J. De Keyser

Imidazoline receptors, non-adrenergic idazoxan binding sites and α2-adrenoceptors in the human central nervous system

Both [3H]clonidine and [3H]idazoxan bind to alpha 2 adrenoceptors. The former also labels imidazoline receptors, and the latter non-adrenergic idazoxan binding sites. In order to investigate whether the imidazoline receptors and non-adrenergic idazoxan binding sites are identical, we compared the binding characteristics of [3H]clonidine and [3H]idazoxan to these sites by radioligand binding experiments on ultra-thin slices and homogenates of human striatum. A good correlation was found between the effect of different ions on the binding characteristics of [3H]clonidine and [3H]idazoxan, and the affinities of most competing drugs. However, clonidine and rilmenidine displayed a 100- and 10-fold lower affinity, respectively, for the idazoxan binding sites than for the imidazoline receptors. Autoradiography with [3H]clonidine showed that high densities of imidazoline receptors were present in the striatum, pallidum, gyrus dentatus of the hippocampus, amygdala, and substantia nigra. Moderate densities were found throughout the cerebral cortex, thalamus and several brainstem nuclei including the nucleus olivarius inferior. Low densities were seen in the cerebellum, spinal cord and pituitary gland. As for the non-adrenergic sites labelled by [3H]idazoxan, the imidazoline receptors can be found in all major brain areas examined. However, there are some striking differences between the concentrations of imidazoline receptors and non-adrenergic idazoxan binding sites in certain brain regions. To reconcile distribution and pharmacologic data, we propose that imidazoline receptors and non-adrenergic idazoxan binding sites represent different proteins or protein complexes and that at least in the nucleus reticularis lateralis and the striatum, imidazoline receptors and non-adrenergic idazoxan binding sites may be physically associated. The regional distribution of alpha 2 adrenoceptors within the human CNS was determined by quantitative autoradiography with [3H]RX821002. The highest densities of alpha 2 adrenoceptors were found in the cerebral and cerebellar cortex, and certain regions in the medulla oblongata (floor of the IV ventricle, reticular formation, hypoglossal nucleus and nucleus olivarius inferior). No alpha 2 adrenoceptors were detected in the pituitary gland. There exists no relationship between the distribution pattern of imidazoline receptors and alpha 2 adrenoceptors, indicating that these binding sites are independent from each other.

The impact of disabilities on quality of life in people with multiple sclerosis

Objective People with Multiple Sclerosis (MS) experience lower levels of quality of life (QOL) than people from the general population. We examined the relative impact of MS-related disabilities on QOL. Method Data were obtained from a sample of 530 patients who completed the Multiple Sclerosis Impact Profile (MSIP), a disability measure based on the International Classification of Functioning,Disabilities and Health (ICF) and two generic health-related QOL measures, the Medical Outcome study Short Form Questionnaire (SF-36) and the World Health Organization Quality Of Life-BREF (WHOQOL-BREF). The impact of disabilities on QOL was estimated using hierarchical multiple regression analyses after controlling for the clinical course of MS. Results Disabilities contributed to a unique and substantial extent to QOL variance. “Impairments in mental functions” was the most important QOL predictor. “Fatigue” showed the highest prevalence and severity scores, while the impact on QOL was limited. The estimated impact on QOL appeared to be dependent on the applied QOL measure: the WHOQOL-BREF was sensitive to disabilities related to all four ICF components, while the SF-36 was only sensitive to disabilities belonging to the body functions and ‘activities’ components. Conclusion Treatment programmes should target impairments in cognitive functioning, emotional functioning and sleep. Interventions are best evaluated using the WHOQOL-BREF.

Astrocytes in chronic active multiple sclerosis plaques express MHC class II molecules

To initiate the inflammatory cascade leading to demyelination in multiple sclerosis (MS) T cells have to recognize their specific myelin antigen, which needs to be presented in the context of major histocompatibility (MHC) class II molecules expressed on antigen presenting cells. Whether astrocytes can express MHC class II molecules in vivo is a controversial issue. We performed double labeling immunohistochemistry in post-mortem samples from nine patients with MS, three patients with a cerebral infraction and six controls. Astrocytes in controls, in normal appearing white matter in MS, and at the boundary of infarctions were MHC class II negative. In contrast, a subset of astrocytes in active chronic plaques immunostained for MHC class II, indicating potential antigen presenting interactions of astrocytes in MS.

[3H]dihydroalprenolol binding to beta adrenergic receptors in multiple sclerosis brain

By using immunocytochemistry we previously reported the absence of beta(2) adrenergic receptors on astrocytes in multiple sclerosis (MS) white matter. Here, we measured beta(1) and beta(2) adrenergic receptor concentrations in postmortem brain sections of six MS patients and six controls by using quantitative autoradiography with [(3)H]dihydroalprenolol. White matter contained no beta(1) adrenergic receptors. In white matter of controls low levels of beta(2) adrenergic receptors were detected. In agreement with the immunohistochemical study, we were unable to detect beta(2) adrenergic receptors in both normal appearing white matter and astrogliotic plaques in MS. Concentrations of beta(1) and beta(2) adrenergic receptors in cerebral cortex were not different between controls and MS patients.

Measuring disability in stroke: relationship between the modified Rankin scale and the Barthel index

Background and purposeThe effectiveness of therapeutic interventions in acute stroke trials is traditionally measured with the modified Rankin scale (mRs) and the Barthel index (BI). The mRs is a global disability scale divided into six steps from total independence to total dependence. The BI assesses ten basal activities of daily living, of which eight assess level of dependence (bathing, grooming, using stairs, dressing, feeding, toilet use, transfers and walking). The aim of this study was to investigate the relationship between the mRs and the total scores and item-scores of the BI.MethodsDuring a period of 3 months mRs and BI scores were collected from two multicentre randomised, placebo-controlled trials with lubeluzole (515 and 519 patients). In each patient we compared the mRs grades with the total BI score and the scores on the ten subitems.ResultsFor both trials there was extensive overlap of BI scores between mRs grades and a wide range in BI scores among patients with mRs grades 3 and 4. We also found discrepancies between the BI item-scores and mRs grades. About 40% of patients with mRs grades 1 (able to carry out all usual activities) and 2 (able to look after own affairs without assistance) were not independent on at least one activity of the BI. In both studies, about 30% of the patients needed help or supervision for walking, although they were classified as mRs 3 (requiring some help but able to walk without assistance).ConclusionsInvestigators in stroke trials use the mRs as a subjective global disability scale, and they do not strictly take into account limitations in performing specific basal activities of daily living, as assessed by the BI, to assign mRs grades.

An often unrecognized cause of thunderclap headache: reversible cerebral vasoconstriction syndrome

Thunderclap headache (TCH) can have several causes of which subarachnoid hemorrhage (SAH) is most common and well known. A rare cause of TCH is the reversible cerebral vasoconstriction syndrome (RCVS) which is characterized by a reversible segmental vasoconstriction of the intracranial vessels. We describe two patients with TCH due to RCVS and the probable precipitating factor, namely, cannabis and an anti-migraine drug. In RCVS, cerebrospinal fluid examination is (near) normal, in contrast to SAH and (primary) cerebral vasculitis. Brain MRI may be normal or shows infarction. MRA can demonstrate vasoconstriction of the great arteries, but a normal MRA does not rule out the diagnosis. Caliber changes on cerebral angiography cannot adequately differentiate between RCVS and vasculitis. Calcium-channel antagonists may be a good therapy and repeated transcranial Doppler ultrasonography can be a reliable non-invasive investigation to monitor the effect of treatment and demonstrate reversibility of the vasoconstriction.

Stability and relative validity of the Multiple Sclerosis Impact Profile (MSIP)

Objective. To examine the stability and relative validity of the Multiple Sclerosis Impact Profile (MSIP) in criterion-related groups. The MSIP is a disease-targeted health impact measure based on a selection of International Classification of Functioning, Disability and Health (ICF) aspects selected by 98 patients and medical and non-medical health professionals. Method. Data were obtained from a postal survey of 377 individuals with Multiple Sclerosis (MS) attending the MS centre of the University Medical Center Groningen (UH) and 153 subjects from the MS patients association. Stability was tested with t-tests for paired samples and intraclass correlation coefficients for repeated measures in a sample of 251 individuals from the UH sample. The Relative Validity (RV) was estimated using the Short Form Questionnaire (SF-36), the World Health Organization Quality of Life-BREF (WHOQOL-BREF), the Disability and Impact Profile (DIP), the Impact on Autonomy Questionnaire (IPAQ) and the Groningen Activity Restriction Scale (GARS). Results. These indicate that the MSIP is a stable measure in time. MSIP scales showed satisfactory and strong RV. In general, the domain-specific activities and participation measures (GARS and IPAQ) performed equally or slightly better than the comparable MSIP-scales, while the MSIP performed better than the multidimensional health impact measures (SF-36, DIP and WHOQOL-BREF). Conclusion. The MSIP demonstrated good stability and RV compared to generic health impact and domain-specific measures.

Serum uric acid, dehydroepiandrosterone sulphate, and apolipoprotein E genotype in benign vs. progressive multiple sclerosis

The majority of patients with multiple sclerosis (MS) experience gradual progression of disability, either as secondary progressive MS (SPMS) or primary progressive MS (PPMS). A subgroup with relapsing–remitting MS shows a benign course with little or no disease progression and minimal disability decades after the first manifestations, so called benign MS (BMS). In our search to identify factors that are associated with progression of MS, we investigated serum levels of uric acid and dehydroepiandrostenedione sulphate (DHEAS), and apolipoprotein (apo)E genotype in 28 patients with BMS, 33 with SPMS, 21 with PPMS, and 29 healthy individuals. We found no significant changes in uric acid levels and apoE genotype between the four groups. Mean DHEAS levels were lower in MS patients compared with healthy controls (Pu2003=u20030.049), but there were no significant differences between the clinical subgroups of MS. In patients with SPMS and PPMS there was no correlation between progression rate and serum levels of either uric acid or DHEAS. Our results suggest that serum levels of uric acid and DHEAS, and apoE genotype do not differ between patients with a benign and progressive course of MS.

Adding a subjective dimension to an ICF-based disability measure for people with multiple sclerosis: development and use of a measure for perception of disabilities

Objective. The subjective dimension of disability, the perception of disability, is a dimension missing from the International Classification of Functioning, Disability and Health (ICF), and from health-related quality of life (HRQOL) instruments. However, it is a highly relevant dimension for clinical practice as perceived disability may identify care needs. We therefore developed a measure for this subjective dimension of disability in multiple sclerosis (MS) and examined the contribution of this dimension to QOL. Method. A measure named the Multiple Sclerosis Impact Profile-Disability Perception (MSIP-DP) was developed to reflect a persons perception of disabilities reported using the original MSIP-disability (MSIP-D) items. MS patients (n = 530) completed both MSIP sections, the medical outcome study short form questionnaire (SF-36), the World Health Organisation Quality Of Life-BREF (WHOQOL-BREF) and questions concerning disease severity. The contribution of disability perception (DP) to QOL in MS was estimated using hierarchical multiple regression analyses after controlling for MS severity. Results. Confirmative factor analysis confirmed the hypothesised disability perception domains that correspond with the related disability domains in the MSIP. DP scales yielded sufficient reliability. DP explained a unique and substantial part of the variance in QOL, particularly the perception of impairments in mental functions. Discussion. Results indicated that the subjective dimension of functioning and health operationalised in the MSIP-DP is a relevant concept in explaining QOL in MS. In clinical practice psychological interventions addressing a patients perception of disability, particularly of impairments in mental functioning, may contribute to QOL.

Timing of birth and disease progression in multiple sclerosis

Background The timing of birth has recently been associated with the risk of developing multiple sclerosis (MS) in later life. Whether the timing of birth also influences the disease course of MS is unknown. Objective To investigate whether the season or month of birth influences the timing of secondary progression or the time to landmark disability outcomes in MS. Methods To allow confirmation of findings, all analyses were performed in duplicate in two large natural history cohorts from geographically distinct but seasonally similar locations in Europe and North America. Kaplan–Meier survival analyses were used to investigate the influence of month and season of birth on 1) the time to and age at the development of secondary progression in patients with a relapsing disease onset and 2) the time to reach an Expanded Disability Status Scale (EDSS) score of 6.0 in patients with primary progressive and relapsing MS. Results No association between the month or season of birth and disease progression could be found, which was reproducible in both natural history cohorts. A seasonal trend was observed for the time to and age at secondary progression in Groningen, with March babies exhibiting a shorter time to and younger age at secondary progression. The birth month affected time to EDSS 6 for those with relapsing MS in British Columbia, with January babies exhibiting a longer time to EDSS 6. Neither finding could be reciprocated in the other natural history cohort. Conclusion The season or month of birth does not appear to influence disease progression of MS.