Publications by authors named "Wolfgang Köhler"

42 Publications

Glatiramer Acetate Treatment in Multiple Sclerosis-Associated Fatigue-Beneficial Effects on Self-Assessment Scales But Not on Molecular Markers.

Biomolecules 2021 Mar 7;11(3). Epub 2021 Mar 7.

Department of Neurology, Universitätsmedizin Rostock, 18057 Rostock, Germany.

Although fatigue is a common symptom in multiple sclerosis (MS), its pathomechanisms are incompletely understood. Glatiramer acetate (GA), an immunomodulatory agent approved for treatment of relapsing-remitting MS (RRMS), possesses unique mechanisms of action and has been shown to exhibit beneficial effects on MS fatigue. The objective of this study was to correlate clinical, neuropsychological, and immunological parameters in RRMS patients with fatigue before and during treatment with GA. In a prospective, open-label, multicenter trial, 30 patients with RRMS and fatigue were treated with GA for 12 months. Inclusion criterion was the presence of fatigue as one of the most frequent and disabling symptoms. Before and during treatment, fatigue was assessed using the Fatigue Severity Scale (FSS), the MS-FSS, and the Modified Fatigue Impact Scale (MFIS). In addition, fatigue and quality of life were assessed using the Visual Analog Scales (VAS). Laboratory assessments included screening of 188 parameters using real-time PCR microarrays followed by further analysis of several cytokines, chemokines, and neurotrophic factors. Fatigue self-assessments were completed in 25 patients. After 12 months of treatment with GA, 13 of these patients improved in all three scales (with the most prominent effects on the MFIS), whereas 5 patients had deteriorated. The remaining 7 patients exhibited inconsistent effects within the three scales. Fatigue and overall quality of life had improved, as assessed via VAS. Laboratory assessments revealed heterogeneous mRNA levels of cytokines, chemokines, and neurotrophic factors. In conclusion, we were not able to correlate clinical and molecular effects of GA in patients with RRMS and fatigue.
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http://dx.doi.org/10.3390/biom11030393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002075PMC
March 2021

Neurofilament light chain as a potential biomarker for monitoring neurodegeneration in X-linked adrenoleukodystrophy.

Nat Commun 2021 03 22;12(1):1816. Epub 2021 Mar 22.

Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria.

X-linked adrenoleukodystrophy (X-ALD), the most frequent monogenetic disorder of brain white matter, is highly variable, ranging from slowly progressive adrenomyeloneuropathy (AMN) to life-threatening inflammatory brain demyelination (CALD). In this study involving 94 X-ALD patients and 55 controls, we tested whether plasma/serum neurofilament light chain protein (NfL) constitutes an early distinguishing biomarker. In AMN, we found moderately elevated NfL with increased levels reflecting higher grading of myelopathy-related disability. Intriguingly, NfL was a significant predictor to discriminate non-converting AMN from cohorts later developing CALD. In CALD, markedly amplified NfL levels reflected brain lesion severity. In rare cases, atypically low NfL revealed a previously unrecognized smoldering CALD disease course with slowly progressive myelin destruction. Upon halt of brain demyelination by hematopoietic stem cell transplantation, NfL gradually normalized. Together, our study reveals that blood NfL reflects inflammatory activity and progression in CALD patients, thus constituting a potential surrogate biomarker that may facilitate clinical decisions and therapeutic development.
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http://dx.doi.org/10.1038/s41467-021-22114-2DOI Listing
March 2021

Predictors of Adherence Among Patients With Multiple Sclerosis Using the BETACONNECT Autoinjector: A Prospective Observational Cohort Study.

Front Neurol 2021 24;12:643126. Epub 2021 Feb 24.

Multiple Sclerosis Center Dresden, Center of Clinical Neuroscience, Neurological Clinic, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.

In patients with multiple sclerosis (MS), non-adherence to disease-modifying drug therapy is associated with an increased rate of MS relapses. Early identification of patients at risk of non-adherence would allow provision of timely and individualized support. The aim of the BETAPREDICT study was to investigate potential predictors of adherence in patients with MS in Germany treated with interferon β-1b (IFNβ-1b) using the BETACONNECT® autoinjector. BETAPREDICT was a national, multi-center, prospective, non-interventional, single-arm, 24-month cohort study of patients with relapsing-remitting MS or clinically isolated syndrome receiving IFNβ-1b via the BETACONNECT® autoinjector (ClinicalTrials.gov: NCT02486640). Injection data were captured by the autoinjector. The primary objective was to determine baseline predictors of compliance, persistence, and adherence to IFNβ-1b treatment after 12- and 24 months using multivariable-adjusted regression. Secondary objectives included evaluation of satisfaction with the autoinjector, injection site pain, vitamin and nutrient supplementation, clinical course, and patient-related outcome measures. Of 165 patients enrolled, 153 were available for analysis (120 with autoinjector data). Seventy-two patients left the study prematurely. Compliance ( = 120), persistence ( = 153), and adherence ( = 120) at 24 months were 89.1, 53.6, and 41.7%, respectively. Compliance at 12- and 24 months was predicted by intake of vitamin D supplements and absence of specific injection site reactions. Positive predictors of persistence included age (at 12- and 24 months) and previous duration of treatment (at 12 months), while intake of vitamins/nutrients other than vitamin D was a negative predictor (at 12 months). Positive predictors of adherence at 24 months were age and being experienced with IFNβ-1b. Higher scores in specific SF-36 subscales were positive predictors of medication-taking behavior at 24 months. Satisfaction with the autoinjector was high at baseline and 24 months (median score: 9 out of 10). Compliance with IFNβ-1b treatment among participants still under observation remained high over a 24-month period, while persistence and adherence continuously declined. Multiple factors affected medication-taking behavior, including patient characteristics, treatment history, injection site reactions, patients' perception of their health and support programs. The importance of these factors may differ among patients according to their individual situation.
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http://dx.doi.org/10.3389/fneur.2021.643126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943887PMC
February 2021

Targeting foam cell formation in inflammatory brain diseases by the histone modifier MS-275.

Ann Clin Transl Neurol 2020 11 30;7(11):2161-2177. Epub 2020 Sep 30.

Department of Pathobiology of the Nervous System, Centre for Brain Research, Medical University of Vienna, Vienna, 1090, Austria.

Objective: To assess class I-histone deacetylase (HDAC) inhibition on formation of lipid-accumulating, disease-promoting phagocytes upon myelin load in vitro, relevant for neuroinflammatory disorders like multiple sclerosis (MS) and cerebral X-linked adrenoleukodystrophy (X-ALD).

Methods: Immunohistochemistry on postmortem brain tissue of acute MS (n = 6) and cerebral ALD (n = 4) cases to analyze activation and foam cell state of phagocytes. RNA-Seq of in vitro differentiated healthy macrophages (n = 8) after sustained myelin-loading to assess the metabolic shift associated with foam cell formation. RNA-Seq analysis of genes linked to lipid degradation and export in MS-275-treated human HAP1 cells and RT-qPCR analysis of HAP1 cells knocked out for individual members of class I HDACs or the corresponding enzymatically inactive knock-in mutants. Investigation of intracellular lipid/myelin content after MS-275 treatment of myelin-laden human foam cells. Analysis of disease characteristic very long-chain fatty acid (VLCFA) metabolism and inflammatory state in MS-275-treated X-ALD macrophages.

Results: Enlarged foam cells coincided with a pro-inflammatory, lesion-promoting phenotype in postmortem tissue of MS and cerebral ALD patients. Healthy in vitro myelin laden foam cells upregulated genes linked to LXRα/PPARγ pathways and mimicked a program associated with tissue repair. Treating these cells with MS-275, amplified this gene transcription program and significantly reduced lipid and cholesterol accumulation and, thus, foam cell formation. In macrophages derived from X-ALD patients, MS-275 improved the disease-associated alterations of VLCFA metabolism and reduced the pro-inflammatory status of these cells.

Interpretation: These findings identify class I-HDAC inhibition as a potential novel strategy to prevent disease promoting foam cell formation in CNS inflammation.
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http://dx.doi.org/10.1002/acn3.51200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664285PMC
November 2020

[Is the Quality Guideline of Care Delivery of Preterm and Mature Infants (QFR-RL) of the Federal Joint Committee (G-BA) a Quality Risk? - An Analysis of the Fulfillment Rate and the Consequences for Care Delivery to Other IC Patients and Imminent Premature Infants at a Regional Network of Perinatal Centers].

Z Geburtshilfe Neonatol 2020 Oct 22;224(5):281-288. Epub 2020 Jul 22.

Neonatologie und Kinderintensivmedizin, Cnopfsche Kinderklinik Nürnberg, Nürnberg.

Background: The quality guideline for care delivery to preterm and mature infants (QFR-RL) places high demands on perinatal centers. In this analysis, the degree of fulfillment was determined. Additionally, care delivery to further patient groups and sufficient nursing staff capacity for care delivery to imminent preterm infants (FG) were evaluated.

Methods: A network of 4 perinatal centers (level 1) with about 10,000 births per year supplied the data on the ratio of 1:1/1:2-care infants, patients per nurse, and nursing staff capacity. This data was statistically evaluated by center, shift, and week day over a period of 5 months for compliance with QFR-RL and DGPM recommendations. Furthermore, imminent preterm infants were recorded and compared with available nursing staff capacity.

Results: In total, the QFR-RL was fulfilled in 88% of shifts (n=1,584). Only one center reached the required 95%. The degree of fulfillment and the number of staff nurses declined from late to night shifts (p<0.001). The ratio of 1:1-care infants was significantly higher when demands were not fulfilled (p<0.001). Only 14.1% of imminent preterm infants could have been attended in accordance with the QFR-RL.

Conclusion: 1:1 care as well as lower nurse staffing in late and night shifts lead to non-fulfillment of requirements and poorer care delivery to other intensive care patients. This was also reflected in the lower degree of fulfillment of DGPM recommendations. Sufficient nursing staff capacity was rare with the consequence that it was almost impossible to deliver care to imminent preterm infants per the guideline.
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http://dx.doi.org/10.1055/a-1167-8488DOI Listing
October 2020

[Non-inflammatory muscle pain].

Dtsch Med Wochenschr 2020 07 2;145(13):887-894. Epub 2020 Jul 2.

Muscle pain as a common symptom in daily practice frequently occurs as a non-specific accompanying symptom in multiple internal and neurological diseases. Primarily inflammatory or autoimmune muscular diseases are causing muscle pain. However, a number of non-inflammatory causes of pain can also be considered for differential diagnosis. These are presented in this article. In principle, a distinction must be made between focal and diffuse muscle pain. As an invasive diagnostic procedure, a muscle biopsy should only be performed as the last step in the diagnostic alogorithm. If diffuse muscle pain is only associated with slight muscle weakness or is completely absent, there is usually a primary rheumatic cause. Statins (HMG-CoA reductase inhibitors) can lead to rhabdomyolysis, muscle fiber atrophy and muscle necrosis by damaging the muscle fiber membrane. Myotonias are autosomal dominant or autosomal recessive inherited disorders of muscle function. The genetic defect leads to pronounced muscle stiffness. The cause of metabolic myopathies can be disorders of the carbohydrate, fat or purine metabolism. Fibromyalgia syndrome (FMS) is a non-inflammatory disease and, according to the current knowledge, recognized as the result of an exposure to physical, biological and psychosocial factors (biopsychological disease model). To help diagnosing FMS, pain regions and core symptoms (fatigue, sleep disturbances) can be detected using questionnaires (Widespread Pain Index [WPI] and Symptom Severity Scale [SSS]).
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http://dx.doi.org/10.1055/a-1068-5210DOI Listing
July 2020

Vorinostat in the acute neuroinflammatory form of X-linked adrenoleukodystrophy.

Ann Clin Transl Neurol 2020 05 2;7(5):639-652. Epub 2020 May 2.

Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria.

Objective: To identify a pharmacological compound targeting macrophages, the most affected immune cells in inflammatory X-linked adrenoleukodystrophy (cerebral X-ALD) caused by ABCD1 mutations and involved in the success of hematopoietic stem cell transplantation and gene therapy.

Methods: A comparative database analysis elucidated the epigenetic repressing mechanism of the related ABCD2 gene in macrophages and identified the histone deacetylase (HDAC) inhibitor Vorinostat as a compound to induce ABCD2 in these cells to compensate for ABCD1 deficiency. In these cells, we investigated ABCD2 and pro-inflammatory gene expression, restoration of defective peroxisomal β-oxidation activity, accumulation of very long-chain fatty acids (VLCFAs) and their differentiation status. We investigated ABCD2 and pro-inflammatory gene expression, restoration of defective peroxisomal ß-oxidation activity, accumulation of very long-chain fatty acids (VLCFA) and differentiation status. Three advanced cerebral X-ALD patients received Vorinostat and CSF and MRI diagnostics was carried out in one patient after 80 days of treatment.

Results: Vorinostat improved the metabolic defects in X-ALD macrophages by stimulating ABCD2 expression, peroxisomal ß-oxidation, and ameliorating VLCFA accumulation. Vorinostat interfered with pro-inflammatory skewing of X-ALD macrophages by correcting IL12B expression and further reducing monocyte differentiation. Vorinostat normalized the albumin and immunoglobulin CSF-serum ratios, but not gadolinium enhancement upon 80 days of treatment.

Interpretation: The beneficial effects of HDAC inhibitors on macrophages in X-ALD and the improvement of the blood-CSF/blood-brain barrier are encouraging for future investigations. In contrast with Vorinostat, less toxic macrophage-specific HDAC inhibitors might improve also the clinical state of X-ALD patients with advanced inflammatory demyelination.
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http://dx.doi.org/10.1002/acn3.51015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261758PMC
May 2020

A smart peek: Processing of rapid visual displays is disturbed in newly diagnosed, cognitively intact MS patients and refers to cognitive performance and disease progression in late stages.

J Neurol Sci 2019 Jun 23;401:118-124. Epub 2019 Apr 23.

Universitätsklinikum Jena, Department of Neurology, Am Klinikum 1, 07747 Jena, Germany. Electronic address:

Background: MS can reduce the speed of information processing (IPS) leading to a variable pattern of cognitive impairment. To better understand this deficit, a separate evaluation of the sensory, cognitive, and motor speed component is required. Tests using rapid visual displays allow for assessment of separate components of information uptake. We utilized such a test to compare deficit profiles at the earlier and later stage of MS and their relation to cognitive ability and disease progression.

Method: Two groups were evaluated: "Early MS" comprised N = 24 patients with disease durations <2 years; "late MS" N = 45 with disease durations >12 years. Rapid visual displays of letters were utilized to derive individual profiles of visual information uptake according to the 'theory of visual attention' (TVA). The resulting data was then compared with measures of disability, fatigue, depression, IPS, visual-spatial ability, verbal and visual memory.

Results: In the EMS group, where cognitive impairment was the exception, three of the four main parameters of visual information uptake were already modified, i.e. processing rate C, storage capacity K, and iconic memory μ. In LMS an additional elevation of the fourth parameter, i.e., the perceptual threshold t was evident. Threshold values were related to most clinical and cognitive measures.

Conclusions: An early deficit pattern of visual information uptake can be detected at a stage, when performance in tests of IPS is still well-preserved. At later disease stages, a single parameter reflecting the threshold of conscious visual perception may provide a valid estimate of cognitive performance and disease progression.
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http://dx.doi.org/10.1016/j.jns.2019.04.031DOI Listing
June 2019

Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X-linked adrenoleukodystrophy.

J Inherit Metab Dis 2019 03 11;42(2):313-324. Epub 2019 Feb 11.

Department Pediatric Oncology/Hematology/SCT, Charité Campus Virchow-Klinikum, Berlin, Germany.

The adult cerebral form of X-linked adrenoleukodystrophy (ACALD), an acute inflammatory demyelinating disease, results in a rapidly progressive neurodegeneration, typically leading to severe disability or death within a few years after onset. We have treated 15 men who had developed ACALD with allogeneic hematopoietic stem cell transplantation (HSCT) from matched donors after myeloablative conditioning with busulfan and cyclophosphamide. All patients engrafted and 11 survived (estimated survival 73 ± 11%), 8 with stable cognition and 7 of them with stable motor function (estimated event-free survival 36 ± 17%). Death after transplantation occurred within the first year after HSCT and was caused either primarily by infection (N = 3) or due to disease progression triggered by infection (N = 1). Patients with minor myelopathic symptoms (N = 4) or with no or mild cerebral symptoms pre-transplant (N = 7) had an excellent outcome. In contrast, no patient with major neurological symptoms associated with an extensive involvement of pyramidal tract fibres in the internal capsule (N = 5) survived without cognitive deterioration. Notably, early leukocyte recovery was associated with dismal outcome for yet unknown reasons. All 10 tested survivors showed a reduction of plasma hexacosanoic acid (C26:0) in the absence of Lorenzo's oil. Over time, the event-free survival could be improved from 2 out of 8 patients (25%) before 2013 to 5 out of 7 patients (71%) thereafter. Therefore, allogeneic HSCT appears to be a suitable treatment option for carefully selected ACALD patients when transplanted from matched donors after myeloablative, busulfan-based conditioning.
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http://dx.doi.org/10.1002/jimd.12044DOI Listing
March 2019

Potential Risks to Stable Long-term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for Children With Cerebral X-linked Adrenoleukodystrophy.

JAMA Netw Open 2018 07 6;1(3):e180769. Epub 2018 Jul 6.

Department of Pediatric Neurology, University Medical Center Göttingen, Göttingen, Germany.

Importance: Allogeneic hematopoietic stem cell transplantation is the standard intervention for childhood cerebral X-linked adrenoleukodystrophy. However, the pretransplant conditions, demyelination patterns, complications, and neurological outcomes of this therapy are not well characterized.

Objectives: To identify the risks to stable neurocognitive survival after hematopoietic stem cell transplantation and to describe subgroups of patients with distinct clinical long-term outcomes.

Design, Setting, And Participants: This case series analyzed the treatment and outcome of a cohort of 36 boys who underwent hematopoietic stem cell transplantation at Charité Universitätsmedizin Berlin, Germany, between January 1, 1997, and October 31, 2014. Case analysis was performed from January 1, 2016, through November 30, 2017. During this retrospective review, the adrenoleukodystrophy-disability rating score and the neurological function score were used. Demyelinating lesions in the brain were quantified by the Loes score.

Main Outcomes And Measures: Overall survival, survival without major functional disabilities, and event-free survival were analyzed. Patients' clinical symptoms, demyelination patterns, and stem cell source were stratified.

Results: Of the 36 boys who underwent hematopoietic stem cell transplantation, the median (range) age was 7.2 (4.2-15.4) years; 18 were presymptomatic and 18 were symptomatic. Twenty-seven patients (75%) were alive at a median (interquartile range [IQR]) follow-up of 108 (40-157) months. Sixteen of 18 presymptomatic patients (89%) survived, and 13 (72%) had an event-free survival with a median (IQR) survival time of 49 (37-115) months. Among the symptomatic patients, 11 of 18 (61%) survived, but only 1 was an event-free survival (6%) (median [IQR] time, 9 [3-22] months). Of the 9 patients who received a bone marrow transplant from a matched family donor, all survived. Among the 36 patients, 6 disease-related deaths (17%) and 3 transplant-related deaths (8%) occurred. Deaths from disease progression (n = 6) occurred only in patients with demyelination patterns other than parieto-occipital. In total, 18 patients (50%) displayed limited parieto-occipital (Loes score <9) or frontal (Loes score <4) demyelination before transplant (favorable). None of these patients died of progressive disease or developed major functional disabilities, 15 of them were characterized by stable neuroimaging after the transplant, and event-free survival was 77% (95% CI, 60%-100%). In contrast, the other 18 patients with more extended parieto-occipital demyelination (n = 6), frontal involvement (n = 4), or other demyelination patterns (n = 8) progressed (unfavorable): 13 patients developed epilepsy and 10 developed major functional disabilities, and their event-free survival was 0%. This newly defined neuroimaging assessment correlated best with neurocognitive deterioration after transplant (hazard ratio, 16.7; 95% CI, 4.7-59.6).

Conclusions And Relevance: All patients with favorable neuroimaging who received matched bone marrow remained stable after transplant, while some of the other patients developed major functional disabilities. Newborn screening for the disease and regular neuroimaging are recommended, and patients who lack a matched bone marrow donor may need to find new therapeutic options.
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http://dx.doi.org/10.1001/jamanetworkopen.2018.0769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324299PMC
July 2018

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

Ther Adv Neurol Disord 2018 28;11:1756286418774973. Epub 2018 May 28.

Department of Neurology, General Hospital Lüdenscheid, Märkische Kliniken GmbH, Germany.

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, < 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.
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http://dx.doi.org/10.1177/1756286418774973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974561PMC
May 2018

Impaired plasticity of macrophages in X-linked adrenoleukodystrophy.

Brain 2018 08;141(8):2329-2342

Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria.

X-linked adrenoleukodystrophy is caused by ATP-binding cassette transporter D1 (ABCD1) mutations and manifests by default as slowly progressive spinal cord axonopathy with associated demyelination (adrenomyloneuropathy). In 60% of male cases, however, X-linked adrenoleukodystrophy converts to devastating cerebral inflammation and demyelination (cerebral adrenoleukodystrophy) with infiltrating blood-derived monocytes and macrophages and cytotoxic T cells that can only be stopped by allogeneic haematopoietic stem cell transplantation or gene therapy at an early stage of the disease. Recently, we identified monocytes/macrophages but not T cells to be severely affected metabolically by ABCD1 deficiency. Here we found by whole transcriptome analysis that, although monocytes of patients with X-linked adrenoleukodystrophy have normal capacity for macrophage differentiation and phagocytosis, they are pro-inflammatory skewed also in patients with adrenomyloneuropathy in the absence of cerebral inflammation. Following lipopolysaccharide activation, the ingestion of myelin debris, normally triggering anti-inflammatory polarization, did not fully reverse the pro-inflammatory status of X-linked adrenoleukodystrophy macrophages. Immunohistochemistry on post-mortem cerebral adrenoleukodystrophy lesions reflected the activation pattern by prominent presence of enlarged lipid-laden macrophages strongly positive for the pro-inflammatory marker co-stimulatory molecule CD86. Comparative analyses of lesions with matching macrophage density in cases of cerebral adrenoleukodystrophy and acute multiple sclerosis showed a similar extent of pro-inflammatory activation but a striking reduction of anti-inflammatory mannose receptor (CD206) and haemoglobin-haptoglobin receptor (CD163) expression on cerebral adrenoleukodystrophy macrophages. Accordingly, ABCD1-deficiency leads to an impaired plasticity of macrophages that is reflected in incomplete establishment of anti-inflammatory responses, thus possibly contributing to the devastating rapidly progressive demyelination in cerebral adrenoleukodystrophy that only in rare cases arrests spontaneously. These findings emphasize monocytes/macrophages as crucial therapeutic targets for preventing or stopping myelin destruction in patients with X-linked adrenoleukodystrophy.
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http://dx.doi.org/10.1093/brain/awy127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061697PMC
August 2018

Adulthood leukodystrophies.

Nat Rev Neurol 2018 02 5;14(2):94-105. Epub 2018 Jan 5.

Division of Neurology, Children's Hospital of Philadelphia, Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.

The leukodystrophies are a group of inherited white matter disorders with a heterogeneous genetic background, considerable phenotypic variability and disease onset at all ages. This Review focuses on leukodystrophies with major prevalence or primary onset in adulthood. We summarize 20 leukodystrophies with adult presentations, providing information on the underlying genetic mutations and on biochemical assays that aid diagnosis, where available. Definitions, clinical characteristics, age of onset, MRI findings and treatment options are all described, providing a comprehensive overview of the current knowledge of the various adulthood leukodystrophies. We highlight the distinction between adult-onset leukodystrophies and other inherited disorders with white matter involvement, and we propose a diagnostic pathway for timely recognition of adulthood leukodystrophies in a routine clinical setting. In addition, we provide detailed clinical information on selected adult-onset leukodystrophies, including X-linked adrenoleukodystrophy, metachromatic leukodystrophy, cerebrotendinous xanthomatosis, hereditary diffuse leukoencephalopathy with axonal spheroids, autosomal dominant adult-onset demyelinating leukodystrophy, adult polyglucosan body disease, and leukoencephalopathy with vanishing white matter. Ultimately, this Review aims to provide helpful suggestions to identify treatable adulthood leukodystrophies at an early stage in the disease course.
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http://dx.doi.org/10.1038/nrneurol.2017.175DOI Listing
February 2018

Information processing deficits as a driving force for memory impairment in MS: A cross--sectional study of memory functions and MRI in early and late stage MS.

Mult Scler Relat Disord 2017 Nov 25;18:119-127. Epub 2017 Sep 25.

Heinrich Heine University, Medical Faculty, Cognitive Psychology and Methodology, Moorenstraße 5, 40225 Düsseldorf, Germany. Electronic address:

Background: Memory impairment (MI) is a common symptom of MS. Previous studies were conflicting in respect to the possible existence of early MI and the role of hippocampal atrophy. The objective of this study was to investigate MI and structural MRI correlates in homogenous groups of early and late MS, controlling for a potential information-processing speed (IPS) deficit, and utilizing multiple memory test paradigms.

Methods: 152 individually matched subjects were recruited: early MS (EMS, N = 25, disease duration 1.0 ± 0.8 years), late MS (LMS, N = 52, 16.5 ± 5.2 years), and corresponding controls. Five memory tests were utilized to account for differences in learning material (verbal, visual), encoding (incidental, intentional), and retrieval (free recall, recognition, recurring recognition). Performance was related to IPS, memory-specific (hippocampal volumes), and unspecific MRI measures (T1/T2LL, brain volume, cortical thickness).

Results: Memory was impaired across all tests in LMS, but not in EMS. LMS-patients were also significantly impaired in IPS which was correlated with several memory scores. Regression analyses revealed IPS and cortical thickness as predictors for visual MI, and IPS, sex, and left hippocampal volume as predictors for verbal MI.

Conclusion: Additionally to direct destructions in memory specific tracts such as the hippocampus, memory decline in MS may also be related to a general factor comprising slowed information-processing and global tissue loss.
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http://dx.doi.org/10.1016/j.msard.2017.09.026DOI Listing
November 2017

Immunoadsorption for autoimmune encephalitis.

Atheroscler Suppl 2017 Nov 2;30:257-263. Epub 2017 Jun 2.

Department of Neurology and Neurological Intensive Care Medicine, Specialist Hospital Hubertusburg, Wermsdorf, Germany.

Autoimmune encephalitis is a severe inflammatory disorder of the brain. The discovery that several non-infectious forms of encephalitis are associated with autoantibodies was a breakthrough in the care of this previously untreatable group of patients. The correlation of antibody type and titer with pattern and severity of symptoms was essential for the initiation of immunotherapies. First line therapy consists of steroids, intravenous immunoglobulins, plasma exchange or immunoadsorption. Rapid elimination of autoantibodies using selective immunoadsorption and avoiding the disadvantage of plasma substitution is a pathophysiologically guided therapeutic approach, and has been proven to be an effective therapeutic option as part of multimodal immunotherapy.
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http://dx.doi.org/10.1016/j.atherosclerosissup.2017.05.041DOI Listing
November 2017

Long-term outcomes of allogeneic haematopoietic stem cell transplantation for adult cerebral X-linked adrenoleukodystrophy.

Brain 2017 Apr;140(4):953-966

Department of Hematology, Oncology and Tumorimmunology, Charité Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.

The adult cerebral inflammatory form of X-linked adrenoleukodystrophy is a rapidly progressive neurodegenerative disease, as devastating as childhood cerebral adrenoleukodystrophy. Allogeneic haematopoietic stem cell transplantation has been demonstrated to provide long-term neurological benefits for boys with the childhood cerebral form, but results in adults are sparse and inconclusive. We analysed data from 14 adult males with adult cerebral adrenoleukodystrophy treated with allogeneic haematopoietic stem cell transplantation on a compassionate basis in four European centres. All presented with cerebral demyelinating lesions and gadolinium enhancement. Median age at diagnosis of adult cerebral adrenoleukodystrophy was 33 years (range 21-48 years). In addition to cerebral inflammation, five patients had established severe motor disability from adrenomyeloneuropathy affecting only the spinal cord and peripheral nerves (Expanded Disability Status Scale score ≥ 6). Eight patients survived (estimated survival 57 ± 13%) with a median follow-up of 65 months (minimum 38 months). Death was directly transplant-/infection-related (n = 3), due to primary disease progression in advanced adult cerebral adrenoleukodystrophy (n = 1), or secondary disease progression (n = 2) after transient multi-organ failure or non-engraftment. Specific complications during stem cell transplantation included deterioration of motor and bladder functions (n = 12) as well as behavioural changes (n = 8). Arrest of progressive cerebral demyelination and prevention of severe loss of neurocognition was achieved in all eight survivors, but deterioration of motor function occurred in the majority (n = 5). Limited motor dysfunction (Expanded Disability Status Scale score < 6) prior to transplantation was associated with significantly improved survival [78 ± 14% (n = 9) versus 20 ± 18%(n = 5); P < 0.05] and maintenance of ambulation (Expanded Disability Status Scale score < 7) post-transplant (78% versus 0%; P = 0.021). In contrast, bilateral involvement of the internal capsule on brain MRI was associated with poorer survival [20 ± 18% (n = 5) versus 78 ± 14% (n = 9); P < 0.05]. This study is the first to support the feasibility, complications and potential long-term neurological benefit of allogeneic haematopoietic stem cell transplantation in adult cerebral adrenoleukodystrophy. Further studies are warranted to attempt to improve outcomes through patient selection and optimization of transplantation protocols.
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http://dx.doi.org/10.1093/brain/awx016DOI Listing
April 2017

Specific phenotype and function of CD56-expressing innate immune cell subsets in human thymus.

J Leukoc Biol 2016 12 28;100(6):1297-1310. Epub 2016 Jun 28.

Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander Universität Erlangen-Nürnberg, University Hospital Erlangen, Erlangen, Germany;

Whereas innate immune cells, such as NK and innate lymphoid cells (ILCs), have been characterized in different human tissues, knowledge on the thymic CD56-expressing cell subsets is limited. In this study, the rare subpopulations of thymic CD56CD3 cells from samples of >100 patients have been successfully analyzed. The results revealed fundamental differences between thymic and peripheral blood (PB) CD56CD3 cells. Thymic tissues lacked immunoregulatory CD56CD16 NK cells but showed two EomesCD56 subsets on which common NK cell markers were significantly altered. CD56CD16 cells expressed high amounts of NKG2A, NKG2D, and CD27 with low CD57. Conversely, CD56CD16 cells displayed high CD127 but low expression of KIR, NKG2D, and natural cytotoxicity receptors (NCRs). Thymic CD56CD3 cells were able to gain cytotoxicity but were especially immunoregulatory cells, producing a broad range of cytokines. Finally, one population of thymic CD56 cells resembled conventional NK cells, whereas the other represented a novel, noncanonical NK subset.
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http://dx.doi.org/10.1189/jlb.1A0116-038RDOI Listing
December 2016

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

Eur Neurol 2016 16;75(5-6):300-6. Epub 2016 Jun 16.

Department of Neurology, General Hospital Lx00FC;denscheid, Lx00FC;denscheid, Germany.

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.
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http://dx.doi.org/10.1159/000447059DOI Listing
September 2017

Quantitative MRI of the spinal cord and brain in adrenomyeloneuropathy: in vivo assessment of structural changes.

Brain 2016 06 11;139(Pt 6):1735-46. Epub 2016 Apr 11.

4 Department of Clinical Neurosciences, Fondazione IRCCS, Istituto Neurologico 'C. Besta', Milano, Italy.

Adrenomyeloneuropathy is the late-onset form of X-linked adrenoleukodystrophy, and is considered the most frequent metabolic hereditary spastic paraplegia. In adrenomyeloneuropathy the spinal cord is the main site of pathology. Differently from quantitative magnetic resonance imaging of the brain, little is known about the feasibility and utility of advanced neuroimaging in quantifying the spinal cord abnormalities in hereditary diseases. Moreover, little is known about the subtle pathological changes that can characterize the brain of adrenomyeloneuropathy subjects in the early stages of the disease. We performed a cross-sectional study on 13 patients with adrenomyeloneuropathy and 12 age-matched healthy control subjects who underwent quantitative magnetic resonance imaging to assess the structural changes of the upper spinal cord and brain. Total cord areas from C2-3 to T2-3 level were measured, and diffusion tensor imaging metrics, i.e. fractional anisotropy, mean, axial and radial diffusivity values were calculated in both grey and white matter of spinal cord. In the brain, grey matter regions were parcellated with Freesurfer and average volume and thickness, and mean diffusivity and fractional anisotropy from co-registered diffusion maps were calculated in each region. Brain white matter diffusion tensor imaging metrics were assessed using whole-brain tract-based spatial statistics, and tractography-based analysis on corticospinal tracts. Correlations among clinical, structural and diffusion tensor imaging measures were calculated. In patients total cord area was reduced by 26.3% to 40.2% at all tested levels (P < 0.0001). A mean 16% reduction of spinal cord white matter fractional anisotropy (P ≤ 0.0003) with a concomitant 9.7% axial diffusivity reduction (P < 0.009) and 34.5% radial diffusivity increase (P < 0.009) was observed, suggesting co-presence of axonal degeneration and demyelination. Brain tract-based spatial statistics showed a marked reduction of fractional anisotropy, increase of radial diffusivity (P < 0.001) and no axial diffusivity changes in several white matter tracts, including corticospinal tracts and optic radiations, indicating predominant demyelination. Tractography-based analysis confirmed the results within corticospinal tracts. No significant cortical volume and thickness reduction or grey matter diffusion tensor imaging values alterations were observed in patients. A correlation between radial diffusivity and disease duration along the corticospinal tracts (r = 0.806, P < 0.01) was found. In conclusion, in adrenomyeloneuropathy patients quantitative magnetic resonance imaging-derived measures identify and quantify structural changes in the upper spinal cord and brain which agree with the expected histopathology, and suggest that the disease could be primarily caused by a demyelination rather than a primitive axonal damage. The results of this study may also encourage the employment of quantitative magnetic resonance imaging in other hereditary diseases with spinal cord involvement.
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http://dx.doi.org/10.1093/brain/aww068DOI Listing
June 2016

Impact of natalizumab treatment on fatigue, mood, and aspects of cognition in relapsing-remitting multiple sclerosis.

Front Neurol 2015 11;6:97. Epub 2015 May 11.

Department of Neurology, Asklepios Fachklinikum Teupitz , Teupitz , Germany.

Background/objective: Fatigue, cognitive, and affective disorders are relevant symptoms in multiple sclerosis (MS). The treatment with Natalizumab has a positive effect on physical disabilities in patients with relapsing-remitting MS (RRMS). Some studies describe improvements in cognition and fatigue over 1 year of treatment. Only little is known about longer treatment effects especially on fatigue, and also on cognition and mood. Therefore, the present retrospective open label observational study investigates the effect of Natalizumab on fatigue, attention, and depression over a treatment period of 2 years.

Methods: About 51 RRMS patients who were treated with Natalizumab (male = 11, female = 40; mean age: 33. 9 ± 9. 1 years) were included. The neuropsychological assessment consisted of different tests of attention (TAP: alertness, divided attention, flexibility, SDMT, PASAT), fatigue (WEIMuS, FSMC), and depression (CES-D). The assessments occurred immediately before the first administration of Natalizumab, after 1 and 2 years of treatment.

Results: Significant improvements were found in aspects of attention and depression from baseline to follow-up 1 [alertness: reaction time (RT) cued, p < 0.05; divided attention: visual RT, p < 0.05; SDMT: p = 0.05; CES-D: p < 0.05] and from baseline to follow-up 2 (divided attention: visual RT: p < 0.001; errors: p < 0.01, omissions: p < 0.05; flexibility: RT, p < 0.05; SDMT: p < 0.01; CES-D: p < 0.05). No significant changes were detected in fatigue, probably because of the small sample size, especially in the second year of treatment (WEIMuS: N = 16, FSMC: N = 8).

Conclusion: The results show a positive effect of Natalizumab on attention in patients with RRMS, and for the first time, also in depression after 2 years of observation, and support the efficacy of the treatment over 2 years. More research is needed for fatigue.
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http://dx.doi.org/10.3389/fneur.2015.00097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426783PMC
June 2015

How reliable is the classification of cognitive impairment across different criteria in early and late stages of multiple sclerosis?

J Neurol Sci 2014 Aug 27;343(1-2):91-9. Epub 2014 May 27.

Department of Neurology, Fachkrankenhaus Hubertusburg, Wermsdorf, Germany.

Background: Prevalence rates of cognitive impairment (CI) in multiple sclerosis (MS) vary between 40% and 80%. Differences in classification criteria for CI may explain this variance.

Objective: This study reviewed and compared classification criteria for CI in patients with early and late MS.

Methods: The paper consists of two parts: a systematic review of published classification criteria and the presentation of new data. Criteria were reviewed in respect to percentage of abnormal parameters and cut-offs concerning standard deviations. Thereafter, criteria were applied to cognitive data of 25 patients with early MS (duration ≤ 2 y), 52 matched patients with late MS (≥ 12 y), and 75 matched controls. The test battery assessed alertness, divided attention, mental flexibility, verbal and visual learning, memory, and visuospatial abilities.

Results: Seventy classification criteria were revealed and grouped into 20 distinct approaches that can be subdivided into three basic classification strategies. Most commonly, CI was defined as performing 1.5 SD or 2 SD below the normative mean in 18-30% of test parameters (n=42). Other criteria utilized cognitive domains (n=6), composite indices (n=8), or combinations of cut-offs and strategies. The stringency of the criteria was correlated with the prevalence rate of CI (r=-.43) and disease duration (r=.48). In the new data, a substantial effect of classification criteria was found with a prevalence rate ranging from 0 to 68% in early and 4 to 81% in late MS. Increased rates of CI in patients vs. controls were found following 18 out of 20 criteria in the sample of late MS. In early MS, an increased rate of CI was only found following a liberal 1.5 SD cut-off criterion. Inter-rater reliability between all criteria was moderate. However, between criteria of comparable stringency the inter-rater reliability was found to be strong.

Conclusion: Classification based on different published criteria is not fully comparable and criteria need to be better homogenized.
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http://dx.doi.org/10.1016/j.jns.2014.05.042DOI Listing
August 2014

Hypomyelinating leukodystrophies: translational research progress and prospects.

Ann Neurol 2014 Jul 24;76(1):5-19. Epub 2014 Jun 24.

Department of Physics and Medical Technology, VU University Medical Center and Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.

Hypomyelinating leukodystrophies represent a genetically heterogeneous but clinically overlapping group of heritable disorders. Current management approaches in the care of the patient with a hypomyelinating leukodystrophy include use of serial magnetic resonance imaging (MRI) to establish and monitor hypomyelination, molecular diagnostics to determine a specific etiology, and equally importantly, careful attention to neurologic complications over time. Emerging research in oligodendrocyte biology and neuroradiology with bedside applications may result in the possibility of clinical trials in the near term, yet there are significant gaps in knowledge in disease classification, characterization, and outcome measures in this group of disorders. Here we review the biological background of myelination, the clinical and genetic variability in hypomyelinating leukodystrophies, and the insights that can be obtained from current MRI techniques. In addition, we discuss ongoing research approaches to define potential outcome markers for future clinical trials.
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http://dx.doi.org/10.1002/ana.24194DOI Listing
July 2014

The vitamin E-binding protein afamin increases in maternal serum during pregnancy.

Clin Chim Acta 2014 Jul 24;434:41-7. Epub 2014 Apr 24.

Division of Genetic Epidemiology, Department of Medical Genetics, Clinical and Molecular Pharmacology, Innsbruck Medical University, Innsbruck, Austria; Vitateq Biotechnology GmbH, Innsbruck, Austria. Electronic address:

Background: Afamin is a liver-derived plasma glycoprotein with vitamin E-binding properties and a putative function in fertility. This study evaluated serum afamin concentrations during and postpartum to uncomplicated pregnancies and investigated a potential association between afamin concentrations and pregnancy outcome.

Methods: Afamin serum concentrations were measured in women with uncomplicated pregnancies in a retrospective cohort (n=466) at different gestational ages and a prospective observational study (n=76) in the first, second and third trimester. Furthermore, afamin was determined in the first trimester in a cross-sectional pilot study including women with preeclampsia (PE), pregnancy-induced hypertension (PIH) and women without pregnancy complications (n=13 each). Finally, expression of afamin was investigated in human placental tissue by RT-PCR and immunohistochemistry.

Results: Afamin concentrations increased linearly almost two-fold during pregnancy in both retrospective and prospective studies in women without pregnancy complications with median afamin serum concentrations of 61.9 mg/l, 79.6 mg/l, and 98.6 mg/l in the first, second, and third trimester, respectively. After delivery, median afamin concentrations decreased to baseline values of 54.6 mg/l. In the pilot study with pregnancy complications, women with PE displayed significantly higher median afamin concentrations than did women with uncomplicated pregnancy (70.0 mg/l vs. 55.4 mg/l, P=0.007). Expression analyses revealed no placental afamin expression at either mRNA or protein level in uncomplicated pregnancy.

Conclusion: A linear increase in the maternally expressed glycoprotein afamin during pregnancy may serve as basic reference for subsequent investigations of afamin in pregnancy-related disorders.
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http://dx.doi.org/10.1016/j.cca.2014.03.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065568PMC
July 2014

Language and cognition in children with metachromatic leukodystrophy: onset and natural course in a nationwide cohort.

Orphanet J Rare Dis 2014 Feb 5;9:18. Epub 2014 Feb 5.

Department of Paediatric Neurology and Developmental Medicine, University Children's Hospital, Hoppe-Seyler-Strasse 1, 72076 Tübingen, Germany.

Background: Metachromatic leukodystrophy (MLD) is a rare, genetic neurodegenerative disease. It leads to progressive demyelination resulting in regression of development and early death. With regard to experimental therapies, knowledge of the natural course of the disease is highly important. We aimed to analyse onset and character of first symptoms in MLD and to provide detailed natural course data concerning language and cognition.

Methods: Patients with MLD were recruited nationwide within the scope of the German research network LEUKONET. 59 patients' questionnaires (23 late-infantile, 36 juvenile) were analysed.

Results: Time from first symptoms (at a median age of 1.5 years in late-infantile and 6 years in juvenile MLD) to diagnosis took one year in late-infantile and two years in juvenile patients on average. Gait disturbances and abnormal movement patterns were first signs in all patients with late-infantile and in most with juvenile MLD. Onset in the latter was additionally characterized by problems in concentration, behaviour and fine motor function (p=0.0011, p<0.0001, and p=0.0012). Half of late-infantile patients did not learn to speak in complete sentences after an initially normal language acquisition. They showed a rapid language decline with first language difficulties at a median age of 2.5 years and complete loss of expressive language within several months (median age 32, range 22-47 months). This was followed by total loss of communication at a median age of around four years. In juvenile patients, language decline was more protracted, and problems in concentration and behaviour were followed by decline in skills for reading, writing and calculating around four years after disease onset.

Conclusions: Our data reflect the natural course of decline in language and cognition in late-infantile and juvenile MLD in a large cohort over a long observation period. This is especially relevant to juvenile patients where the disease course is protracted and prospective studies are hardly feasible. Knowledge of first symptoms may lead to earlier diagnosis and subsequently to a better outcome following therapeutic intervention. Our data may serve as a reference for individual treatment decisions and for evaluation of clinical outcome after treatment intervention.
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http://dx.doi.org/10.1186/1750-1172-9-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922034PMC
February 2014

X-linked adrenoleukodystrophy: very long-chain fatty acid metabolism is severely impaired in monocytes but not in lymphocytes.

Hum Mol Genet 2014 May 20;23(10):2542-50. Epub 2013 Dec 20.

Center for Brain Research, Medical University of Vienna, Spitalgasse 4, Vienna A-1090, Austria.

X-linked adrenoleukodystrophy (X-ALD) is a fatal neurodegenerative disease caused by mutations in the ABCD1 gene, encoding a member of the peroxisomal ABC transporter family. The ABCD1 protein transports CoA-activated very long-chain fatty acids (VLCFAs) into peroxisomes for degradation via β-oxidation. In the severest form, X-ALD patients suffer from inflammatory demyelination of the brain. As the extent of the metabolic defect in the main immune cells is unknown, we explored their phenotypes concerning mRNA expression pattern of the three peroxisomal ABC transporters, VLCFA accumulation and peroxisomal β-oxidation. In controls, ABCD1 expression was high in monocytes, intermediate in B cells and low in T cells; ABCD2 expression was extremely low in monocytes, intermediate in B cells and highest in T cells; ABCD3 mRNA was equally distributed. In X-ALD patients, the expression patterns remained unaltered; accordingly, monocytes, which lack compensatory VLCFA transport by ABCD2, displayed the severest biochemical phenotype with a 6-fold accumulation of C26:0 and a striking 70% reduction in peroxisomal β-oxidation activity. In contrast, VLCFA metabolism was close to control values in B cells and T cells, supporting the hypothesis that sufficient ABCD2 is present to compensate for ABCD1 deficiency. Thus, the vulnerability of the main immune cell types is highly variable in X-ALD. Based on these results, we propose that in X-ALD the halt of inflammation after allogeneic hematopoietic stem cell transplantation relies particularly on the replacement of the monocyte lineage. Additionally, these findings support the concept that ABCD2 is a target for pharmacological induction as an alternative therapeutic strategy.
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http://dx.doi.org/10.1093/hmg/ddt645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990157PMC
May 2014

Fabry disease - underestimated in the differential diagnosis of multiple sclerosis?

PLoS One 2013 28;8(8):e71894. Epub 2013 Aug 28.

Albrecht Kossel Institute for Neuroregeneration, University of Rostock, Rostock, Germany ; Department of Neurology, Dietrich-Bonhoeffer-Klinikum, Neubrandenburg, Germany.

Objective: Fabry disease is a rare X-linked inherited lysosomal storage disorder affecting multiple organ systems. It includes central nervous system involvement via micro- and macroangiopathic cerebral changes. Due to its clinical symptoms and frequent MRI lesions, Fabry disease is commonly misdiagnosed as multiple sclerosis. We present an overview of cases from Fabry centres in Germany initially misdiagnosed with multiple sclerosis and report the clinical, MR-tomographical, and laboratory findings.

Methods: Eleven Fabry patients (one male, ten females) initially diagnosed with multiple sclerosis were identified from 187 patient records (5.9%) and analyzed for presenting symptoms, results of the initial diagnostic workup, and the clinical course of the disease.

Results: Four patients were identified as having a "possible" history of MS, and 7 patients as "definite" cases of multiple sclerosis (revised McDonald criteria). On average, Fabry disease was diagnosed 8.2 years (±9.8 years) after the MS diagnosis, and 12.8 years after onset of first symptoms (±10.3 years). All patients revealed white matter lesions on MRI. The lesion pattern and results of cerebrospinal fluid examination were inconsistent and non-specific. White matter lesion volumes ranged from 8.9 mL to 34.8 mL (mean 17.8 mL±11.4 mL). There was no association between extra-neurological manifestations or enzyme activity and lesion load.

Conclusion: There are several anamnestic and clinical hints indicating when Fabry disease should be considered a relevant differential diagnosis of multiple sclerosis, e.g. female patients with asymmetric, confluent white matter lesions on MRI, normal spinal MR imaging, ectatic vertebrobasilar arteries, proteinuria, or lack of intrathecally derived immunoglobulin synthesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071894PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756019PMC
May 2014

A randomized and controlled study comparing immunoadsorption and plasma exchange in myasthenic crisis.

J Clin Apher 2011 Dec 17;26(6):347-55. Epub 2011 Nov 17.

Department of Neurology and Neurological Intensive Care Medicine, Fachkrankenhaus Hubertusburg, Wermsdorf, Germany.

Myasthenic crisis is the most serious life-threatening event in Myasthenia gravis patients, affecting up to 27% within the first two years after onset of disease. Extracorporeal removal of circulating autoantibodies against the nicotinic acetylcholine receptor (AChRAb) by methods of therapeutic apheresis, e.g. plasma exchange (PE) and immunoadsorption (IA) had been demonstrated as effective treatment especially in acute situations of myasthenic crisis. However, controlled data comparing clinical safety and efficacy of both methods in a clinical study were not available. Here the results of a prospective randomized controlled clinical trial are presented, investigating 19 patients with myasthenic crisis, who were randomized to receive either PE (n = 10) or IA (n = 9) in addition to combined drug treatment. Patients received 3 to 5 (mean 3.5 for PE, and 3.4 for IA) treatments over a period of 7 days with a predefined treatment volume of 1.5 l plasma (i.e., 20-25 ml/kg plasma representing 0.5-0.6 patients' plasma volumes). Clinical courses were monitored using disease specific clinical scores. After initiation of IA or PE the mean value of Myasthenia scores decreased equally until Day 14 of the post-treatment phase. Patients from both treatment groups improved to a stable clinical status of Oosterhuis Classes 1 and 2. Substantial reduction of AChRAb was documented after each session of PE or IA. In the treatment period 16 adverse effects (seven serious adverse events, SAE) in the PE and 10 (1 SAE) in the IA group were observed. In conclusion, IA proved to be equally effective compared with PE treatment in patients with myasthenic crisis. Three to five treatment sessions using low plasma volume dosage of 20-25 ml/kg were adequate to improve clinically relevant symptoms significantly in most patients.
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http://dx.doi.org/10.1002/jca.20317DOI Listing
December 2011

Benefits from sustained-release pyridostigmine bromide in myasthenia gravis: results of a prospective multicenter open-label trial.

Clin Neurol Neurosurg 2010 Nov 21;112(9):781-4. Epub 2010 Jul 21.

Department of Neurology, Geriatric Medicine and Palliative Care, General Hospital, Grosse Parower St, 18435 Stralsund, Germany.

Introduction: For more than 50 years the acetylcholinesterase inhibitor pyridostigmine bromide has been the drug of choice in the symptomatic therapy for myasthenia gravis. The sustained-release dosage form of pyridostigmine (SR-Pyr) is only available in a limited number of countries (e.g. in the United States and Germany). Astonishingly, the therapeutic usefulness of SR-Pyr has not yet been evaluated.

Methods: In this non-interventional prospective open-label trial, 72 patients with stable myasthenia gravis were switched from instant-release dosage forms of pyridostigmine bromide to SR-Pyr. The results from the 37 patients younger than 60 years were separately analyzed.

Results: The initial daily dose of SR-Pyr was 288.1 ± 171.0mg. The drug switch was unproblematic in all patients. The number of daily doses was significantly reduced from 4.3 to 3.6 (p=0.011). The switch to SR-Pyr ameliorated the total quantified myasthenia gravis (QMG) score from 0.9 ± 0.5 to 0.6 ± 0.4 (p<0.001) in all patients and in the younger subgroup. This was accompanied by a significant improvement in the quality of life parameters. The health status valued by EuroQoL questionnaire improved from 0.626 ± 0.286 to 0.782 ± 0.186 (p<0.001). After switching to SR-Pyr, 28 adverse reactions disappeared and 24 adverse reactions occurred less frequent or weaker, however, 17 new adverse reactions were documented.

Conclusions: Our results support the usefulness of SR-Pyr in an individualized therapeutic regimen to improve quality of life regardless of the patient's age in myasthenia gravis.
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http://dx.doi.org/10.1016/j.clineuro.2010.06.018DOI Listing
November 2010

Megalencephalic leukoencephalopathy with cysts without MLC1 defect.

Ann Neurol 2010 Jun;67(6):834-7

Department of Child Neurology, VU University Medical Center, Amsterdam, the Netherlands.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive disease characterized by early infantile macrocephaly and delayed motor and cognitive deterioration. Magnetic resonance imaging (MRI) shows diffusely abnormal and swollen cerebral white matter and subcortical cysts. On follow-up, atrophy ensues. Approximately 80% of MLC patients have mutations in MLC1. We report 16 MLC patients without MLC1 mutations. Eight retained the classical clinical and MRI phenotype. The other 8 showed major MRI improvement. They lacked motor decline. Five had normal intelligence; 3 displayed cognitive deficiency. In conclusion, 2 phenotypes can be distinguished among the non-MLC1 mutated MLC patients: a classical and a benign phenotype.
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http://dx.doi.org/10.1002/ana.21980DOI Listing
June 2010

Leukodystrophies with late disease onset: an update.

Authors:
Wolfgang Köhler

Curr Opin Neurol 2010 Jun;23(3):234-41

Fachkrankenhaus Hubertusburg, Klinik für Neurologie und Neurologische Intensivmedizin, Wermsdorf, Germany.

Purpose Of Review: Knowledge of the metabolic and genetic basis of known and previously unknown leukodystrophies is constantly increasing, opening new treatment options such as enzyme replacement or cell-based therapies. This brief review highlights some recent work, particularly emphasizing results from studies in adulthood leukodystrophies.

Recent Findings: Evidence from recent studies suggests increasing importance of metabolic dysfunctions, for example, in peroxisomal lipid metabolism or energy homeostasis, influencing axonal integrity and oligodendrocyte function and leading to white matter demyelination. In addition, diagnostic and therapeutic progress in metachromatic leukodystrophy, X-linked adrenoleukodystrophy, Krabbe diseases and other rare leukodystrophies with late onset are summarized.

Summary: Better understanding of leukodystrophies in neurological routine practice is of crucial importance for differentiating between other white matter diseases such as toxic, inflammatory or vascular leukoencephalopathies. Many leukodystrophies are particularly important to recognize because specific treatments already exist or are currently under investigation. The article also provides an overview of currently known leukodystrophies in adulthood.
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http://dx.doi.org/10.1097/WCO.0b013e328338313aDOI Listing
June 2010