Spinal cord atrophy in anterior-posterior direction reflects impairment in multiple sclerosis.

OBJECTIVE: To investigate how atrophy is distributed over the cross section of the upper cervical spinal cord and how this relates to functional impairment in multiple sclerosis (MS). METHODS: We analysed the structural brain MRI scans of 54 patients with relapsing-remitting MS (n=22), primary progressive MS (n=9), secondary progressive MS (n=23) and 23 age- and sex-matched healthy controls. We measured the cross-sectional area (CSA), left-right width (LRW) and anterior-posterior width (APW) of the spinal cord at the segmental level C2. We tested for a nonparametric linear relationship between these atrophy measures and clinical impairments as reflected by the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impairment Scale (MSIS). RESULTS: In patients with MS, CSA and APW but not LRW were reduced compared to healthy controls (P<.02) and showed significant correlations with EDSS, MSIS and specific MSIS subscores. CONCLUSION: In patients with MS, atrophy of the upper cervical cord is most evident in the antero-posterior direction. As APW of the cervical cord can be readily derived from standard structural MRI of the brain, APW constitutes a clinically useful neuroimaging marker of disease-related neurodegeneration in MS.

Safety concerns and risk management of multiple sclerosis therapies.

Currently, more than ten drugs have been approved for treatment of relapsing-remitting multiple sclerosis (MS). Newer treatments may be more effective, but have less favorable safety record. Interferon-ß preparations and glatiramer acetate treatment require frequent subcutaneous or intramuscular injections and are only moderately effective, but have very rarely life-threatening adverse effects, whereas teriflunomide and dimethyl fumarate are administered orally and have equal or better efficacy, but have more potentially severe adverse effects. The highly effective therapies fingolimod, natalizumab, daclizumab, and alemtuzumab have more serious adverse effects, some of which may be life-threatening. The choice between drugs should be based on a benefit-risk evaluation and tailored to the individual patient's requirements in a dialogue between the patient and treating neurologist. Patients with average disease activity can choose between dimethyl fumarate and teriflunomide or the "old injectable." Patients with very active MS may choose a more effective drug as the initial treatment. In case of side effects on one drug, switch to another drug can be tried. Suboptimal effect of the first drug indicates escalation to a highly efficacious drug. A favorable benefit-risk balance can be maintained by appropriate patient selection and appropriate risk management on therapy. New treatments will within the coming 1-2 years change our current treatment algorithm for relapsing-remitting MS.

Educational achievements of children of parents with multiple sclerosis: A nationwide register-based cohort study.

Little is known about the impact of parental multiple sclerosis (MS) on offspring's educational attainment. The objective of the study was to examine educational achievements in offspring of parents with MS compared with matched children of parents without MS in a nationwide register-based cohort study. Children of all Danish-born residents with onset between 1950 and 1986 were identified by linking the Danish Multiple Sclerosis Registry with the Civil Registration System. Twins, children with MS, and emigrated persons were excluded. The reference cohort consisted of randomly drawn individuals from the Civil Registration System without parental MS matched 8:1 to the MS offspring by sex and year of birth. Information about education was linked to the cohorts from nationwide educational registries. We included 4177 children of MS parents and 33,416 reference persons. Children of MS parents achieved statistically significant higher average grades than the reference cohort in their final exam of basic school with a mean grade difference of 0.46 (95 % CI 0.22-0.69; p = 0.0002). We found no difference in achievement of educational level above basic school (OR 1.04; 95 % CI 0.98-1.10; p = 0.20). There was a trend toward more MS offspring attaining health-related educations (OR 1.10; 95 % CI 1.00-1.21; p = 0.06). In conclusion, children of MS parents showed a small advantage in grade point average in final examinations in basic school, and they more often tended toward health-related educations. This study revealed no negative consequences of parental MS on grades and highest educational level achieved.

Resting-state connectivity of pre-motor cortex reflects disability in multiple sclerosis.

OBJECTIVE: To characterize the relationship between motor resting-state connectivity of the dorsal pre-motor cortex (PMd) and clinical disability in patients with multiple sclerosis (MS). MATERIALS AND METHODS: A total of 27 patients with relapsing-remitting MS (RR-MS) and 15 patients with secondary progressive MS (SP-MS) underwent functional resting-state magnetic resonance imaging. Clinical disability was assessed using the Expanded Disability Status Scale (EDSS). Independent component analysis was used to characterize motor resting-state connectivity. Multiple regression analysis was performed in SPM8 between the individual expression of motor resting-state connectivity in PMd and EDSS scores including age as covariate. Separate post hoc analyses were performed for patients with RR-MS and SP-MS. RESULTS: The EDSS scores ranged from 0 to 7 with a median score of 4.3. Motor resting-state connectivity of left PMd showed a positive linear relation with clinical disability in patients with MS. This effect was stronger when considering the group of patients with RR-MS alone, whereas patients with SP-MS showed no increase in coupling strength between left PMd and the motor resting-state network with increasing clinical disability. No significant relation between motor resting-state connectivity of the right PMd and clinical disability was detected in MS. CONCLUSIONS: The increase in functional coupling between left PMd and the motor resting-state network with increasing clinical disability can be interpreted as adaptive reorganization of the motor system to maintain motor function, which appears to be limited to the relapsing-remitting stage of the disease.

Disease protection and interleukin-10 induction by endogenous interferon-ß in multiple sclerosis?

OBJECTIVE: An immune activation response resembling virus or type I interferon responses has been observed in untreated multiple sclerosis (MS), but its pathogenic significance is uncertain. We studied the relationship between a type I interferon-like response in untreated patients with MS and disease activity. METHODS: Gene expression was analyzed by real-time reverse transcriptase polymerase chain reaction (PCR) in whole blood samples and by microarray analysis of mononuclear cells from untreated patients with MS, patients with MS treated with IFN-ß, and patients with MS with anti-IFN-ß neutralizing antibodies (NAb). Disease activity was assessed by gadolinium-enhanced magnetic resonance imaging. RESULTS: Eight of 36 untreated patients with MS had spontaneously increased expression of the type I IFN-induced gene MX1. Microarray gene expression analysis demonstrated that patients with increased spontaneous MX1 expression also had increased expression of other genes induced by regular IFN-ß treatment of MS. MX1 expression correlated with FOXP3 and IL10 expression, and IL10 expression correlated negatively with disease activity on magnetic resonance imaging. Further, in vivo IL10 expression was lower in NAb-positive patients than in untreated patients with MS and healthy controls. Finally, ex vivo treatment of mononuclear blood cells with IFN-ß induced the expression of IL10, and this was blocked by the addition of serum from NAb-positive patients with MS. CONCLUSION: Our findings suggest that endogenous IFN-ß may induce the expression of immunoregulatory IL10 in MS and that this might be associated with dampening of inflammatory disease activity.

Identification of new sensitive biomarkers for the in vivo response to interferon-beta treatment in multiple sclerosis using DNA-array evaluation.

OBJECTIVE: Neutralizing antibodies (NAbs) occur in a proportion of multiple sclerosis (MS) patients treated with interferon (IFN)-beta. NAbs impair the effect of treatment. The biological effect of IFN-beta can be measured as the induction of the myxovirus resistance protein A (MxA) molecule. However, other markers could be more sensitive for evaluating the response to IFN-beta. We used DNA array analysis to identify genes that are strongly induced in blood cells by IFN-beta, and measured their expression in MS patients with different NAb levels. METHODS: Gene expression was studied on DNA arrays in untreated patients, in NAb negative patients, and in MS patients with varying NAb levels 9-12 h and 36-48 h after IFN-beta administration. The expression of selected genes was measured by real-time PCR. NAb levels were assessed by a cytopathic effect assay. RESULTS: Several hundred genes were induced 9-12 h after an injection of IFN-beta. The molecules CXCL10, CCL2 and IFI27 were among the most strongly induced. Gene induction was generally much less pronounced after 36-48 h, but IFI27 remained strongly induced. The strong induction of these molecules and MxA was confirmed by real-time PCR. Induction of MxA, CCL2, CXCL10 and IFI27 was reduced in patients with low NAb levels and lost in patients with intermediate/high NAb levels. CONCLUSION: We identify IFI27, CCL2 and CXCL10 as sensitive biomarkers for the response to IFN-beta. The expression of these markers adequately reflects bioactivity of IFN-ss as documented by the decreased induction in low NAb-positive patients and the lost induction in patients with moderate/high NAb levels.

EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases: EFNS task force on the use of intravenous immunoglobulin in treatment of neurological diseases.

Despite high-dose intravenous immunoglobulin (IVIG) is widely used in treatment of a number of immune-mediated neurological diseases, the consensus on its optimal use is insufficient. To define the evidence-based optimal use of IVIG in neurology, the recent papers of high relevance were reviewed and consensus recommendations are given according to EFNS guidance regulations. The efficacy of IVIG has been proven in Guillain-Barré syndrome (level A), chronic inflammatory demyelinating polyradiculoneuropathy (level A), multifocal mononeuropathy (level A), acute exacerbations of myasthenia gravis (MG) and short-term treatment of severe MG (level A recommendation), and some paraneoplastic neuropathies (level B). IVIG is recommended as a second-line treatment in combination with prednisone in dermatomyositis (level B) and treatment option in polymyositis (level C). IVIG should be considered as a second or third-line therapy in relapsing-remitting multiple sclerosis, if conventional immunomodulatory therapies are not tolerated (level B), and in relapses during pregnancy or post-partum period (good clinical practice point). IVIG seems to have a favourable effect also in paraneoplastic neurological diseases (good practice point) [corrected],stiff-person syndrome (level A), some acute-demyelinating diseases and childhood refractory epilepsy (good practice point).

Gene expression analysis of interferon-beta treatment in multiple sclerosis.

Treatment with interferon-beta (IFN-beta) induces the expression of hundreds of genes in blood mononuclear cells, and the expression of several genes has been proposed as a marker of the effect of treatment with IFN-beta. However, to date no molecules have been identified that are stably induced by treatment with IFN-beta. We use DNA microarrays to study gene expression in 10 multiple sclerosis (MS) patients who began de novo treatment with IFN-beta. After the first injection of IFN-beta, the expression of 74 out of 3428 genes changed at least two-fold and statistically significantly (after Bonferroni correction). In contrast, we observed no persisting effects of IFN-beta on gene expression. Among the most strongly induced genes was MXA, which has been used in previous biomarker studies in MS. In addition, the study identified the induction of LGALS9 and TCIR1G, involved in negative regulation of T helper type I immunity and T-cell activation, as novel effects of IFN-beta therapy in MS.

Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis.

OBJECTIVE: Interferon (IFN) beta has repeatedly shown benefit in multiple sclerosis (MS) in reducing the rate of relapse, the disease activity as shown with magnetic resonance imaging and, to some degree, the progression of disability; however, it is unknown how much the therapeutic response depends on the dose, the subgroup involved, and the disease stage. This multicentre, double blind, placebo controlled study explored the dose-response curve by examining the clinical benefit of low dose IFN beta-1a (Rebif), 22 micro g subcutaneously once weekly, in patients with secondary progressive MS. METHODS: A total of 371 patients with clinically definite SPMS were randomised to receive either placebo or subcutaneous IFN beta-1a, 22 micro g once weekly, for 3 years. Clinical assessments were performed every 6 months. The primary outcome was time to sustained disability, as defined by time to first confirmed 1.0 point increase on the Expanded Disability Status Scale (EDSS). Secondary outcomes included a sensitive disability measure and relapse rate. RESULTS: Treatment had no beneficial effect on time to confirmed progression on either the EDSS (hazard ratio (HR) = 1.13; 95% confidence interval (CI) 0.82 to 1.57; p = 0.45 for 22 micro g v placebo) or the Regional Functional Status Scale (HR = 0.93; 95% CI 0.68 to 1.28; p = 0.67). Other disability measures were also not significantly affected by treatment. Annual relapse rate was 0.27 with placebo and 0.25 with IFN (rate ratio = 0.90; 95% CI 0.64 to 1.27; p = 0.55). The drug was well tolerated with no new safety concerns identified. No significant gender differences were noted. CONCLUSIONS: This patient population was less clinically active than SPMS populations studied in other trials. Treatment with low dose, IFN beta-1a (Rebif) once weekly did not show any benefit in this study for either disability or relapse outcomes, including a subgroup with preceding relapses. These results add a point at one extreme of the dose-response spectrum of IFN beta therapy in MS, indicating that relapses in this phase may need treatment with higher doses than in the initial phases.

International consensus statement on the use of disease-modifying agents in multiple sclerosis.

OBJECTIVE: To provide recommendations on the use of disease-modifying agents in the management of multiple sclerosis (MS) and to ensure that treatment will be available to those patients who may benefit. METHODS: An initial draft of the consensus statement was prepared by the Steering Committee and amended in the light of written comments from a group of MS specialists. At a subsequent workshop, the wording of the consensus statement was discussed, modified if necessary, and the participants indicated their level of support using an electronic voting system. A new draft of the statement was then sent to a much larger group of international opinion leaders in MS for further comment. RESULTS: A number of statements were agreed, which outline the criteria for consideration of disease-modifying therapy for MS and recommendations for treatment. Each statement was accepted completely, or with only minor reservations by 95% or more of those present at the workshop. CONCLUSIONS: Periodic reviews and modifications to the statement will be required, as new approaches to the treatment of MS and other therapeutic agents become available.

Analysis of an interferon-gamma gene dinucleotide-repeat polymorphism in Nordic multiple sclerosis patients.

The proinflammatory cytokine interferon (IFN)-gamma has been shown to influence the course of multiple sclerosis (MS). The IFN-gamma (IFNG) contains a multiallelic dinucleotide repeat in intron 1. To investigate whether alleles at this locus influence susceptibility to MS, we performed linkage and familial association analyses on 100 sibling pairs from four Nordic countries, and case-control association analysis on 220 intermediately disabled sporadic MS patients and 266 controls. To determine the effect of the polymorphism on disease outcome, we compared genotype frequencies in the most and least disabled octiles of a total cohort of 913 cases. We also measured IFN-gamma mRNA levels in unstimulated peripheral blood mononuclear cells from 46 MS patients and 27 controls grouped according to IFNG intron 1 genotype. Both nonparametric linkage analysis and transmission disequilibrium testing of the 100 sibling pairs produced negative results. Genotype frequencies for intermediate-MS patients did not differ significantly from those for controls; nor did genotype frequencies in the benign-MS octile differ significantly from those in the severe-MS octle. Comparison of IFN-gamma mRNA levels in genotype-conditioned subgroups revealed no significant differences. Thus, alleles at the IFNG intron 1 dinucleotide repeat appear to affect neither MS susceptibility and severity nor IFN-gamma mRNA expression in vivo.

Early treatment of multiple sclerosis with Rebif (recombinant human interferon beta): design of the study.

Two recent properly controlled trials performed in patients with relapsing-remitting MS have demonstrated that interferon beta substantially improves the evolution of the disease. The results of the Optic Neuritis Treatment Trials suggest that early treatment of patients with isolated optic neuritis may delay the conversion to clinically definite MS (CDMS). Moreover, clinical trials in MS and in immune-mediated diseases indicate that better results are obtained in patients in the early phases of the disease. We present the design of a multicentre, randomized, double-blind, placebo-controlled study of recombinant interferon beta (Rebif-Serono) in patients with a first attack suggestive of MS. The primary objective of the study is to investigate the efficacy of Rebif, administered subcutaneously at the dose of 8 million international units (MIU) once a week for 2 years, on the risk of developing CDMS.

Tolfenamic acid versus propranolol in the prophylactic treatment of migraine.

The prophylactic effect of tolfenamic acid and propranolol was studied in a randomized double-blind cross-over trial of 76 patients with migraine with or without aura. After a 4-week run-in period patients were randomly allocated to treatment with either tolfenamic acid 100 mg three times daily or propranolol 40 mg three times daily for 12 weeks. After a placebo wash-out period of 4 weeks the patients got the alternative drug for 12 weeks; 56 patients completed the study. Both drugs significantly reduced migraine attacks as judged from the reduction in the efficacy parameters (migraine hours, migraine days, and migraine intensity) in the treatment periods compared with the run-in period. No statistical significant difference in any efficacy parameter was found between the two drugs (level 2 alpha = 0.05, alpha = 0.10). The adverse effects showed no statistical difference in frequency between the 2 treatments. Twenty patients discontinued the study: 12 patients on propranolol and 8 patients on tolfenamic acid. Side effects were the cause of premature discontinuation of study medicine in 9 patients during propranolol treatment (dizziness, fatigue, and fall in blood pressure) and in 5 patients during tolfenamic acid treatment (gastrointestinal symptoms).

Prospective evaluation of the effect on initial brain metastases from small cell lung cancer of platinum-etoposide based induction chemotherapy followed by an alternating multidrug regimen.

BACKGROUND: During the 1980s reports describing the effect of systemic chemotherapy on brain metastases from chemosensitive tumours emerged, including a few retrospective reports on small cell lung cancer (SCLC) patients. DESIGN: Previously untreated SCLC patients with no other malignancy, but in some cases with mixed histological subtype, who had symptomatic brain metastases verified by contrast enhanced CT-scan, were treated with a multidrug combination chemotherapy regimen and no cranial irradiation. Radiotherapy was optional at cranial relapse or progression at the discretion of the physician in charge. The intracranial effect was evaluated by 4-weekly CT-scan and neurological examination, according to a standardized scoring system. END POINTS: Intracranial response, duration of response, neurological score, terminal CNS status, and survival. RESULTS: 21 patients were included, corresponding to 8.6% of consecutive SCLC patients at our institution. 8 patients died before follow-up leaving 13 evaluable for response. In the former group, all patients had WHO performance status of 3-4 compared to 6/13 in the latter group. Of the 13 evaluable patients, 1 had early progression in the CNS and 1 had no change. 11 had CT-scan verified response, with a median duration of 135 days. Most patients, including all complete responders, had improvement in their neurological score. 6 out of 11 responders died without active CNS disease. The crude median survival was 111 days, whereas the median survival (early deaths excluded) was 197 days. CONCLUSION: Systemic combination chemotherapy was effective for palliation of initial brain involvement in the majority of patients in a small consecutive series. The role of consolidating cranial irradiation in responders should be assessed by a randomized trial.

Intravenous infusion of Diazemuls in the control of status-like epileptic seizures of different etiology.

This report concerns three patients in whom continuous intravenous infusion of Diazemuls (diazepam dissolved in soya bean oil and emulsified) diluted in 5.5% glucose was used for the controlling of epileptic seizures (status). Diazemuls infusion was effective in one patient with complex partial status epilepticus; in another patient with convulsion secondary to a brain stem infarct, the convulsions were abolished; while only reduced jerking was achieved in the third patient suffering from myoclonic jerks caused by anoxic brain damage. Infusion time ranged from 15 to 33 h. The serum concentrations of diazepam obtained during the infusions were higher than recommended in the literature for treatment of status epilepticus, but could not be correlated to either clinical efficacy or infusion rate.

Endocrine studies in patients with pseudotumor cerebri. Estrogen levels in blood and cerebrospinal fluid.

In 15 patients fulfilling conventional diagnostic criteria for pseudotumor cerebri, anterior and posterior pituitary functions were examined. Eight of 12 female patients with pseudotumor were grossly overweight. Except for a subnormal response of growth hormone level to insulin-induced hypoglycemia in four patients, no major disturbances were found in pituitary, gonadal, thyroid, or adrenal functions. Vasopressin concentration in the cerebrospinal fluid was increased in patients with pseudotumor, whereas cerebrospinal fluid concentration of estrogens was below detection limit.

Motor disturbances in normal-pressure hydrocephalus. Special reference to stance and gait.

Motor disturbances in 16 patients with normal-pressure hydrocephalus were assessed by quantitative registration of handwriting, fine movements of the hand, hand tremor, postural instability, and gait. Tremor intensity was measured using an accelerometer and electronic integration of the accelerometer curves. Postural instability was measured on a computer-assisted force-plate, and computerized analysis of gait was made using an instrumented treadmill. Severe disturbances in motor performance in the upper extremities and postural stability were found. The gait of the hydrocephalic patients was characterized by a very low speed, short steps, ataxia (especially in the vertical direction), and high energy consumption. After shunt operation, significant improvement was found in motor performance in the upper extremities and postural stability, and gait ataxia decreased in all patients to values within the 95% confidence interval of age-matched controls.

Intracranial pressure, conductance to cerebrospinal fluid outflow, and cerebral blood flow in patients with benign intracranial hypertension (pseudotumor cerebri).

Intracranial pressure, conductance to cerebrospinal fluid outflow, and cerebral blood flow were investigated in 14 patients with benign intracranial hypertension (pseudotumor cerebri). Intracranial pressure was increased in 9 patients (20 to 30 mm Hg), borderline in 4 patients (15 to 18 mm Hg), and normal in 1 patient (8 mm Hg). Six patients had plateau waves, and all had B waves in more than 50% of the monitored time. Conductance to cerebrospinal fluid outflow, measured by a lumbo-lumbar perfusion method, was significantly reduced: 0.042 ml X mm Hg-1 X min-1 (+/- 0.004 [SEM]; normal, more than 0.080 ml X mm Hg-1 X min-1). Cerebral blood flow was measured by xenon 133 inhalation and single photon emission computer tomography. Mean hemispheric flow was normal in all cases, averaging 59 +/- 9 ml X 100 gm-1 X min-1. Only 2 patients showed focal low-flow areas. Thus, a disturbance of cerebrospinal fluid circulation seems to be of pathogenetic significance in benign intracranial hypertension.

Cardiac disease in patients with reversible cerebral ischemic events.

The establishment of a possible association between ischemic cerebral attacks and prolapsing mitral valve has been studied in 45 consecutive patients aged 60 years or less with transient cerebral ischemic attacks and reversible ischemic neurological deficits. The study comprised cardiac history, auscultation, electrocardiography and echocardiography. We found only one patient (2%) with mitral valve prolapse but 19 patients (42%) with cardiac abnormalities. Two of the patients with cardiac abnormalities had a flail posterior mitral leaflet, one had ventricular septal defect and one had sclerotic aortic valves. We conclude that all patients with transient cerebral ischemic attacks should be subjected to heart examination, if possible including echocardiography.