Potential Role of Antibodies against Aquaporin-1 in Patients with Central Nervous System Demyelination.

Aquaporins (AQPs; AQP0-AQP12) are water channels expressed in many and diverse cell types, participating in various functions of cells, tissues, and systems, including the central nervous system (CNS). AQP dysfunction and autoimmunity to AQPs are implicated in several diseases. The best-known example of autoimmunity against AQPs concerns the antibodies to AQP4 which are involved in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD), an autoimmune astrocytopathy, causing also CNS demyelination. The present review focuses on the discovery and the potential role of antibodies against AQP1 in the CNS, and their potential involvement in the pathophysiology of NMOSD. We describe (a) the several techniques developed for the detection of the AQP1-antibodies, with emphasis on methods that specifically identify antibodies targeting the extracellular domain of AQP1, i.e., those of potential pathogenic role, and (b) the available evidence supporting the pathogenic relevance of AQP1-antibodies in the NMOSD phenotype.

Early metabolic alterations in the normal­appearing grey and white matter of patients with clinically isolated syndrome suggestive of multiple sclerosis: A proton MR spectroscopic study.

Proton magnetic resonance spectroscopy (1H-MRS) is an advanced method of examining metabolic profiles. The present study aimed to assess in vivo metabolite levels in areas of normal-appearing grey (thalamus) and white matter (centrum semiovale) using 1H-MRS in patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis and compare them to healthy controls (HCs). Data from 35 patients with CIS (CIS group), of which 23 were untreated (CIS-untreated group) and 12 were treated (CIS-treated group) with disease-modifying-therapies (DMTs) at the time of 1H-MRS, and from 28 age- and sex-matched HCs were collected using a 3.0 T MRI and single-voxel 1H-MRS (point resolved spectroscopy sequence; repetition time, 2,000 msec; time to echo, 35 msec). Concentrations and ratios of total N-acetyl aspartate (tNAA), total creatine (tCr), total choline (tCho), myoinositol, glutamate (Glu), glutamine (Gln), Glu + Gln (Glx) and glutathione (Glth) were estimated in the thalamic-voxel (th) and centrum semiovale-voxel (cs). For the CIS group, the median duration from the first clinical attack to 1H-MRS was 102 days (interquartile range, 89.5.-131.5). Compared with HCs, significantly lower Glx(cs) (P=0.014) and ratios of tCho/tCr(th) (P=0.026), Glu/tCr(cs) (P=0.040), Glx/tCr(cs) (P=0.004), Glx/tNAA(th) (P=0.043) and Glx/tNAA(cs) (P=0.015) were observed in the CIS group. No differences in tNAA levels were observed between the CIS and the HC groups; however, tNAA(cs) was higher in the CIS-treated than in the CIS-untreated group (P=0.028). Compared with those in HC group, decreased Glu(cs) (P=0.019) and Glx(cs) levels (P=0.014) and lower ratios for tCho/tCr(th) (P=0.015), Gln/tCr(th) (P=0.004), Glu/tCr(cs) (P=0.021), Glx/tCr(th) (P=0.041), Glx/tCr(cs) (P=0.003), Glx/tNAA(th) (P=0.030) and Glx/tNAA(cs) (P=0.015) were found in the CIS-untreated group. The present findings showed alterations in the normal-appearing grey and white matter of patients with CIS; moreover, the present results suggested an early indirect treatment effect of DMTs on the brain metabolic profile of these patients.

Effects of low molecular weight heparin and fondaparinux on mortality, hemorrhagic and thrombotic complications in COVID-19 patients.

Background: Coronavirus disease 2019 (COVID-19) is associated with increased thrombosis prevalence. However, there are insufficient data supporting the appropriate anticoagulation dose in COVID-19. Objective: We aim to systematically assess the currently available data regarding the effects of different dosing regimens of low molecular weight heparin and/or fondaparinux (LMWH/F) on mortality risk as well as the risk of arterial/venous thrombotic events and hemorrhagic complications in confirmed COVID-19 cases. Design: We conducted a living systematic review and meta-analysis on the effects of different LMWH/F doses on mortality, thrombotic and hemorrhagic events in COVID-19 patients. Data Sources and Methods: MEDLINE, Scopus, Embase, Cochrane Library, Cochrane COVID-19 study register, European Union Drug Regulating Authorities Clinical Trials Database, and ClinicalTrials.gov were searched to detect observational cohort studies and randomized-controlled clinical trials (RCTs) comparing difference doses of LMWH/F among confirmed COVID-19 cases. Results: Thirty-one eligible studies (6 RCTs and 25 cohort studies) with 11,430 hospitalized patients were included. No association was found between LMWH/F and mortality during the following comparisons: (1) no LMWH/F versus any LMWH/F; (2) prophylactic versus higher than prophylactic LMWH/F; (3) prophylactic versus therapeutic LMWH/F; (4) intermediate versus therapeutic LMWH/F; and (5) lower than therapeutic versus therapeutic LMWH/F. Mortality was higher in patients receiving prophylactic versus intermediate LMWH/F (OR = 2.01; 95% CI: 1.19-3.39). However, this effect was mostly driven by observational data. No associations were detected between the intensity of LMWH/F and the risk of thrombotic and hemorrhagic events, except the lower risk for hemorrhage in patients on prophylactic compared to higher LMWH/F doses. Conclusion: The risk for all-cause mortality was higher in patients receiving prophylactic LMWH/F compared to those on an intermediate dose of LMWH/F, based on observational data. These results should be interpreted in light of the moderate quality and heterogeneity of the included studies. Registration: The study protocol has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (Registration number: CRD42021229771).

Guillain-Barré syndrome and fulminant encephalomyelitis following Ad26.COV2.S vaccination: double jeopardy.

This correspondence comments on a published article presenting a case of rhombencephalitis following SARS-CoV-2-vaccination with the mRNA vaccine BNT162b2 (Pfizer/BioNTech). We also present the case of a 47-year-old man who developed Guillain-Barré-syndrome and a fulminant encephalomyelitis 28 days after immunization with Ad26.COV2.S (Janssen/Johnson & Johnson). Based on the presented cases, we underscore the importance of clinical awareness for early recognition of overlapping neuroimmunological syndromes following vaccination against SARS-CoV-2. Additionally, we propose that that role of autoantibodies against angiotensin-converting enzyme 2 (ACE2) and the cell-surface receptor neuropilin-1, which mediate neurological manifestations of SARS-CoV-2, merit further investigation in patients presenting with neurological disorders following vaccination against SARS-CoV-2.

Delayed recurrent enhancing white matter lesions complicating coiling of intracranial aneurysm.

BACKGROUND AND PURPOSE: In recent years, the use of coiling has gained increased popularity for the treatment of intracranial aneurysms, and stroke physicians are confronted with rare pathologies associated with this relatively new and evolving treatment method, such as embolization of pieces of the polymeric filaments from the coils and a subsequent inflammatory response. In particular, white matter enhancing lesions are a rare complication after aneurysm endovascular therapy (EVT), suggesting a foreign body reaction to shedding of hydrophilic coating from the endovascular devices into the blood stream. The description of such a case aims to raise the clinicians' awareness of the symptomatic delayed and recurring inflammatory changes that may occur after endovascular aneurysmal treatment with the use of coiling devices. CASE DESCRIPTION: A 64-year-old woman underwent coiling of a ruptured right posterior communicating artery aneurysm. She was asymptomatic after EVT. One year later, she presented with headache, acoustic hallucinations, paresthesias and left arm weakness. Brain magnetic resonance imaging (MRI) revealed multiple enhancing white matter lesions in the right hemisphere. She was treated with pulse intravenous methylprednisolone, followed by oral prednisolone; all clinical symptoms resolved and imaging findings improved substantially. Two years after tapering the steroids, follow-up symptoms recurred and repeat brain MRI revealed new enhancing white matter lesions. DISCUSSION AND CONCLUSIONS: There is an increasing number of similar reports of enhancing white matter lesions after coiling of intracranial aneurysms, with the incidence estimated to be between 0.5% and 2.3% in different cohort studies. Close monitoring for the appearance of new neurologic symptoms that could suggest delayed brain reactivity should be recommended.

Recurrent Fulminant Tumefactive Demyelination With Marburg-Like Features and Atypical Presentation: Therapeutic Dilemmas and Review of Literature.

Atypical forms of demyelinating diseases with tumor-like lesions and aggressive course represent a diagnostic and therapeutic challenge for neurologists. Herein, we describe a 50-year-old woman presenting with subacute onset of left hemiparesis, memory difficulties and headache. Brain MRI revealed a tumefactive right frontal-parietal lesion with perilesional edema, mass effect and homogenous post-contrast enhancement, along with other small atypical lesions in the white-matter. Brain biopsy of cerebral lesion ruled out lymphoma or any other neoplastic process and patient placed on corticosteroids with complete clinical/radiological remission. Two years after disease initiation, there was disease exacerbation with reappearance of the tumor-like mass. The patient initially responded to high doses of corticosteroids but soon became resistant. Plasma-exchange sessions were not able to limit disease burden. Resistance to therapeutic efforts led to a second biopsy that showed perivascular demyelination, predominantly consisting of macrophages, with a small number of T and B lymphocytes, and the presence of reactive astrocytes, typical of Creutzfeldt-Peters cells. The patient received high doses of cyclophosphamide with substantial clinical/radiological response but relapsed after 7-intensive cycles. She received 4-weekly doses of rituximab with disease exacerbation and brainstem involvement. She eventually died with complicated pneumonia. We present a very rare case of recurrent tumefactive demyelinating lesions, with atypical tumor-like characteristics, with initial response to corticosteroids and cyclophosphamide, but subsequent development of drug-resistance and unexpected exacerbation upon rituximab administration. Our clinical case raises therapeutic dilemmas and points to the need for immediate and appropriate immunosuppression in difficult to treat tumefactive CNS lesions with Marburg-like features.

A longitudinal study of cognitive function in multiple sclerosis: is decline inevitable?

BACKGROUND: Numerous cross-sectional studies report cognitive impairment in multiple sclerosis (MS), but longitudinal studies with sufficiently long-term follow-up are scarce. OBJECTIVE: We aimed to investigate the cognitive 10-year course of a cohort of MS patients. METHODS: 59 patients with clinically isolated syndrome (CIS) or relapsing-remitting (RR) MS were evaluated with Rao's Brief Repeatable Battery of Neuropsychological Tests at baseline and follow-up (at least 10 years later). They constituted 47.2% of 124 consecutive CIS and RRMS patients originally evaluated at baseline. Patients assessed at follow-up were well matched for baseline clinical characteristics with dropouts. RESULTS: The proportion of MS patients with overall cognitive impairment was increased by 10% within the 10-year period. When grouped on the basis of impairment in specific cognitive domains at baseline, patients originally impaired showed improvement at follow-up, while the opposite trend was observed for patients non-impaired at first assessment. A detailed case-by-case investigation revealed mixed evolution patterns, several patients fail in fewer domains at follow-up compared to baseline or failing at different domains at follow-up compared to baseline. CONCLUSIONS: This study suggests a more fluid picture for the evolution of cognitive function in a subgroup of MS patients and contradicts the concept of an inevitable, progressively evolving "dementia".

Hippocampal structural and functional integrity in multiple sclerosis patients with or without memory impairment: a multimodal neuroimaging study.

The increasing evidence for a pure amnestic-like profile in multiple sclerosis (MS) introduces the role of hippocampal formation in MS episodic memory function. The aim of the present study was to investigate structural and functional hippocampal changes in mildly-disabled MS patients with and without memory impairment. Thirty-one MS patients with or without memory impairment and 16 healthy controls (HC) underwent MRI in a 3.0 T MRI scanner. Patients were categorized as memory preserved (MP) and memory impaired (MI) based on verbal and visual memory scores extracted from the Brief Repeatable Neuropsychological Battery. The acquisition protocol included high-resolution 3D-T1-weighted, diffusion weighted imaging and echo-planar imaging sequences for the analysis of hippocampal gray matter (GM) density, perforant pathway area (PPA) tractography, and hippocampal functional connectivity (FC), respectively. Compared to HC, we found decreased left and bilateral hippocampal GM density in MP and MI patients, respectively, decreased fractional anisotropy and increased radial diffusivity on left PPA in MI patients, and reduced FC in MI between left hippocampus and left superior frontal gyrus, precuneus/posterior cingulated cortex and lateral occipital gyrus/angular gyrus. The only differences between MP and MI were found in FC. Specifically, MP patients showed FC changes between left hippocampus and right temporo-occipital fusiform/lingual gyrus (increased FC) as well as supramarginal gyrus (decreased FC). In conclusion, we highlight the early detection of structural hippocampal changes in MS without neuropsychologically-detected memory deficits and decreased hippocampal FC in MS patients with impaired memory performance, when both GM density and PPA integrity are affected.

Anti-NMDA receptor encephalitis presenting as isolated aphasia in an adult.

Anti-NMDA receptor (NMDA-r) encephalitis is a relatively rare cause of autoimmune encephalitis with divergent clinical presentations. We report a case of an adult patient with anti-NMDA-r encephalitis presenting with isolated, abrupt-onset aphasia. Her condition remained unaltered over a period of 6 months. The patients' electroencephalogram findings were typical for NMDA-r encephalitis; however, her magnetic resonance imaging and cerebrospinal fluid analysis were normal. She responded well to immunotherapy, and aphasia eventually resolved. The natural course of the present case contradicts the rapidly progressive nature of typical NMDA-r encephalitis. Furthermore, it broadens the clinical spectrum of anti-NMDA-r encephalitis, to incorporate isolated, nonprogressive aphasia.

CNS Demyelination with TNF-α Blockers.

Tumor necrosis factor-α (TNF-α) blockers are a popular therapeutic choice in a number of inflammatory diseases. Thus far, five TNF- α blockers have been approved for clinical use (etanercept, infliximab, adalimumab, golimumab. and certolizumab). Despite being considered relatively safe, serious side effects associated with immune suppression have been reported, including central and peripheral nervous system (CNS) demyelinating disorders. It is still elusive whether these events are mere coincidence or a side effect of anti-TNF-α use. In this paper, we review the published case reports of CNS demyelination associated with anti-TNF-α therapy and present the follow-up of our 4 previously reported patients who developed neurologic symptoms suggestive of CNS demyelination after having received anti-TNF-α treatment. We also discuss the possible role of TNF-α blockers in demyelination.

The possible effects of the solar and geomagnetic activity on multiple sclerosis.

OBJECTIVES: Increasing observational evidence on the biological effects of Space Weather suggests that geomagnetic disturbances may be an environmental risk factor for multiple sclerosis (MS) relapses. In the present study, we aim to investigate the possible effect of geomagnetic disturbances on MS activity. PATIENTS AND METHODS: MS patient admittance rates were correlated with the solar and geophysical data covering an eleven-year period (1996-2006, 23rd solar cycle). We also examined the relationship of patterns of the solar flares, the coronal mass ejections (CMEs) and the solar wind with the recorded MS admission numbers. RESULTS: The rate of MS patient admittance due to acute relapses was found to be associated with the solar and geomagnetic events. There was a "primary" peak in MS admittance rates shortly after intense geomagnetic storms followed by a "secondary" peak 7-8 months later. CONCLUSION: We conclude that the geomagnetic and solar activity may represent an environmental health risk factor for multiple sclerosis and we discuss the possible mechanisms underlying this association. More data from larger case series are needed to confirm these preliminary results and to explore the possible influence of Space Weather on the biological and radiological markers of the disease.

Capecitabine Induced Multifocal Leukoencephalopathy: Do We Have Always to Switch off the Chemotherapy?

Capecitabine is a well tolerated and safe 5-fluorouracil agent for adjuvant, neoadjuvant chemotherapy or metastatic cases. Neurological side effects require discontinuation of chemotherapy. We report this unique case of a 50-year-old female, who presented an isolated episode of dysarthria and ataxia under bevacizumab, capecitabine, and oxaliplatin treatment due to reversible multifocal leukoencephalopathy that did not recur after readministration of chemotherapy.

Multiple sclerosis and Parkinson's disease: the two faces of neurodegeneration. Report of the first Greek case and review of the literature.

There is still an open debate whether multiple sclerosis (MS) lesions can cause parkinsonian symptoms, or the coexistence of both diseases in the same patient is accidental. Moreover, α-synuclein (α Syn), the hallmark of Parkinson's disease (PD) seems also to play a crucial role in MS. So far, 42 cases of co-occurrence of parkinsonism and MS have been reported, but CSF α Syn measurement is lacking. To our knowledge, we report the first case with concomitant MS and PD diagnosis based on both clinico-radiological and CSF α Syn findings and review of literature.

Immune reconstitution inflammatory syndrome mimicking progressive multifocal leucoencephalopathy in a multiple sclerosis patient treated with natalizumab: a case report and review of the literature.

Natalizumab (NTM) represents an effective drug for the treatment of relapsing-remitting multiple sclerosis (RRMS). Progressive multifocal leucoencephalopathy (PML) is a potential life-threatening complication of NTM treatment. A close follow-up and MRI monitoring of patients under NTM are required to avoid such devastating complications. The case of a 47-year-old woman with RRMS (EDSS 1.5) treated with NTM for 44 months is reported. The patient had a relapse with mild cerebellar symptomatology and visual complaints. MRI revealed a new area of abnormal signal intensity in the subcortical white matter of the right parietal lobe with mild peripheral enhancement. Visual fields showed scotomata mostly of the left eye. NTM was discontinued. JC virus (JCV) polymerase chain reaction (PCR) in cerebrospinal fluid was negative. The patient received IV corticosteroids for 5 days and then monthly for 2 months with subsequent clinical and MRI improvement. On month 4, she presented with a new relapse with severe ataxia, mild behavioral change, increase of cerebellar symptoms and internuclear opthalmoplegia (EDSS 3.5). MRI showed reappearance of the right parietal lobe lesion, with decreased size and less pronounced contrast enhancement. A new 2-cm lesion was noted in the left cerebellar hemisphere with a speckled pattern of contrast enhancement. JCV PCR was negative and the patient was treated with IV corticosteroids. On month 12, she demonstrated clinical and MRI improvement. Although initially PML was highly suspected in this patient, the clinical and MRI findings were supportive of the presence of immune reconstitution inflammatory syndrome (IRIS).

Central Nervous System Demyelination in a Charcot-Marie-Tooth Type 1A Patient.

Introduction. Central nervous system involvement, either clinical or subclinical, has been reported mainly in X-linked Charcot-Marie-Tooth (CMT-X) patients. Case Presentation. We present the case of a 31-year-old man with a genetically confirmed history of CMT1A who developed CNS involvement mimicking multiple sclerosis (MS). Clinical, imaging, and laboratory findings suggested an autoimmune CNS demyelination. Discussion. Although the simultaneous existence of CMT1A and MS could be coincidental we postulate that overexpression of PMP22, the target protein in CMT1A, might influence the immunological self-tolerance to CNS proteins via molecular mimicry, leading to a CNS autoimmune demyelinating disorder.

Lack of association between vitamin D levels and bone mineral density in patients with multiple sclerosis.

BACKGROUND: There is conflicting evidence regarding the association of vitamin D status with bone mineral density (BMD) in adult patients with multiple sclerosis (MS). We evaluated cross-sectionaly the determinants (including vitamin D levels) of low BMD in patients with relapsing-remitting MS (RRMS). METHODS: The BMD at lumbar level (L2-L4) and femoral neck was measured in consecutive adult, ambulatory, RRMS patients by dual-energy X-ray absorptiometry. Blood samples were collected for total serum calcium, phosphorus, magnesium, 25-hydroxyvitamin D(3) and parathormone. Osteopenia and osteoporosis were defined according to the World Health Organization operational BMD definition. MS severity was assessed using the EDSS-score. Cross-sectional associations were evaluated using Spearman's correlation-coefficient and multiple linear regression models. RESULTS: A total of 119 patients were evaluated (mean age 39.2 ± 10.4 years; 40% men). Osteopenia at lumbar spine (L2-L4) and femoral neck was present in 26% (95%CI: 18%-35%) and 50% (95%CI: 41%-60%) of the patients respectively. Osteoporosis was documented at lumbar spine and femoral neck of 3% (95%CI: 0%-8%) and 11% (95%CI: 6%-18%) of the study population respectively. There was no correlation (p>0.1) of 25-hydroxyvitamin D3 levels with any of BMD measurements (including Z- and T-scores) both in lumbar spine and in femoral neck. Increasing MS duration and increasing dosage of intravenous corticosteroids were independently and negatively associated with both lumbar spine and femoral neck BMD. CONCLUSIONS: We documented no correlation between vitamin D levels and decreased BMD at femoral neck and lumbar spine in RRMS patients. Vitamin D insufficiency appears not to be the underlying cause of secondary osteoporosis in MS.

The impact of comorbidity and other clinical and sociodemographic factors on health-related quality of life in Greek patients with Parkinson's disease.

OBJECTIVES: This study was designed to evaluate the impact of other common self-reported comorbid disorders (hypertension, dyslipidemia, ischemic heart disease, diabetes mellitus, minor stroke, arthritis, low back pain or osteoporosis and depression) on health-related Quality of Life (HRQoL) of Parkinson's disease (PD) patients and to explore the association of their HRQoL with various sociodemographic and clinical factors. METHODS: Data about age, gender, education, occupation, income, marital and residential status, social relations, disease duration, functional status, treatment and concomitant diseases were collected of 139 Greek patients (68 men and 71 women) with PD. Patients were consecutively recruited from the outpatient clinic of the first Neurology Department of Athens National University at Aeginition Hospital. Disease severity was assessed using the unified Parkinson's disease rating scale including Hoehn and Yahr and Schwab and England (S&E) scales. HRQoL was measured by the specific Parkinson's disease questionnaire (PDQ-39). A multivariate multiple regression model with normal errors was used for the statistical analysis. RESULTS: The main determinants of HRQoL were low degree of independence measured by the S&E scale (F = 35.942, p < 0.001), social isolation (F = 20.508, p < 0.001), disease duration (F = 14.983, p < 0.001), sleep (F = 6.507, p = 0.013) and gastrointestinal disturbances (F = 4.643, p = 0.035) and the presence of depression (F = 6.022, p = 0.017). CONCLUSION: Among the other chronic comorbidities only depression was associated with a poor HRQoL in PD patients. Functional dependence and social isolation contributed most to worse HRQoL. Our findings suggest that adequate social support and management of depression, sleep and gastrointestinal disturbances could reduce the distress and improve HRQoL in patients with PD.

Serum uric acid levels in patients with Parkinson's disease: their relationship to treatment and disease duration.

UNLABELLED: There is evidence to support that oxidative stress is increased in Parkinson's disease (PD) and contributes to degeneration of dopaminergic neurons. Uric acid (UA), a natural antioxidant in blood and brain tissue, scavenging superoxide, peroxynitrite and hydroxyl radical, was found reduced in the serum of PD patients. In addition low plasma uric acid (UA) levels have been associated with an increased risk of PD. OBJECTIVES: The aim of our study was to investigate serum UA levels in PD patients compared with age-matched healthy controls and their possible relationship with several clinical parameters of PD and pharmaceutical treatment. PATIENTS AND METHODS: We measured serum UA levels in 43 PD patients and 47 healthy volunteers, age and sex-matched. UA levels were correlated with disease duration, severity and treatment. RESULTS: Low UA levels were observed in PD patients compared with controls (p=0.009). Age, Body Mass Index (BMI) and UPDRS III score did not significantly affect serum UA concentrations, whereas gender was found to contribute significantly to UA level (p<0.000). Strong and significant inverse correlations of UA with disease duration (R(s)=-0.397, p=0.009) and daily levodopa dosage (R(p)=-0.498, p=0.026) were observed. These associations were significant for men (R(s)=-0.441, p=0.04 and R(s)=-0.717, p=0.03 respectively), but not for women (R(s)=-0.221, p=0.337 and R(s)=-0.17, p=0.966 respectively). CONCLUSION: Our results suggest that there may be increased consumption of UA as a scavenger in PD, possibly heightened by dopaminergic drug treatment. Given the antioxidant properties of UA, manipulation of its concentrations should be investigated for potential therapeutic strategies of the disease.