In situ tissue profile of rat trigeminal nerve in trigeminal neuralgia using spatial transcriptome sequencing.

BACKGROUND: Trigeminal neuralgia (TN) is the most common neuropathic disorder in the maxillofacial region. The etiology and pathogenesis of TN have not been clearly determined to date, although there are many hypotheses. OBJECTIVE: The goal of this study was to investigate the interactions between different types of cells in TN, particularly the impact and intrinsic mechanism of demyelination on the trigeminal ganglion, and to identify new important target genes and regulatory pathways in TN. METHODS: TN rat models were prepared by trigeminal root compression, and trigeminal nerve tissues were isolated for spatial transcriptome sequencing. The gene expression matrix was reduced dimensionally by PCA and presented by UMAP. Gene function annotation was analyzed by Metascape. The progression of certain clusters and the developmental pseudotime were analyzed using the Monocle package. Modules of the gene coexpression network between different groups were analyzed based on weighted gene coexpression network analysis and assigned AddModuleScore values. The intercellular communication of genes in these networks via ligand-receptor interactions was analyzed using CellPhoneDB analysis. RESULTS: The results suggested that the trigeminal ganglion could affect Schwann cell demyelination and remyelination responses through many ligand-receptor interactions, while the effect of Schwann cells on the trigeminal ganglion was much weaker. Additionally, ferroptosis may be involved in the demyelination of Schwann cells. CONCLUSIONS: This study provides spatial transcriptomics sequencing data on TN, reveals new markers, and redefines the relationship between the ganglion and myelin sheath, providing a theoretical basis and supporting data for future mechanistic research and drug development.

Severe osmotic demyelination syndrome with cortical involvement in the context of severe hyponatremia and central diabetes insipidus: an uncommon presentation of an unusual combination.

BACKGROUND: Osmotic demyelination syndrome (ODS) with cerebral cortical involvement is a rare complication of severe hyponatremia correction. Careful management of hyponatremia is crucial, particularly in patients with risk factors, such as alcohol use disorder and diabetes insipidus. CASE: A patient in his 40s with a history of alcohol use disorder and central diabetes insipidus developed ODS after a 24 mEq/L osmolar increase during the treatment of hyponatremia. The patient's condition progressed into locked-in syndrome and then improved to spastic tetraparesis after cortical basal ganglia ODS improved. DISCUSSION: The differential diagnosis of cortical demyelination includes laminar cortical necrosis, being the interpretation of Apparent Diffusion Coefficient (ADC) MRI sequence is a useful tool.This case underscores the need to investigate and improve diagnosis and treatment strategies in patients with ODS. It also emphasises the significance of careful hyponatremia correction and frequent monitoring, particularly in patients with known risk factors for ODS.

Teenager With Recurrent Ataxia, Ophthalmoplegia, and Encephalopathy Associated With Demyelination: From the National Multiple Sclerosis Society Case Conference Proceedings

A 15-year-old adolescent boy developed subacute ataxia, encephalopathy, ophthalmoplegia, and dysarthria following a sore throat. An MRI examination revealed multifocal enhancing and nonenhancing supratentorial white matter and symmetric brainstem lesions. After 2 additional presentations with worsening symptoms and lesion accumulation, he was ultimately successfully treated with rituximab for his condition.

Demyelination in the medial prefrontal cortex by withdrawal from chronic nicotine causes impaired cognitive memory.

Epidemiological studies revealed deficits in cognitive learning and memory in smokers who withdrawal from smoking, but the molecular mechanisms underlying it is unclear. Here, we employed the novel object recognition task (NORT) to evaluate cognitive memory and found impaired memory and motor skills after withdrawal from chronic nicotine. Myelin sheath hastens the conduction of signals along axons and thus plays a critical role in learning and memory. We found no effect of nicotine withdrawal on the myelination in both of the Ventral tegmental area (VTA) and Nucleus accumbens (NAc) regions, but unexpectedly, we observed a demyelination phenomenon in the medial prefrontal cortex (mPFC) after withdrawal from chronic nicotine. Moreover, we found a positive correlation between the impaired memory and demyelination, and pharmaceutical rescue of myelination by clemastine specifically improved the impaired recognition memory but not the decreased motor skills caused by withdrawal from chronic nicotine. We further found nicotine directly acts on oligodendrocytes with OPCs potential to decrease their myelination process. Taken together, these results demonstrate demyelination in the mPFC causes impaired recognition memory and reveal a potential of enhancing myelination as a therapeutic strategy to alleviate cognitive memory deficits caused by smoking withdrawal.

Pediatric anti-NMDAR encephalitis with demyelination on brain MRI: A single center study.

OBJECTIVE: To explore the clinical characteristics, immunotherapy response, and prognosis of pediatric anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis associated with demyelination on brain magnetic resonance (MRI). METHODS: We retrospectively reviewed the medical records of children diagnosed with anti-NMDAR encephalitis in our hospital between January 2016 and December 2021. All children with evidence of demyelination on brain MRI were included. RESULTS: A total of 183 anti-NMDAR encephalitis children were included; 8.7 % (16/183) of them had demyelination on brain MRI. Nine were positive for myelin oligodendrocyte glycoprotein (MOG)-IgG, while two were positive for both MOG-IgG and glial fibrillary acidic protein (GFAP)-IgG. Four patients had a history of acquired demyelinating syndromes and encephalitis, respectively, while nine (56.3 %) had atypical symptoms of anti-NMDAR encephalitis. All children had supratentorial demyelination on brain MRI; four of them had additional infratentorial lesions. All children received first-line immunotherapy; four were administered repeated first-line immunotherapy and/or rituximab because of poor initial response. During the follow-up, 37.5 % (6/16) of the children relapsed, but all responded well to immunotherapy. There were no significant differences in mRS score before immunotherapy, response to first-line immunotherapy, and long-term prognosis between anti-NMDAR encephalitis children with and without demyelination. However, patients with demyelination were more likely to have a history of acquired demyelinating syndromes or unexplained cortical encephalitis and to relapse. CONCLUSION: Pediatric anti-NMDAR encephalitis can co-occur with demyelination and has a high rate of MOG-IgG positivity. A history of acquired demyelinating syndromes or unexplained cortical encephalitis and atypical symptoms may indicate demyelination in children with anti-NMDAR encephalitis. Pediatric anti-NMDAR encephalitis with demyelination is more likely to relapse and needs a closer follow-up. However, it remains unknown whether more intensive immunotherapy is required in these patients.

Conversion Predictors of Clinically Isolated Syndrome to Multiple Sclerosis in Mexican Patients: A Prospective Study.

BACKGROUND: Clinically Isolated Syndrome (CIS) is the first clinical episode suggestive of Clinical Definite Multiple Sclerosis (CDMS). There are no reports on possible predictors of conversion to CDMS in Mexican mestizo patients. AIM OF THE STUDY: To investigate immunological markers, clinical and paraclinical findings, and the presence of herpesvirus DNA to predict the transition from CIS to CDMS in Mexican patients. METHODS: A single-center prospective cohort study was conducted with newly diagnosed patients with CIS in Mexico between 2006 and 2010. Clinical information, immunophenotype, serum cytokines, anti-myelin protein immunoglobulins, and herpes viral DNA were determined at the time of diagnosis. RESULTS: 273 patients diagnosed with CIS met the enrolment criteria; after 10 years of follow-up, 46% met the 2010 McDonald criteria for CDMS. Baseline parameters associated with conversion to CDMS were motor symptoms, multifocal syndromes, and alterations of somatosensory evoked potentials. The presence of at least one lesion on magnetic resonance imaging was the main factor associated with an increased risk of conversion to CDMS (RR 15.52, 95% CI 3.96-60.79, p = 0.000). Patients who converted to CDMS showed a significantly lower percentage of circulating regulatory T cells, cytotoxic T cells, and B cells, and the conversion to CDMS was associated with the presence of varicella-zoster virus and herpes simplex virus 1 DNA in cerebrospinal fluid and blood. CONCLUSION: There is scarce evidence in Mexico regarding the demographic and clinical aspects of CIS and CDMS. This study shows several predictors of conversion to CDMS to be considered in Mexican patients with CIS.

Familial Mediterranean Fever and multiple sclerosis treated with ocrelizumab: Case report.

BACKGROUND: Familial Mediterranean Fever (FMF) is associated with increased risk of multiple sclerosis (MS). Optimal treatment of patients with comorbid FMF and MS remains uncertain. CASE: A 28-year-old woman with FMF, treated with colchicine, had symptomatic onset of relapsing remitting MS following four simultaneous vaccines. MRI brain with a 7-Tesla magnet demonstrated several areas of leptomeningeal enhancement with predominant linear, spread/fill and rare nodular patterns. Central vein signs were present in supratentorial white matter lesions. She received four cycles of ocrelizumab and achieved no evidence of disease activity (NEDA-3) at 20 months' follow up. DISCUSSION: FMF with incident CNS demyelinating disease demonstrated neuroimaging features typical for classic RRMS including the central vein sign and leptomeningeal enhancement. Treatment with B-cell depleting therapy for FMF-MS led to clinical stability and symptomatic improvement at 20 months' follow up. We add to the sparse literature characterizing the course of FMF as a genetic risk factor for CNS demyelinating disease, demonstrating pathognomonic imaging features of MS on 7 T imaging and treatment efficacy with B-cell depletion.

Secondary Degeneration Impairs Myelin Ultrastructural Development in Adulthood following Adolescent Neurotrauma in the Rat Optic Nerve.

Adolescence is a critical period of postnatal development characterized by social, emotional, and cognitive changes. These changes are increasingly understood to depend on white matter development. White matter is highly vulnerable to the effects of injury, including secondary degeneration in regions adjacent to the primary injury site which alters the myelin ultrastructure. However, the impact of such alterations on adolescent white matter maturation is yet to be investigated. To address this, female piebald-virol-glaxo rats underwent partial transection of the optic nerve during early adolescence (postnatal day (PND) 56) with tissue collection two weeks (PND 70) or three months later (PND 140). Axons and myelin in the transmission electron micrographs of tissue adjacent to the injury were classified and measured based on the appearance of the myelin laminae. Injury in adolescence impaired the myelin structure in adulthood, resulting in a lower percentage of axons with compact myelin and a higher percentage of axons with severe myelin decompaction. Myelin thickness did not increase as expected into adulthood after injury and the relationship between the axon diameter and myelin thickness in adulthood was altered. Notably, dysmyelination was not observed 2 weeks postinjury. In conclusion, injury in adolescence altered the developmental trajectory, resulting in impaired myelin maturation when assessed at the ultrastructural level in adulthood.

Predictive Factors for Magnetic Resonance Imaging Changes Suggestive of Demyelination in Adult Patients with Uveitis Scanned Prior to Commencing Adalimumab Therapy.

PURPOSE: To report the predictive clinical factors for abnormal magnetic resonance imaging (MRI) scans suggestive of demyelination by analysis of MRI's performed for adult non-infectious uveitic patients prior to commencing adalimumab therapy. METHODS: Retrospective case review of 240 patients was conducted in a single tertiary institution between November 2017 and March 2020. Aetiology of underlying disease, clinical characteristics, and MRI outcomes were analysed. RESULTS: The presence of bilateral idiopathic intermediate uveitis (IIU) (p = .0048) and neurological symptoms (p = .028) were highly predictive of an abnormal MRI strongly suggestive of demyelination (MRSSD); 5 out of 64 scans (7.8%) with these clinical characteristics had MRSSD. CONCLUSIONS: Tumor necrosis factor antagonist-induced demyelination is a concern in adalimumab use. We propose an MRI screening protocol to identify those at high risk of demyelination; positive results can be maximised by screening all patients with IIU and those with neurological symptoms.

Osmotic demyelination syndrome in patients with non-Hodgkin lymphoma: a case report and literature review.

INTRODUCTION: Osmotic demyelination syndrome (ODS) is a non-inflammatory process of the central nervous system caused by extracellular osmotic changes, which leads to oligodendrocyte apoptosis and disruption of myelin sheaths, usually affecting patients with underlying systemic conditions that impose susceptibility to osmotic stress. Description of ODS in patients with non-Hodgkin lymphoma (NHL) is limited to a few case reports. METHODS: Here, we report a 44-year-old man with NHL that had an incidental diagnosis of ODS. We conducted a literature review of the published cases of ODS in NHL patients from 1959 to 2020, aiming to describe the characteristics of these patients. RESULTS: A total of seven patients were summarized (four men and three women), including our case and six patients from published reports. Risk factors such as weight loss and alcoholism were reported in five (71.4%) patients. Hyponatremia was found in six (85.7%) of the cases, and none of them had overly rapid sodium correction. Four cases were asymptomatic, and diffuse large B-cell lymphoma was the most common subtype of NHL (85.7%). The outcome was favorable in most cases; only two deaths not directly related to ODS were reported. CONCLUSION: We wish to suggest that systemic and metabolic stress induced by NHL may be associated with the development of central osmotic demyelination, and therefore, NHL may be a novel risk factor for ODS. Clinicians should be aware of ODS in patients with hematological malignancies, even in the absence of traditional risk factors.

CCL21/CCR7 axis regulates demyelination and vascular cognitive impairment in a mouse model for chronic cerebral hypoperfusion.

OBJECTIVES: White matter lesions (WML) are usually accompanied by cognitive decline, which consist of axonal loss and demyelination. CC chemokine ligand 21 (CCL21) and its receptor C-C chemokine receptor 7 (CCR7) belong to the chemokine family, which are involved in many diseases. However, their function in the central nervous system (CNS) is still unexplored. This study aimed to explore the role of CCL21/CCR7 axis in the pathological process of chronic ischemia-induced WML. METHODS: Bilateral common carotid artery stenosis (BCAS) was employed in C57BL/6 mice as the in vivo WML model. Microarray analysis was performed to detect the overall molecular changes induced in the endothelial cells by BCAS. Q-PCR, Western blotting, and immunofluorescence staining were performed to evaluate expression levels of the related molecules. The mice were injected with LV-CCL21-GFP virus in the corpus callosum to overexpress CCL21. WML degree was determined via MRI, and cognitive ability was assessed by Y-maze and novel object recognition tests. Myelin sheath integrity was evaluated via immunofluorescence staining. RESULTS: CCL21 was significantly downregulated in endothelial cells after BCAS and CCL21 overexpression alleviated BCAS-induced cognitive deficits and demyelination. Furthermore, CCR7 was found to be mainly expressed in oligodendrocytes (OLs) after exposed to hypoxia and CCR7 silencing blocked the protective effects induced by CCL21 overexpression. Conclusions CCL21/CCR7 axis may play a key role in demyelination induced by BCAS. This might provide a novel therapeutic target for WML.

Pontine lesion in hyperglycemic crises: Relevance to osmotic demyelination syndrome and posterior reversible encephalopathy syndrome.

We herein describe a case of type 1 diabetes that presented with a pontine lesion during two hyperglycemic crises accompanied by marked fluctuations in serum osmotic pressure and blood pressure. Magnetic resonance imaging showed swollen pons with osmotic demyelination syndrome characteristics accompanying cytotoxic edema at the first crisis. The involvement of vasogenic edema was also assumed in the second crisis. Neurological symptoms were milder than magnetic resonance imaging findings. The patient recovered after 7 days without sequelae in both crises. Based on these findings, a pontine lesion needs to be considered in patients with poorly controlled diabetes showing rapid metabolic and blood pressure changes, as observed in hyperglycemic crises. Cytotoxic edema leading to osmotic demyelination syndrome and vasogenic edema caused by vascular endothelial cell damage might both be involved in the pathogenesis of a pontine lesion.

Childhood Small-Vessel Primary Angiitis of the Central Nervous System: Overlap With MOG-Associated Disease.

BACKGROUND: Childhood (c) primary angiitis of the central nervous system (PACNS) is a rare condition that most often affects small vessels (SV), is nearly exclusively lymphocytic, and devoid of vessel necrosis. Diagnosis of cSV-PACNS is challenging. We noted possible histological overlap of cSV-PACNS with myelin oligodendrocyte glycoprotein disease (MOGAD) on biopsy, prompting a 10-year retrospective review of our experience. MATERIALS AND METHODS: Database-search for brain biopsy cases, age <18 years, performed for an acquired neurological deficit with suspicion of vasculitis, with histological evidence of lymphocytic small-vessel inflammation. RESULTS: We identified 7 patients; 2/7 were serum-positive for anti-MOG antibodies and 1/7 for anti-NMDA antibodies. The remaining 4/7 proved to be idiopathic lymphocytic vasculitis/cSV-PACNS. All 7 showed overlapping features of lymphocytes permeating parenchymal SV walls, vessel wall distortion without fibrinoid necrosis, and absence of microglial clusters or intravascular thrombi. Tissue infarction was confined to a single case of idiopathic lymphocytic vasculitis. Although demyelination was diligently sought, only subtle demyelination was identified in the 2 MOGAD cases and absent in the remainder. CONCLUSION: There is considerable histological overlap between cSV-PACNS and at least some cases of MOGAD or anti-NMDA-encephalitis; at diagnosis, the differential should include cSV-PACNS but correct classification requires post-biopsy serological testing.

Immune-mediated diseases involving central and peripheral nervous systems.

BACKGROUND AND PURPOSE: In addition to combined central and peripheral demyelination, other immune diseases could involve both the central nervous system (CNS) and peripheral nervous system (PNS). METHODS: To identify immune-mediated diseases responsible for symptomatic combined central/peripheral nervous system involvement (ICCPs), we conducted a multicentric retrospective study and assessed clinical, electrophysiological, and radiological features of patients fulfilling our ICCP criteria. RESULTS: Thirty patients (20 males) were included and followed during a median of 79.5 months (interquartile range [IQR] = 43-145). The median age at onset was 51.5 years (IQR = 39-58). Patients were assigned to one of four groups: (i) monophasic disease with concomitant CNS/PNS involvement including anti-GQ1b syndrome (acute polyradiculoneuropathy + rhombencephalitis, n = 2), checkpoint inhibitor-related toxicities (acute polyradiculoneuropathy + encephalitis, n = 3), and anti-glial fibrillary acidic protein astrocytopathy (subacute polyradiculoneuropathy and meningoencephalomyelitis with linear gadolinium enhancements, n = 2); (ii) chronic course with concomitant CNS/PNS involvement including paraneoplastic syndromes (ganglionopathy/peripheral hyperexcitability + limbic encephalitis, n = 4); (iii) chronic course with sequential CNS/PNS involvement including POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome (polyradiculoneuropathy + strokes, n = 2), histiocytosis (polyradiculoneuropathy + lepto-/pachymeningitis, n = 1), and systemic vasculitis (multineuropathy + CNS vasculitis/pachymeningitis, n = 2); and (iv) chronic course with concomitant or sequential CNS/PNS involvement including combined central and peripheral demyelination (polyradiculoneuropathy + CNS demyelinating lesions, n = 10) and connective tissue diseases (ganglionopathy/radiculopathy/multineuropathy + limbic encephalitis/transverse myelitis/stroke, n = 4). CONCLUSIONS: We diagnosed nine ICCPs. The timing of central and peripheral manifestations and the disease course help determine the underlying immune disease. When antibody against neuroglial antigen is identified, CNS and PNS involvement is systematically concomitant, suggesting a common CNS/PNS antigen and a simultaneous disruption of blood-nerve and blood-brain barriers.

An Exchange about "Osmotic Demyelination Syndrome in Patients Hospitalized with Hyponatremia".

In Volume 2, Number 4 of NEJM Evidence, we published an article entitled, "Osmotic Demyelination Syndrome in Patients Hospitalized with Hyponatremia" by MacMillan et al. The article was accompanied by an editorial entitled "Hyponatremia Treatment Guidelines - Have They Gone Too Far?" by Ayus and Moritz. After these articles were published, a group of readers shared feedback about the data presented and the conclusions drawn; their comments are detailed as "Remarks from Readers." We relayed these points to the authors of the original article and the editorial; their responses follow.

Role of Demyelination in the Persistence of Neurological and Mental Impairments after COVID-19.

Long-term neurological and mental complications of COVID-19, the so-called post-COVID syndrome or long COVID, affect the quality of life. The most persistent manifestations of long COVID include fatigue, anosmia/hyposmia, insomnia, depression/anxiety, and memory/attention deficits. The physiological basis of neurological and psychiatric disorders is still poorly understood. This review summarizes the current knowledge of neurological sequelae in post-COVID patients and discusses brain demyelination as a possible mechanism of these complications with a focus on neuroimaging findings. Numerous reviews, experimental and theoretical studies consider brain demyelination as one of the mechanisms of the central neural system impairment. Several factors might cause demyelination, such as inflammation, direct effect of the virus on oligodendrocytes, and cerebrovascular disorders, inducing myelin damage. There is a contradiction between the solid fundamental basis underlying demyelination as the mechanism of the neurological injuries and relatively little published clinical evidence related to demyelination in COVID-19 patients. The reason for this probably lies in the fact that most clinical studies used conventional MRI techniques, which can detect only large, clearly visible demyelinating lesions. A very limited number of studies use specific methods for myelin quantification detected changes in the white matter tracts 3 and 10 months after the acute phase of COVID-19. Future research applying quantitative MRI assessment of myelin in combination with neurological and psychological studies will help in understanding the mechanisms of post-COVID complications associated with demyelination.

Incidence and risk factors of overcorrection in patients presenting with severe hyponatremia to the emergency department.

BACKGROUND: Hyponatremia is one of the most common electrolyte abnormalities. Overcorrection of severe hyponatremia can result in serious neurological complications such as osmotic demyelination syndrome, but the incidence and risk factors of overcorrection and osmotic demyelination have not been thoroughly investigated. METHODS: This is a single-center retrospective cohort study of 50 patients admitted through the emergency department with initial serum sodium (serum Na) < 125 mEq/L between January 2015 and December 2017. Incidence and risk factors of overcorrection and osmotic demyelination were examined. Overcorrection was defined as an increase in serum sodium concentration > 10 mEq/L at 24 h and/or > 18 mEq/L at 48 h, respectively. RESULTS: Six patients (12%) and one patient (2%) had overcorrection at 24 h and 48 h, respectively. A total of 5 (10%) patients had a brain MRI completed after overcorrection, and no patient showed radiologic evidence of osmotic demyelination. Symptomatic hyponatremia at presentation and 3% saline use were associated with the risk of overcorrection in univariable analysis (p < 0.001; p = 0.006, respectively). CONCLUSIONS: Among patients admitted with severe hyponatremia, overcorrection occurred in 14%. Symptomatic hyponatremia at presentation and 3% saline use were associated with the risk of overcorrection.

Thyroid peroxidase antibodies may induce demyelination and oculomotor neuromyotonia in the absence of thyroid eye disease.

INTRODUCTION: The first report of oculomotor neuromyotonia (ONM) in a child induced by thyroid peroxidase antibodies (anti-TPO) in the absence of thyroid eye disease (TED). CASE: 14-year-old girl complained of left eye (LE) paroxysmal upper lid fluttering and ptosis precipitated by hyperventilation or sustained left gaze. On sustained left gaze, right eye (RE) upper lid retraction and LE upper lid fluttering with ptosis ensued. RESULTS: Diagnostic work-up revealed markedly elevated anti-TPO (> 600 IU/ml) and no TED. Brain MRI was normal with no signs of tortuous vessels presenting focal demyelination. We hypothesized that anti-TPO directly induced demyelination and set the ground for right ONM with ephaptic transmission between neurons supplying right medial rectus and levator muscle. CONCLUSIONS: Plethora of theories try to decode the ONM. TED associated ONM is not reported in children but is the second most common cause of ONM in adults, advocated to be of compressive origin. Conversely, this case holds true for cross talk hypothesis. All extraocular muscles must be tested to determine the triggering one. ONM should not be overlooked due to its positive response to carbamazepine.