The contribution of CACNA1A, ATP1A2 and SCN1A mutations in hemiplegic migraine: A clinical and genetic study in Finnish migraine families.

Objective To study the position of hemiplegic migraine in the clinical spectrum of migraine with aura and to reveal the importance of CACNA1A, ATP1A2 and SCN1A in the development of hemiplegic migraine in Finnish migraine families. Methods The International Classification of Headache Disorders 3rd edition criteria were used to determine clinical characteristics and occurrence of hemiplegic migraine, based on detailed questionnaires, in a Finnish migraine family collection consisting of 9087 subjects. Involvement of CACNA1A, ATP1A2 and SCN1A was studied using whole exome sequencing data from 293 patients with hemiplegic migraine. Results Overall, hemiplegic migraine patients reported clinically more severe headache and aura episodes than non-hemiplegic migraine with aura patients. We identified two mutations, c.1816G>A (p.Ala606Thr) and c.1148G>A (p.Arg383His), in ATP1A2 and one mutation, c.1994C>T (p.Thr665Met) in CACNA1A. Conclusions The results highlight hemiplegic migraine as a clinically and genetically heterogeneous disease. Hemiplegic migraine patients do not form a clearly separate group with distinct symptoms, but rather have an extreme phenotype in the migraine with aura continuum. We have shown that mutations in CACNA1A, ATP1A2 and SCN1A are not the major cause of the disease in Finnish hemiplegic migraine patients, suggesting that there are additional genetic factors contributing to the phenotype.

Magnetic Resonance Imaging of Internal Jugular Veins in Multiple Sclerosis: Interobserver Agreement and Comparison with Doppler Ultrasound Examination.

BACKGROUND: Doppler ultrasound (US) has been widely used to evaluate the cervical venous system of multiple sclerosis patients according to the hypothesis of chronic cerebrospinal venous insufficiency with contradictory results. Venous anatomy and pathology can be examined with less operator-dependent magnetic resonance imaging (MRI). Our aim is to assess the interobserver agreement in measuring internal jugular vein (IJV) cross-sectional area (CSA) in MR images and to explore the agreement between US and MRI in the detection of calibers of ≤0.3 cm2 in the IJV CSA in the prospective study. METHODS: Thirty-seven multiple sclerosis patients underwent MRI of the cervical venous system. Two independent neuroradiologists measured the CSA of IJV at the mid-thyroid level. Furthermore, the time from contrast enhancement of common carotid arteries to that of each IJV (transit time in seconds) was assessed, and recorded whether IJV or the vertebral plexus visualized first during the contrast passage. US examination had been performed earlier. RESULTS: Interobserver agreement for assessing IJV CSA in MR images was substantial: the measurements differed >0.5 cm2 between the examiners in only 5 IJVs (7%), Cohen's kappa 0.79. Transit times from common carotid artery to IJV varied between 5.1 and 14.1 sec. Fifteen patients had left-to-right asymmetry in the speed of IJV contrast filling. IJV CSA ≤ 0.3 cm2 was found in 51 IJVs on the basis of US. Ten of these IJVs (19.6%) showed IJV CSA ≤ 0.3 cm2 also in MRI. All IJVs defined as CSA ≤ 0.3 cm2 in MRI met this caliber criterion also in US. CONCLUSIONS: Interobserver agreement at the thyroid level of the IJV was good at MRI measurements. The US defines more IJVs as narrow (CSA ≤ 0.3 cm2) than MRI. The US measurements for IJV CSA are not comparable with these methods. The US seems too sensitive in terms of finding venous stenosis.

[Magnetic resonance imaging of the brain in the monitoring of immune therapy of multiple sclerosis]. / Aivojen magneettikuvaus MS-taudin immunologisen hoidon seurannassa.

Magnetic resonance imaging of the brain is currently the most sensitive method in detecting the lesions caused by multiple sclerosis. Assessment of the immunological treatment response used in the treatment of multiple sclerosis should be based on the clinical picture and brain MRI. T2-, flair- and T1-biased images, gadolinium enhancement and assessment of atrophy are required for MRI monitoring. In the first-line immune therapy MRI is taken at 6 to 12 months after starting the drug therapy, in fingolimod therapy after 6 to 12 months and 1 to 2 years, respectively, and in alemtuzumab and natalizumab therapy after one and two years.

[Update on Current Care Guideline: Multiple sclerosis]. / Kaypa hoite-suosituksen paivitystiivistelma. MS-tauti.

Treatment for relapsing-remitting multiple sclerosis (RRMS) is initiated upon fulfillment of new McDonald 2010 criteria for RRMS. In addition, lumbar puncture is an essential diagnostic method. Interferon-ß, dimethyl fumarate, glatiramer acetate and teriflunomide are the first-line immunomodulating drugs (IMD) for RRMS. If the disease is active according to clinical or MRI evaluation during the first-line IMD treatment, alemtuzumab, fingolimod or natalizumab may be considered as second-line therapies. IMD treatment is discontinued upon the transition of RRMS to secondary progressive phase. Rehabilitation should be considered at every phase of the disease.

A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon ß-1b in patients with multiple sclerosis.

OBJECTIVES: To study the safety and efficacy of vitamin D3 as an add on therapy to interferon ß-1b (IFNB) in patients with multiple sclerosis (MS). METHODS: 1 year, double blind, placebo controlled, randomised study in 66 MS patients. The primary outcomes were T2 burden of disease (BOD) on MRI scans, proportion of patients with serum levels of 25-hydroxyvitamin D (25(OH)D) ≥85 nmol/l or intact parathyroid hormone (PTH) ≤20 ng/l, and number of adverse events. Secondary outcomes were number of MRI enhancing T1 lesions and new T2 lesions, annual relapse rate, changes in the Expanded Disability Status Scale score, timed 25 foot walk test and timed 10 foot tandem walk tests. RESULTS: Median change in BOD was 287 mm(3) in the placebo group and 83 mm(3) in the vitamin D group (p=0.105). Serum levels of 25(OH)D increased from a mean of 54 (range 19-82) nmol/l to 110 (range 67-163) nmol/l in the vitamin D group. 84% of patients reached a serum 25(OH)D level >85 nmol/l in the vitamin D group and 3% in the placebo group (p<0.0001). Patients in the vitamin D group showed fewer new T2 lesions (p=0.286) and a significantly lower number of T1 enhancing lesions (p=0.004), as well as a tendency to reduced disability accumulation (p=0.071) and to improved timed tandem walk (p=0.076). There were no significant differences in adverse events or in the annual relapse rate. CONCLUSION: Vitamin D3 add on treatment to IFNB reduces MRI disease activity in MS. TRIAL REGISTRATION NUMBER: EudraCT number 2007-001958-99 and ClinicalTrialsGov number NCT01339676.

Lambert-Eaton myasthenic syndrome following H1N1-influenza vaccination: a case report.

BACKGROUND: The outbreak of influenza A (H1N1) pandemic during the year 2009 led to the development of several vaccinations against H1N1 virus. In Finland, 2.6 million citizens were vaccinated during pandemic 2009 - 2010 with adjuvanted influenza vaccine, Pandemrix(®) . CLINICAL PRESENTATION: In this case report, we describe a patient with non-paraneoplastic Lambert-Eaton myasthenic syndrome following Pandemrix(®) vaccination. CONCLUSION: Development of various autoimmune diseases in genetically predisposed subjects following exposure to certain environmental factors, including vaccinations, is a well-known entity. Clinicians should be aware of the possibility of the induction of autoimmune diseases following vaccinations and actively ask the relevant clinical history in a newly diagnosed patient with an autoimmune disorder.

Lower brain diffusivity in postpartum period compared to late pregnancy: results from a prospective imaging study of multiple sclerosis patients.

INTRODUCTION: A positive correlation has been observed between multiple sclerosis (MS) disease activity status and the apparent diffusion coefficient (ADC) of the brain. Moreover, the relapse frequency of MS has been reported to decrease during pregnancy and increase postpartum. The aim of this study was to evaluate whether ADC histograms correlate with MS activity during pregnancy and postpartum, with a leading hypothesis that the ADC would increase postpartum compared to pregnancy. METHODS: Magnetic resonance imaging, as well as diffusion-weighted imaging, was performed in 19 patients with relapsing-remitting MS once during the third trimester and once 4-12 weeks postpartum. Brain tissue was extracted from nonbrain tissue with an automated computer program, and whole-brain histograms were generated. New or growing T2 lesions in postpartum images were counted on T2-weighted images. RESULTS: In conventional brain magnetic resonance imaging, a significant increase in T2-lesion load was seen in postpartum images; 58% of patients showed signs of disease activity on their postpartum scan. Despite of this, and contrary to the original hypothesis, whole-brain ADC values were significantly lower in the postpartum period compared to the time of pregnancy. CONCLUSION: This is the first study to address the ADC of the brain during pregnancy and postpartum period. We hypothesize that the higher ADC values observed during pregnancy in this study reflect the physiological status of the cerebral vasculature during pregnancy (generalized vasodilatation of downstream resistance arterioles and an increase of endothelial permeability), which overwhelm the alterations in ADC values normally seen related to MS activity.

Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles.

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.

Consistently replicating locus linked to migraine on 10q22-q23.

Here, we present the results of two genome-wide scans in two diverse populations in which a consistent use of recently introduced migraine-phenotyping methods detects and replicates a locus on 10q22-q23, with an additional independent replication. No genetic variants have been convincingly established in migraine, and although several loci have been reported, none of them has been consistently replicated. We employed the three known migraine-phenotyping methods (clinical end diagnosis, latent-class analysis, and trait-component analysis) with robust multiple testing correction in a large sample set of 1675 individuals from 210 migraine families from Finland and Australia. Genome-wide multipoint linkage analysis that used the Kong and Cox exponential model in Finns detected a locus on 10q22-q23 with highly significant evidence of linkage (LOD 7.68 at 103 cM in female-specific analysis). The Australian sample showed a LOD score of 3.50 at the same locus (100 cM), as did the independent Finnish replication study (LOD score 2.41, at 102 cM). In addition, four previously reported loci on 8q21, 14q21, 18q12, and Xp21 were also replicated. A shared-segment analysis of 10q22-q23 linked Finnish families identified a 1.6-9.5 cM segment, centered on 101 cM, which shows in-family homology in 95% of affected Finns. This region was further studied with 1323 SNPs. Although no significant association was observed, four regions warranting follow-up studies were identified. These results support the use of symptomology-based phenotyping in migraine and suggest that the 10q22-q23 locus probably contains one or more migraine susceptibility variants.

A high-density association screen of 155 ion transport genes for involvement with common migraine.

The clinical overlap between monogenic Familial Hemiplegic Migraine (FHM) and common migraine subtypes, and the fact that all three FHM genes are involved in the transport of ions, suggest that ion transport genes may underlie susceptibility to common forms of migraine. To test this leading hypothesis, we examined common variation in 155 ion transport genes using 5257 single nucleotide polymorphisms (SNPs) in a Finnish sample of 841 unrelated migraine with aura cases and 884 unrelated non-migraine controls. The top signals were then tested for replication in four independent migraine case-control samples from the Netherlands, Germany and Australia, totalling 2835 unrelated migraine cases and 2740 unrelated controls. SNPs within 12 genes (KCNB2, KCNQ3, CLIC5, ATP2C2, CACNA1E, CACNB2, KCNE2, KCNK12, KCNK2, KCNS3, SCN5A and SCN9A) with promising nominal association (0.00041 < P < 0.005) in the Finnish sample were selected for replication. Although no variant remained significant after adjusting for multiple testing nor produced consistent evidence for association across all cohorts, a significant epistatic interaction between KCNB2 SNP rs1431656 (chromosome 8q13.3) and CACNB2 SNP rs7076100 (chromosome 10p12.33) (pointwise P = 0.00002; global P = 0.02) was observed in the Finnish case-control sample. We conclude that common variants of moderate effect size in ion transport genes do not play a major role in susceptibility to common migraine within these European populations, although there is some evidence for epistatic interaction between potassium and calcium channel genes, KCNB2 and CACNB2. Multiple rare variants or trans-regulatory elements of these genes are not ruled out.

Acute treatment of migraine with the selective 5-HT1F receptor agonist lasmiditan--a randomised proof-of-concept trial.

INTRODUCTION: Lasmiditan (COL-144; LY573144) is a novel, highly selective and potent agonist at 5-HT(1F) receptors that lacks vasoconstrictor activity. Preclinical and early clinical experiments predict acute antimigraine efficacy of COL-144 that is mediated through a non-vascular, primarily neural, mechanism. SUBJECTS AND METHODS: In a randomised, multicentre, placebo-controlled, double-blind, group-sequential, adaptive treatment-assignment, proof-of-concept and dose-finding study, we treated 130 subjects in-hospital during a migraine attack. Subjects were allocated to an intravenous dose level of lasmiditan or placebo in small cohorts. The starting dose was 2.5 mg. Subsequent doses were adjusted, up or down, according to the safety and efficacy seen in the preceding cohort. The primary outcome measure was headache response defined as improvement from moderate or severe headache at baseline to mild or no headache at 2 h post-dose. The study was designed to explore the overall dose response relationship but was not powered to differentiate individual doses from placebo, nor to detect effect differences for other migraine symptoms. RESULTS: Forty-two subjects received placebo and 88 received lasmiditan in doses of 2.5-45 mg. Subjects were observed in the clinic for 4 h after treatment and used a diary card to record symptoms and adverse events for up to 24 h. The study was terminated when the 20 mg dose met predefined efficacy stopping rules. Of subjects treated in the 10, 20, 30 and 45 mg lasmiditan dose groups, 54-75% showed a 2 h headache response, compared to 45% in the placebo group (P = 0.0126 for the linear association between response rates and dose levels). Patient global impression at 2 h and lack of need for rescue medication also showed statistically significant linear correlations with dose. Lasmiditan was generally well tolerated. Adverse events were reported by 65% of subjects on lasmiditan and by 43% on placebo and were generally mild. Dizziness, paresthesia and sensations of heaviness (usually limb) were more common on lasmiditan. CONCLUSIONS: At intravenous doses of 20 mg and higher, lasmiditan proved effective in the acute treatment of migraine. Further studies to assess the optimal oral dose and full efficacy and tolerability profile are under way. The non-vascular, neural mechanism of action of lasmiditan may offer an alternative means to treat migraine especially in patients who have contra-indications for agents with vasoconstrictor activity. The clinicaltrials.gov identifier for this study is NCT00384774.

[Update on current care guidelines: diagnostics, treatment and rehabilitation of multiple sclerosis]. / MS-taudin diagnoosi, lääkehoito ja kuntoutus.

Treatment is initiated when the McDonald criteria for relapsing-remitting multiple sclerosis (RRMS) are fulfilled. High-risk patients with clinically isolated syndrome are followed using magnetic resonance imaging for one year after the first imaging. Interferon-beta or glatiramer acetate are the first-line immunomodulating drugs (IMD) for RRMS. MxA protein is measured 12 and 24 months after initiation of Interferon-beta to evaluate possible development of neutralizing antibodies. If MxA protein may not be detected repeatedly interferon-beta treatment is discontinued. If the disease is active in spite of treatment with first-line IMD, natalizumab may be considered as a second-line therapy. IMD is stopped when the transition to secondary progressive phase has occurred (or upon transition to secondary progressive phase).

Recurrent lymphocytic meningitis positive for herpes simplex virus type 2.

We found the prevalence of recurrent lymphocytic meningitis associated with herpes simplex virus type 2 (HSV-2) was 2.2/100,000 population in Finland during 1996-2006, higher than previous estimates. PCR was most sensitive in detecting HSV-2 DNA from cerebrospinal fluid if the sample was taken 2-5 days after symptom onset.

Valsalva maneuver as migraine inducer: a case report of a woman with patent foramen ovale and an ischemic stroke.

The association between patent foramen ovale, ischemic stroke, and migraine with aura is well known. It is, however, complicated and generates a considerable debate about the features and clinical consequences of the phenomenon. We report a case of a woman for whom patent foramen ovale has possibly acted as an inducer of both migraine attacks and ischemic stroke.

Association between Ménière's disease and vestibular migraine.

OBJECTIVE: The aim of the present study was to evaluate complaints in people with Ménière's disease (MD) with and without migraine and headache to study the association between MD and Vestibular Migraine (VM). We believe this will help us understand if these two disorders represent a disease continuum in that they may share a common aetiology. METHODS: The study used a retrospective design and included data of 911 patients with MD from the Finnish Ménière Federation database. The study participants had a mean age of 60.2 years, mean duration of disease of 12.6 years, and 78.7% of the participants were females. The questionnaire data comprised of both disease specific and impact related questions. The data were analyzed using the Mann-Whitney U test, the Kruskal Wallis H test, logistic regression analyses, and decision tree analysis. RESULTS: Migraine and headache was reported by 190 subjects (20.9%) and 391 subjects (42.9%) respectively. We found that patients that could be classified as VM in the study (i.e., those with frequent vertigo spells associated with migraine) more often reported complaints of severe MD symptoms, had reduced health-related quality of life, suffered more from anxiety, had more neurological complaints, and experienced a reduced sense of coherence than the non-migraneous patients with MD. However, neither the decision tree analysis nor the logistic regression analysis could reliably discriminate VM from MD patients. CONCLUSION: Our study results confirm that MD is frequently associated with headache and migraine. In addition, results also indicate that migraine provokes the severity of MD. We suggest that MD and VM may share similar pathophysiological mechanisms. Hence, the future MD classification systems should include a category referred to as 'MD with migraine' that will include patients with VM.

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families.

Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small effect, or a combination of the two hypotheses. In 8,319 individuals across 1,589 migraine families, we calculated migraine polygenic risk scores (PRS) and found a significantly higher common variant burden in familial cases (n = 5,317, OR = 1.76, 95% CI = 1.71-1.81, p = 1.7 × 10-109) compared to population cases from the FINRISK cohort (n = 1,101, OR = 1.32, 95% CI = 1.25-1.38, p = 7.2 × 10-17). The PRS explained 1.6% of the phenotypic variance in the population cases and 3.5% in the familial cases (including 2.9% for migraine without aura, 5.5% for migraine with typical aura, and 8.2% for hemiplegic migraine). The results demonstrate a significant contribution of common polygenic variation to the familial aggregation of migraine.

Comorbidity in Finnish migraine families.

The objective of the study was to investigate comorbidity of migraine in Finnish migraine families. One thousand consecutive participants in the Finnish Migraine Gene Project reported their medical illnesses in addition to migraine and headache. Migraine patients (n=678) reported significantly more hypotension (OR 1.43, CI 95% 1.02-2.01), allergy (OR 1.83, CI 95% 1.34-2.51) and psychiatric disorders (OR 4.09, CI 95% 2.11-7.92) compared to their family members without migraine (n=322). Subgroup analyses demonstrated that especially women and the group fulfilling the criteria for both migraine with and without aura were likely to have additional disorders besides their migraine. Interestingly, male migraineurs with aura reported a significant association with stroke and epilepsy. Familial migraine is comorbid with hypotension, allergy and psychiatric disorders. The association between migraine with aura and stroke and epilepsy among men of the studied families warrants further study. Clinical, pathophysiological and genetic implications of these results are discussed.

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine.

Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10(-8)) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

Guidelines for the organization of headache education in Europe: the headache school.

According to its mission statement, one of the goals of the European Headache Federation (EHF) is to "educate Europe" about headache through the teaching of the key health personnel, such as young physicians and all those involved in headache management, about the seriousness of headache disorders. The countries of Europe share a close geographical proximity that facilitates international exchanges, particularly between university faculties. In recent years, this has, indeed, been the working basis of European educational endeavours in the field of headache. For a number of years, annual summer schools were organized in different European countries and a permanent Summer Headache School was set up in Cambridge (to be held every alternate year). The last summer headache school was held in Vilnius in 2002. In the past decade, a patronage scheme was also set up, which, combining two or more countries (one developed, one or more developing), allowed international exchanges of doctors and students for training purposes. In some centres, participants were also able to gain clinical practice and research experience by staying at the host institutions for extended periods of time. As a result of all this activity there have emerged, in Europe, "clusters" of people with a particular interest in headache. However, the rapid growth of insight into headache (new molecules, new headache categories, etc.) has contributed to a widening of the scientific gap between developing and developed countries. Moreover, in the past four years, due to the relative restriction of national/international drug company budgets, it has proved possible to organize only relatively inexpensive teaching courses. As a result, countries whose medical communities had been developing a "headache culture" now find themselves destined to be increasingly held back. Therefore, the EHF, in order to promote education on headache in Europe at national level, felt there was a need for guidelines for the organization of educational courses that meet uniform standards of excellence and in terms of code of conduct: guaranteed courses that will attract investors and those seeking to increase their knowledge, skills and understanding in the area of primary and secondary headache. The guidelines, presented here, specify the ideal length of a headache course, the number of lectures it should include, as well as the ideal number of participants and teachers. A sample course outline is provided, together with a checklist to help the organizers to meet the criteria for an EHF-approved headache school.

Late radiation effects in the dog brain: correlation of MRI and histological changes.

PURPOSE: To determine the correlation between sequential changes in the brain of dogs after irradiation, as detected by magnetic resonance imaging (MRI), with the eventual appearance of histological lesions. Histology was performed 77-115 weeks after irradiation. MATERIALS AND METHODS: Groups of five beagle dogs were irradiated to the brain with single doses of 10, 12, 14 or 16 Gy of 6 MV photons, at the 100% iso-dose. Sequential MRIs were taken to detect changes in the brain for 77-115 weeks after irradiation. Dose-effect relationships were established for changes in the brain as detected by MRI, computerized tomography (CT), gross morphology and histology. The doses that caused a specified response in 50% of the animals (ED(50)+/-SE) were calculated from these dose-effect relationships for each endpoint. RESULTS: The ED50 values (+/-SE) for focal and diffuse changes on T2-weighted MR images were 11.0+/-1.1 and 10.8+/-0.9 Gy, respectively. The ED50 values (+/-SE) for contrast enhancement on T1-weighted MR images and on CT were 13.4+/-0.6 and 13.0+/-0.6 Gy, respectively. It was 11.4+/-0.6 Gy for any type of histological lesion (haemorrhage, reactive change or glial scar) 77-115 weeks after irradiation. For a macroscopic lesion the ED50 (+/-SE) value was 13.0+/-1.1 Gy. CONCLUSIONS: The presence of focal or diffuse changes on T2-weighted MR images was the best indicator for the eventual appearance of any type of histological lesion in the dog brain after irradiation with single doses of photons. The ED50 for any histological lesion did not differ significantly from the ED50 for a focal (P>0.35) or diffuse (P=0.3) change on T2-weighted MR images.