BackgroundMultiple Sclerosis (MS) is sometimes misdiagnosed in people with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to discuss two CADASIL patients who were misdiagnosed with MS and review the literature for similar cases.MethodsIn addition to reporting our two cases, we searched the literature and all available databases for CADASIL cases with clinical or radiological features suggestive of MS.ResultsWe reported two CADASIL cases misdiagnosed as MS. The review identified 12 reports describing 19 cases with CADASIL and inflammatory or MS-like features. The most prevalent features were sensory manifestations (76.2%), followed by motor manifestations (71.4%), gait imbalance (66.7%) and migraine (61.9%). Majority of the patients (90.5%) had either small vessel disease, demyelinating lesions, or both. Our cases shared these predominant features.Conclusion CADASIL may occasionally present with MS like inflammatory features, . The term "inflammatory CADASIL" can be considered when such red flags are present in atypical MS patients. Genetic testing is imperative for suspected CADASIL.

The failure of relapses and white matter lesions to properly explain long-term disability and progression in multiple sclerosis is compounded by its artificial separation into relapsing remitting, secondary progressive, and primary progressive pigeonholes. The well-known epidemiological disconnection between relapses and long-term disability progression has been rediscovered as "progression independent of relapse activity", i.e. smouldering multiple sclerosis. This smouldering associated worsening proceeds despite early and prolonged use of disease modification therapies, even those that are highly effective at preventing relapses and new/enhancing white matter lesions on MRI. We recognise that smouldering associated worsening and relapse/lesion associated worsening coexist, to varying extents. The extent of cortical demyelination has been shown to correlate significantly with the severity of diffuse injury in normal appearing white matter (post mortem histopathologically (r = 0.55; P = 0.001), and in vivo with MRI (r = -0.6874; P = 0.0006)) and does so independently of white matter lesion burden. Axon loss in the normal appearing white matter explains disability in multiple sclerosis better than focal white matter lesions do. Smouldering associated worsening typically manifests as a length-dependent central axonopathy. We propose a unifying model for multiple sclerosis pathogenesis, wherein accumulation of cortical lesion burden predisposes associated normal appearing white matter to diffuse injury, whilst also intensifying damage within white matter lesions. Our novel two-hit hypothesis implicates cortical disease as a culprit for smouldering multiple sclerosis, abetted by active focal inflammation in the white matter (and vice versa). Substantiation of the two-hit hypothesis would advance the importance of specific therapeutic intervention for (and monitoring of) cortical/meningeal inflammation in people with multiple sclerosis.

BackgroundQuality standards (QS) for people with multiple sclerosis (PwMS) are suboptimal, ambiguous and restricted to certain patient subgroups and care pathways.AimDevelop and pilot MS metrics measuring service provision quality to identify areas for improvement.MethodsA multidisciplinary Working Group developed clinician and patient-reported metrics and standardised data collection forms through an iterative process.ResultsMetrics covered: referral; diagnosis; treatment; annual review; general management; education. Pilot (n=76) showed: 31% of PwMS were referred to MS specialist within 4 weeks of suspected/confirmed demyelination; 28% and 56% had uncomplicated MS confirmed and were offered specialist MS nurse appointment, respectively, within 4 weeks of specialist referral; 75% of eligible PwMS were offered disease-modifying therapy within 8 weeks of confirmed MS diagnosis; 85% had comprehensive multidisciplinary team (MDT) annual review; 90% had a defined point of contact within the MS service; 86% of unscheduled contacts by PwMS, MDT or general practitioners were responded to within 3 days; 53% of MS services maintained a single database of PwMS; and 76% of PwMS were offered ongoing education. Data collection continues and updated findings will be reported.DiscussionMS metrics/data forms are feasible for routine clinical settings, simple to interpret and provide a valuable benchmark for guiding MS service improvements.

A 31 year old lady was admitted with worsening of right sided hemiparesis, on a background five month history of mild right upper limb weakness, and upper limb sensory ataxia. MRI revealed a longitudinally enhancing intrinsic cord lesion from C2-C7 with severe cord expansion, raising initial suspicion for ependymoma. Inflammatory aetiology was considered due to multiple areas of involvement, with T2-weighted signal change within the cervical and thoracic spine, and brain. CSF revealed 4 mononuclear cells, normal protein, normal CSF-serum glucose ratio, T lymphocyte predominance on histology, and no neoplastic cells on flow cytometry. Testing for tuberculosis was negative, including CSF, and extensive imaging did not reveal malignancy. Aquaporin-4 antibodies were positive, and the patient showed marked improvement to intravenous steroids and oral taper, with significant radiological resolution at two months. This case highlights an unusual presentation of NMO, with progressive history over five months, and unusual radiological findings, including severe cord expansion. Positive aquaporin-4 antibody and excellent clinical and radiological response to immunosuppressive therapy confirmed the diagnosis. We took this opportunity to review the clinical presentation and MRI findings in 31 of our five year NMO patient cohort (26 aquaporin-4 antibody positive, 3 anti-MOG positive and 2 seronegative).

Background: White matter lesions are frequently detected using brain magnetic resonance imaging (MRI) performed for various indications. Most are microangiopathic, but demyelination, including multiple sclerosis (MS), is an important cause; conventional MRI cannot always distinguish between these pathologies. The proportion of lesions with a central vein on 7-T T2*-weighted MRI prospectively distinguishes demyelination from microangiopathic lesions. Objective: To test whether 3-T T2*-weighted MRI can differentiate MS from microangiopathic brain lesions. Methods: A total of 40 patients were studied. Initially, a test cohort of 10 patients with MS and 10 patients with microangiopathic white matter lesions underwent 3-T T2*-weighted brain MRI. Anonymised scans were analysed blind to clinical data, and simple diagnostic rules were devised. These rules were applied to a validation cohort of 20 patients (13 with MS and 7 with microangiopathic lesions) by a blinded observer. Results: Within the test cohort, all patients with MS had central veins visible in >45% of brain lesions, while the rest had central veins visible in <45% of lesions. By applying diagnostic rules to the validation cohort, all remaining patients were correctly categorised. Conclusion: 3-T T2*-weighted brain MRI distinguishes perivenous MS lesions from microangiopathic lesions. Clinical application of this technique could supplement existing diagnostic algorithms.

A 79-year-old lady was admitted with rapid onset weakness in both legs with a mid-throacic sensory level. She had a preceding history of viral upper respiratory infection. She was recently treated for breast cancer 12 months' previously. Within 24 hours she developed complete paraplegia and the MRI scan revealed extensive T2W high signal changes throughout the spinal cord with discrete contrast enhancement and expansion of the cord. CSF showed 7 mononuclear cells with low CSF glucose (vs serum) and high CSF protein. Investigations revealed positive aquaporin-4 antibodies and she rapidly improved after a course of intravenous steroids followed by oral steroid taper. Extensive screen for an underlying malignancy was negative. Given the temporal relationship with cancer, a diagnosis of possible paraneoplastic syndrome was made as per established criteria (Graus et al. 2004).We took this opportunity to review the MRI findings in 18 of our recent NMO patient cohort (15 aquaporin-4 antibody positive, 1 anti-MOG positive and 2 seronegative). We compared this against the established radiological criteria (Miller DH et al, 2008) for NMO.We discuss the possibility of NMO being a rare paraneoplastic phenomenon and review the radiological findings in our cohort of NMO patients against established criteria.

Background White matter lesions are frequently detected using brain MRI performed for various indications. Most are microangiopathic but demyelination, including multiple sclerosis, is an important cause and conventional MRI cannot always distinguish between these pathologies. The proportion of lesions with a central vein on 7T T2*-weighted MRI prospectively distinguishes demyelination from microangiopathic white matter lesions. Objective To test whether 3T T2*-weighted MRI can differentiate multiple sclerosis patients from patients with microangiopathic brain lesions. Methods Forty patients were studied. Initially a test cohort of 10 patients with multiple sclerosis and 10 patients with microangiopathic white matter lesions underwent brain 3T MRI. Anonymised scans were analysed blind to clinical data, and simple diagnostic rules were devised, which were applied to a validation cohort of 20 patients (13 with multiple sclerosis and 7 with microangiopathic lesions). Results Within the test cohort, all patients with multiple sclerosis had central veins visible in >45% of lesions, while the others all had central veins visible in <45% of lesions. By applying diagnostic rules to the validation cohort, all 20 patients were correctly categorised. Conclusion T2*-weighted 3T MRI distinguishes multiple sclerosis from microangiopathic brain white matter lesions. Clinical application of this technique could supplement existing diagnostic algorithms.

Background Degeneration of central nervous system normal appearing white matter (NAWM) underlies disability and progression in multiple sclerosis (MS). Axon loss typifies NAWM degeneration. Objective To assess correlation between cortical lesion load and magnetisation transfer ratio (MTR) of the NAWM in MS, in order to test the hypothesis that cortical lesions cause NAWM degeneration. Methods Nineteen patients with MS underwent 7T magnetisation-prepared-rapid-acquisition-gradient-echo (MPRAGE), and magnetisation transfer ratio (MTR) brain MRI. Cortical lesions were identified using MPRAGE and MTR images of cortical ribbons. White matter lesions (WMLs) were segmented using MPRAGE images. WML maps were subtracted from white matter volumes to produce NAWM masks. Pearson correlation was calculated for NAWM MTR vs cortical lesion load, and WML volumes. Results Cortical lesion volumes and counts all had significant correlation with NAWM mean MTR. The strongest correlation was with cortical lesion volumes obtained using MTR images (r=−0.6874, p=0.0006). WML volume had no significant correlation with NAWM mean MTR (r=−0.08706, p=0.3615). Conclusion Our findings are consistent with the hypothesis that cortical lesions cause NAWM degeneration. This implicates cortical lesions in the pathogenesis of NAWM axon loss, which underpins long-term disability and progression in MS.

Importance: There is no single test that is diagnostic for multiple sclerosis (MS), and existing diagnostic criteria are imperfect. This can lead to diagnostic delay. Some patients require multiple (sometimes invasive) investigations, and extensive clinical follow-up to confirm or exclude a diagnosis of MS. A diagnostic biomarker that is pathologically specific for the inflammatory demyelination in MS could overhaul current diagnostic algorithms.Objective: To prospectively assess the diagnostic value of visualizing central veins in brain lesions with magnetic resonance imaging (MRI) for patients with possible MS for whom the diagnosis is uncertain.Design: Prospective longitudinal cohort study. The reference standard is a clinical diagnosis that is arrived at (after a mean follow-up of 26 months) by the treating neurologist with a specialist interest in MS. The 7-T MRI scans were analyzed at baseline, by physicians blinded to the clinical data, for the presence of visible central veins.Setting: Academic MS referral center.Participants: A consecutive sample of 29 patients referred with possible MS who had brain lesions detected on clinical MRI scans but whose condition remained undiagnosed despite expert clinical and radiological assessments.Exposure: Seven-Tesla MRI using a T2*-weighted sequence.Main Outcomes and Measures: The proportion of patients whose condition was correctly diagnosed as MS or as not MS, using 7-T MRI at study onset, compared with the eventual diagnosis reached by treating physicians blinded to the result of the MRI scan.Results: Of the 29 patients enrolled and scanned using 7-T MRI, so far 22 have received a clinical diagnosis. All 13 patients whose condition was eventually diagnosed as MS had central veins visible in the majority of brain lesions at baseline. All 9 patients whose condition was eventually not diagnosed as MS had central veins visible in a minority of lesions.Conclusions and Relevance: In our study, T2*-weighted 7-T MRI had 100% positive and negative predictive value for the diagnosis of MS. Clinical application of this technique could improve existing diagnostic algorithms.

OBJECTIVE: To investigate the myelination status of cortical lesions in MS.

Background: Degeneration of central nervous system normal appearing white matter (NAWM) underlies disability and progression in multiple sclerosis (MS). Axon loss typifies NAWM degeneration. Objective: The objective of this paper is to assess correlation between cortical lesion load and magnetisation transfer ratio (MTR) of the NAWM in MS. This was in order to test the hypothesis that cortical lesions cause NAWM degeneration. Methods: Nineteen patients with MS underwent 7 Tesla magnetisation-prepared-rapid-acquisition-gradient-echo (MPRAGE), and magnetisation transfer ratio (MTR) brain magnetic resonance imaging (MRI). Cortical lesions were identified using MPRAGE and MTR images of cortical ribbons. White matter lesions (WMLs) were segmented using MPRAGE images. WML maps were subtracted from white matter volumes to produce NAWM masks. Pearson correlation was calculated for NAWM MTR vs cortical lesion load, and WML volumes. Results: Cortical lesion volumes and counts all had significant correlation with NAWM mean MTR. The strongest correlation was with cortical lesion volumes obtained using MTR images ( r = −0.6874, p = 0.0006). WML volume had no significant correlation with NAWM mean MTR ( r = −0.08706, p = 0.3615). Conclusion: Our findings are consistent with the hypothesis that cortical lesions cause NAWM degeneration. This implicates cortical lesions in the pathogenesis of NAWM axon loss, which underpins long-term disability and progression in MS.

T-2*-weighted magnetic resonance imaging at 7 T has recently been shown to allow differentiation between white-matter multiple sclerosis lesions and asymptomatic white-matter lesions, by the presence or absence of a detectable central blood vessel. The aim of the present work is to improve the technique by increasing the sensitivity to veins at both 3 T and 7 T, and to assess the benefit of ultra-high-field imaging.Signal-to-noise ratio (SNR) measurements and simulations are used to compare the sensitivity of magnitude T-2*-weighted and susceptibility-weighted images for the detection of small veins (<1 pixel in diameter), both with and without the use of gadolinium. The simulations are used to predict the optimal scanning parameters in order to increase the sensitivity to these veins at both field strengths, and to reduce the inherent dependence on vessel orientation. The sensitivities of the sequences at both field strengths are compared, theoretically and experimentally, in order to quantify the benefit of imaging at ultra-high-field.Subjects with multiple sclerosis (MS) are scanned at both field strengths, using the optimised sequence parameters, as well as those used in previously published work, and the optimisation is shown to improve the detection of veins within lesions. (c) 2011 Elsevier Ireland Ltd. All rights reserved.

GML (a.u) CNR Multi-modal post mortem MRI at 7T to detect and quantify multiple sclerosis cortical grey matter pathology Olivier E. Mougin, Niraj Mistry, Penny A Gowland, Nikos Evangelou, and Klaus Schmierer Sir Peter Mansfield Magnetic Resonance Centre, University of Nottingham, Nottingham, Select, United Kingdom, Institute of Neuroscience, Nottingham, Select, United Kingdom, Barts and The London School of Medicine & Dentistry, Blizard Institute, Centre for Neuroscience & Trauma (Neuroimmunology Group), London, United Kingdom