Annika Reynberg Langkilde

A Single, Early Magnetic Resonance Imaging Study in the Diagnosis of Multiple Sclerosis

BACKGROUND A diagnosis of multiple sclerosis in patients who present for the first time with a clinically isolated syndrome (CIS) can be established with brain magnetic resonance imaging (MRI) if the MRI demonstrates demyelinating lesions with dissemination in space (DIS) and dissemination in time (DIT). OBJECTIVE To investigate the diagnostic performance of a single MRI study obtained within the first 3 months after symptom onset in a cohort of patients with a CIS suggestive of multiple sclerosis at presentation. DESIGN Multicenter inception cohort with a follow-up of at least 24 months. SETTING Referral hospitals. Patients Patients with CIS onset between April 1, 1995, and September 30, 2004, who fulfilled the following criteria were included: (1) age of 14 to 50 years and (2) clinical follow-up for at least 24 months after CIS onset or until development of clinically definite multiple sclerosis (CDMS), if this occurred within 2 years. Main Outcome Measure All patients underwent 2 comparable brain MRI examinations, the first within 3 months (early) and the second between 3 and 12 months (delayed) after CIS onset. We defined DIS using several existing MRI criteria, and DIT was inferred when there were simultaneous gadolinium-enhancing and nonenhancing lesions on a single MRI. RESULTS Two hundred fifty patients were included in the study. The comparison of the diagnostic performance of various MRI criteria for identifying early converters to CDMS showed similar sensitivity and specificity between early and delayed MRIs. In addition, the use of less stringent criteria for DIS yielded better sensitivity and similar specificity, particularly when assessed in the first weeks after CIS onset. CONCLUSION A single brain MRI study that demonstrates DIS and shows both gadolinium-enhancing and nonenhancing lesions that suggest DIT is highly specific for predicting the early development of CDMS, even when the MRI is performed within the first 3 months after the onset of a CIS.

A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis

Objective: To investigate if IV immunoglobulin (IVIG) treatment in the acute phase of optic neuritis (ON) could improve visual outcome and reduce MRI disease activity 6 months after onset of ON. Methods: Sixty-eight patients with ON were randomized within 4 weeks from onset of symptoms. Thirty-four patients were randomized to IVIG 0.4 g/kg body wt, and 34 patients were randomized to placebo. Infusions were given at days 0, 1, 2, 30, and 60. Contrast sensitivity, visual acuity, and color vision were measured at baseline and after 1 week, 1 month, and 6 months. Pattern reversal visual evoked potential studies and gadolinium-enhanced MRI were performed at baseline and after 1 and 6 months. Clinical relapses during follow-up were recorded. Results: There was no difference in the primary outcome, contrast sensitivity after 6 months, between patients randomized to treatment with IVIG or placebo. In addition, there was no significant difference in the secondary outcome measures, improvement in the visual function measures and MRI, at any time during follow-up. At baseline, a significantly higher number of patients in the IVIG group had one or more enhancing lesions on MRI and IVIG-treated patients had a significantly higher number of enhancing lesions on MRI than patients treated with placebo. No difference was found in number of patients with one or more enhancing lesions or number of enhancing lesions in subsequent scans between treatment groups. Number of relapses was equal in the two treatment groups during follow-up. Conclusions: There was no effect of IV immunoglobulin (IVIG) on long-term visual function following acute optic neuritis, nor was there an effect of IVIG treatment in reducing latency on visual evoked potentials and thus preserving function of axons of the optic nerve.

Hippocampal volume changes in healthy subjects at risk of unipolar depression

Unipolar depression is moderately heritable. It is unclear whether structural brain changes associated with unipolar depression are present in healthy persons at risk of the disorder. Here we investigated whether a genetic predisposition to unipolar depression is associated with structural brain changes. A priori, hippocampal volume reductions were hypothesized. Using a high-risk study design, magnetic resonance imaging brain scans were obtained from 59 healthy high-risk subjects having a co-twin with unipolar depression, and 53 healthy low-risk subjects without a first-degree family history of major psychiatric disorder. High-risk twins had smaller hippocampal volumes than low-risk twins (p<0.04). The finding was most pronounced in DZ twins. Groups did not differ on global brain tissue volumes or regional tissue volumes assessed in exploratory voxel-wise whole cerebrum analyses. In conclusion, hippocampal volume reduction may index a predisposition to develop depression and thus may be predictive of future onset of the disorder. Further studies are needed to elucidate the role of (shared) environmental and genetic factors.

Functional MRI of the visual cortex and visual testing in patients with previous optic neuritis

The volume of cortical activation as detected by functional magnetic resonance imaging (fMRI) in the visual cortex has previously been shown to be reduced following optic neuritis (ON). In order to understand the cause of this change, we studied the cortical activation, both the size of the activated area and the signal change following ON, and compared the results with results of neuroophthalmological testing. We studied nine patients with previous acute ON and 10 healthy persons served as controls using fMRI with visual stimulation. In addition to a reduced activated volume, patients showed a reduced blood oxygenation level dependent (BOLD) signal increase and a greater asymmetry in the visual cortex, compared with controls. The volume of visual cortical activation was significantly correlated to the result of the contrast sensitivity test. The BOLD signal increase correlated significantly to both the results of the contrast sensitivity test and to the Snellen visual acuity. Our results indicate that fMRI is a useful method for the study of ON, even in cases where the visual acuity is severely impaired. The reduction in activated volume could be explained as a reduced neuronal input; however, the greater asymmetry might point to a cortical reorganization as a consequence of neuronal damage. Future fMRI studies in ON will add to the understanding of the neural adaptive behaviour following ON.

CD4 T cell activation and disease activity at onset of multiple sclerosis

We studied CD4 T cell activation in patients with clinically isolated syndromes (CIS) suggesting an initial attack of multiple sclerosis. The percentage of blood CD26+ CD4 T cells was increased in these patients, and correlated with magnetic resonance imaging disease activity and clinical disease severity. In contrast, the percentage of CD25+ CD4 T cells in cerebrospinal fluid correlated negatively with the cerebrospinal fluid concentration of myelin basic protein and the presence of IgG oligoclonal bands. These results suggest that distinct systemic and intrathecal T cell activation states correlate with disease activity and risk of subsequently developing MS in CIS patients.

Muscle structural changes in mitochondrial myopathy relate to genotype

Abstract.It is well known that morphological changes at the cellular level occur in muscle of patients with mitochondrial myopathy (MM), but changes in muscle structure with fat infiltration and gross variation of muscle fiber size with giant fibers, normally encountered in the muscular dystrophies, have typically not been associated with mitochondrial disease. We investigated gross and microscopic muscle morphology in thigh muscles by muscle biopsy and MRI in 16 patients with MM, and compared findings with those obtained in muscular dystrophy patients and healthy subjects. Changes of muscle architecture, similar to those found in the group of muscular dystrophy patients occurred consistently in patients with a high mutation load for single, largescale deletions of mtDNA, but were absent in all patients with the 3243A→G mtDNA point mutation. Dystrophic changes of muscle architecture were also present in one MM patient with a unique, sporadic mutation in the mtDNA tRNAMet gene. These findings provide evidence that morphological changes in muscle of MM patients are common and may resemble those of muscular dystrophies, but that development of dystrophic-like changes in muscle relate to genotype.

CD8+ T cell activation correlates with disease activity in clinically isolated syndromes and is regulated by interferon-β treatment

Abstract An increased percentage of blood CD8 + T cells from patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) was found to express CD26 and CD69. The percentage of CD26 or CD69 positive CD8 + T cells was higher in patients with MRI evidence of disease dissemination in space or with active MRI lesions than in the remaining patients. Treatment of MS with interferon (IFN)-β resulted in a decrease in the percentage of CD26 and CD71 positive CD8 + T cells and an increase in the percentage of CD8 + T cells that expressed interleukin (IL)-10 and IL-13. CD8 + T cell activation in MS may be linked to disease activity already at disease onset, and is regulated by treatment with IFN-β.

The effect of alternate-day caloric restriction on the metabolic consequences of 8 days of bed rest in healthy lean men: a randomized trial

Physical activity and alternate-day fasting/caloric restriction may both ameliorate aspects of the metabolic syndrome, such as insulin resistance, visceral fat mass accumulation, and cognitive impairment by overlapping mechanisms. The purpose of this study was to test the hypothesis that alternate-day caloric restriction (ADCR) with overall energy balance would reduce insulin resistance and accumulation of visceral fat, in addition to improving cognitive functions, after 8 consecutive days in bed. Healthy, lean men (n = 20) were randomized to 1) 8 days of bed rest with three daily isoenergetic meals (control group, n = 10); and 2) 8 days of bed rest with 25% of total energy requirements every other day and 175% of total energy requirements every other day (ADCR group). Oral glucose tolerance testing, dual-energy X-ray absorptiometry (DXA) scans, magnetic resonance imaging of the abdomen and brain, V̇o2max, and tests for cognitive function were performed before and after bed rest. In addition, daily fasting blood samples and 24-h glucose profiles by continuous glucose monitoring system were assessed during the 8 days of bed rest period. Bed rest induced insulin resistance, visceral fat accumulation, and worsening of mood. No positive effects emerged from ADCR on these negative health outcomes. Compared with the control group, ADCR was associated with improved and steadier glycemic control on fasting days and higher glycemic fluctuation and indexes of insulin resistance on overeating days. In contrast to our hypothesis, the metabolic impairment induced by 8 days of bed rest was not counteracted by ADCR with overall energy balance. NEW & NOTEWORTHY Alternate-day caloric restriction without overall energy reduction does not ameliorate the metabolic impairment induced in lean men by 8 days of bed rest.

High-Target Versus Low-Target Blood Pressure Management During Cardiopulmonary Bypass to Prevent Cerebral Injury in Cardiac Surgery Patients: A Randomized Controlled Trial

Background: Cerebral injury is an important complication after cardiac surgery with the use of cardiopulmonary bypass. The rate of overt stroke after cardiac surgery is 1% to 2%, whereas silent strokes, detected by diffusion-weighted magnetic resonance imaging, are found in up to 50% of patients. It is unclear whether a higher versus a lower blood pressure during cardiopulmonary bypass reduces cerebral infarction in these patients. Methods: In a patient- and assessor-blinded randomized trial, we allocated patients to a higher (70–80 mm Hg) or lower (40–50 mm Hg) target for mean arterial pressure by the titration of norepinephrine during cardiopulmonary bypass. Pump flow was fixed at 2.4 L·min−1·m−2. The primary outcome was the total volume of new ischemic cerebral lesions (summed in millimeters cubed), expressed as the difference between diffusion-weighted imaging conducted preoperatively and again postoperatively between days 3 and 6. Secondary outcomes included diffusion-weighted imaging–evaluated total number of new ischemic lesions. Results: Among the 197 enrolled patients, mean (SD) age was 65.0 (10.7) years in the low-target group (n=99) and 69.4 (8.9) years in the high-target group (n=98). Procedural risk scores were comparable between groups. Overall, diffusion-weighted imaging revealed new cerebral lesions in 52.8% of patients in the low-target group versus 55.7% in the high-target group (P=0.76). The primary outcome of volume of new cerebral lesions was comparable between groups, 25 mm3 (interquartile range, 0–118 mm3; range, 0–25 261 mm3) in the low-target group versus 29 mm3 (interquartile range, 0–143 mm3; range, 0–22 116 mm3) in the high-target group (median difference estimate, 0; 95% confidence interval, −25 to 0.028; P=0.99), as was the secondary outcome of number of new lesions (1 [interquartile range, 0–2; range, 0–24] versus 1 [interquartile range, 0–2; range, 0–29] respectively; median difference estimate, 0; 95% confidence interval, 0–0; P=0.71). No significant difference was observed in frequency of severe adverse events. Conclusions: Among patients undergoing on-pump cardiac surgery, targeting a higher versus a lower mean arterial pressure during cardiopulmonary bypass did not seem to affect the volume or number of new cerebral infarcts. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02185885.

Diagnostic challenges in combined multiple sclerosis and centronuclear myopathy

The first case of combined centronuclear myopathy and multiple sclerosis is reported. The difficulties of diagnosing multiple sclerosis in patients with muscular disorders associated with the central nervous system involvement are discussed.