Malou Janssen

Smooth Pursuit Eye Movement Deficits in Patients with Whiplash and Neck Pain are Modulated by Target Predictability

Study Design. This is a cross-sectional study. Objective. The purpose of this study is to support and extend previous observations on oculomotor disturbances in patients with neck pain and whiplash-associated disorders (WADs) by systematically investigating the effect of static neck torsion on smooth pursuit in response to both predictably and unpredictably moving targets using video-oculography. Summary of Background Data. Previous studies showed that in patients with neck complaints, for instance due to WAD, extreme static neck torsion deteriorates smooth pursuit eye movements in response to predictably moving targets compared with healthy controls. Methods. Eye movements in response to a smoothly moving target were recorded with video-oculography in a heterogeneous group of 55 patients with neck pain (including 11 patients with WAD) and 20 healthy controls. Smooth pursuit performance was determined while the trunk was fixed in 7 static rotations relative to the head (from 45° to the left to 45° to right), using both predictably and unpredictably moving stimuli. Results. Patients had reduced smooth pursuit gains and smooth pursuit gain decreased due to neck torsion. Healthy controls showed higher gains for predictably moving targets compared with unpredictably moving targets, whereas patients with neck pain had similar gains in response to both types of target movements. In 11 patients with WAD, increased neck torsion decreased smooth pursuit performance, but only for predictably moving targets. Conclusion. Smooth pursuit of patients with neck pain is affected. The previously reported WAD-specific decline in smooth pursuit due to increased neck torsion seems to be modulated by the predictability of the movement of the target. The observed oculomotor disturbances in patients with WAD are therefore unlikely to be induced by impaired neck proprioception alone. Level of Evidence: 3

Phenotypic and functional characterization of T cells in white matter lesions of multiple sclerosis patients

T cells are considered pivotal in the pathology of multiple sclerosis (MS), but their function and antigen specificity are unknown. To unravel the role of T cells in MS pathology, we performed a comprehensive analysis on T cells recovered from paired blood, cerebrospinal fluid (CSF), normal-appearing white matter (NAWM) and white matter lesions (WML) from 27 MS patients with advanced disease shortly after death. The differentiation status of T cells in these compartments was determined by ex vivo flow cytometry and immunohistochemistry. T-cell reactivity in short-term T-cell lines (TCL), generated by non-specific stimulation of T cells recovered from the same compartments, was determined by intracellular cytokine flow cytometry. Central memory T cells predominated in CSF and effector memory T cells were enriched in NAWM and WML. WML-derived CD8+ T cells represent chronically activated T cells expressing a cytotoxic effector phenotype (CD95L and granzyme B) indicative for local antigenic stimulation (CD137). The same lesions also contained higher CD8+ T-cell frequencies expressing co-inhibitory (TIM3 and PD1) and co-stimulatory (ICOS) T-cell receptors, yet no evidence for T-cell senescence (CD57) was observed. The oligoclonal T-cell receptor (TCR) repertoire, particularly among CD8+ T cells, correlated between TCL generated from anatomically separated WML of the same MS patient, but not between paired NAWM and WML. Whereas no substantial T-cell reactivity was detected towards seven candidate human MS-associated autoantigens (cMSAg), brisk CD8+ T-cell reactivity was detected in multiple WML-derived TCL towards autologous Epstein–Barr virus (EBV) infected B cells (autoBLCL). In one MS patient, the T-cell response towards autoBLCL in paired intra-lesional TCL was dominated by TCRVβ2+CD8+ T cells, which were localized in the parenchyma of the respective tissues expressing a polarized TCR and CD8 expression suggesting immunological synapse formation in situ. Collectively, the data suggest the involvement of effector memory cytotoxic T cells recognizing antigens expressed by autoBLCL, but not the assayed human cMSAg, in WML of MS patients.

Eye movements in patients with Whiplash Associated Disorders: A systematic review

BackgroundMany people with Whiplash Associated Disorders (WAD) report problems with vision, some of which may be due to impaired eye movements. Better understanding of such impaired eye movements could improve diagnostics and treatment strategies.This systematic review surveys the current evidence on changes in eye movements of patients with WAD and explains how the oculomotor system is tested.MethodsNine electronic data bases were searched for relevant articles from inception until September 2015. All studies which investigated eye movements in patients with WAD and included a healthy control group were screened for inclusion. Qualifying studies were retrieved and independently assessed for methodological quality using the Methodology Checklists provided by the Scottish Intercollegiate Guidelines Network.ResultsFourteen studies out of 833 unique hits were included. Ten studies reported impaired eye movements in patients with WAD and in four studies no differences compared to healthy controls were found. Different methods of eye movement examination were used in the ten studies: in five studies, the smooth pursuit neck torsion test was positive, in two more the velocity and stability of head movements during eye-coordination tasks were decreased, and in another three studies the cervico-ocular reflex was elevated.ConclusionsOverall the reviewed studies show deficits in eye movement in patients with WAD, but studies and results are varied. When comparing the results of the 14 relevant publications, one should realise that there are significant differences in test set-up and patient population. In the majority of studies patients show altered compensatory eye movements and smooth pursuit movements which may impair the coordination of head and eyes.

Cervico-ocular Reflex Is Increased in People With Nonspecific Neck Pain

Background Neck pain is a widespread complaint. People experiencing neck pain often present an altered timing in contraction of cervical muscles. This altered afferent information elicits the cervico-ocular reflex (COR), which stabilizes the eye in response to trunk-to-head movements. The vestibulo-ocular reflex (VOR) elicited by the vestibulum is thought to be unaffected by afferent information from the cervical spine. Objective The aim of the study was to measure the COR and VOR in people with nonspecific neck pain. Design This study utilized a cross-sectional design in accordance with the STROBE statement. Methods An infrared eye-tracking device was used to record the COR and the VOR while the participant was sitting on a rotating chair in darkness. Eye velocity was calculated by taking the derivative of the horizontal eye position. Parametric statistics were performed. Results The mean COR gain in the control group (n=30) was 0.26 (SD=0.15) compared with 0.38 (SD=0.16) in the nonspecific neck pain group (n=37). Analyses of covariance were performed to analyze differences in COR and VOR gains, with age and sex as covariates. Analyses of covariance showed a significantly increased COR in participants with neck pain. The VOR between the control group, with a mean VOR of 0.67 (SD=0.17), and the nonspecific neck pain group, with a mean VOR of 0.66 (SD=0.22), was not significantly different. Limitations Measuring eye movements while the participant is sitting on a rotating chair in complete darkness is technically complicated. Conclusions This study suggests that people with nonspecific neck pain have an increased COR. The COR is an objective, nonvoluntary eye reflex and an unaltered VOR. This study shows that an increased COR is not restricted to patients with traumatic neck pain.

Intrathecal CD4(+) and CD8(+) T-cell responses to endogenously synthesized candidate disease-associated human autoantigens in multiple sclerosis patients.

MS pathology is potentially orchestrated by autoreactive T cells, but the antigens recognized remain unknown. A novel APC/T‐cell platform was developed to determine intrathecal CD4+ and CD8+ T‐cell responses to candidate MS‐associated autoantigens (cMSAg) in clinically isolated syndrome (CIS, n = 7) and MS (n = 6) patients. Human cMSAg encoding open reading frames (n = 8) were cloned into an Epstein–Barr virus (EBV)‐based vector to express cMSAg at high levels in EBV‐transformed B‐cells (BLCLs). Human cMSAg cloned were myelin‐associated and ‐oligodendrocyte glycoprotein, myelin basic protein, proteolipid protein, ATP‐dependent potassium channel ATP‐dependent inwards rectifying potassium channel 4.1, S100 calcium‐binding protein B, contactin‐2, and neurofascin. Transduced BLCLs were used as autologous APC in functional T‐cell assays to determine cMSAg‐specific T‐cell frequencies in cerebrospinal fluid derived T‐cell lines (CSF‐TCLs) by intracellular IFN‐γ flow cytometry. Whereas all CSF‐TCL responded strongly to mitogenic stimulation, no substantial T‐cell reactivity to cMSAg was observed. Contrastingly, measles virus fusion protein‐specific CD4+ and CD8+ T‐cell clones, used as control of the APC/T‐cell platform, efficiently recognized transduced BLCL expressing their cognate antigen. The inability to detect substantial T‐cell reactivity to eight human endogenously synthesized cMSAg in autologous APC do not support their role as prominent intrathecal T‐cell target antigens in CIS and MS patients early after onset of disease.

T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention

Interleukin-17-expressing CD4+ T helper 17 (Th17) cells are considered as critical regulators of multiple sclerosis disease activity. However, depending on the species and pro-inflammatory milieu, Th17 cells are functionally heterogeneous, consisting of subpopulations that differentially produce interleukin-17, interferon-gamma and granulocyte macrophage colony-stimulating factor. In the current study, we studied distinct effector phenotypes of human Th17 cells and their correlation with disease activity in multiple sclerosis patients. T helper memory populations single- and double-positive for C-C chemokine receptor 6 (CCR6) and CXC chemokine receptor 3 (CXCR3) were functionally assessed in blood and/or cerebrospinal fluid from a total of 59 patients with clinically isolated syndrome, 35 untreated patients and 24 natalizumab-treated patients with relapsing-remitting multiple sclerosis, and nine patients with end-stage multiple sclerosis. Within the clinically isolated syndrome group, 23 patients had a second attack within 1 year and 26 patients did not experience subsequent attacks during a follow-up of >5 years. Low frequencies of T helper 1 (Th1)-like Th17 (CCR6+CXCR3+), and not Th17 (CCR6+CXCR3-) effector memory populations in blood strongly associated with a rapid diagnosis of clinically definite multiple sclerosis. In cerebrospinal fluid of clinically isolated syndrome and relapsing-remitting multiple sclerosis patients, Th1-like Th17 effector memory cells were abundant and showed increased production of interferon-gamma and granulocyte macrophage colony-stimulating factor compared to paired CCR6+ and CCR6-CD8+ T cell populations and their blood equivalents after short-term culturing. Their local enrichment was confirmed ex vivo using cerebrospinal fluid and brain single-cell suspensions. Across all pro-inflammatory T helper cells analysed in relapsing-remitting multiple sclerosis blood, Th1-like Th17 subpopulation T helper 17.1 (Th17.1; CCR6+CXCR3+CCR4-) expressed the highest very late antigen-4 levels and selectively accumulated in natalizumab-treated patients who remained free of clinical relapses. This was not found in patients who experienced relapses during natalizumab treatment. The enhanced potential of Th17.1 cells to infiltrate the central nervous system was supported by their predominance in cerebrospinal fluid of early multiple sclerosis patients and their preferential transmigration across human brain endothelial layers. These findings reveal a dominant contribution of Th1-like Th17 subpopulations, in particular Th17.1 cells, to clinical disease activity and provide a strong rationale for more specific and earlier use of T cell-targeted therapy in multiple sclerosis.

Eye stabilization reflexes in traumatic and non-traumatic chronic neck pain patients

BACKGROUND Many chronic neck pain patients experience problems with vision. These problems are possibly induced by deviations of the eye stabilization reflexes. It is not known whether these eye reflex alterations occur both in traumatic and non-traumatic neck pain patients. OBJECTIVE To investigate if the cervico-ocular reflex (COR) and the vestibulo-ocular reflex (VOR) are changed in tertiary care patients with prolonged, chronic neck pain with various origin of complaints. DESIGN Cross sectional study. METHODS Ninety-one chronic neck pain patients were subdivided into three groups by origin of complaints, and compared with healthy controls. COR and VOR gains were measured with an infrared eye tracking device with the subject sitting on a rotating chair in a darkened room and with the head fixed. RESULTS Neck pain patients had a higher COR gain (median 0.41, IQR 0.289) compared with healthy controls (median 0.231, IQR 0.179). The mean COR gain did not differ between the three patient groups (Whiplash Associated Disorders 0.444 (SD 0.221); traumatic 0.397 (SD0.205); non-traumatic 0.468 (SD0.236)). There was no difference in VOR gain between the groups. CONCLUSION Chronic neck pain patients, who already received primary care, still have an elevated cervico-ocular reflex. The origin of complaints did not seem to be associated with this deviant oculomotor behavior.

Small effects of neck torsion on healthy human voluntary eye movements

PurposeAlthough several lines of research suggest that the head and eye movement systems interact, previous studies have reported that applying static neck torsion does not affect smooth pursuit eye movements in healthy controls. This might be due to several methodological issues. Here we systematically investigated the effect of static neck torsion on smooth pursuit and saccadic eye movement behavior in healthy subjects.MethodsIn twenty healthy controls, we recorded eye movements with video-oculography while their trunk was in static rotation relative to the head (7 positions from 45° to the left to 45° to right). The subject looked at a moving dot on the screen. In two separate paradigms, we evoked saccadic and smooth pursuit eye movements, using both predictable and unpredictable target motions.ResultsSmooth pursuit gain and saccade peak velocity decreased slightly with increasing neck torsion. Smooth pursuit gains were higher for predictable target movements than for unpredictable target movements. Saccades to predictable targets had lower latencies, but reduced gains compared to saccades to unpredictable targets. No interactions between neck torsion and target predictability were observed.ConclusionApplying static neck torsion has small effects on voluntary eye movements in healthy subjects. These effects are not modulated by target predictability.

Nudging in de Nederlandse samenleving

hol terwijl in de groep niet-geneeskunde studenten juist veel personen wel op de hoogte hiervan blijken te zijn. De in de enquête voorgestelde maatregel om alcoholische drank (2x) duurder te maken om alcoholgebruik terug te dringen werd door 81% van de respondenten als effectief beoordeeld. Een advies van de huisarts zou slechts door 74% worden opgevolgd. Het advies van de huisarts wordt iets vaker opgevolgd door de geneeskundestudenten met 77% dan door overige studenten met 72%. Naast het duurder maken van alcohol komen een aantal duidelijke ideeën uit het onderzoek naar voren die als preventieve maatregelen door de overheid zouden kunnen worden uitgevoerd, zoals weergegeven in Box 1.