathy: a nationwide cohort study in South Korea.

Background: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare disease, and the potential risk of cancer in patients with CIDP remains an important concern during treatment. However, a comprehensive epidemiological study examining this association is yet to be conducted. This study aimed to investigate the incidence of cancer in patients with CIDP in South Korea using data from the Korean Health Insurance Review and Assessment Service (HIRA) database. Methods: Data from the HIRA database between January 2016 and June 2021 were analyzed. The actual incidence of cancer in patients with CIDP was compared with the expected incidence based on the general population statistics in South Korea, with adjustments for age. Results: In total, 888 patients with CIDP were included in the analysis, of whom 50 (5.63% of malignancy incidence) were newly diagnosed with cancer during the study period. Among the patients with CIDP diagnosed with cancer, 32 (64.00%) were aged 60 years or older, and 36 (72.00%) were male. The observed number of cancer diagnoses corresponded to an incidence rate of 5.63%, with a standardized incidence ratio (SIR) of 2.83 (95% confidence interval [CI]: 1.89-4.39) compared to the expected cancer incidence rate of 2.00%. Notably, the SIR for malignancies of lymphoid, hematopoietic, and related tissues, excluding malignant immunoproliferative diseases, multiple myeloma, and plasma cell neoplasms (C81-96, except C88 and C90), was the highest at 8.51 (95% CI: 4.18-19.83). Conclusion: Our study shows a potential association between CIDP and an increased risk of hematological malignancies, which is consistent with previous investigations. Further studies are required to better understand the relationship between CIDP and cancer.

Ferritin loss in astrocytes reduces spinal cord oxidative stress and demyelination in the experimental autoimmune encephalomyelitis (EAE) model.

Demyelinating diseases such as multiple sclerosis (MS) cause myelin degradation and oligodendrocyte death, resulting in the release of toxic iron and iron-induced oxidative stress. Astrocytes have a large capacity for iron transport and storage, however the role of astrocytic iron homeostasis in demyelinating disorders is not completely understood. Here we investigate whether astrocytic iron metabolism modulates neuroinflammation, oligodendrocyte survival, and oxidative stress following demyelination. To this aim, we conditionally knock out ferritin in astrocytes and induce experimental autoimmune encephalomyelitis (EAE), an autoimmune-mediated model of demyelination. Ferritin ablation in astrocytes reduced the severity of disease in both the acute and chronic phases. The day of onset, peak disease severity, and cumulative clinical score were all significantly reduced in ferritin KO animals. This corresponded to better performance on the rotarod and increased mobility in ferritin KO mice. Furthermore, the spinal cord of ferritin KO mice display decreased numbers of reactive astrocytes, activated microglia, and infiltrating lymphocytes. Correspondingly, the size of demyelinated lesions, iron accumulation, and oxidative stress were attenuated in the CNS of ferritin KO subjects, particularly in white matter regions of the spinal cord. Thus, deleting ferritin in astrocytes reduced neuroinflammation, oxidative stress, and myelin deterioration in EAE animals. Collectively, these findings suggest that iron storage in astrocytes is a potential therapeutic target to lessen CNS inflammation and myelin loss in autoimmune demyelinating diseases.

Infrared spectral profiling of demyelinating activity in multiple sclerosis brain tissue.

Multiple sclerosis (MS) is a leading cause of non-traumatic disability in young adults. The highly dynamic nature of MS lesions has made them difficult to study using traditional histopathology due to the specificity of current stains. This requires numerous stains to track and study demyelinating activity in MS. Thus, we utilized Fourier transform infrared (FTIR) spectroscopy to generate holistic biomolecular profiles of demyelinating activities in MS brain tissue. Multivariate analysis can differentiate MS tissue from controls. Analysis of the absorbance spectra shows profound reductions of lipids, proteins, and phosphate in white matter lesions. Changes in unsaturated lipids and lipid chain length indicate oxidative damage in MS brain tissue. Altered lipid and protein structures suggest changes in MS membrane structure and organization. Unique carbohydrate signatures are seen in MS tissue compared to controls, indicating altered metabolic activities. Cortical lesions had increased olefinic lipid content and abnormal membrane structure in normal appearing MS cortex compared to controls. Our results suggest that FTIR spectroscopy can further our understanding of lesion evolution and disease mechanisms in MS paving the way towards improved diagnosis, prognosis, and development of novel therapeutics.

Acute hemorrhagic leukoencephalopathy: a case report and literature review.

Introduction and importance: Acute hemorrhagic leukoencephalopathy (AHLE) is a rare and devastating condition that can present with various neurological symptoms. The predisposing and initiating factors of AHLE are not fully understood. AHLE has a high morbidity and significant mortality rates, however, our case presents a surviving young girl. Case presentation: Thirteen years old previously healthy girl was referred to the emergency department due to drowsiness, preceded by an upper respiratory infection 10 days earlier. Firstly, she was treated empirical with antiviral medication (Acyclovir) directed to herpes simplex virus and intravenous (IV) methylprednisolone pulses. When she did not respond well, intravenous immunoglobulin was administrated, which helped with the end-result diagnosis based on clinical and imaging findings. Clinical discussion: AHLE is a fatal rare demyelinating disease characterized by an acute rapidly progressive fulminant inflammation of the white matter, it is usually misdiagnosed due to being a diagnosis of exclusion, and the much more common other diseases, including infectious encephalitis, meningitis, fulminant multiple sclerosis, other causes of acute disseminated encephalomyelitis. Different types of CNS infiltrates, such as neutrophils in AHLE and lymphocytes in acute disseminated encephalomyelitis, do not support the idea of differentiating the two diseases. The process of differentiating between these two diseases relies mostly on laboratory and imaging findings, which are well demonstrated in this case report. Conclusion: The authors conclude this report by highlighting the dearth in published knowledge about this disease, and encouraging further studies be conducted about this topic.

Optical coherence tomography angiography measurements in neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody disease: A systematic review and meta-analysis.

PURPOSE: Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) are immune-mediated disorders that can often manifest with optic neuritis (ON) among other symptoms. Optical coherence tomography angiography (OCTA) is an emerging diagnostic method that can quantify retinal capillary blood flow and vessel density (VD), which have been shown to be affected in NMOSD and MOGAD. Hence, we aimed to systematically review the studies addressing retinal microvasculature using OCTA in these diseases. DESIGN: Systematic review and meta-analysis. METHODS: PubMed, EMBASE, and Web of Sciences were systematically searched to identify articles addressing OCTA measurements in patients with NMOSD or MOGAD. Following the data extraction, a meta-analysis was performed on the study population and OCTA types amongst at least two homogenous studies. RESULTS: Twenty-two studies on NMOSD, MOGAD, or both were included. Parafoveal superficial retinal capillary plexus (SRCP) VD and radial peripapillary capillary (RPC) VD were diminished in NMOSD ON+ and NMOSD ON- groups compared to healthy controls (HCs). In addition, both the SRCP VD and RPC VD were significantly reduced in NMOSD ON+ compared to NMOSD ON-. However, meta-analysis for deep retinal capillary plexus (DRCP) did not show a significant difference between NMOSD patients and HCs, or among ON+ and ON- patients. Furthermore, there was no significant difference in foveal avascular zone (FAZ) area size between NMOSD patients and HCs. Regarding MOGAD, the meta-analysis showed decreased parafoveal SRCP VD and RPC VD in MOGAD ON+ patients compared to HCs. Comparing NMOSD ON+ and MOGAD ON+, a meta-analysis was conducted for RPC VD, which showed no significant difference between the two groups. CONCLUSIONS: This systematic review and meta-analysis confirmed reduced VD in the macular and peripapillary areas in NMOSD and MOGAD eyes, particularly in the parafoveal SRCP and RPC, which is further impacted by prior ON.

Stable excess mortality in a multiple sclerosis cohort diagnosed 1970-2010.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is associated with excess mortality. The use of disease-modifying treatments (DMTs) has recently been associated with survival benefits. METHODS: A regional MS database was linked with national registries. People with MS (pwMS) diagnosed in 1971-2010 were included and followed up until the end of the year 2019. Five matched controls were acquired for every person with MS. DMTs included in the analyses were interferon and glatiramer acetate. RESULTS: Median follow-up time of the 1795 pwMS was 20.0 years (range 0.1-48.7 years). Survival did not differ between decades of diagnosis (p = 0.20). Amongst pwMS, male sex (adjusted hazard ratio [aHR] 1.70; 95% confidence interval [CI] 1.41-2.06), higher age at diagnosis (aHR 1.83; 95% CI 1.65-2.03 per 10-year increment) and primary progressive disease course (aHR 1.29; 95% CI 1.04-1.60) were independently associated with poorer survival. DMT use was associated with better survival (p < 0.0001) and better survival during follow-up (aHR 0.56; 95% CI 0.38-0.81). Compared to matched controls, median life expectancy was 8-9 years shorter in pwMS with survival diverging from controls during the first decade after diagnosis, more clearly in men than women. CONCLUSION: Despite DMT use being associated with better survival, relative life expectancy of pwMS did not change over five decades in Western Finland. Male sex was an independent risk factor for death amongst pwMS, but excess mortality was higher in women. More work and methods are needed to improve survival in pwMS.

Relapsing tumefactive demyelination lesions: A unique, distinct inflammatory brain pathology.

We report the case of a patient suffering from biopsy-proven relapsing tumefactive demyelinating lesions (TDLs) of the central nervous system who had five relapses in 16 years. No signs/symptoms suggestive of alternative pathologies emerged during the follow-up. A limited benefit was observed with intravenous (IV) high-dose steroids, while both plasma exchange and IV immunoglobulin G (IgG) administration were ineffective. A long-lasting (9 years) but transient clinical stabilization was obtained with cyclophosphamide. Our case supports the view that recurrent TDL is a relapsing brain inflammation not belonging to multiple sclerosis (MS) or myelin oligodendrocyte glycoprotein (MOG)-/AQP4-associated disorders. TDL concept and clinical features should be revised.

The kappa free light chains index is an accurate diagnostic biomarker for paediatric multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) may occur before the age of 18. Differentiation between paediatric MS (PedMS) and other demyelinating syndromes (ODSs) is challenging. In adult with MS, the kappa free light chain (KFLC) index has proven to be a reliable marker of intrathecal Ig synthesis. OBJECTIVE: To assess the diagnostic value of the KFLC index in a cohort of patients with paediatric-onset, inflammatory disorders of the CNS. METHODS: We included 73 patients and divided them into four groups: PedMS (n = 16), ODS (n = 17), encephalitis and/or inflammatory epilepsy (EE, n = 15), and controls without inflammatory CNS diseases (n = 25). The KFLC index was calculated and compared with the results of the oligoclonal bands determination. RESULTS: The KFLC index was higher in the PedMS group (median (interquartile range (IQR)): 150.9 (41.02-310.6)) than in the ODS (3.37 (2.22-8.11)), the EE (5.53 (2.31-25.81)) and the control group (3.41 (2.27-5.08)), respectively. The best KFLC index cut-off for differentiating between patients with PedMS and controls was 6.83 (sensitivity: 100%; specificity: 92%). A KFLC index over 93.77 indicated that the patient is very likely to have PedMS (sensitivity: 68%; specificity: 100%). CONCLUSION: The KFLC index is a reliable tool for the diagnosis of MS in a paediatric population.

Is there a prodrome to NMOSD? An investigation of neurologic symptoms preceding the first NMOSD attack.

BACKGROUND: It is unknown whether people with aquaporin-4 antibody positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD) experience a prodrome, although a few cases report AQP4 + serology up to 16 years before the first attack. OBJECTIVES: To evaluate whether individuals with AQP4-IgG + NMOSD have prodromal neurologic symptoms preceding the first attack. METHODS: We reviewed medical records of participants meeting the 2015 diagnostic criteria for AQP4-IgG + NMOSD from four demyelinating disease centres in the Canadian NMOSD cohort study CANOPTICS. We searched for neurologic symptoms occurring at least 30 days before the first attack. RESULTS: Of 116 participants with NMOSD, 17 (14.7%) had prodromal neurologic symptoms. The median age was 48 years (range 25-83) at first attack; 16 (94.1%) were female. Participants presented with numbness/tingling (n = 9), neuropathic pain (n = 5), visual disturbance (n = 4), tonic spasms (n = 2), Lhermitte sign (n = 2), severe headache (n = 2), incoordination (n = 2), weakness (n = 1), psychosis (n = 1) or seizure (n = 1). Of eight who underwent magnetic resonance imaging (MRI) brain, orbits and/or spinal cord, five had T2 lesions. Within 1.5-245 months (median 14) from the onset of prodromal neurologic symptoms, participants experienced their first NMOSD attack. CONCLUSIONS: One in seven people with NMOSD experienced neurologic symptoms before their first attack. Further investigation of a possible NMOSD prodrome is warranted.

B-cell Depletion Therapy in Pediatric Neuroinflammatory Disease.

PURPOSE OF REVIEW: B-cell depletion therapy, including anti-CD20 and anti-CD19 therapies, is increasingly used for a variety of autoimmune and conditions, including those affecting the central nervous system. However, B-cell depletion therapy use can be complicated by adverse effects associated with administration and immunosuppression. This review aims to summarize the application of anti-CD20 and anti-CD19 therapies for the pediatric neurologist and neuroimmunologist. RECENT FINDINGS: Most existing literature come from clinical trials with adult patients, although more recent studies are now capturing the effects of these therapies in children. The most common side effects include infusion related reactions and increased infection risk from immunosuppression. Several strategies can mitigate infusion related reactions. Increased infections due to persistent hypogammaglobulinemia can benefit from replacement immunoglobulin. B-cell depletion therapies can be safe and effective in pediatric patients. Anticipation and mitigation of common adverse effects through primary prevention strategies, close monitoring, and appropriate symptomatic management can improve safety and tolerability.

Successful treatment of relapsed and refractory CIDP with ofatumumab: a first case report.

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous but treatable immune-mediated neuropathy. Ofatumumab (OFA) is a fully human anti-CD20 monoclonal antibody that has shown promising efficacy in central demyelinating diseases, such as multiple sclerosis (MS). However, there is a lack of studies on the usage of OFA in peripheral demyelinating diseases, particularly CIDP. A case of relapsed and refractory CIDP with an ineffective response to conventional immunotherapy and intolerance to rituximab (RTX) but a positive response to subcutaneous injections of OFA is presented. Case presentation: The patient, a 46-year-old man diagnosed with CIDP, received high-dose intravenous methylprednisolone, intravenous immunoglobulin (IVIG), and plasma exchange(PE) during the acute phase of the disease, and long-term oral administration of prednisone, azathioprine (AZA), and mycophenolate mofetil (MMF) during the remission phase. However, the patient suffered six relapses over a five-year period, and because of these, along with an ineffective response to conventional immunotherapy, and intolerance to RTX, subcutaneous injections of OFA were selected as a prophylactic treatment against relapses. After a total of six injections of OFA, CD19+B cells were substantially depleted. The patient has been followed for more than 23 months without relapse. Conclusions: This case demonstrates the effectiveness and good tolerability of OFA in the treatment of relapsed and refractory CIDP. Further studies are needed to investigate the efficacy and safety of OFA in patients with relapsed and refractory CIDP, especially in those who have shown an ineffective response to conventional immunotherapy and are intolerant to RTX.

Chronic Inflammatory Demyelinating Polyneuropathy Following Lumbar Spine Surgery in a Patient With Sarcoidosis.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare relapsing-remitting autoimmune polyneuropathy that targets peripheral nerves and has been associated in the literature with sarcoidosis. The goal of this study is to report the clinical case of a 61-year-old man with sarcoidosis who developed CIDP following lumbar spine surgery. The patient presented at their clinic visit with lumbar back pain and underwent a dome laminoplasty at L2-3, L3-4, and L4-5 with no known complications. Approximately four hours postoperatively, he developed bilateral lower extremity weakness most prominent along the tibialis anterior and extensor hallucis longus (L4-S1) as well as saddle anesthesia. An MRI revealed no acute changes concerning compression. Electromyography (EMG) was performed six months postoperatively, which revealed absent F waves along the peroneal and tibial nerves as well as decreased amplitude consistent with an underlying axonal neuropathy. He was referred to a neurologist for a second opinion where a diagnosis of CIDP was made. Intravenous immune globulin treatment was initiated, and the patient felt improvement in his symptoms. This case highlights the association between sarcoidosis and CIDP and discusses the pathophysiology of the disease. In patients with sarcoidosis and weakness following lumbar surgery with a negative MRI, CIDP should be on the differential.

The epilepsy phenotype of KCNK4-related neurodevelopmental disease.

INTRODUCTION: Potassium ion channels play a crucial role in maintaining cellular electrical stability and are implicated in various epilepsies. Heterozygous pathogenic variants in KCNK4 cause a recognizable neurodevelopmental syndrome with facial dysmorphism, hypertrichosis, epilepsy, intellectual disability (ID), and gingival overgrowth (FHEIG). To date, no more than nine patients with FHEIG have been described worldwide and still little is known about epileptic phenotype in KCNK4-related disease. METHODS: We identified a novel de novo p.(Gly139Arg) variant in KCNK4 in a patient with drug-resistant nocturnal seizures, mild ID, and dysmorphic features. In silico analyses of the variant strongly suggest a gain-of-function effect. We conducted a retrospective review of previously published cases, focusing on the epileptic features and response to various treatments. RESULTS: To date, epilepsy has been reported in 8/10 patients with KCNK4-related disease. The mean age of seizure onset was 1.8 years, and the most common seizure type was focal to bilateral tonic-clonic (5/8). Sodium channel blockers and valproate were effective in the majority of patients, but in 3/8 the epilepsy was drug-resistant. Our patient showed improved seizure control after treatment with the carbonic anhydrase inhibitor sulthiame. Interestingly, the patient showed features of peripheral nerve hyperexcitability syndrome, a phenomenon not previously described in potassium channelopathies caused by increased K+ conductance. CONCLUSION: Gain-of-function variants in KCNK4 cause a spectrum of epilepsies, ranging from benign isolated epilepsy to epileptic encephalopathy, with focal to bilateral tonic-clonic seizures being the most commonly observed. Importantly, a subgroup of patients present with a mild extra-neurological phenotype without characteristic facial dysmorphism or generalized hypertrichosis. This report expands the phenotypic spectrum of KNCK4-associated disease and provides new insights into the clinical heterogeneity of this rare neurodevelopmental 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.

Contactin -Associated protein1 Regulates Autophagy by Modulating the PI3K/AKT/mTOR Signaling Pathway and ATG4B Levels in Vitro and in Vivo.

Contactin-associated protein1 (Caspr1) plays an important role in the formation and stability of myelinated axons. In Caspr1 mutant mice, autophagy-related structures accumulate in neurons, causing axonal degeneration; however, the mechanism by which Caspr1 regulates autophagy remains unknown. To illustrate the mechanism of Caspr1 in autophagy process, we demonstrated that Caspr1 knockout in primary neurons from mice along with human cell lines, HEK-293 and HeLa, induced autophagy by downregulating the PI3K/AKT/mTOR signaling pathway to promote the conversion of microtubule-associated protein light chain 3 I (LC3-I) to LC3-II. In contrast, Caspr1 overexpression in cells contributed to the upregulation of this signaling pathway. We also demonstrated that Caspr1 knockout led to increased LC3-I protein expression in mice. In addition, Caspr1 could inhibit the expression of autophagy-related 4B cysteine peptidase (ATG4B) protein by directly binding to ATG4B in overexpressed Caspr1 cells. Intriguingly, we found an accumulation of ATG4B in the Golgi apparatuses of cells overexpressing Caspr1; therefore, we speculate that Caspr1 may restrict ATG4 secretion from the Golgi apparatus to the cytoplasm. Collectively, our results indicate that Caspr1 may regulate autophagy by modulating the PI3K/AKT/mTOR signaling pathway and the levels of ATG4 protein, both in vitro and in vivo. Thus, Caspr1 can be a potential therapeutic target in axonal damage and demyelinating diseases.

Chronic inflammatory demyelinating polyneuropathy. A case description.

Patients affected by chronic inflammatory demyelinating polyradiculoneuropathy require close follow up due to the neuronal demyelination along with axonal degeneration associated with the disease process, giving the opportunity to the medical team of adequating therapeutics and other medical interventions, according to the evolution of the symptoms, to prevent irreversible axonal degeneration.