Dronabinol Is a Safe Long-Term Treatment Option for Neuropathic Pain Patients.

Treatment of neuropathic pain (NP) symptoms associated with multiple sclerosis (MS) is frequently insufficient. Yet, cannabis is still rarely offered for treatment of pain. This clinical trial aimed at showing the positive benefit-risk ratio of dronabinol. Two hundred forty MS patients with central NP entered a 16-weeks placebo-controlled phase-III study followed by a 32-weeks open-label period. One hundred patients continued therapy for overall up to 119 weeks. Primary endpoint was change of pain intensity on the 11-point Numerical Rating Scale over a 16-weeks treatment period. Safety was assessed on the basis of adverse reactions (ARs), signs of dependency and abuse. Pain intensity during 16-weeks dronabinol and placebo treatment was reduced by 1.92 and 1.81 points without significant difference in between (p = 0.676). Although the proportion of patients with ARs was higher under dronabinol compared to placebo (50.0 vs. 25.9%), it decreased during long-term use of dronabinol (26%). No signs of drug abuse and only one possible case of dependency occurred. The trial results demonstrate that dronabinol is a safe long-term treatment option.

Escalation Therapy of Steroid Refractory Multiple Sclerosis Relapse with Tryptophan Immunoadsorption - Observational Multicenter Study with 147 Patients.

BACKGROUND: A marked proportion of multiple sclerosis (MS) relapses is followed by incomplete recovery. Our aim was to considerably increase the evidence of the clinical use of immunoadsorption (IA) as escalation therapy for patients with MS relapse. METHODS: A retrospective multicenter study was performed in MS patients with steroid refractory relapse who were treated with tryptophan IA. The main outcome parameter was change of acute relapse-related disability assessed by Expanded Disability Status Scale (EDSS) and visual acuity (VA) measurements for patients with optic neuritis (ON). IA treatments were performed using single-use tryptophan adsorbers. RESULTS: Data of 147 MS patients and 786 single IA treatments were analyzed. Treatment with IA was commenced in mean 32 ± 35 days after the onset of relapse. One hundred and five out of 147 patients (71.4%) improved functionally after mean 5.4 IA treatments within 7-10 days. EDSS improved from median 5 (interquartile range, IQR 3.5) to 4 (IQR 2.5) (p < 0.001). In patients with ON (n = 32), VA improved after the IA series in 84% of cases from median 0.2 (IQR 0.6) to 0.6 (IQR 0.66) (p < 0.001). In 98.9% of IA treatments, no clinically relevant side effect was reported. CONCLUSION: Tryptophan IA was found to be effective and well tolerated as escalation therapy for MS relapse.

Experience of gratitude, awe and beauty in life among patients with multiple sclerosis and psychiatric disorders.

BACKGROUND: Feelings of gratitude and awe facilitate perceptions and cognitions that go beyond the focus of illness and include positive aspects of one's personal and interpersonal reality, even in the face of disease. We intended to measure feelings of gratitude, awe, and experiences of beauty in life among patients with multiple sclerosis and psychiatric disorders, particularly with respect to their engagement in specific spiritual/religious practices and their life satisfaction. METHODS: We conducted a cross-sectional survey with standardized questionnaires to measure engagement in various spiritual practices (SpREUK-P) and their relation to experiences of Gratitude, Awe and Beauty in Life and life satisfaction (BMLSS-10). In total, 461 individuals (41 ± 13 years; 68% women) with multiple sclerosis (46%) and depressive (22%) or other psychiatric disorders (32%) participated. RESULTS: Among participants, 23% never, 43% rarely, 24% often, and 10% frequently experienced Gratitude. In contrast, 41% never, 37% rarely, 17% often, and 6% frequently experienced Awe. Beauty in Life was never experienced by 8% of the sample, and 28% rarely, 46% often, and 18% frequently experienced it. Gratitude (F = 9.2; p = .003) and Beauty in Life (F = 6.0; p = .015) were experienced significantly more often by women than men. However, the experience of Awe did not differ between women and men (F = 2.2; n.s.). In contrast to our hypothesis, Gratitude/Awe cannot explain any relevant variance in patients' life satisfaction (R2 = .04). Regression analyses (R2 = .42) revealed that Gratitude/Awe can be predicted best by a person's engagement in religious practices, followed by other forms of spiritual practices and life satisfaction. Female gender was a weak predictor and underlying disease showed no effect. CONCLUSIONS: Gratitude/Awe could be regarded as a life orientation towards noticing and appreciating the positive in life--despite the symptoms of disease. Positive spirituality/religiosity seems to be a source of gratitude and appreciation in life, whereas patients with neither spiritual nor religious sentiments (R-S-) seem to have a lower awareness for these feelings.

Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.

OBJECTIVE: To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci. METHODS: We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease. RESULTS: We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934(T) at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10(-8)) near EOMES, rs2150702(G) in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10(-8)), and rs6718520(A) in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10(-8)). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10(-6) , some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1). INTERPRETATION: We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS.

CT and DSA for evaluation of spontaneous intracerebral lobar bleedings.

Purpose: This study retrospectively examined the extent to which computed tomography angiography (CTA) and digital subtraction angiography (DSA) can help identify the cause of lobar intracerebral bleeding. Materials and methods: In the period from 2002 to 2020, data from patients who were >18 years at a university and an academic teaching hospital with lobar intracerebral bleeding were evaluated retrospectively. The CTA DSA data were reviewed separately by two neuroradiologists, and differences in opinion were resolved by consensus after discussion. A positive finding was defined as an underlying vascular etiology of lobar bleeding. Results: The data of 412 patients were retrospectively investigated. DSA detected a macrovascular cause of bleeding in 125/412 patients (33%). In total, sixty patients had AVMs (15%), 30 patients with aneurysms (7%), 12 patients with vasculitis (3%), and 23 patients with dural fistulas (6%). The sensitivity, specificity, positive and negative predictive values, and accuracy of CTA compared with DSA were 93, 97, 100, and 97%. There were false-negative CTA readings for two AVMs and one dural fistula. Conclusion: The DSA is still the gold standard diagnostic modality for detecting macrovascular causes of ICH; however, most patients with lobar ICH can be investigated first with CTA, and the cause of bleeding can be found. Our results showed higher sensitivity and specificity than those of other CTA studies.

Increase in relapse rate during assisted reproduction technique in patients with multiple sclerosis.

The objective was to determine if there is an increased risk to develop exacerbations in patients with multiple sclerosis (MS) after assisted reproduction technique (ART). An increase in annual relapse rate (ARR) was described after ART in a small cohort of patients. We investigated the associations between ART and relapse rate (RR) in 23 MS patients who underwent 78 hormonal stimulations in total. There was a statistically significant increase in the RR following ART independent of the hormonal approach or the time interval between the stimulations. These results suggest that female MS patients who wish to have children should be informed that the RR may be increasing if ART is necessary.

Spinal cord atrophy in spinocerebellar ataxia type 3 and 6 : impact on clinical disability.

OBJECTIVE: To quantify spinal cord atrophy and its impact on clinical disability in spinocerebellar ataxia (SCA) type 3 and 6. METHODS: Atrophy of the upper spinal cord was assessed by high resolution T1-weighted MRI of patients with SCA3 (n = 14) and SCA6 (n = 10). Furthermore, two groups of age- and sex-matched healthy control subjects (n = 24,) corresponding to the two SCA groups, were studied. Images were post-processed by a semi-automated volumetry method combining a marker based segmentation and an automatic histogram method facilitating highly reliable quantification and morphometry of the upper cervical cord in vivo. RESULTS: We found a significant reduction of normalized mean crosssectional area of the spinal cord in SCA3 (p < 0.0005), whereas in SCA6 patients normalized mean crosssectional area was in the normal range (p = 0.379). No correlation was found between spinal cord atrophy and disease duration as well as CAG repeat length in both subtypes. In SCA6 a negative dependency between clinical disability, as expressed by the International Cooperative Ataxia Rating Scale as a well established ataxia score, and the mean cross-sectional area was found (p = 0.02). A similar correlation was observed in SCA3 but did not reach statistical significance. CONCLUSION: Our results quantify for the first time in vivo spinal cord atrophy as a non-cerebellar neurodegenerative process in SCA3. Our results suggest MR volumetry of the upper cervical cord as a marker of functional importance in SCA3 and SCA6.

Tryptophan immunoadsorption during pregnancy and breastfeeding in patients with acute relapse of multiple sclerosis and neuromyelitis optica.

BACKGROUND: Up to every fourth woman with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) suffers a clinically relevant relapse during pregnancy. High doses of steroids bear some serious risks, especially within the first trimester of pregnancy. Immunoadsorption (IA) is an effective and more selective treatment option in disabling MS relapse than plasma exchange. Data on the use of IA during pregnancy and breastfeeding are scarce. METHODS: In this retrospective multicenter study, we analyzed the safety and efficacy of IA treatment in acute relapses during pregnancy or breastfeeding. The primary outcome parameter - change of acute relapse-related disability after IA - was assessed using Expanded Disability Status Scale (EDSS) and visual acuity (VA) measurements for patients with optic neuritis (ON). RESULTS: A total of 24 patients were analyzed, 23 with relapsing-remitting MS, and 1 with NMOSD. Twenty patients were treated with IA during pregnancy. Four patients received IA postnatally during the breastfeeding period. Treatment was started at a mean 22.5 [standard deviation (SD) 13.9] days after onset of relapse. Patients were treated with a series of 5.8 (mean, SD 0.7) IA treatments within 7-10 days. Sixteen patients received IA because of steroid-refractory relapse, eight were treated without preceding steroid pulse therapy. EDSS improved clinically relevant from 3.5 [median, interquartile range (IQR) 2] before IA to 2.5 (median, IQR 1.1) after IA, p < 0.001. In patients with ON, VA improved in four out of five patients. Altogether, in 83% of patients, a rapid and marked improvement of relapse-related symptoms was observed after IA with either a decrease of ⩾1 EDSS grade or improvement in VA ⩾20%. No clinically relevant side effect was reported in 138 IA treatments. CONCLUSIONS: Tryptophan-IA was found to be effective and well tolerated in MS/NMOSD relapses, both as an escalation option after insufficient response to steroid pulse therapy and as first-line relapse treatment during pregnancy and breastfeeding.

Efficacy of mitoxantrone and intrathecal triamcinolone acetonide treatment in chronic progressive multiple sclerosis patients.

Treatment approaches are rare for chronic progressive patients with multiple sclerosis (MS). Objective was to evaluate the clinical benefit of repeated intrathecal application of the sustained release steroid triamcinolone acetonide or the administration of mitoxantrone (MIX) in 2 similar cohorts of chronic progressive patients with MS in an open-label fashion. Expanded Disability Status Scale scores significantly decreased after the first 6 intraspinal triamcinolone acetonide injections, which were performed every third day, and then remained stable. Walking distance significantly increased and did not reduce until the end of the 1-year-long trial period. Mitoxantrone treatment did not improve the Expanded Disability Status Scale score; however, no further significant deterioration appeared. Walking distance did not significantly decrease. Both treatment regimens were safe; the patients experienced nearly no adverse effects. Triamcinolone acetonide application provided a clinical benefit, whereas MIX administration prevented further worsening of MS symptoms. We stress that only specialists with a broad experience in intraspinal triamcinolone acetonide application and MIX administration should perform both kinds of therapy only after a careful information and risk-benefit evaluation in cooperation with the patient. Future trials will show the efficacy of combination of both treatment approaches in chronic progressive patients with MS.

Association of the HLA region with multiple sclerosis as confirmed by a genome screen using >10,000 SNPs on DNA chips.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, with a complex genetic background. Here, we present a genome screen for association in small scale, employing 11,555 single nucleotide polymorphisms (SNPs) on DNA chips for genotyping 100 MS patients stratified for HLA-DR2+ and 100 controls. More than 500 SNPs revealed significant differences between cases and controls before Bonferroni correction. A fraction of these SNPs was reanalysed in two additional cohorts of patients and controls, using high-throughput genotyping methods. A marker on chromosome 6p21.32 (rs2395182) yielded the highest significance level, validating the established HLA-DR association.

Repeat intrathecal triamcinolone acetonide application reduces acute occurring painful dysesthesia in patients with relapsing remitting multiple sclerosis.

We describe four patients with relapsing remitting multiple sclerosis (RRMS) who experienced a relapse with acute onset of painful sensations. Pain sensations disappeared in two of them and markedly reduced in the other ones after repeat application of intrathecal triamcinolone acetonide (TCA) following a prior unsuccessful treatment with intravenous steroids. TCA administration was well tolerated and no serious side effects occurred. Repeated intrathecal TCA injection may provide a substantial benefit in RRMS patients with acute onset of pain due to an inflammatory lesion within the spinal cord.

An extended association screen in multiple sclerosis using 202 microsatellite markers targeting apoptosis-related genes does not reveal new predisposing factors.

Apoptosis, the programmed death of cells, plays a distinct role in the etiopathogenesis of Multiple sclerosis (MS), a common disease of the central nervous system with complex genetic background. Yet, it is not clear whether the impact of apoptosis is due to altered apoptotic behaviour caused by variations of apoptosis-related genes. Instead, apoptosis in MS may also represent a secondary response to cellular stress during acute inflammation in the central nervous system. Here, we screened 202 apoptosis-related genes for association by genotyping 202 microsatellite markers in initially 160 MS patients and 160 controls, both divided in 4 sets of pooled DNA samples, respectively. When applying Bonferroni correction, no significant differences in allele frequencies were detected between MS patients and controls. Nevertheless, we chose 7 markers for retyping in individual DNA samples, thereby eliminating 6 markers from the list of candidates. The remaining candidate, the ERBB3 gene microsatellite, was genotyped in additional 245 MS patients and controls. No association of the ERBB3 marker with the disease was detected in these additional cohorts. In consequence, we did not find further evidence for apoptosis-related genes as predisposition factors in MS.

PTPRC (CD45) is not associated with multiple sclerosis in a large cohort of German patients.

BACKGROUND: Since contradictory results have been reported, we reanalysed the 77C-->G transition in exon 4 of the protein-tyrosine phosphatase receptor-type C (PTPRC also known as CD45) in a large cohort of German MS patients and controls. Different isoforms of the protein are expressed, depending on alternative splicing of exons 4 (CD45RA), 5 (CD45RB) and 6 (CD45RC) (CD45RO, exons 4-6 spliced out). The 77C-->G transition does not change the amino acid sequence, but it is probably part of a motif necessary for splicing leading to the isoform CD45RA. The expression of CD45RA is increased in 77C/G heterozygous individuals. The aim of the study was to clarify the importance of the PTPRC 77C-->G transition in our German cohort of MS patients. METHODS: PCR products of exon 4 were digested using endonuclease MspI. The resulting restriction fragments of the wildtype C allele are 198 and 62 bp in length. In the G allele an additional restriction site is present yielding fragments of 114 and 84 bp. RESULTS: The G allele was identified in 10 of the 347 controls (1.4%) and in 7 of 454 MS patients (0.8%; Table 1). No homozygous individuals were found either in the control or in the patient group. Genetic association between the PTPRC 77C-->G transition and MS susceptibility was excluded in the MS cohort. In addition, subgrouping patients according to differences in the clinical course of MS or according to HLA-DRB1*15 status did not yield significant differences. CONCLUSIONS: The 77C-->G transition in exon 4 of the PTPRC gene may contribute to MS susceptibility only in very few families, if at all, but it is not relevant for the majority of MS cases, including virtually all German patients.

Efficacy and safety of repeated intrathecal triamcinolone acetonide application in progressive multiple sclerosis patients.

Available immunomodulatory and conventional steroid treatment options for patients with progressive multiple sclerosis (MS) only provide limited symptomatic benefit. We performed an open trial on the short-term and long-term efficacy and safety of repeated intrathecal application of the sustained release steroid triamcinolone acetonide (TCA) in 36 progressive MS patients. Six TCA administrations, performed every third day, reduced the EDSS score (initial: 5.6+/-0.93 [mean+/-S.D.]; end: 4.9+/-1.0; p<0.001) and increased the walking distance (WD) (initial: 294+/-314 m; end: 604+/-540 m; p<0.001). Twenty MS patients continued intrathecal TCA treatment with one TCA injection performed with a variable frequency ranging from 6 to 12 weeks. Both EDSS and walking distance remained stable in these patients until the end of the follow-up investigation period. No serious side effects occurred. We conclude that repeated intrathecal TCA injection provides substantial benefit for progressive MS patients with predominantly spinal symptoms.

Faith as a resource in patients with multiple sclerosis is associated with a positive interpretation of illness and experience of gratitude/awe.

The aim of this cross-sectional anonymous survey with standardized questionnaires was to investigate which resources to cope were used by patients with multiple sclerosis (MS). We focussed on patients' conviction that their faith might be a strong hold in difficult times and on their engagement in different forms of spirituality. Consecutively 213 German patients (75% women; mean age 43 ± 11 years) were enrolled. Fifty-five percent regarded themselves as neither religious nor spiritual (R-S-), while 31% describe themselves as religious. For 29%, faith was a strong hold in difficult times. This resource was neither related to patients' EDSS scores, and life affections, fatigue, negative mood states, life satisfaction nor to Positive attitudes. Instead it was moderately associated with a Reappraisal strategy (i.e., and positive interpretation of illness) and experience of gratitude/awe. Compared to spiritual/religious patients, R-S- individuals had significantly (P < .0001) lower Reappraisal scores and lower engagement in specific forms of spiritual practices. The ability to reflect on what is essential in life, to appreciate and value life, and also the conviction that illness may have meaning and could be regarded as a chance for development was low in R-S- individuals which either may have no specific interest or are less willing to reflect these issues.

A newborn with Pierre Robin sequence after preconceptional mitoxantrone exposure of a female with multiple sclerosis.

Multiple sclerosis is a common disease of young adults in which accidental and unplanned pregnancies under disease modifying or immunosuppressive therapies may occur. The experience with mitoxantrone (MIX) especially in the first trimenon is very limited, until now only one case of a pregnant woman with MS who was exposed to MIX in early pregnancy and delivered a growth restricted but healthy child was published. We report a case of a secondary progressive MS patient who was exposed periconceptionally to MIX and delivered a child with Pierre Robin Sequence (PRS), a syndrome with the main features of glossoptosis, micrognathia, and palate clefts. PRS is a very rare defect and therefore a causal relation with MIX seems possible.

Immunomodulation and postpartum relapses in patients with multiple sclerosis.

Multiple sclerosis (MS) mainly affects young women during a life period with desire for children. Relapse rate decreases during pregnancy and rises after delivery. Therefore, studies on satisfactory postpartum relapse prevention and its efficacy are essential. Previous smaller and uncontrolled studies suggested that intravenous immunoglobulin (IVIG) administration reduced the relapse rate following delivery. The objective of our observational study was to compare the efficacy of IVIG application, treatment with other immunomodulatory compounds or no treatment at all on the postpartal relapse rate in female MS patients from our pregnancy database. One hundred and twenty four pregnancies were followed in a partly prospective design. Relapse rate was reduced during pregnancy (p50.001) and increased during the initial 3 months after delivery in all MS patients (p50.001). The relapse rate reduction showed only a trend in favour of the IVIG-treated women, probably due to the small number of patients. However, analysing the expected number of relapses, IVIG treated patients had significantly less relapses postpartum than the untreated control group matched for disease activity before and during pregnancy (χ(2), p= 0.013). The results suggest that IVIG could be an option to prevent postpartum relapse of MS.

Benefit of repetitive intrathecal triamcinolone acetonide therapy in predominantly spinal multiple sclerosis: prediction by upper spinal cord atrophy.

Intrathecal injection of triamcinolone acetonide (TCA) has been shown to provide substantial benefit in a subset of progressive multiple sclerosis (MS) patients with predominant spinal symptoms. We examined whether atrophy of the upper spinal cord (USC) as measured by MRI can serve as a predictive marker for response to repetitive intrathecal TCA application. Repetitive administration of 40 mg TCA was performed in 31 chronic progressive MS patients up to six times within 3 weeks. Expanded Disability Status Scale (EDSS) and maximum walking distance (WD) were assessed before and after the treatment cycle. Cervical 3D T1-weighted images were acquired on a 1.5T scanner at baseline. Mean cross-sectional area of the USC was determined using a semi-automated volumetry method. Results were compared with a group of 29 healthy controls to group patients into those with and without atrophy. Results show a negative correlation between the degree of USC atrophy and treatment benefit. A higher treatment benefit in patients with little USC atrophy but short initial maximum WD was observed. Absence of USC atrophy as measured on MRI is a predictive marker for intrathecal TCA therapy outcome in progressive MS. Patients with initial poor walking abilities, but only little or no atrophy, benefited most from TCA therapy.