Postvaccination Immunogenicity of BNT162b2 SARS-CoV-2 Vaccine and Its Predictors in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: We prospectively compared the postvaccination immunity to messenger ribonucleic acid BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine of our pediatric patients over 12 years old with inflammatory bowel disease (IBD) to that of healthy controls and looked for predictors of its robustness. METHODS: Anti-receptor binding domain, anti-spike S2, and anti-nucleocapsid immunoglobin-G (IgG) and immunoglobin-A levels were measured in 139 pediatric patients with IBD [65 fully vaccinated (2 doses), median age 16.3, interquartile range (IQR) 15.2-17.8 years, median time from vaccination (IQR) 61.0 (42.0-80.0) days] and 1744 controls (46, 37-57 years) using microblot array. RESULTS: All IBD and control patients developed positive anti-receptor binding domain IgG antibodies at comparable titers. The proportion of observations with positive anti-spike S2 IgG was higher in patients with IBD than in controls [63% vs 21%, odds ratio 2.99 (1.51-5.90)], as was its titer [median (IQR) 485 (92-922) vs 79 [33-180] IU/mL]. Anti-receptor binding domain and anti-spike S2 IgG levels were associated with IBD status. We found an association between anti-spike S2 IgG levels and time since vaccination (ß -4.85, 95% CI -7.14 to 2.71, P = 0.0001), history of SARS-CoV-2 polymerase chain reaction positivity (206.76, 95% CI 39.93-374.05, P = 0.0213), and anti-tumor necrosis factor treatment (-239.68, 95% CI -396.44-83.55, P = 0.0047). Forty-three percent of patients reported vaccination side effects (mostly mild). Forty-six percent of observations with positive anti-nucleocapsid IgG had a history of SARS-CoV-2 infection. CONCLUSIONS: Patients with IBD produced higher levels of postvaccination anti-spike S2 antibodies than controls. Previous SARS-CoV-2 infection is associated with higher production of postvaccination antibodies and anti-tumor necrosis factor treatment with lower production.

Relapsing MRI-negative myelitis associated with myelin-oligodendrocyte glycoprotein autoantibodies: a case report.

BACKGROUND: Serum antibodies to myelin-oligodendrocyte glycoprotein (MOG) are biomarkers of MOG-IgG-associated disorder (MOGAD), a demyelinating disease distinct from both multiple sclerosis and aquaporin-4-IgG neuromyelitis optica spectrum disorder. The phenotype of MOGAD is broad and includes optic neuritis, transverse myelitis, and acute demyelinating encephalomyelitis. Myelitis is common with MOGAD and typically results in acute and severe disability, although prospects for recovery are often favorable with prompt immunotherapy. CASE PRESENTATION: This contribution presents a unique case report of a young male patient exhibiting relapsing myelitis with normal spinal cord and brain magnetic resonance imaging. Comprehensive diagnostic assessment revealed myelin-oligodendrocyte glycoprotein-IgG-associated disorder. CONCLUSION: MOGAD is one of the conditions which should be considered in MRI-negative myelitis. The diagnosis, however, may prove difficult, especially if the patient is not exhibiting other neurological symptoms of MOGAD. Conus or epiconus involvement is common in MOGAD; the patient reported herein exhibited incomplete rostral epiconus symptoms which, together with somatosensory evoked potential abnormalities, led to the diagnosis.

Diffusion magnetic resonance imaging reveals tract-specific microstructural correlates of electrophysiological impairments in non-myelopathic and myelopathic spinal cord compression.

BACKGROUND AND PURPOSE: Non-myelopathic degenerative cervical spinal cord compression (NMDC) frequently occurs throughout aging and may progress to potentially irreversible degenerative cervical myelopathy (DCM). Whereas standard clinical magnetic resonance imaging (MRI) and electrophysiological measures assess compression severity and neurological dysfunction, respectively, underlying microstructural deficits still have to be established in NMDC and DCM patients. The study aims to establish tract-specific diffusion MRI markers of electrophysiological deficits to predict the progression of asymptomatic NMDC to symptomatic DCM. METHODS: High-resolution 3 T diffusion MRI was acquired for 103 NMDC and 21 DCM patients compared to 60 healthy controls to reveal diffusion alterations and relationships between tract-specific diffusion metrics and corresponding electrophysiological measures and compression severity. Relationship between the degree of DCM disability, assessed by the modified Japanese Orthopaedic Association scale, and tract-specific microstructural changes in DCM patients was also explored. RESULTS: The study identified diffusion-derived abnormalities in the gray matter, dorsal and lateral tracts congruent with trans-synaptic degeneration and demyelination in chronic degenerative spinal cord compression with more profound alterations in DCM than NMDC. Diffusion metrics were affected in the C3-6 area as well as above the compression level at C3 with more profound rostral deficits in DCM than NMDC. Alterations in lateral motor and dorsal sensory tracts correlated with motor and sensory evoked potentials, respectively, whereas electromyography outcomes corresponded with gray matter microstructure. DCM disability corresponded with microstructure alteration in lateral columns. CONCLUSIONS: Outcomes imply the necessity of high-resolution tract-specific diffusion MRI for monitoring degenerative spinal pathology in longitudinal studies.

Small-nerve-fiber pathology in critical illness documented by serial skin biopsies.

INTRODUCTION: Small-fiber pathology can develop in the acute phase of critical illness and may explain chronic sensory impairment and pain in critical care survivors. METHODS: Eleven adult ischemic stroke patients in a neurocritical care unit were enrolled in an observational cohort study. Intraepidermal nerve fiber density (IENFD) in the distal leg was assessed on admission to the intensive care unit and 10-14 days later, together with electrophysiological testing. RESULTS: Of the 11 patients recruited, 9 (82%) had sepsis or multiple-organ failure. Median IENFD on admission (5.05 fibers/mm) decreased significantly to 2.18 fibers/mm (P < 0.001), and abnormal IENFD was found in 6 patients (54.5%). Electrodiagnostic signs of large-fiber neuropathy and/or myopathy were found in 6 patients (54.5%), and autonomic dysfunction was found in 2 patients (18.2%). CONCLUSION: Serial IENFD measurements confirmed the development of small-fiber sensory involvement in the acute phase of critical illness.

Screening for dysphagia in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), dysphagia is an important and common clinical symptom. Although often overlooked and underdiagnosed, it can have a significant impact on a patient's life, including social integration, and it can lead to malnutrition, aspiration pneumonia, and suffocation, i.e., life-threatening complications. Early detection of dysphagia is essential to prevent these risks. However, the optimal screening method and the inter-relationship between different methods used for dysphagia screening are not clear. The aim of this study was to compare the diagnostic performance of a simple question about swallowing problems, the DYsphagia in MUltiple Sclerosis (DYMUS) swallowing questionnaire, and the Timed Water Swallowing Test (TWST) to detect dysphagia in people with relapsing-remitting MS (RRMS). METHODS: Patients with MS were asked about subjective swallowing difficulties and, regardless of their response, completed the DYMUS questionnaire and underwent the TWST at their routine follow-up visit. Patients with at least one positive screening method were offered an objective assessment of swallowing function using the Fiberoptic Endoscopic Evaluation of Swallowing (FEES). The results were statistically analyzed and correlated with demographic and MS-related parameters. RESULTS: Of the 304 people with RRMS enrolled in the study, 46 (15.1 %) reported having subjective difficulty swallowing when asked a simple question. The DYMUS questionnaire was positive in 59 (19.4 %) of the 304 patients; 51 (16.8 %) had an abnormality on the TWST. A clear correlation (r = 0.351, p < 0.01) was found between the DYMUS and TWST results, but a significant proportion of patients (about half) had an abnormality on only one of these tests. The positivity of at least one of the screening methods used (DYMUS or TWST) had a better chance of identifying a patient with dysphagia than a simple question (p < 0.001). Of the patients with a positive result for difficulty swallowing, 37 underwent FEES, which confirmed dysphagia in 94.6% of this subgroup. Patients with higher Expanded Disability Status Scale (EDSS) scores, female gender, and older age were at higher risk of developing dysphagia. CONCLUSION: The DYMUS questionnaire and TWST had a confirmed potential to identify more patients with dysphagia than a simple question about swallowing problems. However, our study found only a partial overlap between DYMUS and TWST; a combination of these two methods was more sensitive in identifying patients with MS at risk of dysphagia. Furthermore, the screening showed excellent specificity: almost 95 % of the positively screened patients had dysphagia confirmed by objective methods. Age, female gender, and a higher EDSS score appear to be potential risk factors for dysphagia in patients with MS.

Genetic Landscape of Amyotrophic Lateral Sclerosis in Czech Patients.

Background: Genetic factors are involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS) and constitute a link to its association with frontotemporal dementia (FTD). Gene-targeted therapies for some forms of ALS (C9orf72, SOD1) have recently gained momentum. Genetic architecture in Czech ALS patients has not been comprehensively assessed so far. Objective: We aimed to deliver pilot data on the genetic landscape of ALS in our country. Methods: A cohort of patients with ALS (n = 88), recruited from two Czech Neuromuscular Centers, was assessed for hexanucleotide repeat expansion (HRE) in C9orf72 and also for genetic variations in other 36 ALS-linked genes via next-generation sequencing (NGS). Nine patients (10.1%) had a familial ALS. Further, we analyzed two subgroups of sporadic patients - with concomitant FTD (n = 7) and with young-onset of the disease (n = 22). Results: We detected the pathogenic HRE in C9orf72 in 12 patients (13.5%) and three other pathogenic variants in FUS, TARDBP and TBK1, each in one patient. Additional 7 novel and 9 rare known variants with uncertain causal significance have been detected in 15 patients. Three sporadic patients with FTD (42.9%) were harbouring a pathogenic variant (all HRE in C9orf72). Surprisingly, none of the young-onset sporadic patients harboured a pathogenic variant and we detected no pathogenic SOD1 variant in our cohort. Conclusion: Our findings resemble those from other European populations, with the highest prevalence of HRE in the C9orf72 gene. Further, our findings suggest a possibility of a missing genetic variability among young-onset patients.

Evidence-based commentary on the diagnosis, management, and further research of degenerative cervical spinal cord compression in the absence of clinical symptoms of myelopathy.

Degenerative cervical myelopathy (DCM) represents the final consequence of a series of degenerative changes in the cervical spine, resulting in cervical spinal canal stenosis and mechanical stress on the cervical spinal cord. This process leads to subsequent pathophysiological processes in the spinal cord tissues. The primary mechanism of injury is degenerative compression of the cervical spinal cord, detectable by magnetic resonance imaging (MRI), serving as a hallmark for diagnosing DCM. However, the relative resilience of the cervical spinal cord to mechanical compression leads to clinical-radiological discordance, i.e., some individuals may exhibit MRI findings of DCC without the clinical signs and symptoms of myelopathy. This degenerative compression of the cervical spinal cord without clinical signs of myelopathy, potentially serving as a precursor to the development of DCM, remains a somewhat controversial topic. In this review article, we elaborate on and provide commentary on the terminology, epidemiology, natural course, diagnosis, predictive value, risks, and practical management of this condition-all of which are subjects of ongoing debate.

Predictive factors of multiple sclerosis relapse after the first demyelinating event: A 5-year follow-up.

There is a growing need to discover the characteristics that predict prognostic factors after the first demyelinating event. In this study of 141 patients that met the 2017 McDonald criteria, a higher number of oligoclonal bands, cervical spinal cord demyelinating lesions, and sensory involvement were identified as independent predictors of the second demyelinating event during the 5-year follow-up period in patients who experienced the first demyelinating event. The identification of the aforementioned risk variables will make it possible to identify patients who are more likely to exhibit early second demyelinating event, implying more frequent monitoring and consideration of early application of highly effective disease-modifying treatment.

Case report: Diagnostic challenge: a new multiple sclerosis "relapse" leading to the diagnosis of anaplastic astrocytoma.

Cerebral tumors and multiple sclerosis (MS) can show overlapping clinical and magnetic resonance imaging (MRI) features and even occur concurrently. Due to the emergence of new symptoms, not usually MS related, an MRI was conducted in a 29-year-old woman with relapsing-remitting MS and showed a significant size progression of a parieto-occipital lesion, with mild clinical correlates, such as blurred vision, difficulty in speaking, and headache. Contrast-enhanced MRI and fluorothymidine positron-emission tomography (PET) did not point toward neoplasm, a lesion biopsy, however, showed astrocytoma, which was confirmed as grade III astrocytoma after the radical resection of the tumor. In the case of an atypical lesion, a tumor should be considered in patients with MS. A small fraction of high-grade gliomas show no enhancement on MRI and no hypermetabolism on PET. Biopsy proved to be the essential step in a successful diagnostic workup. To the best of our knowledge, this is the first case of anaplastic astrocytoma with these radiological features reported in a patient with MS.

Prediabetes/early diabetes-associated neuropathy predominantly involves sensory small fibres.

The aim of this study was to investigate the characteristics of prediabetes (preDM) and early (<3 years) diabetes mellitus type 2 (eDM2)-associated neuropathy and the value of recently proposed diagnostic criteria for diabetic sensorimotor polyneuropathy (DSPN). A prospective case-control study in a group of 48 consecutive patients with eDM2, 16 preDM patients and 40 age- and sex-matched normoglycaemic controls was performed. Clinical and laboratory diagnostic tests were used to detect neuropathic abnormalities; these were further classified in terms of recent diagnostic criteria. Criteria for confirmed DSPN based on abnormal nerve conduction (NC) studies were met in 7 (14.6%) eDM2 patients compared to no control (p < 0.05), and the proportion significantly increased to 37.5% compared to 2.5% controls (p < 0.001), if intraepidermal nerve fibre density (IENFD) was used as an alternative criterion in addition to NC. The subclinical DSPN criteria based on NC abnormalities were met in 4.2% eDM2 patients, while the proportion of preDM and eDM2 cases with subclinical sensory small-fibre involvement documented by IENFD reached 12.5% and 22.9% compared with 2.5% controls (p = 0.005 for eDM2). The absolute IENFD values from distal leg were significantly lower in both eDM2 (p < 0.0001) and preDM patients (p = 0.005) compared to controls. Neuropathy associated with preDM/eDM2 predominantly involves sensory small fibres.

Intensive Circuit Class Therapy in Patients with Relapsing-Remitting Multiple Sclerosis.

OBJECTIVE: Long-term physiotherapy is of considerable benefit to patients with multiple sclerosis (MS) who have motor dysfunction or gait impairment. The aim of this study was to determine the effectiveness of a 12-week intensive circuit class therapy for patients with MS, with a wider focus on fatigue and gait ability. METHODS: A total of 46 patients with relapsing-remitting MS were divided randomly into 2 groups: 23 patients (mean Expanded Disability Status Scale (EDSS) 2.33 ± 0.74) participated in an intensive 12-week course of intensive circuit class therapy, and 23 patients (mean EDSS 2.04 ± 0.63) served as a control group. The EDSS, Timed Up and Go (TUG) test and Four-Stage Balance Test (FSBT) made up the physical testing part, supplemented by questionnaires such as the Modified Fatigue Impact Scale (MFIS), 12-Item Multiple Sclerosis Walking Scale (MSWS-12), Beck Depression Inventory (BDI) and 36-Item Short Form Survey (SF-36). RESULTS: Significant improvements were found among intensive circuit class therapy-exercising patients in FSBT (p < 0.05), TUG test (p < 0.01), MFIS (p < 0.01), BDI (p < 0.05), MSWS-12 (p < 0.05) and the 3 subscales of SF-36 after 12 weeks of intensive circuit class therapy, while there were no significant changes in the control group. CONCLUSION: Intensive circuit class therapy is an effective therapeutic approach for improving gait and balance problems in patients with MS. It has also proved to alleviate fatigue and symptoms of depression.

Continuum of sensory profiles in diabetes mellitus patients with and without neuropathy and pain.

BACKGROUND: Quantitative sensory testing (QST) assesses the functional integrity of small and large nerve fibre afferents and central somatosensory pathways; QST was assumed to provide insight into the mechanisms of neuropathy. We analysed QST profiles and phenotypes in patients with diabetes mellitus to study whether these could differentiate patients with and without pain and neuropathy. METHODS: A standardized QST protocol was performed and 'loss and gain of function' abnormalities were analysed in four groups of subjects: diabetic patients with painful (pDSPN; n = 220) and non-painful distal symmetric polyneuropathy (nDSPN; n = 219), diabetic patients without neuropathy (DM; n = 23) and healthy non-diabetic subjects (n = 37). Based on the QST findings, diabetic subjects were further stratified into four predefined prototypic phenotypes: sensory loss (SL), thermal hyperalgesia (TH), mechanical hyperalgesia (MH) and healthy individuals. RESULTS: Patients in the pDSPN group showed the greatest hyposensitivity ('loss of function'), and DM patients showed the lowest, with statistically significant increases in thermal, thermal pain, mechanical and mechanical pain sensory thresholds. Accordingly, the frequency of the SL phenotype was significantly higher in the pDSPN subgroup (41.8%), than expected (p < 0.0042). The proportion of 'gain of function' abnormalities was low in both pDSPN and nDSPN patients without significant differences. CONCLUSIONS: There is a continuum in the sensory profiles of diabetic patients, with a more pronounced sensory loss in pDSPN group probably reflecting somatosensory nerve fibre degeneration. An analysis of 'gain of function' abnormalities (allodynia, hyperalgesia) did not offer a key to understanding the pathophysiology of spontaneous diabetic peripheral neuropathic pain. SIGNIFICANCE: This article, using quantitative sensory testing profiles in large cohorts of diabetic patients with and without polyneuropathy and pain, presents a continuum in the sensory profiles of diabetic patients, with more pronounced 'loss of function' abnormalities in painful polyneuropathy patients. Painful diabetic polyneuropathy probably represents a 'more progressed' type of neuropathy with more pronounced somatosensory nerve fibre degeneration. The proportion of 'gain of function' sensory abnormalities was low, and these offer limited understanding of pathophysiological mechanisms of spontaneous neuropathic pain.

Risk factors for depression and anxiety in painful and painless diabetic polyneuropathy: A multicentre observational cross-sectional study.

BACKGROUND: Despite the high prevalence of depression and anxiety in chronic pain conditions, current knowledge concerning emotional distress among painful diabetic polyneuropathy (pDSPN) and other diabetes mellitus (DM) sufferers is limited. METHODS: This observational multicentre cohort study employed the Hospital Anxiety and Depression Scale, the Beck Depression Inventory II and the State-Trait Anxiety Inventory to assess symptoms of depression and anxiety in several groups with diabetes, as well as in a control group. The study cohort included 347 pDSPN patients aged 63.4 years (median), 55.9% males; 311 pain-free diabetic polyneuropathy (nDSPN) patients aged 63.7 years, 57.9% males; 50 diabetes mellitus (DM) patients without polyneuropathy aged 61.5 years, 44.0% males; and 71 healthy controls (HC) aged 63.0 years, 42.3% males. The roles played in emotional distress were explored in terms of the biological, the clinical (diabetes-, neuropathy- and pain-related), the socio-economic and the cognitive factors (catastrophizing). RESULTS: The study disclosed a significantly higher prevalence of the symptoms of depression and anxiety not only in pDSPN (46.7% and 60.7%, respectively), but also in patients with nDSPN (24.4% and 44.4%) and DM without polyneuropathy (22.0% and 30.0%) compared with HCs (7.0% and 14.1%, p < 0.001). Multiple regression analysis demonstrated the severity of pain and neuropathy, catastrophic thinking, type 2 DM, lower age and female sex as independent contributors to depression and anxiety. CONCLUSIONS: In addition to the severity of neuropathic pain and its cognitive processing, the severity of diabetic polyneuropathy and demographic factors are key independent contributors to emotional distress in diabetic individuals. SIGNIFICANCE: In large cohorts of well-defined painless and painful diabetic polyneuropathy patients and diabetic subjects without polyneuropathy, we found a high prevalence of the symptoms of depression and anxiety, mainly in painful individuals. We have confirmed neuropathic pain, its severity and cognitive processing (pain catastrophizing) as dominant risk factors for depression and anxiety. Furthermore, some demographic factors (lower age, female sex), type 2 diabetes mellitus and severity of diabetic polyneuropathy were newly identified as important contributors to emotional distress independent of pain.

Walk and Run Test in Patients with Degenerative Compression of the Cervical Spinal Cord.

Impaired gait is one of the cardinal symptoms of degenerative cervical myelopathy (DCM) and frequently its initial presentation. Quantitative gait analysis is therefore a promising objective tool in the disclosure of early cervical cord impairment in patients with degenerative cervical compression. The aim of this cross-sectional observational cohort study was to verify whether an objective and easily-used walk and run test is capable of detecting early gait impairment in a practical proportion of non-myelopathic degenerative cervical cord compression (NMDCC) patients and of revealing any correlation with severity of disability in DCM. The study group consisted of 45 DCM patients (median age 58 years), 126 NMDCC subjects (59 years), and 100 healthy controls (HC) (55.5 years), all of whom performed a standardized 10-m walk and run test. Walking/running time/velocity, number of steps and cadence of walking/running were recorded; analysis disclosed abnormalities in 66.7% of NMDCC subjects. The DCM group exhibited significantly more pronounced abnormalities in all walk/run parameters when compared with the NMDCC group. These were apparent in 84.4% of the DCM group and correlated closely with disability as quantified by the modified Japanese Orthopaedic Association scale. A standardized 10-m walk/run test has the capacity to disclose locomotion abnormalities in NMDCC subjects who lack other clear myelopathic signs and may provide a means of classifying DCM patients according to their degree of disability.

Local and Systemic Expression Pattern of MMP-2 and MMP-9 in Complex Regional Pain Syndrome.

Matrix metalloproteinases (MMP)-2 and MMP-9 play important roles in inflammation as well as in pain processes. For this reason, we compared the concentrations of these enzymes in skin and serum of patients with complex regional pain syndrome (CRPS), other pain diseases and healthy subjects. We analyzed ipsi- and contralateral skin biopsies of 18 CRPS patients, as well as in 10 pain controls and 9 healthy subjects. Serum samples were analyzed from 20 CRPS, 17 pain controls and 17 healthy subjects. All samples were analyzed with ELISA. Concentrations were then compared to clinical data as well as to quantitative sensory testing data.MMP-2 was increased in both ipsi- and contralateral skin biopsies of CRPS patients compared to healthy subjects. While low ipsilateral MMP-2 was associated with trophic changes, contralateral MMP-2 inversely correlated with the CRPS severity. MMP-9 was also locally increased in ipsilateral CRPS skin, and higher ipsi- and contralateral MMP-9 levels correlated with CRPS severity. We conclude that MMP-2 and MMP-9 are differently expressed depending on the clinical phenotype in CRPS. PERSPECTIVE: This article describes an upregulation of MMPs in CRPS and pain controls and shows different expression of MMP-2 and -9 depending on clinical phenotype in CRPS. These results provide evidence that MMP-2 and -9 play a key role in CRPS pathophysiology.

Sensory and pain modulation profiles of ongoing central neuropathic extremity pain in multiple sclerosis.

BACKGROUND: Central neuropathic extremity pain (CNEP) is the most frequent type of pain in multiple sclerosis (MS). The aim of the present study was to evaluate sensory and pain modulation profiles in MS patients with CNEP. METHODS: In a single-centre observational study, a group of 56 CNEP MS patients was compared with 63 pain-free MS patients and with a sex- and age-adjusted control group. Standardized quantitative sensory testing (QST) and dynamic QST (dQST) protocols comprising temporal summation and conditioned pain modulation tests were used to compare sensory profiles. RESULTS: Loss-type QST abnormalities in both thermal and mechanical QST modalities prevailed in both MS subgroups and correlated significantly with higher degree of disability expressed as Expanded Disability Status Scale (EDSS). Comparison of sensory phenotypes disclosed a higher frequency of the 'sensory loss' prototypic sensory phenotype in the CNEP subgroup (30%) compared with pain-free MS patients (6%; p = .003). CONCLUSION: The role of aging process and higher lesion load in the spinothalamocortical pathway might be possible explanation for pain development in this particular 'deafferentation' subtype of central neuropathic pain in MS. We were unable to support the role of central sensitization or endogenous facilitatory and inhibitory mechanisms in the development of CNEP in MS. SIGNIFICANCE: This article presents higher prevalence of the 'sensory loss' prototypic sensory phenotype in multiple sclerosis patients with central extremity neuropathic pain compared to pain-free patients. Higher degree of disability underlines the possible role of higher lesion load in the somatosensory pathways in this particular 'deafferentation' type of central neuropathic pain.

In vivo Molecular Signatures of Cervical Spinal Cord Pathology in Degenerative Compression.

Degenerative cervical myelopathy (DCM) is a severe consequence of degenerative cervical spinal cord (CSC) compression. The non-myelopathic stage of compression (NMDC) is highly prevalent and often progresses to disabling DCM. This study aims to disclose markers of progressive neurochemical alterations in NMDC and DCM by utilizing an approach based on state-of-the-art proton magnetic resonance spectroscopy (1H-MRS). Proton-MRS data were prospectively acquired from 73 participants with CSC compression and 47 healthy controls (HCs). The MRS voxel was centered at the C2 level. Compression-affected participants were clinically categorized as NMDC and DCM, radiologically as mild (MC) or severe (SC) compression. CSC volumes and neurochemical concentrations were compared between cohorts (HC vs. NMDC vs. DCM and HC vs. MC vs. SC) with general linear models adjusted for age and height (pFWE < 0.05) and correlated to stenosis severity, electrophysiology, and myelopathy symptoms (p < 0.05). Whereas the ratio of total creatine (tCr) to total N-acetylaspartate (tNAA) increased in NMDC (+11%) and in DCM (+26%) and SC (+21%), myo-inositol/tNAA, glutamate + glutamine/tNAA, and volumes changed only in DCM (+20%, +73%, and -14%) and SC (+12%, +46%, and -8%, respectively) relative to HCs. Both tCr/tNAA and myo-inositol/tNAA correlated with compression severity and volume (-0.376 < r < -0.259). Myo-inositol/tNAA correlated with myelopathy symptoms (r = -0.670), whereas CSC volume did not. Short-echo 1H-MRS provided neurochemical signatures of CSC impairment that reflected compression severity and clinical significance. Whereas volumetry only reflected clinically manifest myelopathy (DCM), MRS detected neurochemical changes already before the onset of myelopathy symptoms.

Detailed Phenotype of GLA Variants Identified by the Nationwide Neurological Screening of Stroke Patients in the Czech Republic.

Fabry disease (FD) is a rare X-linked disorder of glycosphingolipid metabolism caused by pathogenic variants within the alpha-galactosidase A (GLA) gene, often leading to neurological manifestations including stroke. Multiple screening programs seeking GLA variants among stroke survivors lacked detailed phenotype description, making the interpretation of the detected variant's pathogenicity difficult. Here, we describe detailed clinical characteristics of GLA variant carriers identified by a nationwide stroke screening program in the Czech Republic. A total of 23 individuals with 8 different GLA variants were included in the study. A comprehensive diagnostic workup was performed by a team of FD specialists. The investigation led to the suggestion of phenotype reclassification for the G325S mutation from late-onset to classical. A novel variant R30K was found and was classified as a variant of unknown significance (VUS). The typical manifestation in our FD patients was a stroke occurring in the posterior circulation with an accompanying pathological finding in the cerebrospinal fluid. Moreover, we confirmed that cornea verticillata is typically associated with classical variants. Our findings underline the importance of detailed phenotype description and data sharing in the correct identification of pathogenicity of gene variants detected by high-risk-population screening programs.

Clinical phenotypes and classification algorithm for complex regional pain syndrome.

OBJECTIVE: We pursued the hypothesis that complex regional pain syndrome (CRPS) signs observed by neurologic examination display a structure allowing for alignment of patients to particular phenotype clusters. METHODS: Clinical examination data were obtained from 3 independent samples of 444, 391, and 202 patients with CRPS. The structure among CRPS signs was analyzed in sample 1 and validated with sample 2 using hierarchical clustering. For patients with CRPS in sample 3, an individual phenotype score was submitted to k-means clustering. Pain characteristics, quantitative sensory testing, and psychological data were tested in this sample as descriptors for phenotypes. RESULTS: A 2-cluster structure emerged in sample 1 and was replicated in sample 2. Cluster 1 comprised minor injury eliciting CRPS, motor signs, allodynia, and glove/stocking-like sensory deficits, resembling a CRPS phenotype most likely reflecting a CNS pathophysiology (the central phenotype). Cluster 2, which consisted of edema, skin color changes, skin temperature changes, sweating, and trophic changes, probably represents peripheral inflammation, the peripheral phenotype. In sample 3, individual phenotype scores were calculated as the sum of the mean values of signs from each cluster, where signs from cluster 1 were coded with 1 and from cluster 2 with -1. A k-means algorithm separated groups with 78, 36, and 88 members resembling the peripheral, central, and mixed phenotypes, respectively. The central phenotype was characterized by cold hyperalgesia at the affected limb. CONCLUSIONS: Statistically determined CRPS phenotypes may reflect major pathophysiologic mechanisms of peripheral inflammation and central reorganization.

Conversion of clinically isolated syndrome to multiple sclerosis: a prospective study.

BACKGROUND: Multiple sclerosis (MS) begins with an acute clinical attack (clinically isolated syndrome) in approximately 85% of patients. The conversion rate from clinically isolated syndrome to multiple sclerosis has been documented at 30% to 82% in previous studies. When an individual presents for evaluation after a single episode of inflammation of the CNS, several decisions regarding follow-up in subsequent years need to be made, including that of whether or not to start a therapy. There is, therefore, an emerging need to identify the predictive factors that anticipate conversion from CIS to MS. METHODS: This paper presents a single-center prospective longitudinal study aimed at identification of the most powerful independent predictors for conversion from CIS to MS, utilizing the 2010 McDonald MS criteria and focusing on selected demographic, clinical, radiographical (magnetic resonance imaging - MRI), cerebrospinal fluid (predominantly oligoclonal bands - OCB) and electrophysiological parameters (multimodal sensory and motor-evoked potentials - EP). Two independent outcomes meeting MS criteria are evaluated: development of second clinical relapse (clinically definite multiple sclerosis) and progression in magnetic resonance imaging (based on new MRI T2 brain and/or spinal cord lesions). CIS patients were followed clinically and MRI was repeated at one and two years within the course of a follow-up period of at least 24 months (median 27, range 24-36 months). RESULTS: Of the 64 CIS patients enrolled who completed at least a 2-year follow-up period (42 women and 22 men, median age 36.5, range 22-66 years), 45 (70.3%) (29 women and 16 men, median age 38; range 22-66 years) fulfilled the 2010 McDonald criteria for MS by dissemination in space (DIS) and time (DIT) over the follow-up period. Twenty-nine CIS patients converted to MS through a clinically symptomatic attack, and 16 CIS patients developed new T2 lesions on MRI, while 19 patients without progression remained stable as CIS. Confirmed among potential predictors for the conversion of CIS patients to MS were increased (>10) baseline MRI T2-hyperintense lesions (odds ratio (OR) 3.107, p = 0.046), OCB positivity (OR 5.958, p = 0.003) and subclinical EP abnormality (OR 14.400, p = 0.003). Multivariate statistical models (logistic regression and Cox proportional hazards regression models) confirmed these parameters as independent predictors of high sensitivity (84%) and acceptable specificity (63%). CONCLUSION: In addition to accepted predictors for the conversion of CIS to MS (i.e. baseline MRI T2 lesion load and OCB positivity), already implemented in current diagnostic criteria for MS, this study demonstrates, in addition, the high predictive value of subclinical multimodal evoked potential abnormalities.