Comparison of Unenhanced and Gadolinium-Enhanced Imaging in Multiple Sclerosis: Is Contrast Needed for Routine Follow-Up MRI?

BACKGROUND AND PURPOSE: Gadolinium enhanced MRI is routinely used for follow-up of patients with multiple sclerosis. Our aim was to evaluate whether enhancing multiple sclerosis lesions on follow-up MR imaging can be detected by visual assessment of unenhanced double inversion recovery and FLAIR sequences. MATERIALS AND METHODS: A total of 252 consecutive MRIs in 172 adult patients with a known diagnosis of multiple sclerosis were reviewed. The co-presence or absence of associated double inversion recovery and FLAIR signal abnormality within contrast-enhancing lesions was recorded by 3 neuroradiologists. In a subset of patients with prior comparisons, the number of progressive lesions on each of the 3 sequences was assessed. RESULTS: A total of 34 of 252 MRIs (13%) demonstrated 55 enhancing lesions, of which 52 (95%) had corresponding hyperintensity on double inversion recovery and FLAIR. All lesions were concordant between double inversion recovery and FLAIR, and the 3 enhancing lesions not visible on either sequence were small (<2 mm) and cortical/subcortical (n = 2) or periventricular (n = 1). A total of 17 (22%) of the 76 MRIs with a prior comparison had imaging evidence of disease progression: Ten (59%) of these showed new lesions on double inversion recovery or FLAIR only, 6 (35%) showed progression on all sequences, and 1 (6%) was detectable only on postcontrast T1, being located in a region of confluent double inversion recovery and FLAIR abnormality. CONCLUSIONS: There was a high concordance between enhancing lesions and hyperintensity on either double inversion recovery or FLAIR. Serial follow-up using double inversion recovery or FLAIR alone may capture most imaging progression, but isolated enhancing lesions in confluent areas of white matter abnormality could present a pitfall for this approach.

Glioma imaging in Europe: A survey of 220 centres and recommendations for best clinical practice.

OBJECTIVES: At a European Society of Neuroradiology (ESNR) Annual Meeting 2015 workshop, commonalities in practice, current controversies and technical hurdles in glioma MRI were discussed. We aimed to formulate guidance on MRI of glioma and determine its feasibility, by seeking information on glioma imaging practices from the European Neuroradiology community. METHODS: Invitations to a structured survey were emailed to ESNR members (n=1,662) and associates (n=6,400), European national radiologists' societies and distributed via social media. RESULTS: Responses were received from 220 institutions (59% academic). Conventional imaging protocols generally include T2w, T2-FLAIR, DWI, and pre- and post-contrast T1w. Perfusion MRI is used widely (85.5%), while spectroscopy seems reserved for specific indications. Reasons for omitting advanced imaging modalities include lack of facility/software, time constraints and no requests. Early postoperative MRI is routinely carried out by 74% within 24-72 h, but only 17% report a percent measure of resection. For follow-up, most sites (60%) issue qualitative reports, while 27% report an assessment according to the RANO criteria. A minority of sites use a reporting template (23%). CONCLUSION: Clinical best practice recommendations for glioma imaging assessment are proposed and the current role of advanced MRI modalities in routine use is addressed. KEY POINTS: • We recommend the EORTC-NBTS protocol as the clinical standard glioma protocol. • Perfusion MRI is recommended for diagnosis and follow-up of glioma. • Use of advanced imaging could be promoted with increased education activities. • Most response assessment is currently performed qualitatively. • Reporting templates are not widely used, and could facilitate standardisation.

Early primary biliary cholangitis is characterised by brain abnormalities on cerebral magnetic resonance imaging.

BACKGROUND: Brain change can occur in primary biliary cholangitis (PBC), potentially as a result of cholestatic and/or inflammatory processes. This change is linked to systemic symptoms of fatigue and cognitive impairment. AIM: To identify whether brain change occurs early in PBC. If the change develops early and is progressive, it may explain the difficulty in treating these symptoms. METHODS: Early disease brain change was explored in 13 patients with newly diagnosed biopsy-proven precirrhotic PBC using magnetisation transfer, diffusion-weighted imaging and 1 H magnetic resonance spectroscopy. Results were compared to 17 healthy volunteers. RESULTS: Cerebral magnetisation transfer ratios were reduced in early PBC, compared to healthy volunteers, in the thalamus, putamen and head of caudate with no greater reduction in patients with greater symptom severity. Mean apparent diffusion coefficients were increased in the thalamus only. No 1 H magnetic resonance spectroscopy abnormalities were seen. Serum manganese levels were elevated in all PBC patients, but no relationship was seen with imaging or symptom parameters. There were no correlations between neuroimaging data, laboratory data, symptom severity scores or age. CONCLUSIONS: This is the first study to be performed in this precirrhotic patient population, and we have highlighted that neuroimaging changes are present at a much earlier stage than previously demonstrated. The neuroimaging abnormalities suggest that the brain changes seen in PBC occur early in the pathological process, even before significant liver damage has occurred. If such changes are linked to symptom pathogenesis, this could have important implications for the timing of second-line-therapy use.

The role of functional dopamine-transporter SPECT imaging in parkinsonian syndromes, part 1.

SUMMARY: As we defeat infectious diseases and cancer, one of the greatest medical challenges facing us in the mid-21st century will be the increasing prevalence of degenerative disease. Those diseases, which affect movement and cognition, can be the most debilitating. Dysfunction of the extrapyramidal system results in increasing motor disability often manifest as tremor, bradykinesia, and rigidity. The common pathologic pathway of these diseases, collectively described as parkinsonian syndromes, such as Parkinson disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies, is degeneration of the presynaptic dopaminergic pathways in the basal ganglia. Conventional MR imaging is insensitive, especially in early disease, so functional imaging has become the primary method used to differentiate a true parkinsonian syndrome from vascular parkinsonism, drug-induced changes, or essential tremor. Unusually for a modern functional imaging technique, the method most widely used in European clinics depends on SPECT and not PET. This SPECT technique (described in the first of 2 parts) commonly reports dopamine-transporter function, with decreasing striatal uptake demonstrating increasingly severe disease.

The role of functional dopamine-transporter SPECT imaging in parkinsonian syndromes, part 2.

SUMMARY: The functional imaging technique most widely used in European clinics to differentiate a true parkinsonian syndrome from vascular parkinsonism, drug-induced changes, or essential tremor is dopamine-transporter SPECT. This technique commonly reports dopamine-transporter function, with decreasing striatal uptake demonstrating increasingly severe disease. The strength of dopamine-transporter SPECT is that nigrostriatal degeneration is observed in both clinically inconclusive parkinsonism and early, even premotor, disease. In this clinical review (Part 2), we present the dopamine-transporter SPECT findings in a variety of neurodegenerative diseases, including multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies. The findings in vascular parkinsonism, drug-induced parkinsonism, and essential tremor are also described. It is hoped that this technique will be the forerunner of a range of routinely used, process-specific ligands that can identify early degenerative disease and subsequently guide disease-modifying interventions.

Age independently affects myelin integrity as detected by magnetization transfer magnetic resonance imaging in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a heterogeneous disorder with a progressive course that is difficult to predict on a case-by-case basis. Natural history studies of MS have demonstrated that age influences clinical progression independent of disease duration. OBJECTIVE: To determine whether age would be associated with greater CNS injury as detected by magnetization transfer MRI. MATERIALS AND METHODS: Forty MS patients were recruited from out-patient clinics into two groups stratified by age but with similar clinical disease duration as well as thirteen controls age-matched to the older MS group. Images were segmented by automated programs and blinded readers into normal appearing white matter (NAWM), normal appearing gray matter (NAGM), and white matter lesions (WMLs) and gray matter lesions (GMLs) in the MS groups. WML and GML were delineated on T2-weighted 3D fluid-attenuated inversion recovery (FLAIR) and T1 weighted MRI volumes. Mean magnetization transfer ratio (MTR), region volume, as well as MTR histogram skew and kurtosis were calculated for each region. RESULTS: All MTR measures in NAGM and MTR histogram metrics in NAWM differed between MS subjects and controls, as expected and previously reported by several studies, but not between MS groups. However, MTR measures in the WML did significantly differ between the MS groups, in spite of no significant differences in lesion counts and volumes. CONCLUSIONS: Despite matching for clinical disease duration and recording no significant WML volume difference, we demonstrated strong MTR differences in WMLs between younger and older MS patients. These data suggest that aging-related processes modify the tissue response to inflammatory injury and its clinical outcome correlates in MS.

Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3 T MRI study.

OBJECTIVE: It is not established whether myalgic encephalomyelitis/chronic fatigue syndrome (CFS) is associated with structural brain changes. The aim of this study was to investigate this by conducting the largest voxel-based morphometry study to date in CFS. METHODS: High-resolution structural 3 T cerebral MRI scanning was carried out in 26 patients with CFS and 26 age- and gender-matched healthy volunteers. Voxel-wise generalised linear modelling was applied to the processed MR data using permutation-based non-parametric testing, forming clusters at t>2.3 and testing clusters for significance at p<0.05, corrected for multiple comparisons across space. RESULTS: Significant voxels (p<0.05, corrected for multiple comparisons) depicting reduced grey matter volume in the CFS group were noted in the occipital lobes (right and left occipital poles; left lateral occipital cortex, superior division; and left supracalcrine cortex), the right angular gyrus and the posterior division of the left parahippocampal gyrus. Significant voxels (p<0.05, corrected for multiple comparisons) depicting reduced white matter volume in the CFS group were also noted in the left occipital lobe. CONCLUSION: These data support the hypothesis that significant neuroanatomical changes occur in CFS, and are consistent with the complaint of impaired memory that is common in this illness; they also suggest that subtle abnormalities in visual processing, and discrepancies between intended actions and consequent movements, may occur in CFS.

Management of incidental findings during imaging research in "healthy" volunteers: current UK practice.

OBJECTIVES: Incidental findings (IF) are becoming increasingly common due to the proliferation of imaging research. IFs can be life-changing for "healthy" volunteers. This study examined variation in IF management in UK research studies of healthy volunteers, including comparison with ethical and legal guidelines, thus providing baseline data and informing future practice. METHODS: Questionnaire of participant background [medical/non-medical; radiologist/non-radiologist; years as principal investigator (PI)], type of research (involving children or not), institutional policy, volunteer information, radiologist involvement in reporting scans and IF disclosure mechanisms. Investigator's current and perceived "ideal" practice was examined. Participants were PIs performing imaging research of healthy volunteers approved by UK ethics committees (2006-2009). RESULTS: 63/146 (43%) surveys completed. 54/61 (88.5%) had site-specific guidelines. Information commonly provided to volunteers should IF be found: personal data (51/62; 82%), contingency plans (54/62; 87%) and disclosure to general practitioner (GP)/treating physician (47/62; 76%). PIs used different strategies for image review. Commonest: radiologist reports research scans only when researcher suspicious of IF [15/57 (26%) compared with 5/28 (16%) in ideal practice]. Commonest ideal reporting strategy: routine reporting by specialist radiologists [9/28 (29%) compared with 8/57 (14%) in current practice]. 49/56 (87.5%) have a standardised disclosure contingency plan, usually involving GP. PIs most commonly disclosed IFs to volunteers when judged relevant (27/58; 47%), most commonly face to face (22/54; 41%), by volunteer's GP (26/60; 43%). Background of PI influenced consent, reporting and disclosure practice. CONCLUSION: There is wide variation in handling IFs in UK imaging research. Much of the current practice contravenes the vague existing legal and ethical guidelines, and is unlikely to be in the best interests of volunteers or researchers.

Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas.

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

Conventional MRI evaluation of gliomas.

MRI using T(1) weighted, T(2) weighted and gadolinium-enhanced sequences plays a central clinical role in diagnosis, characterisation, surveillance and therapeutic monitoring of gliomas. Such conventional MRI protocols provide high resolution multiplanar structural information, and substantially improved tissue characterisation compared with CT. However, the MRI signal lacks biological specificity, e.g. T(2) weighted dependent signal abnormality is dominated by tissue water content, and contrast enhancement reflects a non-specific increase in blood-brain barrier permeability. This limits non-invasive glioma diagnosis, characterisation and therapeutic planning and assessment of active tumour load may be confounded by treatment-related effects. The complex features of glioma morphology and often subtle changes between MRI examinations are also frequently difficult to detect reliably by visual inspection of the images, even by an experienced radiologist. Moreover, the most widely used response criteria in clinical practice and therapeutic trials rely on linear measurements of enhancing tumour and are further challenged by the irregular shape and heterogeneous composition of gliomas. This contributes to the poor correlation of these criteria with hard clinical endpoints. While conventional MRI is widely available and provides essential anatomical information, the lack of pathology-specific biomarkers available from standard MRI sequences and methods of image analysis used limit overall diagnostic and prognostic efficacy of the examination.

Incidental findings found in "healthy" volunteers during imaging performed for research: current legal and ethical implications.

Incidental findings found in "healthy" volunteers during research imaging are common and have important implications for study design and performance, particularly in the areas of informed consent, subjects' rights, clinical image analysis and disclosure. In this study, we aimed to determine current practice and regulations concerning information that should be given to research subjects when obtaining consent, reporting of research images, who should be informed about any incidental findings and the method of disclosure. We reviewed all UK, European and international humanitarian, legal and ethical agencies' guidance. We found that the guidance on what constitutes incidental pathology, how to recognise it and what to do about it is inconsistent between agencies, difficult to find and less complete in the UK than elsewhere. Where given, guidance states that volunteers should be informed during the consent process about how research images will be managed, whether a mechanism exists for identifying incidental findings, arrangements for their disclosure, the potential benefit or harm and therapeutic options. The effects of incidentally discovered pathology on the individual can be complex and far-reaching. Radiologist involvement in analysis of research images varies widely; many incidental findings might therefore go unrecognised. In conclusion, guidance on the management of research imaging is inconsistent, limited and does not address the interests of volunteers. Improved standards to guide management of research images and incidental findings are urgently required.

Reduction in cerebral atrophy associated with ethyl-eicosapentaenoic acid treatment in patients with Huntington's disease.

Ultra-pure ethyl-eicosapentaenoic acid (ethyl-EPA), a semi-synthetic ethyl ester of eicosapentaenoic acid, is associated with clinical improvement in motor functioning in Huntington's disease. The aim was to determine the extent to which it might reduce the rate of progress of cerebral atrophy. High-resolution cerebral magnetic resonance imaging scans were acquired at baseline, 6 months and 1 year in up to 34 patients with stage I or II Huntington's disease who took part in a randomized, double-blind, placebo-controlled trial of ethyl-EPA. For each subject and each pair of structural images, the two-timepoint brain volume change was calculated in a double-blind manner. Significant group-level reductions in brain atrophy were observed in the head of the caudate nucleus and the posterior thalamus. These findings show that treatment with ethyl-EPA is associated with significant reduction in brain atrophy, particularly in the caudate and thalamus. No other drug tested in Huntington's disease has shown this effect.

Inclusion or exclusion of intratumoral vessels in relative cerebral blood volume characterization in low-grade gliomas: does it make a difference?

We assessed the influence of inclusion (method 1) and exclusion (method 2) of intratumoral vessels when determining maximum relative cerebral blood volume (rCBVmax) in 3 types of low-grade gliomas (LGGs): astrocytomas, oligoastrocytomas, and oligodendrogliomas. Method 1 yielded significantly higher mean rCBVmax than method 2. However, only method 2 demonstrated a significant (P = .026) association between rCBVmax and membership of a differently ranked histologic category. Exclusion of intratumoral vessels appears, therefore, preferable when determining rCBVmax in LGGs.

Regional brain metabolite abnormalities in inherited prion disease and asymptomatic gene carriers demonstrated in vivo by quantitative proton magnetic resonance spectroscopy.

INTRODUCTION: Inherited prion diseases are caused by mutations in the gene which codes for prion protein (PrP), leading to proliferation of abnormal PrP isomers in the brain and neurodegeneration; they include Gerstmann-Sträussler-Scheinker disease (GSS), fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). METHODS: We studied two patients with symptomatic inherited prion disease (P102L) and two pre-symptomatic P102L gene carriers using quantitative magnetic resonance spectroscopy (MRS). Short echo time spectra were acquired from the thalamus, caudate region and frontal white matter, metabolite levels and ratios were measured and z-scores calculated for individual patients relative to age-matched normal controls. MRS data were compared with structural magnetic resonance imaging. RESULTS: One fCJD case had generalised atrophy and showed increased levels of myo-inositol (MI) in the thalamus (z=3.7). The other had decreased levels of N-acetylaspartate (z=4) and diffuse signal abnormality in the frontal white matter. Both asymptomatic gene carriers had normal imaging, but increased frontal white matter MI (z=4.3, 4.1), and one also had increased MI in the caudate (z=5.3). CONCLUSION: Isolated MI abnormalities in asymptomatic gene carriers are a novel finding and may reflect early glial proliferation, prior to significant neuronal damage. MRS provides potential non-invasive surrogate markers of early disease and progression in inherited prion disease.

MRS shows abnormalities before symptoms in familial Alzheimer disease.

BACKGROUND: Pathologic change in Alzheimer disease (AD) begins some years before symptoms. MRS has the potential to detect metabolic abnormalities reflecting this early pathologic change. Presenilin 1 (PS1) and amyloid precursor protein (APP) mutation carriers have a nearly 100% risk of developing AD and may be studied prior to symptom onset. METHODS: Short echo time proton MR spectra were acquired from a midline posterior cingulate voxel in presymptomatic carriers of PS1 or APP mutations ("presymptomatic mutation carriers" [PMCs]; n = 7) and age- and sex-matched control subjects (n = 6). Ratios of N-acetyl aspartate (NAA), myo-inositol (MI), and choline-containing compounds (Cho) to creatine (Cr) were measured and NAA/MI calculated. Regression analyses and t tests were performed after log transformation. RESULTS: PMC and control subjects were matched for age and sex. PMC subjects were 1.7 to 21.6 years (mean 9.8 years) before expected symptom onset, predicted from family-specific mean age at onset. Age did not significantly affect metabolite ratios. Geometric mean ratios in control subjects were as follows: NAA/Cr = 1.75, MI/Cr = 0.59, and NAA/MI = 2.95. NAA/Cr and NAA/MI were significantly reduced in PMC relative to controls (NAA/Cr mean decrease 10% [95% CI 2 to 18%]; NAA/MI mean decrease 25% [95% CI 3 to 44%]). MI/Cr was increased in PMC, but the differences did not achieve significance (19% increase [95% CI 1% decrease to 41% increase]; p = 0.07)). In PMCs, reduction in NAA/MI (p = 0.001) and MI/Cr (p = 0.002) were related to proximity of expected age at onset. CONCLUSIONS: Metabolic changes are detectable in presymptomatic mutation carriers years before expected onset of Alzheimer disease. Their magnitude is related to proximity of expected age at onset.

Short TE quantitative proton magnetic resonance spectroscopy in variant Creutzfeldt-Jakob disease.

Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative disorder. Clinical diagnosis is difficult in the early stages as the disease often presents with non-specific psychiatric and neurological symptoms. To investigate the diagnostic potential of quantitative short TE in vivo MRS, and the nature and anatomical distribution of biochemical abnormalities in vCJD, localised single-voxel spectra (TE/TR 30 ms/2,000 ms) were acquired from three brain regions: thalami, caudate nuclei and frontal white matter. Metabolite concentrations and ratios from three patients with definite or probable vCJD were compared with eight normal age-matched controls. Abnormal signal on T2-weighted MRI was apparent in the pulvinar region in all vCJD patients; this region also showed greatly increased myo-inositol [MI] (mean 2.5-fold, P=0.01) and decreased N-acetyl-aspartate (NAA; mean 2-fold, P=0.01). Two patients also showed increased [MI] (z=17, 11; one with decreased NAA, z=-12) in normal-appearing caudate nuclei. The magnitude of metabolite abnormalities in the thalami in moderately advanced vCJD suggests a potential role in earlier diagnosis. Short TE protocols allow the measurement of MI, which adds discriminant power to the MRS examination.

Isolated central nervous system involvement in adult T-cell lymphoma/leukaemia.

Central nervous system (CNS) presentation of adult T-cell lymphoma/leukaemia is rare, and almost invariably associated with systemic disease. We report an unusual manifestation of adult T-cell lymphoma/leukaemia, with isolated CNS involvement and unusual imaging findings. We also describe objective response to antiviral therapy. To our knowledge, this is the first report of such presentation and response.

Posterior reversible encephalopathy syndrome: a possible late interaction between cytotoxic agents and general anaesthesia.

A 49-year-old woman who had previously received treatment with cytotoxic drugs for metastatic gestational trophoblastic disease (GTD) presented with a witnessed tonic-clonic seizure, headache, confusion and blindness, 6 days after the uneventful administration of a general anaesthetic and 2 months after cessation of chemotherapy. Magnetic resonance imaging showed relatively symmetrical, subcortical, white matter abnormalities, predominantly affecting the occipital, posterior temporal and parietal lobes and the cerebellum. T2-dependent abnormalities and elevated regional apparent diffusion coefficient were present in a pattern typical for posterior reversible encephalopathy syndrome (PRES). The clinical and radiological manifestations were resolved completely with supportive therapy. This case of PRES may be a late complication of gemcitabine or cisplatin therapy precipitated by a general anaesthetic, or associated electrolyte or blood pressure disturbance.