Publications by authors named "Mark Stettner"

48 Publications

Corneal confocal microscopy differentiates inflammatory from diabetic neuropathy.

J Neuroinflammation 2021 Apr 8;18(1):89. Epub 2021 Apr 8.

Department of Neurology and Center for Translational and Behavioral Neurosciences (C-TNBS), University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Background: Immune-mediated neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP) are treatable neuropathies. Among individuals with diabetic neuropathy, it remains a challenge to identify those individuals who develop CIDP. Corneal confocal microscopy (CCM) has been shown to detect corneal nerve fiber loss and cellular infiltrates in the sub-basal layer of the cornea. The objective of the study was to determine whether CCM can distinguish diabetic neuropathy from CIDP and whether CCM can detect CIDP in persons with coexisting diabetes.

Methods: In this multicenter, case-control study, participants with CIDP (n = 55) with (n = 10) and without (n = 45) diabetes; participants with diabetes (n = 58) with (n = 28) and without (n = 30) diabetic neuropathy, and healthy controls (n = 58) underwent CCM. Corneal nerve fiber density (CNFD), corneal nerve fiber length (CNFL), corneal nerve branch density (CNBD), and dendritic and non-dendritic cell density, with or without nerve fiber contact were quantified.

Results: Dendritic cell density in proximity to corneal nerve fibers was significantly higher in participants with CIDP with and without diabetes compared to participants with diabetic neuropathy and controls. CNFD, CNFL, and CNBD were equally reduced in participants with CIDP, diabetic neuropathy, and CIDP with diabetes.

Conclusions: An increase in dendritic cell density identifies persons with CIDP. CCM may, therefore, be useful to differentiate inflammatory from non-inflammatory diabetic neuropathy.
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http://dx.doi.org/10.1186/s12974-021-02130-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033689PMC
April 2021

Observational cohort study of neurological involvement among patients with SARS-CoV-2 infection.

Ther Adv Neurol Disord 2021 26;14:1756286421993701. Epub 2021 Feb 26.

Department of Neurology and Center for Translational and Behavioral Neurosciences (C-TNBS), University Medicine Essen, Hufelandstraße 55, Essen, 45147, Germany.

Background: A growing number of reports suggest that infection with SARS-CoV-2 often leads to neurological involvement; however, data on the incidence and severity are limited to mainly case reports and retrospective studies.

Methods: This prospective, cross-sectional study of 102 SARS-CoV-2 PCR positive patients investigated the frequency, type, severity and risk factors as well as underlying pathophysiological mechanisms of neurological involvement (NIV) in COVID-19 patients.

Results: Across the cohort, 59.8% of patients had NIV. Unspecific NIV was suffered by 24.5%, mainly general weakness and cognitive decline or delirium. Mild NIV was found in 9.8%; most commonly, impaired taste or smell. Severe NIV was present in 23.5%; half of these suffered cerebral ischaemia. Incidence of NIV increased with respiratory symptoms of COVID-19. Mortality was higher with increasing NIV severity. Notably, 83.3% with severe NIV had a pre-existing neurological co-morbidity. All cerebrospinal fluid (CSF) samples were negative for SARS-CoV-2 RNA, and SARS-CoV-2 antibody quotient did not suggest intrathecal antibody synthesis. Of the patients with severe NIV, 50% had blood-brain barrier (BBB) disruption and showed a trend of elevated interleukin levels in CSF. Antibodies against neuronal and glial epitopes were detected in 35% of the patients tested.

Conclusion: Cerebrovascular events were the most frequent severe NIV and severe NIV was associated with high mortality. Incidence of NIV increased with respiratory symptoms and NIV and pre-existing neurological morbidities were independent risk factors for fatality. Inflammatory involvement due to BBB disruption and cytokine release drives NIV, rather than direct viral invasion. These findings might help physicians define a further patient group requiring particular attention during the pandemic.
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http://dx.doi.org/10.1177/1756286421993701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934032PMC
February 2021

Neurological Manifestations of COVID-19 Feature T Cell Exhaustion and Dedifferentiated Monocytes in Cerebrospinal Fluid.

Immunity 2021 01 23;54(1):164-175.e6. Epub 2020 Dec 23.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany. Electronic address:

Patients suffering from Coronavirus disease 2019 (COVID-19) can develop neurological sequelae, such as headache and neuroinflammatory or cerebrovascular disease. These conditions-termed here as Neuro-COVID-are more frequent in patients with severe COVID-19. To understand the etiology of these neurological sequelae, we utilized single-cell sequencing and examined the immune cell profiles from the cerebrospinal fluid (CSF) of Neuro-COVID patients compared with patients with non-inflammatory and autoimmune neurological diseases or with viral encephalitis. The CSF of Neuro-COVID patients exhibited an expansion of dedifferentiated monocytes and of exhausted CD4 T cells. Neuro-COVID CSF leukocytes featured an enriched interferon signature; however, this was less pronounced than in viral encephalitis. Repertoire analysis revealed broad clonal T cell expansion and curtailed interferon response in severe compared with mild Neuro-COVID patients. Collectively, our findings document the CSF immune compartment in Neuro-COVID patients and suggest compromised antiviral responses in this setting.
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http://dx.doi.org/10.1016/j.immuni.2020.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831653PMC
January 2021

NK cell markers predict the efficacy of IV immunoglobulins in CIDP.

Neurol Neuroimmunol Neuroinflamm 2020 11 2;7(6). Epub 2020 Oct 2.

From the Department of Neurology (A.K.M., M.F., F.S., C.K., M.S.), Research Group for Clinical and Experimental Neuroimmunology, University Hospital Essen; Department of Neurology (M.K.H., H.-P.H., B.C.K.), Medical Faculty, Heinrich-Heine University Duesseldorf; Department of Neurology with Institute of Translational Neurology (G.M.Z.H.), University Hospital Münster; and Oncology and Tumor Immunology (S.C.), Charité University Medicine, Berlin, Germany.

Objective: To assess whether IV immunoglobulins (IVIgs) as a first-line treatment for chronic inflammatory demyelinating polyneuropathy (CIDP) have a regulative effect on natural killer (NK) cells that is related to clinical responsiveness to IVIg.

Methods: In a prospective longitudinal study, we collected blood samples of 29 patients with CIDP before and after initiation of IVIg treatment for up to 6 months. We used semiquantitative PCR and flow cytometry in the peripheral blood to analyze the effects of IVIg on the NK cells. The results were correlated with clinical aspects encompassing responsiveness.

Results: We found a reduction in the expression of several typical NK cell genes 1 day after IVIg administration. Flow cytometry furthermore revealed a reduced cytotoxic CD56 NK cell population, whereas regulatory CD56 NK cells remained mostly unaffected or were even increased after IVIg treatment. Surprisingly, the observed effects on NK cells almost exclusively occurred in IVIg-responsive patients with CIDP.

Conclusions: The correlation between the altered NK cell population and treatment efficiency suggests a crucial role for NK cells in the still speculative mode of action of IVIg treatment. Analyzing NK cell subsets after 24 hours of treatment initiation appeared as a predictive marker for IVIg responsiveness. Further studies are warranted investigating the potential of NK cell status as a routine parameter in patients with CIDP before IVIg therapy.

Classification Of Evidence: This study provides Class I evidence that NK cell markers predict clinical response to IVIg in patients with CIDP.
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http://dx.doi.org/10.1212/NXI.0000000000000884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577535PMC
November 2020

The Utility of Corneal Nerve Fractal Dimension Analysis in Peripheral Neuropathies of Different Etiology.

Transl Vis Sci Technol 2020 08 28;9(9):43. Epub 2020 Aug 28.

Division of Research, Weill Cornell Medicine-Qatar, Doha, Qatar.

Purpose: Quantification of corneal confocal microscopy (CCM) images has shown a significant reduction in corneal nerve fiber length (CNFL) in a range of peripheral neuropathies. We assessed whether corneal nerve fractal dimension (CNFrD) analysis, a novel metric to quantify the topological complexity of corneal subbasal nerves, can differentiate peripheral neuropathies of different etiology.

Methods: Ninety patients with peripheral neuropathy, including 29 with diabetic peripheral neuropathy (DPN), 34 with chronic inflammatory demyelinating polyneuropathy (CIDP), 13 with chemotherapy-induced peripheral neuropathy (CIPN), 14 with human immunodeficiency virus-associated sensory neuropathy (HIV-SN), and 20 healthy controls (HCs), underwent CCM for estimation of corneal nerve fiber density (CNFD), CNFL, corneal nerve branch density (CNBD), CNFrD, and CNFrD adjusted for CNFL (ACNFrD).

Results: In patients with DPN, CIDP, CIPN, or HIV-SN compared to HCs, CNFD ( = 0.004-0.0001) and CNFL ( = 0.05-0.0001) were significantly lower, with a further significant reduction among subgroups. CNFrD was significantly lower in patients with CIDP compared to HCs and patients with HIV-SN ( = 0.02-0.0009) and in patients with DPN compared to HCs and patients with HIV-SN, CIPN, or CIDP ( = 0.001-0.0001). ACNFrD was lower in patients with CIPN, CIDP, or DPN compared to HCs ( = 0.03-0.0001) and in patients with DPN compared to those with HIV-SN, CIPN, or CIDP ( = 0.01-0.005).

Conclusions: CNFrD can detect a distinct pattern of corneal nerve loss in patients with DPN or CIDP compared to those with CIPN or HIV-SN and controls.

Translational Relevance: Various peripheral neuropathies are characterized by a comparable degree of corneal nerve loss. Assessment of corneal nerve topology by CNFrD could be useful in differentiating neuropathies based on the pattern of loss.
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http://dx.doi.org/10.1167/tvst.9.9.43DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463182PMC
August 2020

Corneal Confocal Microscopy Demonstrates Corneal Nerve Loss in Patients With Trigeminal Neuralgia.

Front Neurol 2020 24;11:661. Epub 2020 Jul 24.

Department of Neurology, University Medicine Essen, Essen, Germany.

The diagnosis of trigeminal neuralgia (TN) is challenging due to the lack of objective diagnostics. Corneal confocal microscopy (CCM) is a non-invasive ophthalmic imaging technique, which allows quantification of corneal nerve fibers arising from the trigeminal ganglion and may allow the assessment of neurodegeneration in TN. CCM was undertaken in 11 patients with TN and 11 age-matched healthy controls. Corneal nerve fiber density (CNFD), corneal nerve branch density, corneal nerve fiber length (CNFL), corneal nerve fiber width, corneal nerve fiber area, and dendritic cell and non-dendritic cell density with or without nerve fiber contact were quantified. Patients with TN had significantly lower CNFD and CNFL but no difference for any other corneal nerve or dendritic cell parameter in the ipsilateral and the contralateral cornea compared to the control group. There was no significant difference in corneal nerve and cell parameters between patients with TN with and without involvement of the ophthalmic nerve (V1) or with nerve vessel conflict. Corneal confocal microscopy is a rapid non-invasive imaging technique that identifies symmetrical corneal nerve loss in patients with TN.
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http://dx.doi.org/10.3389/fneur.2020.00661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393442PMC
July 2020

Not all world leaders use Twitter in response to the COVID-19 pandemic: impact of the way of Angela Merkel on psychological distress, behaviour and risk perception.

J Public Health (Oxf) 2020 08;42(3):644-646

University of Duisburg-Essen, Clinic for Psychosomatic Medicine and Psychotherapy, LVR University Hospital Essen, 45147 Essen, Germany.

At a time of growing governmental restrictions and 'physical distancing' in order to decelerate the spread of COVID-19, psychological challenges are increasing. Social media plays an important role in maintaining social contact as well as exerting political influence. World leaders use it not only to keep citizens informed but also to boost morale and manage people's fears. However, some leaders do not follow this approach; an example is the German Chancellor. In a large online survey, we aimed to determine levels of COVID-19 fear, generalized anxiety, depression, safety behaviour, trust in government and risk perception in Germany. A total of 12 244 respondents participated during the period of restraint and the public shutdown in March 2020. Concurrent with the German Chancellor's speech, a reduction of anxiety and depression was noticeable in the German population. It appears that, in addition to using social media platforms like Twitter, different-and sometimes more conservative-channels for providing information can also be effective.
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http://dx.doi.org/10.1093/pubmed/fdaa060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239128PMC
August 2020

Redefining the heterogeneity of peripheral nerve cells in health and autoimmunity.

Proc Natl Acad Sci U S A 2020 04 15;117(17):9466-9476. Epub 2020 Apr 15.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster 48149, Germany;

Peripheral nerves contain axons and their enwrapping glia cells named Schwann cells (SCs) that are either myelinating (mySCs) or nonmyelinating (nmSCs). Our understanding of other cells in the peripheral nervous system (PNS) remains limited. Here, we provide an unbiased single cell transcriptomic characterization of the nondiseased rodent PNS. We identified and independently confirmed markers of previously underappreciated nmSCs and nerve-associated fibroblasts. We also found and characterized two distinct populations of nerve-resident homeostatic myeloid cells that transcriptionally differed from central nervous system microglia. In a model of chronic autoimmune neuritis, homeostatic myeloid cells were outnumbered by infiltrating lymphocytes which modulated the local cell-cell interactome and induced a specific transcriptional response in glia cells. This response was partially shared between the peripheral and central nervous system glia, indicating common immunological features across different parts of the nervous system. Our study thus identifies subtypes and cell-type markers of PNS cells and a partially conserved autoimmunity module induced in glia cells.
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http://dx.doi.org/10.1073/pnas.1912139117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196786PMC
April 2020

Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.

Brain 2020 04;143(4):1127-1142

NeuroCure Clinical Research Center and Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health and Max Delbrueck Center for Molecular Medicine, Berlin, Germany.

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.
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http://dx.doi.org/10.1093/brain/awaa062DOI Listing
April 2020

Genotype-phenotype correlation in a novel ABHD12 mutation underlying PHARC syndrome.

J Peripher Nerv Syst 2020 06 24;25(2):112-116. Epub 2020 Feb 24.

Department of Neurology, University Hospital Essen, Essen, Germany.

PHARC syndrome is a rare neurodegenerative disorder caused by mutations in the ABHD12 gene. It is a genetically heterogeneous and clinically variable disease, which is characterized by demyelinating polyneuropathy, hearing loss, cerebellar ataxia, retinitis pigmentosa, and early-onset cataract and can easily be misdiagnosed as other neurologic disorders with a similar clinical picture, such as Charcot-Marie-Tooth disease and Refsum disease. We describe the genotype-phenotype correlation of two siblings with a novel genotype underlying PHARC syndrome. The genotype was identified using next-generation sequencing. We examined both patients by means of thorough history taking and clinical examination, nerve conduction studies (NCS), brain imaging, and optical coherence tomography to establish a genotype-phenotype correlation. We identified a novel homozygous point mutation (c.784C > T, p.Arg262*) in the ABHD12 gene. This mutation was detected in both siblings, who had bilateral hearing loss and cataracts, signs of cerebellar ataxia, and neuropathy with a primarily demyelinating pattern in NCS. In one case, retinitis pigmentosa was also evident. As PHARC syndrome is a rare autosomal recessive disorder, our findings highlight the importance of an interdisciplinary diagnostic workup with clinical and molecular genetic testing to avoid a misdiagnosis as Charcot-Marie-Tooth disease or Refsum disease.
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http://dx.doi.org/10.1111/jns.12367DOI Listing
June 2020

A rare case of a completely thrombosed bilobed giant intracranial aneurysm of the anterior cerebral artery with spontaneous parent vessel thrombosis: case report.

BMC Neurol 2019 Nov 23;19(1):297. Epub 2019 Nov 23.

Department of Neurosurgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Background: A huge spherical intracranial mass can sometimes be misdiagnosed, due to the lack of typical radiographic features. Thrombosed giant intracranial aneurysms (GIAs) are an uncommon but still a possible differential diagnosis that must be kept in mind to guarantee the best surgical approach and resection of the lesion. We describe an extremely rare case of a huge bifrontal mass mimicking a cystic echinococcosis, in which the surgery unveiled a completely thrombosed GIA of the left anterior cerebral artery (ACA).

Case Presentation: A 61-year-old patient complained about intermittent weakness of the right leg, mild holocephalic headache, beginning cognitive deficits and lethargy. Magnetic resonance imaging (MRI) showed a huge partially calcified and bilobed frontal mass with peripheral edema. Based on a time-resolved angiography with interleaved Stochastic trajectories MRI (TWIST-MRI), a vascular origin of the lesion was considered unlikely. Therefore, the surgery was performed under the suspicion of a cystic echinococcosis but revealed a bilobed GIA of the left ACA with a parent vessel thrombosis. Although only a limited left frontal craniotomy was performed, a proximal control of the parent vessel could be ensured, and the aneurysm was successfully clipped. The patient showed postoperatively no new neurological deficits.

Conclusions: Completely thrombosed GIAs with parent vessel thrombosis are rare lesions that might be misdiagnosed if typical radiographic features are missing. Thus, in case of an intracranial spherical mass with signs of intralesional hemorrhage and mural calcifications, presence of a completely thrombosed GIA should be considered as a possible differential diagnosis.
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http://dx.doi.org/10.1186/s12883-019-1529-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875162PMC
November 2019

Glyphosate-based herbicide: a risk factor for demyelinating conditions of the peripheral nervous system?

Neural Regen Res 2019 Dec;14(12):2079-2080

Department of Neurology, University Medicine Essen, University Duisburg-Essen, Essen, Germany.

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http://dx.doi.org/10.4103/1673-5374.262579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788227PMC
December 2019

A fatal case of daclizumab-induced liver failure in a patient with MS.

Neurol Neuroimmunol Neuroinflamm 2019 03 21;6(2):e539. Epub 2019 Jan 21.

Department of Neurology (M.S., A.K.M., R.P., C.K.), University Hospital Essen; Clinic of Neurology with Institute of Translational Neurology (C.C.G., A.S.-M., H.W., S.G.M.), University Hospital Münster, University Münster; Institute of Neuropathology (A.J.), University Hospital Essen; and Institute of Pathology (H.A.B.), University Hospital Essen, Germany.

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http://dx.doi.org/10.1212/NXI.0000000000000539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369971PMC
March 2019

Differential impact of pure glyphosate and glyphosate-based herbicide in a model of peripheral nervous system myelination.

Acta Neuropathol 2018 12 16;136(6):979-982. Epub 2018 Nov 16.

Department of Neurology, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany.

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http://dx.doi.org/10.1007/s00401-018-1938-4DOI Listing
December 2018

CIDP, myasthenia gravis, and membranous glomerulonephritis - three autoimmune disorders in one patient: a case report.

BMC Neurol 2018 Aug 14;18(1):113. Epub 2018 Aug 14.

Department of Neurology, Essen University Hospital, Hufelandstrasse 55, 45147, Essen, Germany.

Background: We present a patient fulfilling the electrophysiological criteria for definite chronic inflammatory demyelinating polyneuropathy (CIDP), antibody-positive myasthenia gravis (MG), and membranous glomerulonephritis (MGN) confirmed by biopsy. To our knowledge, this is the first case of the concomitant appearance of these three autoimmune diseases in a single patient.

Case Representation: A 42-year-old Caucasian male presented with rapidly progressive gait disturbance, distal weakness of the lower extremities, ascending hypoesthesia, impaired fine motor skills, and beginning cranial nerve palsy showing dysarthrophonia, facial paralysis, and eye movement abnormalities and was diagnosed as rapid onset (atypical) CIDP. After 3 months, the patient complained of increasing physical exhaustion, reduction of his walking distance, worsening of the residual dysphagia, and dysarthria with an inability to swallow. AChR antibodies (17.0 nmol/L, RF < 0.4) and titin antibodies were positive and repetitive nerve stimulation showed an abnormal decrement matching the criteria of myasthenia gravis. Over time the patient developed severe acute-on-chronic renal failure with high-grade proteinuria resulting in generalized edema followed by secondary hyperparathyroidism and dialysis-dependent renal failure. Renal biopsy confirmed beginning anti-phospholipase A2 receptor antibody membranous nephropathy.

Conclusion: All three diseases are of autoimmune origin with distinctive immunopathogenetic mechanisms. The present case of CIDP, MG, and MGN occurring in one patient indicates a common underlying immune mechanism in these distinct conditions, including the involvement of autoantibodies and T cells.
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http://dx.doi.org/10.1186/s12883-018-1120-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092826PMC
August 2018

Costs of illness in chronic inflammatory demyelinating polyneuropathy in Germany.

Muscle Nerve 2018 11 3;58(5):681-687. Epub 2018 Oct 3.

Department of Neurology, Philipps-University of Marburg, Marburg, Germany.

Introduction: Cost of illness studies are essential to estimate societal costs of chronic inflammatory demyelinating polyneuropathy (CIDP) and identify cost-driving factors.

Methods: In total, 108 patients were recruited from 3 specialized neuroimmunological clinics. Costs were calculated for a 3-month period, including direct and indirect costs. The following outcomes were assessed: inflammatory neuropathy cause and treatment disability scale, Mini-Mental State Examination, Beck Depression Inventory, Charlson comorbidity index, EuroQol-5D, World Health Organization quality of life instrument, and socioeconomic status. Univariate and multivariate analyses were applied to identify cost-driving factors.

Results: Total quarterly costs were €11,333. Direct costs contributed to 83% of total costs (€9,423), whereas indirect costs accounted for 17% (€1,910) of total costs. The cost of intravenous immunoglobulin (IVIg) was the main determinant of total costs (67%). Reduced health-related quality of life and depressive symptoms were identified as independent predictors of higher total costs.

Discussion: CIDP is associated with high societal costs, mainly resulting from the cost of IVIg treatment. Muscle Nerve 58: 681-687, 2018.
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http://dx.doi.org/10.1002/mus.26315DOI Listing
November 2018

Trapped in the epineurium: early entry into the endoneurium is restricted to neuritogenic T cells in experimental autoimmune neuritis.

J Neuroinflammation 2018 Aug 1;15(1):217. Epub 2018 Aug 1.

Department of Neurology, Medical Faculty, Heinrich Heine University Duesseldorf, 40225, Duesseldorf, Germany.

Background: Autoimmune polyneuropathies are acquired inflammatory disorders of the peripheral nervous system (PNS) characterized by inflammation, demyelination, and axonal degeneration. Although the pathogenesis has not been fully elucidated, T cells recognizing self-antigens are believed to initiate inflammation in a subgroup of patients. However, the route and time of T cell entry into the PNS have not yet been described in detail. In this study, we analyzed both kinetics as well as localization of retrovirally transfected green fluorescent protein (GFP)-expressing neuritogenic T lymphocytes in experimental autoimmune neuritis (EAN).

Methods: T lymphocytes obtained from rats following EAN induction by immunization with peripheral nerve protein peptide P2 were retrovirally engineered to express GFP. Non-specific T cells were negatively selected by in vitro restimulation, whereas GFP-expressing neuritogenic T cells (reactive to P2) were adoptively transferred into healthy rats (AT-EAN). Antigen-specific T cell tracking and localization was performed by flow cytometry and immunohistochemistry during the course of disease.

Results: After induction of autoimmune neuritis, P2-reactive T cells were detectable in the liver, spleen, lymph nodes, lung, peripheral blood, and the sciatic nerves with distinct kinetics. A significant number of GFP T cells appeared early in the lung with a peak at day four. In the peripheral nerves within the first days, GFP-negative T cells rapidly accumulated and exceeded the number of GFP-expressing cells, but did not enter the endoneurium. Very early after adoptive transfer, T cells are found in proximity to peripheral nerves and in the epineurium. However, only GFP-expressing neuritogenic T cells are able to enter the endoneurium from day five after transfer.

Conclusions: Our findings suggest that neuritogenic T cells invade the PNS early in the course of disease. However, neuritogenic T cells cross the blood-nerve barrier with a certain delay without preference to dorsal roots. Further understanding of the pathophysiological role of autoagressive T cells may help to improve therapeutic strategies in immune-mediated neuropathies.
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http://dx.doi.org/10.1186/s12974-018-1259-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090976PMC
August 2018

Lysophosphatidic acid propagates post-injury Schwann cell dedifferentiation through LPA signaling.

Neurosci Lett 2018 Jan 16;662:136-141. Epub 2017 Oct 16.

Department of Neurology, Medical Faculty, University Duisburg-Essen, Essen, Germany.

Lysophosphatidic acid (LPA) is a pleiotropic signaling lipid that acts as ligand for at least six specific G-protein coupled receptors. Schwann cells (SC) are known to mainly express the LPA receptor subtype. An emerging body of evidence has linked LPA with injury-induced peripheral nerve demyelination as well as neuropathic pain. However, the molecular mechanisms underlying its demyelinating effect have not been conclusively elucidated. We aimed to decipher the demyelinating effect in vitro as well as in vivo by studying markers of SC differentiation and dedifferentiation: Myelinated dorsal root ganglia (DRG) cultures were treated either with LPA, LPA plus AM095 (LPA antagonist) or vehicle. Myelin content was subsequently investigated by Sudan Black staining and immunocytochemistry. In vivo, we performed sciatic nerve crush in C57BL/6 mice treated with AM095 at 10mg/kg. In DRG cultures, LPA caused a significant reduction of myelin as demonstrated by both Sudan Black staining and immunocytochemical analysis of myelin basic protein. Demyelination was paralleled by an upregulation of TNF-alpha as well as downregulation of Sox10, a marker for SC differentiation. LPA mediated effects were largely blocked by the addition of the LPA receptor antagonist AM095. In the in vivo model, AM095 treatment prior to crush injury increased Sox10 expression in SCs in the distal nerve stump while reducing the number of cells expressing the SC dedifferentiation marker Sox2. Additionally, TNF-alpha immunofluorescence was reduced in CD11b-positive cells. These data indicate that LPA may be a critical factor that shifts SCs towards a post-injury phenotype and contributes to the onset of Wallerian degeneration.
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http://dx.doi.org/10.1016/j.neulet.2017.10.023DOI Listing
January 2018

CIDP and other inflammatory neuropathies in diabetes - diagnosis and management.

Nat Rev Neurol 2017 Oct 15;13(10):599-611. Epub 2017 Sep 15.

Weill Cornell Medicine-Qatar, Education City, PO Box 24144, Doha, Qatar.

Distal symmetric polyneuropathy (DSPN) is the most common neuropathy to occur in diabetes mellitus. However, patients with diabetes can also develop inflammatory neuropathies, the most common and most treatable of which is chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Whether diabetes is a risk factor for CIDP remains under debate. Early studies suggested that patients with diabetes were at increased risk of CIDP, but epidemiological studies failed to confirm the association, and subsequent data have re-opened the debate. Inadequate interpretation of investigations and differentials between CIDP and other neuropathies that can occur in diabetes, such as DSPN, diabetic radiculoplexus neuropathies and vasculitic multiple mononeuropathy, might mean that CIDP is under-recognized. Despite a response rate of >80% to first-line therapies for CIDP in patients with or without diabetes, those with diabetes often present with greater disability owing to late referral and axonal pathology attributed to DSPN. The increasing worldwide prevalence of diabetes creates an urgent need to improve identification of potentially treatable neuropathies, such as CIDP. In this Review, we consider the features of CIDP in patients with diabetes, and discuss how these features can be used to differentiate the condition from other neuropathies. We also review the management options for CIDP and other inflammatory neuropathies in patients with diabetes.
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http://dx.doi.org/10.1038/nrneurol.2017.123DOI Listing
October 2017

The Role of Peripheral Myelin Protein 2 in Remyelination.

Cell Mol Neurobiol 2018 Mar 26;38(2):487-496. Epub 2017 Apr 26.

Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany.

The protein component of the myelin layer is essential for all aspects of peripheral nerves, and its deficiency can lead to structural and functional impairment. The presence of peripheral myelin protein 2 (P2, PMP2, FABP8, M-FABP) in Schwann cells has been known for decades and shown recently to be involved in the lipid homeostasis in the peripheral neural system. However, its precise role during de- and remyelination has yet to be elucidated. To this end, we assessed remyelination after sciatic nerve crush injury in vivo, and in an experimental de/remyelination ex vivo myelinating culture model in P2-deficient (P2 ) and wild-type (WT) animals. In vivo, the nerve crush paradigm revealed temporal structural and functional changes in P2 mice as compared to WT animals. Concomitantly, P2 DRG cultures demonstrated the presence of shorter internodes and enlarged nodes after ex vivo de/remyelination. Together, these data indicate that P2 may play a role in remyelination of the injured peripheral nervous system, presumably by affecting the nodal and internodal configuration.
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http://dx.doi.org/10.1007/s10571-017-0494-0DOI Listing
March 2018

Prospects of estrogen receptor β activation in the treatment of castration-resistant prostate cancer.

Oncotarget 2017 May;8(21):34971-34979

Department of Urology, University Medical Center Goettingen, Germany.

Advanced prostate cancer can develop into castration-resistant prostate cancer (CRPC). This process is mediated either by intratumoral ligand synthesis or by mutations or aberrations of the androgen receptor (AR) or its cofactors. To date, no curative therapy for CRPC is available, as AR-targeted therapies eventually result in the development of resistance. The human prostate cancer cell line VCaP (vertebral cancer of the prostate) overexpresses AR and its splice variants (ARVs) as a mechanism of resistance to androgen-deprivation therapy (ADT) of external and intratumoral origin. In the present study, we demonstrate that stimulating estrogen receptor β activity with the specific agonist 8β-VE2 in VCaP cells in successive stages of ADT induced a time- and dose-dependent decrease in cell survival and an increase in apoptosis. Furthermore, 8β-VE2 treatment reduced the overexpression of the AR as well as ARVs in VCaP cells under maximum ADT. Our results indicate that decreased survival of the androgen-dependent CRPC cells employing apoptosis together with the regulative effect on AR expression could have beneficial effects over current AR-targeting therapies.
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http://dx.doi.org/10.18632/oncotarget.16496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471027PMC
May 2017

Dimethyl fumarate accelerates peripheral nerve regeneration via activation of the anti-inflammatory and cytoprotective Nrf2/HO-1 signaling pathway.

Acta Neuropathol 2017 03 20;133(3):489-491. Epub 2017 Jan 20.

Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany.

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http://dx.doi.org/10.1007/s00401-017-1676-zDOI Listing
March 2017

Subcutaneous immunoglobulins in the treatment of chronic immune-mediated neuropathies.

Ther Adv Neurol Disord 2016 Jul 6;9(4):336-43. Epub 2016 Apr 6.

Department of Neurology, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany.

Intravenous immunoglobulins represent an established therapy for the treatment of chronic immune-mediated neuropathies, specifically chronic inflammatory demyelinating polyradiculoneuropathies (CIDPs) as well as multifocal motor neuropathies (MMNs). For the treatment of antibody deficiency syndromes, subcutaneous immunoglobulins (SCIgs) have represented a mainstay for decades. An emerging body of evidence suggests that SCIg might also exhibit clinical efficacy in CIDP and MMN. This article reviews the current evidence for clinical effectiveness, as well as safety of SCIg for the treatment of immune-mediated neuropathies, and addresses remaining open questions in this context. We conclude that despite the need for controlled long-term studies to demonstrate long-term efficacy of SCIg in immune-mediated neuropathies, SCIg may already represent a potential therapeutic alternative for selected patients.
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http://dx.doi.org/10.1177/1756285616641583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916522PMC
July 2016

Fampridine-PR (prolonged released 4-aminopyridine) is not effective in patients with inflammatory demyelination of the peripheral nervous system.

J Peripher Nerv Syst 2016 06;21(2):85-7

Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.

Fampridine-PR is a voltage-gated potassium channel inhibitor potentially improving nerve conduction in demyelinated axons. Based on its established clinical efficacy in patients with demyelination in the central nervous system, we assessed if fampridine-PR is also effective in patients with inflammatory demyelination of the peripheral nerve. In this small open-label study, 10 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) were treated with fampridine-PR 10 mg BID for 28 days and assessed clinically as well as by nerve conduction studies. In this study, Fampridine-PR failed to improve CIDP based on clinical measures and nerve conduction studies. Our findings suggest that Fampridine-PR appears to be ineffective in demyelinating polyneuropathies. These observations may indicate a more complex mode of action beyond improving action potential conduction in demyelinated axons.
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http://dx.doi.org/10.1111/jns.12169DOI Listing
June 2016

Corneal confocal microscopy in chronic inflammatory demyelinating polyneuropathy.

Ann Clin Transl Neurol 2016 02 28;3(2):88-100. Epub 2015 Dec 28.

Department of Neurology Medical Faculty Research Group for Clinical and Experimental Neuroimmunology Heinrich-Heine University Dusseldorf Germany.

Objective: There is an unmet need for better diagnostic tools to further delineate clinical subsets of heterogeneous chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) to facilitate treatment decisions. Corneal confocal microscopy (CCM) is a noninvasive and reproducible nerve imaging technique. This study evaluates the potential of CCM as a diagnostic surrogate in CIDP and MMN.

Methods: In a cross-sectional prospective approach, 182 patients and healthy controls were studied using CCM to quantify corneal nerve damage and immune cell infiltration.

Results: Patients with CIDP and MMN had a reduction in corneal nerve fiber (CNF) measures and an increase in corneal immune cell infiltrates. In CIDP, CNF parameters decreased with increasing duration of disease. The number of dendritic cells in proximity to CNFs was increased in patients with early disease and correlated with the degree of motor affection. A further reduction in CNF parameters and an increase in nondendritic cells were observed in patients with painful neuropathy. In CIDP patients with antineuronal antibodies the number of nondendritic cells was increased.

Interpretation: Our findings suggest that CNF loss may reflect severity of neuropathy and quantification of distinct cells around the CNF plexus may help in stratifying CIDP subtypes, clinical course, and disease activity. However, further longitudinal studies are required before CCM can be considered as a valid surrogate endpoint for patients with CIDP and MMN.
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http://dx.doi.org/10.1002/acn3.275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748316PMC
February 2016

Neuronal ADAM10 Promotes Outgrowth of Small-Caliber Myelinated Axons in the Peripheral Nervous System.

J Neuropathol Exp Neurol 2015 Nov;74(11):1077-85

From the Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf (GMzH, AD, FS, MS, CB, HCL, H-PH, BCK); and Department of Neuropathology, Georg-August-University (RS); and Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine (RS), Göttingen, Germany; and Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts (MT).

The regulation of myelination and axonal outgrowth in the peripheral nervous system is controlled by a complex signaling network involving various signaling pathways. Members of the A Disintegrin And Metalloproteinase (ADAM) family are membrane-anchored proteinases with both proteolytic and disintegrin characteristics that modulate the function of signaling molecules. One family member, ADAM17, is known to influence myelination by cleaving and thus regulating one of the key signals, neuregulin-1, which controls peripheral nervous system myelination. A similar function for ADAM10 had been suggested by previous in vitro studies. Here, we assessed whether ADAM10 exerts a similar function in vivo and deleted ADAM10 in a cell type-specific manner in either neurons or Schwann cells. We found that ADAM10 is not required in either Schwann cells or neurons for normal myelination during development or for remyelination after injury. Instead, ADAM10 is required specifically in neurons for the outgrowth of myelinated small-fiber axons in vitro and after injury in vivo. Thus, we report for the first time a neuron-intrinsic function of ADAM10 in axonal regeneration that is distinct from that of the related protein family member ADAM17 and that may have implications for targeting ADAM function in nervous system diseases.
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http://dx.doi.org/10.1097/NEN.0000000000000253DOI Listing
November 2015

Isoniazid-induced polyneuropathy in a tuberculosis patient - implication for individual risk stratification with genotyping?

Brain Behav 2015 Aug 29;5(8):e00326. Epub 2015 May 29.

Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Germany.

Background: Development of polyneuropathy (PNP) under treatment for tuberculosis (TB), including isoniazid (INH), is a highly relevant adverse drug effect. The NAT2 acetylation status is a predictor of potential toxic effects of INH. The question as to whether individual risk stratification by genotyping is useful to avoid suffering of patients and to lower costs for the health care system is of considerable clinical importance.

Case Presentation: After drug treatment for TB, including INH, a 23-year-old man developed severe PNP. During the treatment, laboratory results have been indicating incipient liver and renal injury. Later, molecular genetic analyses were performed and revealed a variation in the NAT2 gene and the c1/c2 genotype of the CYP2E1 gene, both described to contribute to an elevated risk for anti-tuberculostatic-induced liver damages (ATIL).

Conclusion: The combination of metabolizer genotypes should be taken into account as a cause for toxic effects and the development of PNP. Individual genotyping, performed before medication or at least if an elevation of liver parameters is observed, may reduce the risk of severe cases of PNP by early adjustment of treatment. Our case study indicates that evaluation of individual risk stratification with systematic pharmacogenetic genotyping of metabolizer gene combinations in the context of TB treatment should be addressed in clinical studies with larger cohorts.
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http://dx.doi.org/10.1002/brb3.326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559012PMC
August 2015

Long-term Therapy With Interleukin 6 Receptor Blockade in Highly Active Neuromyelitis Optica Spectrum Disorder.

JAMA Neurol 2015 Jul;72(7):756-63

Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany.

Importance: Neuromyelitis optica (NMO) is characterized by disabling relapses of optic neuritis and myelitis and the presence of aquaporin 4 antibodies (AQP4-abs). Interleukin 6, which is significantly elevated in serum and cerebrospinal fluid of patients with NMO, induces AQP4-ab production by plasmablasts and represents a novel therapeutic target.

Objective: To evaluate the long-term safety and efficacy of tocilizumab, a humanized antibody targeting the interleukin 6 receptor, in NMO and NMO spectrum disorder.

Design, Setting, And Participants: Retrospective observational study with 10 to 51 months of follow-up between December 2010 and February 2015, in neurology departments at tertiary referral centers. Participants were 8 female patients of white race/ethnicity with highly active AQP4-ab-seropositive NMO (n = 6) and NMO spectrum disorder (n = 2) whose disease had been resistant to previous medications, including B-cell depletion, and who switched to tocilizumab (6-8 mg/kg of body weight per dose).

Main Outcomes And Measures: Annualized relapse rate, Expanded Disability Status Scale score, spinal cord and brain magnetic resonance imaging, AQP4-ab titers, pain levels (numerical rating scale), and adverse effects.

Results: Patients were followed up for a mean (SD) of 30.9 (15.9) months after switching to tocilizumab. Two of eight patients received add-on therapy with monthly corticosteroid pulses (temporary) or azathioprine, respectively. During tocilizumab treatment, the median annualized relapse rate significantly decreased from 4.0 (interquartile range, 3.0-5.0) in the year before tocilizumab therapy to 0.4 (interquartile range, 0.0-0.8) (P = .008), and the median Expanded Disability Status Scale score significantly decreased from 7.3 (interquartile range, 5.4-8.4) to 5.5 (interquartile range, 2.6-6.5) (P = .03). Active magnetic resonance imaging lesions were seen in 6 of 8 patients at tocilizumab initiation and in 1 of 8 patients at the last magnetic resonance imaging. Three patients remained relapse free during tocilizumab treatment. In 5 patients, a total of 8 relapses occurred, 4 within the first 2½ months of therapy. Five attacks were associated with delayed tocilizumab administration (≥40 days), and 6 attacks were associated with reduced tocilizumab dosage (6 vs 8 mg/kg). The AQP4-ab titers (P = .02) and pain levels (P = .02) dropped significantly during tocilizumab treatment. Adverse effects included moderate cholesterol elevation in 6 of 8 patients, infections in 4 of 8 patients, and deep venous thrombosis and neutropenia in one patient each.

Conclusions And Relevance: Prolonged tocilizumab therapy may be safe and effective from early treatment phases onward for otherwise therapy-resistant highly active NMO and NMO spectrum disorder. Relapse patterns indicate that adherence to a regular therapeutic regimen with monthly infusions of tocilizumab (8 mg/kg) may increase efficacy.
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http://dx.doi.org/10.1001/jamaneurol.2015.0533DOI Listing
July 2015

The Lindau Nobel Laureate Meeting 2014--do something that you enjoy!

Authors:
Mark Stettner

J Peripher Nerv Syst 2014 Dec;19(4):343

Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany.

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http://dx.doi.org/10.1111/jns.12095DOI Listing
December 2014

Heat exposure and bicycling trigger recurrent aseptic meningitis: a case report.

BMC Neurol 2014 Dec 31;14:230. Epub 2014 Dec 31.

Department of Neurology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Background: Aseptic meningitis associated with herpes simplex virus type 2 often has a relapsing-remitting clinical phenotype. Factors that lead to disease activation and reactivation are currently incompletely understood.

Case Presentation: We describe the case of a 49-year-old Caucasian man who developed recurrent episodes of herpes simplex virus type 2-associated aseptic meningitis in the setting of heat exposure and bicycling. This case is compelling in that substantial data were available to the examining physicians on the amount of physical exercise and heat exposure. Strenuous physical activities or heat exposure in isolation did not cause re-occurrence of clinical signs and symptoms.

Conclusions: This case illustrates that the dual activation of mechanical and temperature receptors in dorsal root ganglia may lead to the recurrent reactivation and afferent dissemination of latent herpes simplex virus type 2 in some patients.
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http://dx.doi.org/10.1186/s12883-014-0230-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301064PMC
December 2014