•Protein mapping in brain lesions by MALDI imaging.•Specific molecular ion masses correlate with different remyelination extents.•Detection of cortical lesions by MALDI imaging.•Identification of ...endogenous thymosin beta-4 in partially remyelinated brain lesions.
Multiple sclerosis is a disease of the central nervous system characterized by recurrent inflammatory demyelinating lesions in the early disease stage. Lesion formation and mechanisms leading to lesion remyelination are not fully understood. Matrix Assisted Laser Desorption Ionisation Mass Spectrometry imaging (MALDI–IMS) is a technology which analyses proteins and peptides in tissue, preserves their spatial localization, and generates molecular maps within the tissue section. In a pilot study we employed MALDI imaging mass spectrometry to profile and identify peptides and proteins expressed in normal-appearing white matter, grey matter and multiple sclerosis brain lesions with different extents of remyelination. The unsupervised clustering analysis of the mass spectra generated images which reflected the tissue section morphology in luxol fast blue stain and in myelin basic protein immunohistochemistry. Lesions with low remyelination extent were defined by compounds with molecular weight smaller than 5300Da, while more completely remyelinated lesions showed compounds with molecular weights greater than 15,200Da. An in-depth analysis of the mass spectra enabled the detection of cortical lesions which were not seen by routine luxol fast blue histology. An ion mass, mainly distributed at the rim of multiple sclerosis lesions, was identified by liquid chromatography and tandem mass spectrometry as thymosin beta-4, a protein known to be involved in cell migration and in restorative processes. The ion mass of thymosin beta-4 was profiled by MALDI imaging mass spectrometry in brain slides of 12 multiple sclerosis patients and validated by immunohistochemical analysis. In summary, our results demonstrate the ability of the MALDI–IMS technology to map proteins within the brain parenchyma and multiple sclerosis lesions and to identify potential markers involved in multiple sclerosis pathogenesis and/or remyelination.
Background
Anxiety disorders are the most frequent mental disorders. Among the different subtypes, specific phobias are the commonest. Due to the ongoing SARS-CoV-19 pandemic, blood-injury-injection ...phobia (BII) has gained wider attention in the context of large-scale vaccination campaigns and public health. In this BII phobia mini-review and case report, we describe the successful treatment of a severe BII phobia case with combined fainting and psychogenic non-epileptic seizures (PNES) and demonstrate the role of specialized outpatient care.
Case Report
The patient was a 28-year-old woman. She suffered from intense fear and recurrent fainting with regard to needles, injections, injuries, and at the sight of blood since early childhood. Medical history revealed infrequent events suggestive of PNES following panic attacks after sustained exposure to phobic stimuli. Family history was positive for circulation problems and BII fears. Psychopathological evaluation confirmed BII phobia symptoms and diagnosis was made according to the DSM-5. The Multidimensional Blood/Injury Phobia Inventory short version (MBPI-K) revealed severe manifestation of the disease. Neurological examination was ordinary. Repeated electroencephalography detected no epileptic pattern. Cranial magnetic resonance imaging showed normal morphology. Treatment was carried out by a seasoned, multidisciplinary team. Cognitive behavior therapy and exposure were performed. Modification of standard treatment protocol was necessary due to hurdles posed by recurrent fainting and a severe panic-triggered dissociative PNES during
in vivo
exposure. Modification was implemented by limiting
in vivo
exposure intensity to moderate anxiety levels. In addition to applied muscle tension and ventilation techniques, increased psychoeducation, cognitive restructuring, and distress tolerance skills (e.g., ice pack, verbal self-instructions) were used to strengthen the patient's situational control during
in vivo
exposure. A total of 15 sessions were performed. Therapy success was proven by 83% reduction in MBPI-K rating, SARS-CoV-19 vaccination, and a blood draw without psychological assistance, fainting, or seizure.
Conclusion
Taken together, this case demonstrates the potential of and need for specialized outpatient care and individualized treatment for severe BII phobia patients in order to provide them the perspective to have necessary medical procedures done and get vaccinated.
Background. The pharmacological treatment options of Parkinson’s disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual ...differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation. In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient’s psychovegetative symptoms subsided. Conclusions. The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression.
Summary The autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome is a genetic disorder caused by a mutation in the autoimmune regulator (AIRE) gene. Immune deficiency, ...hypoparathyroidism and Addison’s disease due to autoimmune dysfunction are the major clinical signs of APECED. We report on a 21-year-old female APECED patient with two inactivating mutations in the AIRE gene. She presented with sudden onset of periodic nausea. Adrenal insufficiency was diagnosed by means of the ACTH stimulation test. Despite initiation of hormone replacement therapy with hydrocortisone and fludrocortisone, nausea persisted and the patient developed cognitive deficits and a loss of interest which led to the diagnosis of depression. She was admitted to the psychiatric department for further diagnostic assessment. An EEG showed a focal epileptic pattern. Glutamic acid decarboxylase (GAD) antibodies, which had been negative eight years earlier, were now elevated in serum and in the cerebrospinal fluid. Oligoclonal bands were positive indicating an inflammatory process with intrathecal antibody production in the central nervous system (CNS). The periodic nausea was identified as dialeptic seizures, which clinically presented as gastrointestinal aura followed by episodes of reduced consciousness that occurred about 3–4 times per day. GAD antibody-associated limbic encephalitis (LE) was diagnosed. Besides antiepileptic therapy, an immunosuppressive treatment with corticosteroids was initiated followed by azathioprine. The presence of nausea and vomiting in endocrine patients with autoimmune disorders is indicative of adrenal insufficiency. However, our case report shows that episodic nausea may be a symptom of epileptic seizures due to GAD antibodies-associated LE in patients with APECED. Learning points: Episodic nausea cannot only be a sign of Addison’s disease, but can also be caused by epileptic seizures with gastrointestinal aura due to limbic encephalitis. GAD antibodies are not only found in diabetes mellitus type 1, but they are also associated with autoimmune limbic encephalitis and can appear over time. Limbic encephalitis can be another manifestation of autoimmune disease in patients with APECED/APS-1 that presents over the time course of the disease.
IMPORTANCE: Reliable biomarkers associated with disability worsening in multiple sclerosis (MS) are still needed. OBJECTIVE: To determine a possible association of intrathecal IgG synthesis and early ...disability worsening as measured by Expanded Disability Status Scale (EDSS) scoring in patients with relapsing-remitting MS or clinically isolated syndrome. DESIGN, SETTING, AND PARTICIPANTS: Cerebrospinal fluid measurements and clinical data from the observational longitudinal German national multiple sclerosis cohort were analyzed. Patients were recruited between August 2010 and November 2015 from 18 centers. Data analysis was completed from August 2018 to December 2018. EXPOSURE: Patients were offered standard immunotherapies per national treatment guidelines. MAIN OUTCOMES AND MEASURES: A possible association between intrathecal IgG synthesis and risk of EDSS worsening 4 years after study inclusion was tested as the primary end point by multivariable binomial regression analysis. Kaplan-Meier analysis with a log-rank test was used to assess the association of intrathecal IgG synthesis with the time to EDSS worsening. Associations between intrathecal IgM or IgA synthesis and other cerebrospinal fluid parameters and EDSS worsening were analyzed as exploratory end points. Data collection began before the hypotheses were formulated. RESULTS: Of all 1376 patients in the German Competence Network of Multiple Sclerosis cohort, 703 patients were excluded owing to missing cerebrospinal fluid or EDSS data. Of the 673 included patients, 459 (68.2%) were women. The mean (SD) age at baseline was 34 (10) years. Intrathecal IgG synthesis was associated with a higher risk of EDSS worsening after 4 years (odds ratio, 2.02 95% CI, 1.15-3.58; P = .01), independent of the occurrence of relapses and disease-modifying therapy. Additionally, intrathecal IgG synthesis was associated with earlier EDSS worsening; 4 years after study entry, worsening occurred in 28.4% (95% CI, 22.7%-34.1%) and 18.1% (95% CI, 12.4%-23.9%) of patients with and without intrathecal IgG synthesis, respectively. No association of other routine cerebrospinal fluid parameters with EDSS worsening was found. CONCLUSIONS AND RELEVANCE: Patients with new diagnoses of relapsing-remitting multiple sclerosis or clinically isolated syndrome with intrathecal IgG synthesis had a higher risk of and shorter time to EDSS worsening across a 4-year period of follow-up. Intrathecal IgG synthesis is a potentially useful marker for disability worsening in patients with multiple sclerosis and may be useful for early treatment decisions.
Pain is frequent in multiple sclerosis (MS) and includes different types, with neuropathic pain (NP) being most closely related to MS pathology. However, prevalence estimates vary largely, and causal ...relationships between pain and biopsychosocial factors in MS are largely unknown. Longitudinal studies might help to clarify the prevalence and determinants of pain in MS. To this end, we analyzed data from 410 patients with newly diagnosed clinically isolated syndrome or relapsing-remitting MS participating in the prospective multicenter German National MS Cohort Study (NationMS) at baseline and after 4 years. Pain was assessed by self-report using the PainDETECT Questionnaire. Neuropsychiatric assessment included tests for fatigue, depression, and cognition. In addition, sociodemographic and clinical data were obtained. Prevalence of pain of any type was 40% and 36% at baseline and after 4 years, respectively, whereas prevalence of NP was 2% and 5%. Pain of any type and NP were both strongly linked to fatigue, depression, and disability. This link was even stronger after 4 years than at baseline. Moreover, changes in pain, depression, and fatigue were highly correlated without any of these symptoms preceding the others. Taken together, pain of any type seems to be much more frequent than NP in early nonprogressive MS. Moreover, the close relationship between pain, fatigue, and depression in MS should be considered for treatment decisions and future research on a possible common pathophysiology.
Background
Cognitive impairment (CI) affects approximately one-third of the patients with early multiple sclerosis (MS) and clinically isolated syndrome (CIS). Little is known about factors ...predicting CI and progression after initial diagnosis.
Methods
Neuropsychological screening data from baseline and 1-year follow-up of a prospective multicenter cohort study (NationMS) involving 1123 patients with newly diagnosed MS or CIS were analyzed. Employing linear multilevel models, we investigated whether demographic, clinical and conventional MRI markers at baseline were predictive for CI and longitudinal cognitive changes.
Results
At baseline, 22% of patients had CI (impairment in ≥2 cognitive domains) with highest frequencies and severity in processing speed and executive functions. Demographics (fewer years of academic education, higher age, male sex), clinical (EDSS, depressive symptoms) but no conventional MRI characteristics were linked to baseline CI. At follow-up, only 14% of patients showed CI suggesting effects of retesting. Neither baseline characteristics nor initiation of treatment between baseline and follow-up was able to predict cognitive changes within the follow-up period of 1 year.
Conclusions
Identification of risk factors for short-term cognitive change in newly diagnosed MS or CIS is insufficient using only demographic, clinical and conventional MRI data. Change-sensitive, re-test reliable cognitive tests and more sophisticated predictors need to be employed in future clinical trials and cohort studies of early-stage MS to improve prediction.
Abstract In a genome wide association study consisting of 592 German multiple sclerosis (MS) patients and 825 controls we were able to replicate the association of the HLA region with MS ...independently of previous case control studies. No SNPs outside the HLA region reached a genome wide level of significance. Nevertheless, we found suggestive evidence for an association of MS with variants in two new genes, the VAV2 gene and the gene for ZNF433.
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