Christian A. Vedeler

Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration

The present study examined the extent and distribution of lymphocyte infiltration in demyelinated lesions in the cerebral cortex of multiple sclerosis (MS) patients. Tissue sections from the brain of 10 MS patients and five patients without neurological disease were double labeled for myelin basic protein and the lymphocyte markers C D3, C D4, C D8, C D45RO, and C D20. The highest density of C D3- positive T cells was found in MS white matter lesions (40.4/10 high power fields (hpf)). Fewer T cells were detected in cortical lesions that extended through both white and gray matter (12.1/10 hpf; P B-0.001). The lowest number of T cells was detected in intracortical demyelinated lesions (1.1/10 hpf). This was equal to the lymphocyte density in nondemyelinated cerebral cortex within the same tissue block (1.1/10 hpf) or cerebral cortex in control brains (1.8/10 hpf). A similar distribution was found using the C D4, C D8, and C D45RO markers. C D20-positive B cells were scarce in all specimens examined. These data indicate that areas of intracortical demyelination in chronic MS are not associated with an increased number of lymphocytes, or an altered distribution of lymphocyte subsets, when compared with control areas in MS and control patients. This finding indicates that the extent of lymphocyte infiltration in MS lesions is dependent on lesion location.

Screening for tumours in paraneoplastic syndromes: report of an EFNS Task Force

Background:  Paraneoplastic neurological syndromes (PNS) almost invariably predate detection of the malignancy. Screening for tumours is important in PNS as the tumour directly affects prognosis and treatment and should be performed as soon as possible.

Management of paraneoplastic neurological syndromes: report of an EFNS Task Force.

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer on the nervous system. An overview of the management of classical PNS, i.e. paraneoplastic limbic encephalitis, subacute sensory neuronopathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus‐myoclonus, Lambert–Eaton myasthenic syndrome and paraneoplastic peripheral nerve hyperexcitability is given. Myasthenia gravis and paraproteinemic neuropathies are not included in this report. No evidence‐based recommendations were possible, but good practice points were agreed by consensus. Urgent investigation is indicated, especially in central nervous system (CNS) syndromes, to allow tumour therapy to be started early and prevent progressive neuronal death and irreversible disability. Onconeural antibodies are of great importance in the investigation of PNS and can be used to focus tumour search. PDG‐PET is useful if the initial radiological tumour screen is negative. Early detection and treatment of the tumour is the approach that seems to offer the greatest chance for PNS stabilization. Immune therapy usually has no or modest effect on the CNS syndromes, whereas such therapy is beneficial for PNS affecting the neuromuscular junction. Symptomatic therapy should be offered to all patients with PNS.

IL‐6: an early marker for outcome in acute ischemic stroke

Objectives –  Inflammation plays an important role in the pathophysiology of stroke. We correlated interleukin (IL)‐6, IL‐10, C‐reactive protein (CRP) and T‐lymphocyte subtype levels in acute ischemic stroke patients with stroke volume and clinical outcome.

Reactive microglia in multiple sclerosis lesions have an increased expression of receptors for the Fc part of IgG

Receptors for the Fc part of IgG, FcRI (CD64), FcRII (CD32), and FcRIII (CD16) were studied by indirect immunoperoxidase staining of cryostat sections from normal and multiple sclerosis (MS) brains. Microglia in the parenchyma of normal white matter had a dendritic morphology, and were weakly stained by monoclonal antibodies (mAbs) to FcRI, FcRII, and FcRIII. In active MS lesions reactive microglia were strongly stained by the mAbs 32.2 (FcRI), IV-3 (FcRII), and 3G8 (FcRIII). Perivascular macrophages were stained by all anti-FcR mAbs in both normal white matter and in MS lesions, whereas endothelial cells were stained by the anti-FcRIII mAb only. The FcR on microglia and perivascular macrophages may be of functional importance in antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, and local immunoregulation. FcR on endothelium may be of importance in binding and transportation of immune complexes into the CNS. FcR mediated functions may consequently be highly relevant to the pathogenesis of MS.

Disability and prognosis in multiple sclerosis: demographic and clinical variables important for the ability to walk and awarding of disability pension

Objective: To evaluate disability and prognosis in an untreated population-based incidence cohort of multiple sclerosis (MS) patients. Methods: The Expanded Disability Status Scale (EDSS) score was recorded in 220 MS patients. Disease progression was assessed by life table analysis with different endpoints and multivariate Cox regression analysis was performed for evaluation of prognostic factors. Results: The probability of being alive after 15 years was 94.8+1.8% (s.e.), of managing without a wheelchair (EDSS57.0) 75.8+3.2%, of walking without walking assistance (EDSS56.0) 60.3+3.6%, and of not being awarded a disability pension 46.0+3.7%. The probability of still having a relapsing-remitting (RR) course after 15 years was 62.0+4.1%. A RR course and long interval between the initial (onset) and second episode (43 years) predicted favorable outcome. There was also a trend towards favorable outcome in patients with optic neuritis, sensory symptoms and low age at onset, but these factors were associated with the RR course. Motor symptoms and high age at onset indicated unfavorable outcome, but these factors were associated with the primary progressive course. Conclusions: A RR course and long inter-episode intervals in the early phase of the disease were associated with a better outcome. Other onset characteristics indicating a favorable outcome were associated with the RR course while characteristics indicating an unfavorable outcome were associated with the PP course.

Mutations in ABHD12 Cause the Neurodegenerative Disease PHARC: An Inborn Error of Endocannabinoid Metabolism

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is a neurodegenerative disease marked by early-onset cataract and hearing loss, retinitis pigmentosa, and involvement of both the central and peripheral nervous systems, including demyelinating sensorimotor polyneuropathy and cerebellar ataxia. Previously, we mapped this Refsum-like disorder to a 16 Mb region on chromosome 20. Here we report that mutations in the ABHD12 gene cause PHARC disease and we describe the clinical manifestations in a total of 19 patients from four different countries. The ABHD12 enzyme was recently shown to hydrolyze 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter that acts on cannabinoid receptors CB1 and CB2. Our data therefore represent an example of an inherited disorder related to endocannabinoid metabolism. The endocannabinoid system is involved in a wide range of physiological processes including neurotransmission, mood, appetite, pain appreciation, addiction behavior, and inflammation, and several potential drugs targeting these pathways are in development for clinical applications. Our findings show that ABHD12 performs essential functions in both the central and peripheral nervous systems and the eye. Any future drug-mediated interference with this enzyme should consider the potential risk of long-term adverse effects.

Systemic complement activation following human acute ischaemic stroke

The brain tissue damage after stroke is mediated partly by inflammation induced by ischaemia–reperfusion injury where the complement system plays a pivotal role. In the present study we investigated systemic complement activation and its relation to C‐reactive protein (CRP), a known complement activator, and other inflammatory mediators after acute ischaemic stroke. Sequential plasma samples from 11 acute stroke patients were obtained from the time of admittance to hospital and for a follow‐up period of 12 months. Nine healthy gender‐ and age‐matched subjects served as controls. The terminal SC5b‐9 complement complex (TCC), CRP, soluble adhesion molecules (L‐, E‐ and P‐ selectin, ICAM, VCAM) and cytokines [tumour necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐8] were analysed. All parameters were within normal values and similar to the controls the first hours after stroke. Terminal complement complex (TCC) increased significantly from 0·54 to 0·74 AU/ml at 72 h (P = 0·032), reached maximum at 7 days (0·90 AU/ml, P < 0·001), was still significantly increased at 12 days (0·70 AU/ml, P = 0·009) and thereafter normalized. CRP increased significantly from 1·02 to 2·11 mg/l at 24 h (P = 0·023), remained significantly increased for 1 week (2·53–2·94 mg/l, P = 0·012–0·017) and thereafter normalized. TCC and C‐reactive protein (CRP) correlated significantly (r = 0·36, P < 0·001). The increase in TCC and CRP correlated to the size of infarction (r = 0·80 and P = 0·017 for TCC; r = 0·72 and P = 0·043 for CRP). No significant changes were seen for adhesion molecules and cytokines. In conclusion, transitory systemic complement activation takes place after stroke. The early rise in CRP and the following TCC increase suggest a possible role for CRP in complement activation, which may contribute to inflammation after stroke.

Immunoglobulin G Fc-receptor (FcγR) IIA and IIIB polymorphisms related to disability in MS

Objective: MS is immunologically mediated in genetically susceptible individuals. Receptors for the Fc fragment of immunoglobulin G (IgG) (FcγR) link the humoral and cellular immune responses by targeting immune complexes to effector cells. Different FcγR show variability in their distribution, strength, and capacity of binding different IgG subclasses. Methods: To investigate the role of FcγR in MS, 136 MS patients and 96 matched controls were genotyped for FcγRIIA and FcγRIIIB gene polymorphisms; the results were correlated to disease susceptibility and severity measured by the Expanded Disability Status Scale (EDSS). Results: The allele frequencies of the FcγRIIA and FcγRIIIB did not differ significantly between the MS patients and the controls. Patients homozygous for the FcγRIIIB neutrophil antigen (NA) 1 allele had a significantly more benign course of MS than patients heterozygous or homozygous for the FcγRIIIB NA2 allele. Patients homozygous for the FcγRIIA histidine (H) allele also had a more benign course of MS than patients heterozygous or homozygous for the FcγRIIA arginine (R) allele. Conclusion: The results implicate FcγRIIIB and to a lesser extent FcγRIIA as disease-modifying genes in MS. FcγRIIIB NA1/NA1 and FcγRIIA H/H bind more efficient IgG1/IgG3 and IgG2 subclasses, respectively, than FcγRIIIB NA2/NA2 and FcγRIIA R/R. A more effective processing of circulating immune complexes may be one mechanism for better clinical outcome in MS.

Altered antibody pattern to Epstein-Barr virus but not to other herpesviruses in multiple sclerosis: a population based case-control study from western Norway

OBJECTIVE The prevalence of anti-EBV antibodies was studied in a group of 144 patients with multiple sclerosis and 170 age, sex, and area matched controls from the county of Hordaland, western Norway. The prevalence of three other herpesviruses, herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV), were also included. METHODS Antibodies to various virus antigens were determined by enzyme linked immunosorbent assay (ELISA) and indirect immunfluorescence (IIF) in serum samples from 144 patients with multiple sclerosis and 170 controls. RESULTS All of the 144 patients with multiple sclerosis had IgG antibodies to EBV compared with 162 of 170 controls (p=0.008). The frequency of IgG antibodies to EBV capsid antigen (VCA), nuclear antigen (EBNA), and early antigen (EA) was significantly higher in patients with multiple sclerosis compared with the controls (p<0.000001, p=0.01, and p<0.0001 respectively). The presence of antibodies was independent of the initial course of the disease and the disease activity at the time of blood sampling. The prevalence of IgG antibodies to HSV, CMV, and VZV did not differ between cases and controls. CONCLUSION The results suggest a role for EBV in the aetiology of multiple sclerosis.