Publications by authors named "Martijn R Tannemaat"

60 Publications

Accuracy of patient-reported data for an online patient registry of autoimmune myasthenia gravis and Lambert-Eaton myasthenic syndrome.

Neuromuscul Disord 2021 07 29;31(7):622-632. Epub 2021 May 29.

Department of Neurology, Leiden University Medical Center, the Netherlands.

Disorders of the neuromuscular junction (NMJ) comprise a spectrum of rare diseases causing muscle fatigability and weakness, leading to life-long effects on quality of life. We established the Dutch-Belgian registry for NMJ disorders, based on a unique combination of patient- and physician-reported information. Information on natural course, disease burden, prevalence of complications and comorbidity is collected through patient-reported standardized questionnaires and verified using medical documentation. Currently, the registry contains information of 565 Myasthenia Gravis (MG) patients and 38 Lambert-Eaton myasthenic syndrome (LEMS) patients, constituting approximately 25% (MG) and 80% (LEMS) of patients in the Netherlands. This is a very large registry, with the highest participation rate per capita. In addition to confirming many disease characteristics previously described in the literature, this registry provides several novel insights. The reported rate of potentially corticosteroid-related comorbidity, including hypertension, heart disease, osteoporosis and type 2 diabetes was high, emphasizing the need to commence corticosteroid-sparing immune suppressive treatment as soon as possible. The reported rate of other auto-immune diseases is far higher than previously expected: 27% of MG and 38% of LEMS patients, and a surprisingly high number of MG patients (47%) is unaware of their antibody status. In conclusion, this registry provides a valuable collection of information regarding MG and LEMS disease course. Continuous collection of annual follow-up data will provide further longitudinal insights in disease burden, course and treatment effect.
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http://dx.doi.org/10.1016/j.nmd.2021.05.006DOI Listing
July 2021

Preoperative Electroencephalography-Based Machine Learning Predicts Cognitive Deterioration after Subthalamic Deep Brain Stimulation.

Mov Disord 2021 Jun 3. Epub 2021 Jun 3.

Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

Background: Subthalamic deep brain stimulation (STN DBS) may relieve refractory motor complications in Parkinson's disease (PD) patients. Despite careful screening, it remains difficult to determine severity of alpha-synucleinopathy involvement which influences the risk of postoperative complications including cognitive deterioration. Quantitative electroencephalography (qEEG) reflects cognitive dysfunction in PD and may provide biomarkers of postoperative cognitive decline.

Objective: To develop an automated machine learning model based on preoperative EEG data to predict cognitive deterioration 1 year after STN DBS.

Methods: Sixty DBS candidates were included; 42 patients had available preoperative EEGs to compute a fully automated machine learning model. Movement Disorder Society criteria classified patients as cognitively stable or deteriorated at 1-year follow-up. A total of 16,674 EEG-features were extracted per patient; a Boruta algorithm selected EEG-features to reflect representative neurophysiological signatures for each class. A random forest classifier with 10-fold cross-validation with Bayesian optimization provided class-differentiation.

Results: Tweny-five patients were classified as cognitively stable and 17 patients demonstrated cognitive decline. The model differentiated classes with a mean (SD) accuracy of 0.88 (0.05), with a positive predictive value of 91.4% (95% CI 82.9, 95.9) and negative predictive value of 85.0% (95% CI 81.9, 91.4). Predicted probabilities between classes were highly differential (hazard ratio 11.14 [95% CI 7.25, 17.12]); the risk of cognitive decline in patients with high probabilities of being prognosticated as cognitively stable (>0.5) was very limited.

Conclusions: Preoperative EEGs can predict cognitive deterioration after STN DBS with high accuracy. Cortical neurophysiological alterations may indicate future cognitive decline and can be used as biomarkers during the DBS screening. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28661DOI Listing
June 2021

Prevalence and associated factors of fatigue in autoimmune myasthenia gravis.

Neuromuscul Disord 2021 07 24;31(7):612-621. Epub 2021 Apr 24.

Department of Neurology, Leiden University Medical Center, the Netherlands.

Fatigue is usually defined as a subjective perception of lacking energy, mentally or physically, with a difficulty sustaining voluntary activities. It is a common symptom of many diseases and most likely has a multifactorial cause. In myasthenia gravis (MG), fatigue has a high prevalence and is correlated with female sex and disease severity. However, no large scale studies have been performed. Therefore, we aimed to evaluate fatigue in the Dutch participants (n = 420) of the Dutch-Belgian Myasthenia Patient Registry using an online survey. Additional information was obtained on mood, sleep, coping, quality of life, disease severity, physical activities and medication. Severe fatigue was present in 62% with a mean score of 37.1 ± 13.2 points. Fatigue severity and prevalence increased significantly with disease severity. A positive correlation was found for female gender, BMI, disease severity and depressive symptoms. A negative correlation was found for strenuous physical activities and older age. The strong association with disease severity suggests that fatigue should be recognized as an element of the symptomatology of MG. The observed association between strenuous activity and fatigue and differences in coping style between fatigued and non-fatigued patients warrant future clinical trials on exercise and cognitive behavioral therapy.
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http://dx.doi.org/10.1016/j.nmd.2021.04.002DOI Listing
July 2021

Coordinated changes in the expression of Wnt pathway genes following human and rat peripheral nerve injury.

PLoS One 2021 13;16(4):e0249748. Epub 2021 Apr 13.

Laboratory for Neuroregeneration, Netherlands Institute for Neuroscience, An Institute of the Royal Academy of Arts and Sciences, Amsterdam, The Netherlands.

A human neuroma-in continuity (NIC), formed following a peripheral nerve lesion, impedes functional recovery. The molecular mechanisms that underlie the formation of a NIC are poorly understood. Here we show that the expression of multiple genes of the Wnt family, including Wnt5a, is changed in NIC tissue from patients that underwent reconstructive surgery. The role of Wnt ligands in NIC pathology and nerve regeneration is of interest because Wnt ligands are implicated in tissue regeneration, fibrosis, axon repulsion and guidance. The observations in NIC prompted us to investigate the expression of Wnt ligands in the injured rat sciatic nerve and in the dorsal root ganglia (DRG). In the injured nerve, four gene clusters were identified with temporal expression profiles corresponding to particular phases of the regeneration process. In the DRG up- and down regulation of certain Wnt receptors suggests that nerve injury has an impact on the responsiveness of injured sensory neurons to Wnt ligands in the nerve. Immunohistochemistry showed that Schwann cells in the NIC and in the injured nerve are the source of Wnt5a, whereas the Wnt5a receptor Ryk is expressed by axons traversing the NIC. Taken together, these observations suggest a central role for Wnt signalling in peripheral nerve regeneration.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249748PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043392PMC
October 2021

Can novel non-invasive autonomic tests help discriminate between pure autonomic failure and multiple system atrophy?

Auton Neurosci 2021 03 26;231:102773. Epub 2021 Jan 26.

Department of Neurology and Clinical Neurophysiology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, the Netherlands.

Background: Pure autonomic failure (PAF) and multiple system atrophy (MSA) are rare disorders causing severe autonomic failure. Their initially similar clinical presentation may lead to years of diagnostic difficulties. Improving the differentiation would have an important impact on patients and families in view of better prediction of disease progression.

Objective: To investigate whether several new non-invasive autonomic tests are beneficial in discriminating between PAF and MSA.

Methods: Patients and controls underwent two tests examining the autonomic innervation of the skin (Sudoscan and water-induced skin wrinkling) and one test measuring retinal nerve fiber layer thickness in the eye.

Results: The skin vasomotor tests yielded differences between the disease and control groups, but did not discriminate between PAF and MSA. No differences in retinal nerve fiber layer thickness were found between the groups.

Conclusion: The tests applied in this study may help to confirm autonomic failure but did not support the differential diagnosis between PAF and MSA.
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http://dx.doi.org/10.1016/j.autneu.2021.102773DOI Listing
March 2021

Measuring CMAPs in addition to MEPs can distinguish peripheral ischemia from spinal cord ischemia during endovascular aortic repair.

Clin Neurophysiol Pract 2021 11;6:16-21. Epub 2020 Dec 11.

Department of Neurology, Leiden University Medical Center, the Netherlands.

Objective: Spinal cord injury is a devastating complication after endovascular thoracic and thoracoabdominal aneurysm repair (EVAR). Motor evoked potentials (MEPs) can be monitored to detect spinal cord injury, but may also be affected by peripheral ischemia caused by femoral artery sheaths. We aimed to determine the incidence of peripheral ischemia during EVAR, and whether central and peripheral ischemia can be distinguished using compound muscle action potentials (CMAPs).

Methods: We retrospectively analyzed all EVAR procedures between March 1st 2015 and January 1st 2020 during which MEPs were monitored. Peripheral ischemia was defined as both a reduction in MEP amplitudes reversed by removing the femoral sheaths and no clinical signs of immediate post-procedural paraparesis. All other MEP decreases were defined as central ischemia.

Results: A significant MEP decrease occurred in 14/27 (52%) of all procedures. Simultaneous CMAP amplitude reduction was observed in 7/8 (88%) of procedures where peripheral ischemia occurred, and never in procedures with central ischemia.

Conclusions: MEP reductions due to peripheral ischemia are common during EVAR. A MEP-reduction without a CMAP decrease indicates central ischemia.

Significance: CMAP measurements can help to distinguish central from peripheral ischemia, potentially reducing the chance of misinterpreting of MEP amplitude declines as centrally mediated, without affecting sensitivity.
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http://dx.doi.org/10.1016/j.cnp.2020.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804348PMC
December 2020

GDNF Gene Therapy to Repair the Injured Peripheral Nerve.

Front Bioeng Biotechnol 2020 30;8:583184. Epub 2020 Oct 30.

Laboratory for Neuroregeneration, Netherlands Institute for Neuroscience, Institute of the Royal Academy of Arts and Sciences, Amsterdam, Netherlands.

A spinal root avulsion is the most severe proximal peripheral nerve lesion possible. Avulsion of ventral root filaments disconnects spinal motoneurons from their target muscles, resulting in complete paralysis. In patients that undergo brachial plexus nerve repair, axonal regeneration is a slow process. It takes months or even years to bridge the distance from the lesion site to the distal targets located in the forearm. Following ventral root avulsion, without additional pharmacological or surgical treatments, progressive death of motoneurons occurs within 2 weeks (Koliatsos et al., 1994). Reimplantation of the avulsed ventral root or peripheral nerve graft can act as a conduit for regenerating axons and increases motoneuron survival (Chai et al., 2000). However, this beneficial effect is transient. Combined with protracted and poor long-distance axonal regeneration, this results in permanent function loss. To overcome motoneuron death and improve functional recovery, several promising intervention strategies are being developed. Here, we focus on GDNF gene-therapy. We first introduce the experimental ventral root avulsion model and discuss its value as a proxy to study clinical neurotmetic nerve lesions. Second, we discuss our recent studies showing that GDNF gene-therapy is a powerful strategy to promote long-term motoneuron survival and improve function when target muscle reinnervation occurs within a critical post-lesion period. Based upon these observations, we discuss the influence of timing of the intervention, and of the duration, concentration and location of GDNF delivery on functional outcome. Finally, we provide a perspective on future research directions to realize functional recovery using gene therapy.
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http://dx.doi.org/10.3389/fbioe.2020.583184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673415PMC
October 2020

The feasibility of quantitative MRI of extra-ocular muscles in myasthenia gravis and Graves' orbitopathy.

NMR Biomed 2021 01 7;34(1):e4407. Epub 2020 Sep 7.

CJ Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.

Although quantitative MRI can be instrumental in the diagnosis and assessment of disease progression in orbital diseases involving the extra-ocular muscles (EOM), acquisition can be challenging as EOM are small and prone to eye-motion artefacts. We explored the feasibility of assessing fat fractions (FF), muscle volumes and water T2 (T2 ) of EOM in healthy controls (HC), myasthenia gravis (MG) and Graves' orbitopathy (GO) patients. FF, EOM volumes and T2 values were determined in 12 HC (aged 22-65 years), 11 MG (aged 28-71 years) and six GO (aged 28-64 years) patients at 7 T using Dixon and multi-echo spin-echo sequences. The EOM were semi-automatically 3D-segmented by two independent observers. MANOVA and t-tests were used to assess differences in FF, T2 and volume of EOM between groups (P < .05). Bland-Altman limits of agreement (LoA) were used to assess the reproducibility of segmentations and Dixon scans. The scans were well tolerated by all subjects. The bias in FF between the repeated Dixon scans was -0.7% (LoA: ±2.1%) for the different observers; the bias in FF was -0.3% (LoA: ±2.8%) and 0.03 cm (LoA: ± 0.36 cm ) for volume. Mean FF of EOM in MG (14.1% ± 1.6%) was higher than in HC (10.4% ± 2.5%). Mean muscle volume was higher in both GO (1.2 ± 0.4 cm ) and MG (0.8 ± 0.2 cm ) compared with HC (0.6 ± 0.2 cm ). The average T2 for all EOM was 24.6 ± 4.0 ms for HC, 24.0 ± 4.7 ms for MG patients and 27.4 ± 4.2 ms for the GO patient. Quantitative MRI at 7 T is feasible for measuring FF and muscle volumes of EOM in HC, MG and GO patients. The measured T2 was on average comparable with skeletal muscle, although with higher variation between subjects. The increased FF in the EOM in MG patients suggests that EOM involvement in MG is accompanied by fat replacement. The unexpected EOM volume increase in MG may provide novel insights into underlying pathophysiological processes.
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http://dx.doi.org/10.1002/nbm.4407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757175PMC
January 2021

Fatigue in patients with myasthenia gravis. A systematic review of the literature.

Neuromuscul Disord 2020 08 1;30(8):631-639. Epub 2020 Jul 1.

Department of Neurology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands.

Myasthenia Gravis (MG) is a chronic autoimmune disease affecting the neuromuscular junction. Although a hallmark of MG is muscle fatigability due to dysfunction of the neuromuscular junction (peripheral fatigue), a large number of MG patients also report symptoms of central fatigue, defined as an experienced lack of energy, physically and/or mentally. We systematically reviewed the literature on all aspects of central fatigue in MG. Results were categorized in 5 domains: prevalence, diagnosis, pathophysiology, treatment or impact. The prevalence of patient-reported fatigue varies between 42 and 82%, which is significantly higher than in control subjects. Fatigue severity is usually assessed with standardized questionnaires, but the choice of questionnaire varies widely between studies. The pathophysiology of fatigue is unknown, but it is strongly associated with depressive symptoms, female gender and disease severity. Fatigue is also highly prevalent in ocular MG and patients in remission, suggesting a multifactorial origin. Fatigued MG patients have a lower quality of life. Pharmacological treatment of MG is associated with improvement of fatigue and promising results have been found with physical and psychological training programs. Fatigue is a highly prevalent symptom of MG with a severe negative impact on quality of life. Physicians treating patients with MG should be aware of this symptom, as it may be treatable with physical or psychological training programs.
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http://dx.doi.org/10.1016/j.nmd.2020.06.010DOI Listing
August 2020

Combining timed GDNF and ChABC gene therapy to promote long-distance regeneration following ventral root avulsion and repair.

FASEB J 2020 08 16;34(8):10605-10622. Epub 2020 Jun 16.

Laboratory for Neuroregeneration, Netherlands Institute for Neuroscience, An Institute of the Royal Academy of Arts and Sciences, Amsterdam, the Netherlands.

Ventral root avulsion leads to severe motoneuron degeneration and prolonged distal nerve denervation. After a critical period, a state of chronic denervation develops as repair Schwann cells lose their pro-regenerative properties and inhibitory factors such as CSPGs accumulate in the denervated nerve. In rats with ventral root avulsion injuries, we combined timed GDNF gene therapy delivered to the proximal nerve roots with the digestion of inhibitory CSPGs in the distal denervated nerve using sustained lentiviral-mediated chondroitinase ABC (ChABC) enzyme expression. Following reimplantation of lumbar ventral roots, timed GDNF-gene therapy enhanced motoneuron survival up to 45 weeks and improved axonal outgrowth, electrophysiological recovery, and muscle reinnervation. Despite a timed GDNF expression period, a subset of animals displayed axonal coils. Lentiviral delivery of ChABC enabled digestion of inhibitory CSPGs for up to 45 weeks in the chronically denervated nerve. ChABC gene therapy alone did not enhance motoneuron survival, but led to improved muscle reinnervation and modest electrophysiological recovery during later stages of the regeneration process. Combining GDNF treatment with digestion of inhibitory CSPGs did not have a significant synergistic effect. This study suggests a delicate balance exists between treatment duration and concentration in order to achieve therapeutic effects.
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http://dx.doi.org/10.1096/fj.202000559RDOI Listing
August 2020

The degree of prematurity affects functional brain activity in preterm born children at school-age: An EEG study.

Early Hum Dev 2020 09 6;148:105096. Epub 2020 Jun 6.

Department of Child Neurology, Amsterdam University Medical Centers, De Boelelaan 1118, 1081 HZ Amsterdam, the Netherlands. Electronic address:

Prematurely born children are at higher risk for long-term adverse motor and cognitive outcomes. The aim of this paper was to compare quantitative measures derived from electroencephalography (EEG) between extremely (EP) and very prematurely (VP) born children at 9-10 years of age. Fifty-five children born <32 weeks' of gestation underwent EEG at 9-10 years of age and were assessed for motor development and cognitive outcome. Relative frequency power and functional connectivity, as measured by the Phase Lag Index (PLI), were calculated for all frequency bands. Per subject, power spectrum and functional connectivity results were averaged over all channels and pairwise PLI values to explore differences in global frequency power and functional connectivity between EP and VP children. Brain networks were constructed for the upper alpha frequency band using the Minimum Spanning Tree method and were compared between EP and VP children. In addition, the relationships between upper alpha quantitative EEG results and cognitive and motor outcomes were investigated. Relative power and functional connectivity were significantly higher in VP than EP children in the upper alpha frequency band, and VP children had more integrated networks. A strong positive correlation was found between relative upper alpha power and motor outcome whilst controlling for gestational age, age during EEG recording, and gender (ρ = 0.493, p = 0.004). These results suggest that 9-10 years after birth, the effects of the degree of prematurity can be observed in terms of alterations in functional brain activity and that motor deficits are associated with decreases in relative upper alpha power.
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http://dx.doi.org/10.1016/j.earlhumdev.2020.105096DOI Listing
September 2020

The face of myasthenia gravis.

Neurology 2020 07 10;95(2):89-90. Epub 2020 Jun 10.

From the Department of Neurology, Leiden University Medical Center, the Netherlands.

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http://dx.doi.org/10.1212/WNL.0000000000009782DOI Listing
July 2020

T relaxation-time mapping in healthy and diseased skeletal muscle using extended phase graph algorithms.

Magn Reson Med 2020 11 19;84(5):2656-2670. Epub 2020 Apr 19.

Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands.

Purpose: Multi-echo spin-echo (MSE) transverse relaxometry mapping using multi-component models is used to study disease activity in neuromuscular disease by assessing the T of the myocytic component (T ). Current extended phase graph algorithms are not optimized for fat fractions above 50% and the effects of inaccuracies in the T calibration remain unexplored. Hence, we aimed to improve the performance of extended phase graph fitting methods over a large range of fat fractions, by including the slice-selection flip angle profile, a through-plane chemical-shift displacement correction, and optimized calibration of T .

Methods: Simulation experiments were used to study the influence of the slice flip-angle profile with chemical-shift and T estimations. Next, in vivo data from four neuromuscular disease cohorts were studied for different T calibration methods and T estimations.

Results: Excluding slice flip-angle profiles or chemical-shift displacement resulted in a bias in T up to 10 ms. Furthermore, a wrongly calibrated T caused a bias of up to 4 ms in T . For the in vivo data, one-component calibration led to a lower T compared with a two-component method, and T decreased with increasing fat fractions.

Conclusion: In vivo data showed a decline in T for increasing fat fractions, which has important implications for clinical studies, especially in multicenter settings. We recommend using an extended phase graph-based model for fitting T from MSE sequences with two-component T calibration. Moreover, we recommend including the slice flip-angle profile in the model with correction for through-plane chemical-shift displacements.
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http://dx.doi.org/10.1002/mrm.28290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496817PMC
November 2020

Lowering the cutoff value for increment increases the sensitivity for the diagnosis of Lambert-Eaton myasthenic syndrome.

Muscle Nerve 2020 07 22;62(1):111-114. Epub 2020 Apr 22.

Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

Background: Increment of compound muscle action potential amplitude is a diagnostic hallmark of Lambert-Eaton myasthenic syndrome (LEMS). Making a diagnosis can be challenging, therefore, a proper cutoff for abnormal increment is highly relevant for improved recognition of this rare disease.

Methods: We determined the sensitivity and specificity of 60% and 100% cutoff values in all consecutive patients who underwent increment testing in our hospital from 1999 to 2016.

Results: We included 156 patients, 63 with LEMS and 93 without LEMS. Sensitivity of a 60% cutoff for increment testing was 77.8% (95% confidence interval 65.5%-87.3%) and 58.7% (45.6%-71.0%) for 100%. Specificity was 98.9% (94.2%-100%) and 100% (96.1%-100%) using a threshold of 60% and 100%, respectively.

Conclusions: Lowering the cutoff value for abnormal increment to 60% greatly increases sensitivity to diagnose LEMS without an overt loss in specificity.
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http://dx.doi.org/10.1002/mus.26885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318278PMC
July 2020

Myasthenia Gravis Impairment Index: Sensitivity for Change in Generalized Muscle Weakness.

J Neuromuscul Dis 2020 ;7(3):297-300

Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

Introduction: The recently developed Myasthenia Gravis Impairment Index (MGII) is a promising measure as it has less floor effects and a higher relative efficiency in its responsiveness to treatment effect compared to other MG measures. This study aimed at validating the MGII in a Dutch cohort of MG patients and analyzing the sensitivity of MGII compared to MG-ADL for changes in generalized weakness.

Methods: We analyzed (generalized items of; -gen) MGII, quantitative myasthenia gravis (QMG), Myasthenia Gravis Activities of Daily Living (MG-ADL), EQ-5D visual analog, Myasthenia Gravis Composite (MGC) and ACTIVLIM (an ADL questionnaire focusing on generalized weakness) scores in a prospective cohort of 99 MG patients. We investigated correlations between MGII and other outcome measures. We used a generalized linear model to assess whether MGIIgen had an additional sensitivity on top of MG-ADLgen for changes (Δ) in QMGgen in individual patients.

Results: MGII had a lower floor effect (4%) compared to QMG (6%), MG-ADL (11%) and MGC (16%). MGII correlated well with QMG (r = 0.68), MG-ADL (r = 0.83) and MGC (r = 0.74). As expected, the correlations with EQ visual analog and ACTIVLIM were lower (r = - 0.57 and - 0.48). ΔMGIIgen had an additional value on top of ΔMG-ADLgen in the prediction of ΔQMGgen (B = 0.54, p = 0.01).

Discussion: The MGII score was cross-culturally validated in a Dutch cohort of MG patients. MGII had a higher sensitivity for generalized weakness than MG-ADL.
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http://dx.doi.org/10.3233/JND-200484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369124PMC
March 2021

Repetitive ocular vestibular evoked myogenic potentials in myasthenia gravis.

Neurology 2020 04 26;94(16):e1693-e1701. Epub 2020 Mar 26.

From the Department of Neurology (R.H.P.d.M., K.R.K., U.A.B, J.J.V., M.R.T.), Leiden University Medical Center, the Netherlands; and Departments of Ophthalmology (M.A.W., K.P.W.) and Neurology (K.P.W.), University Hospital Zurich, University of Zurich, Switzerland.

Objective: To validate the repetitive ocular vestibular evoked myogenic potentials (RoVEMP) test for diagnostic use in myasthenia gravis (MG) and to investigate its value in diagnostically challenging subgroups.

Methods: The RoVEMP test was performed in 92 patients with MG, 22 healthy controls, 33 patients with a neuromuscular disease other than MG (neuromuscular controls), 4 patients with Lambert-Eaton myasthenic syndrome, and 2 patients with congenital myasthenic syndrome.

Results: Mean decrement was significantly higher in patients with MG (28.4% ± 32.2) than in healthy controls (3.2% ± 13.9; < 0.001) or neuromuscular controls (3.8% ± 26.9; < 0.001). With neuromuscular controls as reference, a cutoff of ≥14.3% resulted in a sensitivity of 67% and a specificity of 82%. The sensitivity of the RoVEMP test was 80% in ocular MG and 63% in generalized MG. The RoVEMP test was positive in 6 of 7 patients with seronegative MG (SNMG) with isolated ocular weakness. Of 10 patients with SNMG with negative repetitive nerve stimulation (RNS) results, 73% had an abnormal RoVEMP test. The magnitude of decrement was correlated with the time since the last intake of pyridostigmine (B = 5.40; = 0.019).

Conclusions: The RoVEMP test is a new neurophysiologic test that, in contrast to RNS and single-fiber EMG, is able to measure neuromuscular transmission of extraocular muscles, which are the most affected muscles in MG. Especially in diagnostically challenging patients with negative antibody tests, negative RNS results, and isolated ocular muscle weakness, the RoVEMP test has a clear added value in supporting the diagnosis of MG.

Classification Of Evidence: This study provides Class III evidence that RoVEMP distinguishes MG from other neuromuscular diseases.
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http://dx.doi.org/10.1212/WNL.0000000000009306DOI Listing
April 2020

Emerging therapies for autoimmune myasthenia gravis: Towards treatment without corticosteroids.

Neuromuscul Disord 2020 02 14;30(2):111-119. Epub 2019 Dec 14.

Department of Neurology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.

Myasthenia gravis is an autoimmune disease characterized by dysfunction of the neuromuscular junction. Current treatment is based on lifestyle advice, symptomatic treatment, immunosuppressive drugs and thymectomy. Corticosteroids remain the cornerstone of treatment beside symptomatic medication due to their low cost, wide availability and fast mode of action. However, long term steroid use carries substantial risks of severe adverse side effects. Therefore, non-steroidal immunosuppressive drugs are commonly added to the treatment. Unfortunately, they have a delayed-onset effect and evidence of their efficacy appears to be difficult to obtain. Several trials using drugs that have had clear positive results in other immunological disorders have failed in myasthenia. This failure may in part be related to difficulties in the design of clinical trial for myasthenia, which has a fluctuating disease course involving weakness that may be difficult to assess quantitively. This problem is exacerbated by the tendency of most clinical trials to select patients with a stable, but severe disease. Future trials should: select patients with weakness and fatigability that is completely explained by their myasthenia gravis, use a design that avoids the exclusion of patients with recent changes in medication, and explore the possibilities to completely avoid the use of corticosteroids.
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http://dx.doi.org/10.1016/j.nmd.2019.12.003DOI Listing
February 2020

Heterogeneity and shifts in distribution of muscle weakness in myasthenia gravis.

Neuromuscul Disord 2019 09 26;29(9):664-670. Epub 2019 Jul 26.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

The distribution of muscle weakness in myasthenia gravis (MG) patients with acetylcholine receptor (AChR) antibodies is highly variable. As muscle groups respond differently to therapeutic interventions, it is important to acknowledge this variability. We analysed the distribution of muscle weakness in 225 AChR MG patients over time. On the basis of combinations of muscle weakness, seven phenotypes were defined: 'ocular' (O), 'bulbar' (B), 'neck/limbs/respiratory' (NLR), or a combination (O+B, O+NLR, B+NLR and O+B+NLR). MG remained restricted to ocular weakness in 5%, whereas 7% never had ocular weakness. At last follow-up, ocular or bulbar weakness had resolved more frequently than NLR weakness (40%, 38% and 25%; p = 0.003, respectively). Patients with O, B or OB phenotype at baseline had a higher age at onset and were more frequently male than patients with NLR, ONLR, BNLR or OBNLR phenotype (52.7 ± 17.5 vs. 44.0 ± 18.9; p = 0.007 and 64% vs. 37%; p = 0.002, respectively). MG patients have heterogeneous distributions of muscle weakness and frequently shift between phenotypes. The phenotypic variations found in AChR MG suggest that also other factors aside from the AChR antibody mediated immune response are of importance in determining the disease expression in MG.
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http://dx.doi.org/10.1016/j.nmd.2019.07.006DOI Listing
September 2019

Enhanced regeneration and reinnervation following timed GDNF gene therapy in a cervical ventral root avulsion.

Exp Neurol 2019 11 16;321:113037. Epub 2019 Aug 16.

Laboratory for Neuroregeneration, Netherlands Institute for Neuroscience, An institute of the Royal Academy of Arts and Sciences, Amsterdam, The Netherlands; Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognition research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Avulsion of spinal nerve roots is a severe proximal peripheral nerve lesion. Despite neurosurgical repair, recovery of function in human patients is disappointing, because spinal motor neurons degenerate progressively, axons grow slowly and the distal Schwann cells which are instrumental to supporting axon extension lose their pro-regenerative properties. We have recently shown that timed GDNF gene therapy (dox-i-GDNF) in a lumbar plexus injury model promotes axon regeneration and improves electrophysiological recovery but fails to stimulate voluntary hind paw function. Here we report that dox-i-GDNF treatment following avulsion and re-implantation of cervical ventral roots leads to sustained motoneuron survival and recovery of voluntary function. These improvements were associated with a twofold increase in motor axon regeneration and enhanced reinnervation of the hand musculature. In this cervical model the distal hand muscles are located 6,5 cm from the reimplantation site, whereas following a lumber lesion this distance is twice as long. Since the first signs of muscle reinnervation are observed 6 weeks after the lesion, this suggests that regenerating axons reached the hand musculature before a critical state of chronic denervation has developed. These results demonstrate that the beneficial effects of timed GDNF-gene therapy are more robust following spinal nerve avulsion lesions that allow reinnervation of target muscles within a relatively short time window after the lesion. This study is an important step in demonstrating the potential of timed GDNF-gene therapy to enhance axon regeneration after neurosurgical repair of a severe proximal nerve lesion.
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http://dx.doi.org/10.1016/j.expneurol.2019.113037DOI Listing
November 2019

Ocular Weakness in Myasthenia Gravis: Changes in Affected Muscles are a Distinct Clinical Feature.

J Neuromuscul Dis 2019 ;6(3):369-376

Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

Introduction: In this study we quantitatively describe ocular weakness patterns in myasthenia gravis (MG) to help neurologists in making the clinical diagnosis and to investigate how the current outcome measures reflect ocular weakness in MG.

Methods: We investigated ptosis and diplopia patterns in a retro- and prospective cohort of 306 MG patients. Diplopia was systematically examined by testing extra-ocular muscle (EOM) fatigability in two horizontal and four oblique directions for 60 seconds.

Results: Of patients with initial symmetric ptosis, 40% developed asymmetric ptosis at the second visit. Changes in form of ptosis occurred less often in seronegative MG patients (50%) than in patients with acetylcholine receptor (AChR) antibodies (70%) or muscle-specific kinase (MuSK) antibodies (69%) (p = 0.038). Of patients with diplopia on the first visit, double vision contained both a vertical and horizontal component in 95%. At the second visit, 83% manifested diplopia in other gaze directions. The mean time (in seconds) to diplopia was 11.6±14.0 and the mean time to ptosis was 27.6±19.8. Diplopia or ptosis manifested within 30 seconds in 87% and 58%, respectively. Patients who manifested diplopia after 30 seconds, reported no limitations due to diplopia.

Discussion: Changes in the gaze directions in which diplopia occurs or ptosis side occur frequently in MG. In diagnostically challenging cases, we recommend testing ptosis and diplopia in multiple gaze directions for 30-60 seconds during at least two follow-up visits to maximize the chance of observing changes in ocular weakness patterns.
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http://dx.doi.org/10.3233/JND-190407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839603PMC
February 2020

A systematic review of MEG-based studies in Parkinson's disease: The motor system and beyond.

Hum Brain Mapp 2019 06 7;40(9):2827-2848. Epub 2019 Mar 7.

Amsterdam UMC, location VUmc, Department of Neurology, Amsterdam Neuroscience, Amsterdam, the Netherlands.

Parkinson's disease (PD) is accompanied by functional changes throughout the brain, including changes in the electromagnetic activity recorded with magnetoencephalography (MEG). An integrated overview of these changes, its relationship with clinical symptoms, and the influence of treatment is currently missing. Therefore, we systematically reviewed the MEG studies that have examined oscillatory activity and functional connectivity in the PD-affected brain. The available articles could be separated into motor network-focused and whole-brain focused studies. Motor network studies revealed PD-related changes in beta band (13-30 Hz) neurophysiological activity within and between several of its components, although it remains elusive to what extent these changes underlie clinical motor symptoms. In whole-brain studies PD-related oscillatory slowing and decrease in functional connectivity correlated with cognitive decline and less strongly with other markers of disease progression. Both approaches offer a different perspective on PD-specific disease mechanisms and could therefore complement each other. Combining the merits of both approaches will improve the setup and interpretation of future studies, which is essential for a better understanding of the disease process itself and the pathophysiological mechanisms underlying specific PD symptoms, as well as for the potential to use MEG in clinical care.
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http://dx.doi.org/10.1002/hbm.24562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594068PMC
June 2019

A prospective, double-blind, randomized, placebo-controlled study on the efficacy and safety of influenza vaccination in myasthenia gravis.

Vaccine 2019 02 16;37(7):919-925. Epub 2019 Jan 16.

Department of Neurology, Leiden University Medical Center, the Netherlands.

Objective: To investigate the efficacy and safety of an influenza vaccination in patients with myasthenia gravis with acetylcholine receptor antibodies (AChR MG).

Methods: An influenza vaccination or placebo was administered to 47 AChR MG patients. Before and 4 weeks after administration blood samples and clinical outcome scores were obtained. Antibodies to the vaccine strains A/California/7/2009 (H1N1)pdm09, A/Hong Kong/4801/14 (H3N2) and B/Brisbane/060/08 were measured using the hemagglutination-inhibition (HI) assay and disease-specific AChR antibody titers were measured with a radio-immunoprecipitation assay. Forty-seven healthy controls (HC) were vaccinated with the same influenza vaccine to compare antibody titers.

Results: A post-vaccination, seroprotective titer (HI ≥ 1:40) was achieved in 89.4% of MG patients vs. 93.6% in healthy controls for the H3N2 strain, 95.7% vs 97.9% for the H1N1 strain and 46.8 vs 51% for the B-strain. A seroprotective titer for all three strains of the seasonal influenza vaccine was reached in 40.4% (19/47) of the MG group and in 51% (24/47) of the HC group. Immunosuppressive medication did not significantly influence post geomean titers (GMT). The titers of disease-specific AChR antibodies were unchanged 4 weeks after vaccination. The clinical outcome scores showed no exacerbation of MG symptoms.

Conclusion: The antibody response to an influenza vaccination in patients with AChR MG was not different from that in healthy subjects, even in AChR MG patients using immunosuppressive medication. Influenza vaccination does not induce an immunological or clinical exacerbation of AChR MG.

Clinical Trial Registry: The influenza trial is listed on clinicaltrialsregister.eu under 2016-003138-26.
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http://dx.doi.org/10.1016/j.vaccine.2019.01.007DOI Listing
February 2019

Timed GDNF gene therapy using an immune-evasive gene switch promotes long distance axon regeneration.

Brain 2019 02;142(2):295-311

Laboratory for Neuroregeneration, Netherlands Institute for Neuroscience, an institute of the Royal Academy of Arts and Sciences, Amsterdam, The Netherlands.

Neurosurgical repair in patients with proximal nerve lesions results in unsatisfactory recovery of function. Gene therapy for neurotrophic factors is a powerful strategy to promote axon regeneration. Glial cell line-derived neurotrophic factor (GDNF) gene therapy promotes motor neuron survival and axon outgrowth; however, uncontrolled delivery of GDNF results in axon entrapment. We report that time-restricted GDNF expression (1 month) using an immune-evasive doxycycline-inducible gene switch attenuated local axon entrapment in avulsed reimplanted ventral spinal roots, was sufficient to promote long-term motor neuron survival (24 weeks) and facilitated the recovery of compound muscle action potentials by 8 weeks. These improvements were associated with an increase in long-distance regeneration of motor axons. In contrast, persistent GDNF expression impaired axon regeneration by inducing axon entrapment. These findings demonstrate that timed expression can resolve the deleterious effect of uncontrolled growth factor delivery and shows that inducible growth factor gene therapy can be employed to enhance the efficacy of axon regeneration after neurosurgical repair of a proximal nerve lesion in rats. This preclinical study is an important step in the ongoing development of a neurotrophic factor gene therapy for patients with severe proximal nerve lesions.
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http://dx.doi.org/10.1093/brain/awy340DOI Listing
February 2019

Clinical correlates of quantitative EEG in Parkinson disease: A systematic review.

Neurology 2018 11 5;91(19):871-883. Epub 2018 Oct 5.

From the Department of Neurology (V.J.G., J.M., J.J.v.H., M.R.T., M.F.C.), Leiden University Medical Center; Department of Clinical Neurophysiology and MEG Center (V.J.G., L.I.B., A.A.G., C.J.S.) and Alzheimer Center, Department of Neurology (A.A.G.), VU University Medical Center, Amsterdam; and Department of Neurology (M.F.C.), Haga Teaching Hospital, The Hague, the Netherlands.

Objective: To assess the relevance of quantitative EEG (qEEG) measures as outcomes of disease severity and progression in Parkinson disease (PD).

Methods: Main databases were systematically searched (January 2018) for studies of sufficient methodologic quality that examined correlations between clinical symptoms of idiopathic PD and cortical (surface) qEEG metrics.

Results: Thirty-six out of 605 identified studied were included. Results were classified into 4 domains: cognition (23 studies), motor function (13 studies), responsiveness to interventions (7 studies), and other (10 studies). In cross-sectional studies, EEG slowing correlated with global cognitive impairment and with diffuse deterioration in other domains. In longitudinal studies, decreased dominant frequency and increased θ power, reflecting EEG slowing, were biomarkers of cognitive deterioration at an individual level. Results on motor dysfunction and treatment yielded contrasting findings. Studies on functional connectivity at an individual level and longitudinal studies on other domains or on connectivity measures were lacking.

Conclusion: qEEG measures reflecting EEG slowing, particularly decreased dominant frequency and increased θ power, correlate with cognitive impairment and predict future cognitive deterioration. qEEG could provide reliable and widely available biomarkers for nonmotor disease severity and progression in PD, potentially promoting early diagnosis of nonmotor symptoms and an objective monitoring of progression. More studies are needed to clarify the role of functional connectivity and network analyses.
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http://dx.doi.org/10.1212/WNL.0000000000006473DOI Listing
November 2018

Quantitative EEG reflects non-dopaminergic disease severity in Parkinson's disease.

Clin Neurophysiol 2018 08 29;129(8):1748-1755. Epub 2018 May 29.

Department of Neurology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

Objective: In Parkinson's Disease (PD), measures of non-dopaminergic systems involvement may reflect disease severity and therefore contribute to patient-selection for Deep Brain Stimulation (DBS). There is currently no determinant for non-dopaminergic disease severity. In this exploratory study, we investigated whether quantitative EEG reflects non-dopaminergic disease severity in PD.

Methods: Sixty-three consecutive PD patients screened for DBS were included (mean age 62.4 ± 7.2 years, 32% females). Relative spectral powers and the Phase-Lag-Index (PLI) reflecting functional connectivity were analysed on routine EEGs. Non-dopaminergic disease severity was quantified using the SENS-PD score and its subdomains; motor-severity was quantified using the MDS-UPDRS III.

Results: The SENS-PD composite score correlated with a spectral ratio ((δ + θ)/(α1 + α2 + β) powers) (global spectral ratio Pearson's r = 0.4, 95% Confidence Interval (95%CI) 0.1-0.6), and PLI in the α2 band (10-13 Hz) (r = -0.3, 95%CI -0.5 to -0.1). These correlations seem driven by the subdomains cognition and psychotic symptoms. MDS-UPDRS III was not significantly correlated with EEG parameters.

Conclusions: EEG slowing and reduced functional connectivity in the α2 band were associated with non-dopaminergic disease severity in PD.

Significance: The described EEG parameters may have complementary utility as determinants of non-dopaminergic involvement in PD.
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http://dx.doi.org/10.1016/j.clinph.2018.04.752DOI Listing
August 2018

Video-EEG during tilt-table testing is an invaluable aid for understanding syncope.

Clin Neurophysiol 2018 07 24;129(7):1498-1499. Epub 2018 Apr 24.

Cardiac Arrhythmia and Syncope Centre, Department of Medicine (Cardiovascular Division), University of Minnesota Medical School, Minneapolis, MN, USA.

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http://dx.doi.org/10.1016/j.clinph.2018.03.047DOI Listing
July 2018

Corneal nerve fiber size adds utility to the diagnosis and assessment of therapeutic response in patients with small fiber neuropathy.

Sci Rep 2018 03 16;8(1):4734. Epub 2018 Mar 16.

Weill Cornell Medicine-Qatar, Doha, Qatar.

Small fiber neuropathy (SFN) is a common feature of many inflammatory diseases, often presenting with pain and disability. SFN is diagnosed using symptoms, thermal threshold testing, and intra-epidermal nerve fiber quantification. Corneal confocal microscopy (CCM) is an ophthalmic imaging technique which non-invasively quantifies corneal nerve fiber (CNF) density, branch density and length, and has comparable diagnostic and superior ability to identify nerve regeneration compared to skin biopsy. CNF size (width and area) depends upon the number of fibers within each nerve, as well as pathology (e.g., swelling), and may provide additional sensitivity to diagnose SFN and identify nerve repair. We have compared the utility of the standard CCM variables employed to CNF size in patients with diabetic sensorimotor polyneuropathy or sarcoidosis-associated SFN, and in patients with SFN following cibinetide administration, an agent which promotes nerve repair. The results show that: 1) CNF width distribution and area depend upon neuropathy severity; 2) CNF area, density, branch density and length possess comparable discriminatory power for diagnosing neuropathy; 3) CNF area is related to length by a quadratic function which is predictive for both healthy subjects and those with SFN; 4) CNF area is a useful variable for quantifying change in CNF morphology.
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http://dx.doi.org/10.1038/s41598-018-23107-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856845PMC
March 2018

Distinct representation of muscle weakness in QMG and MG-ADL.

Lancet Neurol 2018 03;17(3):204-205

Department of Neurology, Leiden University Medical Centre, 2333 ZA Leiden, Netherlands.

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http://dx.doi.org/10.1016/S1474-4422(18)30037-1DOI Listing
March 2018

Outcome of Carpal Tunnel Release and the Relation With Depression.

J Hand Surg Am 2018 01 23;43(1):16-23. Epub 2017 Sep 23.

Department of Neurosurgery, Leiden University Medical Centre, Leiden, The Netherlands.

Purpose: To examine the relation between depressive symptoms and outcome of carpal tunnel release (CTR).

Methods: Prospective study in a general hospital with data collection at baseline and 3 and 12 months after CTR. We quantified depressive symptoms using the Center for Epidemiologic Studies Depression (CES-D) scale and performed multivariable analyses on 2 outcome measures: (1) carpal tunnel syndrome (CTS) symptoms (Boston Carpal Tunnel Questionnaire [BCTQ]) and (2) palmar pain, focusing on preoperative CES-D and BCTQ score, sex, age, alcohol use, diabetes, and severity of nerve conduction abnormalities.

Results: We included 227 patients. Before surgery, patients with depression had a higher BCTQ score than patients without depression. After 1 year, depressed patients had a higher BCTQ score and more palmar pain. The CES-D decreased by a median of 2 points from baseline to 1 year. This correlated with the decrease in BCTQ score. Multivariable analyses showed that preoperative depression had a small but statistically significant influence on palmar pain, but not on postoperative BCTQ score.

Conclusions: Depression is not an independent predictor of residual CTS symptoms 1 year after CTR. Depressive symptoms in patients with CTS decrease after CTR, along with a decrease in CTS symptoms. The nature of this relationship is unknown. Patients with CTS and depression may expect a somewhat higher degree of palmar pain after CTR, the clinical relevance of which is small.

Type Of Study/level Of Evidence: Prognostic II.
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http://dx.doi.org/10.1016/j.jhsa.2017.08.020DOI Listing
January 2018

Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain.

Invest Ophthalmol Vis Sci 2017 05;58(6):BIO52-BIO60

Araim Pharmaceuticals, Tarrytown, New York, United States.

Purpose: Sarcoidosis frequently is complicated by small nerve fiber loss (SNFL), which can be quantified using corneal confocal microscopy (CCM). Prior studies suggest that the innate repair receptor agonist cibinetide reverses corneal nerve loss. This phase 2b, 28-day, randomized trial of 64 subjects with sarcoid-associated SNFL and neuropathic pain assessed the effect of cibinetide on corneal nerve fiber area (CNFA) and regenerating intraepidermal fibers (GAP-43+) as surrogate endpoints for disease modification, pain severity, and functional capacity (6-minute walk test [6MWT]).

Methods: Cibinetide (1, 4, or 8 mg/day) was compared to placebo. The primary study endpoint was a change in CNFA at 28 days.

Results: The placebo-corrected mean change from baseline CNFA (μm2) at day 28 was 109 (95% confidence interval [CI], -429, 647), 697 (159, 1236; P = 0.012), and 431 (-130, 992) in the 1, 4, and 8 mg groups, respectively. Intraepidermal GAP-43+ fibers increased in the 4 mg group (P = 0.035). Further, changes in CNFA correlated with changes in GAP-43+ (ρ = 0.575; P = 0.025) and 6MWT (ρ = 0.645; P = 0.009). Pain improved significantly in all groups, with subjects having moderate-severe pain reporting a clinically meaningful placebo-corrected decrease in pain intensity in the 4 mg group (P = 0.157).

Conclusions: Cibinetide significantly increased small nerve fiber abundance in the cornea and skin, consistent with a disease modifying effect. The relationships between CNFA and other clinical measures of disease support its use as a surrogate endpoint to assess potential disease modifying therapies for neuropathy.
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http://dx.doi.org/10.1167/iovs.16-21291DOI Listing
May 2017
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