A randomized controlled trial of a web-based mindfulness programme for people with MS with and without a history of recurrent depression.

BACKGROUND: Evidence shows small positive effects associated with psychological treatments for people with multiple sclerosis (PwMS). In a recent meta-analysis, the treatment with the largest effect size was a mindfulness-based intervention (MBI). OBJECTIVES: We aimed to determine whether an Internet-delivered MBI was beneficial for PwMS. Furthermore, we aimed to investigate history of recurrent depression as a moderator of treatment outcome. METHODS: Participants (N = 132) were assessed based on whether they had a history of recurrent depression, then stratified and randomized to MBI or waitlist. Outcomes were assessed at baseline, post-intervention, and 3 and 6 months. RESULTS: The MBI group reported significantly improved depressive symptoms (primary outcome) compared with the waitlist (p = 0.046, Cohen's d = 0.39). Those with a history of recurrent depression benefitted significantly more than those without (p = 0.034, d = 0.66). There were benefits for health-related quality of life (HRQoL) in the MBI, irrespective of depression history (p = 0.009, d = 0.5). Pain interference was less overall in the MBI group (p < 0.001, d = 0.2), but change over time did not differ from waitlist. There were no treatment effects for anxiety, pain severity or fatigue. CONCLUSION: The Internet-delivered MBI significantly improved depressive symptoms and HRQoL in PwMS. For depression, the benefits were greater for those with a history of recurrent depression. TRIAL REGISTRATION: ACTRN12618001260213, available at: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375598.

Diagnosis, differential diagnosis and misdiagnosis of Susac syndrome.

BACKGROUND AND PURPOSE: Susac syndrome (SuS) is an inflammatory condition of the brain, eye and ear. Diagnosis can be challenging, and misdiagnosis is common. METHODS: This is a retrospective review of the medical records of 32 adult patients from an Australasian cohort of SuS patients. RESULTS: An alternative diagnosis prior to SuS was made in 30 patients (94%) with seven patients receiving two or more diagnoses. The median time to diagnosis of SuS was 3 months (range 0.5-100 months). The commonest misdiagnoses were migraine in 10 patients (31%), cerebral vasculitis in six (19%), multiple sclerosis in five (16%) and stroke in five (16%). Twenty-two patients were treated for alternative diagnoses, 10 of whom had further clinical manifestations prior to SuS diagnosis. At presentation seven patients (22%) met criteria for definite SuS, 19 (59%) for probable SuS and six (19%) for possible SuS. Six patients (19%) presented with brain-eye-ear involvement, 14 with brain-ear (44%), six with brain-eye (19%) and six (19%) with only brain involvement. In patients with the complete triad of symptoms the median delay to diagnosis was 3 months (range 1-9 months) compared to 5.25 months (range 0.5-100 months) for patients with encephalopathy and ocular symptoms at presentation. CONCLUSIONS: Susac syndrome patients are frequently misdiagnosed at initial presentation, despite many having symptoms or radiological features that are red flags for the diagnosis. Delayed diagnosis can lead to patient morbidity. The varied ways in which SuS can present, and clinician failure to consider or recognize SuS, appear to be the main factors leading to misdiagnosis.

Multiple sclerosis: structural and functional integrity of the visual system following alemtuzumab therapy.

OBJECTIVE: To investigate potential neuroprotective and pro-remyelinating effects of alemtuzumab in multiple sclerosis (MS), using the visual pathway as a model. METHODS: We monitored clinical, multifocal visual evoked potential (mfVEP) and MRI outcomes in 30 patients commencing alemtuzumab for relapsing MS, and a reference group of 20 healthy controls (HCs), over 24 months. Change in mfVEP latency was the primary endpoint; change in optic radiation (OR) lesion diffusion metrics and Mars letter contrast sensitivity over the course of the study were secondary endpoints. RESULTS: In patients, we observed a mean shortening of mfVEP latency of 1.21 ms over the course of the study (95% CI 0.21 to 2.21, p=0.013), not altered by correction for age, gender, disease duration or change in OR T2 lesion volume. Mean mfVEP latency in the HC group increased over the course of the study by 0.72 ms (not significant). Analysis of chronic OR T2 lesions (patients) showed an increase in normalised fractional anisotropy and axial diffusivity between baseline and 24 months (both p<0.01). Mean Mars letter contrast sensitivity was improved at 24 months vs baseline (p<0.001), and driven by an early improvement, in both patients and HC. CONCLUSION: We found evidence of partial lesion remyelination after alemtuzumab therapy, indicating either natural restoration in the context of a 'permissive' local milieu; or potentially an independent, pro-reparative mechanism of action. The visual system presents a unique opportunity to study function-structure specific effects of therapy and inform the design of future phase 2 MS remyelination trials.

Development of a Web-Based Mindfulness Program for People With Multiple Sclerosis: Qualitative Co-Design Study.

BACKGROUND: Mindfulness-based stress reduction is an efficacious treatment for people with chronic health problems; however, it is highly intensive and time-consuming, which is a barrier for service provision. OBJECTIVE: This study aims to develop an internet-delivered adapted version of mindfulness-based stress reduction for people with multiple sclerosis to make the intervention more accessible. METHODS: We co-designed a web-based mindfulness program with end users, that is, people with multiple sclerosis (N=19). Iterative feedback was also collected from a subsample of the initial group of end users (n=11), and the program was reviewed by experts (n=8). RESULTS: We identified three main themes common to people with multiple sclerosis: dealing with uncertainty and fears for the future, grief and loss, and social isolation. These themes were incorporated into narratives throughout the program. People with multiple sclerosis who reviewed the program gave feedback that the program was relatable, feasible, and acceptable. Experts agreed that the program appropriately represented the main tenets of mindfulness. Iterative feedback was used to further refine the program. CONCLUSIONS: The web-based mindfulness program that we developed was viewed positively by both experts and end users. The program reflects common concerns for people with multiple sclerosis and has the potential to meet important unmet psychological needs. A randomized controlled trial was planned to determine the efficacy of the program.

Successful implementation of an automated electronic support system for patient safety monitoring: The alemtuzumab in multiple sclerosis safety systems (AMS3) study.

BACKGROUND: Alemtuzumab is a highly effective treatment for relapsing-remitting multiple sclerosis (MS) but requires ongoing pathology monitoring for autoimmune adverse effects. The Alemtuzumab in MS Safety Systems (AMS3) study evaluated the implementation of an automated pathology-monitoring system. OBJECTIVES: To develop an efficient automated clinical decision support system (CDSS) to electronically prompt and track pathology collection and to provide prescribers and patients with customised alerts of abnormal results for identified risks. METHODS: A total of 10 patients with relapsing-remitting MS treated with alemtuzumab were enrolled to test the system. Standard care laboratory monitoring was performed and compared to the performance of the CDSS. RESULTS: The automated CDSS, an integrated patient smartphone application and an additional pre-screening tool were all successfully developed. Compliance with pathology monitoring was 96.7%. The automated analysis of pathology results was significantly faster than standard care neurologist review (p < 0.001). The system correctly identified and alerted abnormalities, including one case of immune thrombocytopenia (ITP) while the treating neurologist was on leave, enabling prompt treatment of serious adverse events. During the course of the study, the CDSS was deployed throughout Australia. CONCLUSION: We successfully developed automated pathology monitoring with a CDSS, demonstrating real-world benefits of high compliance and timely alerting of important results.

The evaluation of an online mindfulness program for people with multiple sclerosis: study protocol.

BACKGROUND: Multiple sclerosis (MS) is a neurological disease of the central nervous system and is associated with many psychosocial symptoms that are difficult to manage including low mood, anxiety, fatigue and pain, as well as low health-related quality of life. Internet-based psychosocial interventions that use mindfulness-based approaches are gathering much attention in recent literature, particularly in the treatment of chronic illnesses. However, no large randomized controlled trials have been done examining the efficacy of such interventions for people with MS (PwMS). METHODS/DESIGN: This study is a randomised controlled trial of an online mindfulness-based intervention (MBI) for PwMS. Participants will be randomised to receive either the MBI or offered the intervention after a waiting period. All participants will be assessed to determine whether they have a history of recurrent depressive disorder. The primary outcome will be severity of depression, according to the Centre of Epidemiology Depression Scale. Secondary outcomes will be anxiety severity, fatigue, pain and quality of life. Assessments will be conducted pre, post-treatment, at three and six-month follow-up. The online mindfulness-based program was developed in collaboration with end-users (n = 19 PwMS) who gave feedback about what would be feasible and acceptable, and the draft program was reviewed by both experts and patients. DISCUSSION: Multiple sclerosis is the most common acquired chronic neurological disease amongst young adults and is associated with a range of symptoms that can be difficult to cope with. In face-to-face interventions, a MBI demonstrated the largest effect in a recent meta-analysis of psychological treatments for PwMS, but MBIs for PwMS have not been delivered online. Hence, this trial will confirm whether MBIs can be efficacious when delivered online. A range of symptoms are assessed as outcomes so that the nature of benefits associated with the online MBI can be ascertained. TRIAL REGISTRATION: ACTRN12618001260213 . Date of Registration: 25/07/2018.

A real-world clinical validation for AI-based MRI monitoring in multiple sclerosis.

Modern management of MS targets No Evidence of Disease Activity (NEDA): no clinical relapses, no magnetic resonance imaging (MRI) disease activity and no disability worsening. While MRI is the principal tool available to neurologists for monitoring clinically silent MS disease activity and, where appropriate, escalating treatment, standard radiology reports are qualitative and may be insensitive to the development of new or enlarging lesions. Existing quantitative neuroimaging tools lack adequate clinical validation. In 397 multi-center MRI scan pairs acquired in routine practice, we demonstrate superior case-level sensitivity of a clinically integrated AI-based tool over standard radiology reports (93.3% vs 58.3%), relative to a consensus ground truth, with minimal loss of specificity. We also demonstrate equivalence of the AI-tool with a core clinical trial imaging lab for lesion activity and quantitative brain volumetric measures, including percentage brain volume loss (PBVC), an accepted biomarker of neurodegeneration in MS (mean PBVC -0.32% vs -0.36%, respectively), whereas even severe atrophy (>0.8% loss) was not appreciated in radiology reports. Finally, the AI-tool additionally embeds a clinically meaningful, experiential comparator that returns a relevant MS patient centile for lesion burden, revealing, in our cohort, inconsistencies in qualitative descriptors used in radiology reports. AI-based image quantitation enhances the accuracy of, and value-adds to, qualitative radiology reporting. Scaled deployment of these tools will open a path to precision management for patients with MS.

Presumptive isolated neurosarcoidosis involving eloquent structures: An argument for empirical TNF-α inhibition.

There are clinical and radiological phenotypes characteristic of neurosarcoidosis. Histopathologic confirmation is preferred, however, biopsy is associated with a significant risk of morbidity when only eloquent neural structures are involved and where there is no systemic disease. We present a series of patients with isolated neurosarcoidosis and suggest circumstances where an empirical, closely monitored, trial of tumour-necrosis-factor-alpha inhibitor therapy can improve outcome and diagnostic confidence.

Treatment satisfaction in patients with relapsing-remitting multiple sclerosis initiated on teriflunomide in routine clinical practice: Australian observational data.

Background: Adherence and persistence are critical to optimising therapeutic benefit from disease-modifying therapies (DMTs) in relapsing-remitting multiple sclerosis (RRMS). This prospective, open-label, multicentre, observational study (AubPRO), conducted in 13 hospital-based neurology clinics around Australia, describes treatment satisfaction in patients newly initiated on teriflunomide (Aubagio) and evaluates the use of an electronic patient-reported outcome (PRO) tool. Methods: Patients (≥18 years) newly initiated on teriflunomide (14 mg/day) were followed up at 24 and 48 weeks. Patients completed questionnaires and pill counts electronically using MObile Data in Multiple Sclerosis. The primary endpoint was treatment satisfaction, measured by the Treatment Satisfaction Questionnaire for Medication (TSQM, V.1.4), at week 48. Secondary endpoints included treatment satisfaction at week 24, other PRO scales, clinical outcomes, medication adherence and safety. Results: Patients (n=103; 54 (52.4%) treatment naive) were mostly female (n=82 (79.6%)), aged 49.5 (11.8) years, with MS duration since symptom onset of 9.1 (11.8) years and a median Expanded Disability Status Scale score of 1.0. Mean treatment satisfaction scores were high (≥60%) across all domains of the TSQM V.1.4 at week 24 and at week 48. Compared with week 24, week 48 treatment satisfaction increased for patients who were treatment naïve and for those previously on another oral or injectable DMT. Over 48 weeks, PROs remained stable across a range of measures including disability, physical health, emotional health and mobility, and there were improvements in work capacity and daily life activity. Adherence was high throughout the study with mean compliance (pill counts) of 93.2%±6.26%, and 98 of 103 (95.1%) patients remained relapse-free. Conclusion: This cohort of Australian patients with RRMS, newly initiated on teriflunomide, and treated in a real-world clinical practice setting, reported high treatment satisfaction and adherence at 24 and 48 weeks. Patient-reported measures of disability remained stably low, work capacity and daily life activity improved, and most patients remained relapse-free.

Overlapping central and peripheral nervous system syndromes in MOG antibody-associated disorders.

OBJECTIVE: Antibodies to myelin oligodendrocyte glycoprotein (MOG) are associated with CNS demyelination inclusive of optic neuritis (ON) and transverse myelitis (TM). To examine whether peripheral nervous system (PNS) involvement is associated with MOG antibody-associated disorders (MOGAD), we performed detailed characterization of an Australasian MOGAD cohort. METHODS: Using a live cell-based assay, we diagnosed 271 adults with MOGAD (2013-2018) and performed detailed clinical and immunologic characterization on those with likely PNS involvement. RESULTS: We identified 19 adults with MOGAD and PNS involvement without prior TM. All patients had CNS involvement including ON (bilateral [n = 3], unilateral [n = 3], and recurrent [n = 7]), a cortical lesion (n = 1), meningoencephalitis (n = 1), and subsequent TM (n = 4). Clinical phenotyping and neurophysiology were consistent with acute inflammatory demyelinating polyneuropathy (n = 1), myeloradiculitis (n = 3), multifocal motor neuropathy (n = 1), brachial neuritis (n = 2), migrant sensory neuritis (n = 3), and paresthesia and/or radicular limb pain (n = 10). Onset MRI spine was consistent with myeloradiculitis with nerve root enhancement in 3/19 and normal in 16/19. Immunotherapy resulted in partial/complete PNS symptom resolution in 12/15 (80%) (steroids and/or IV immunoglobulin n = 9, rituximab n = 2, and plasmapheresis n = 1). We identified serum antibodies targeting neurofascin 155, contactin-associated protein 2, or GM1 in 4/16 patients with MOGAD PNS compared with 0/30 controls (p = 0.01). There was no binding to novel cell surface antigens using an in vitro myelinating sensory neuronal coculture model. CONCLUSIONS: Myeloradiculitis, combined central and peripheral demyelination syndromes, and inflammatory neuropathies may be associated with MOGAD and may be immunotherapy responsive. We identified a subgroup who may have pathology mediated by coexistent autoantibodies.

Serum Exosome MicroRNAs Predict Multiple Sclerosis Disease Activity after Fingolimod Treatment.

We and others have previously demonstrated the potential for circulating exosome microRNAs to aid in disease diagnosis. In this study, we sought the possible utility of serum exosome microRNAs as biomarkers for disease activity in multiple sclerosis patients in response to fingolimod therapy. We studied patients with relapsing-remitting multiple sclerosis prior to and 6 months after treatment with fingolimod. Disease activity was determined using gadolinium-enhanced magnetic resonance imaging. Serum exosome microRNAs were profiled using next-generation sequencing. Data were analysed using univariate/multivariate modelling and machine learning to determine microRNA signatures with predictive utility. Accordingly, we identified 15 individual miRNAs that were differentially expressed in serum exosomes from post-treatment patients with active versus quiescent disease. The targets of these microRNAs clustered in ontologies related to the immune and nervous systems and signal transduction. While the power of individual microRNAs to predict disease status post-fingolimod was modest (average 77%, range 65 to 91%), several combinations of 2 or 3 miRNAs were able to distinguish active from quiescent disease with greater than 90% accuracy. Further stratification of patients identified additional microRNAs associated with stable remission, and a positive response to fingolimod in patients with active disease prior to treatment. Overall, these data underscore the value of serum exosome microRNA signatures as non-invasive biomarkers of disease in multiple sclerosis and suggest they may be used to predict response to fingolimod in future clinical practice. Additionally, these data suggest that fingolimod may have mechanisms of action beyond its known functions.

Precision therapy for neuromyelitis optica spectrum disorder: A retrospective analysis of the use of class-switched memory B-cells for individualised rituximab dosing schedules.

BACKGROUND: B-cell depleting treatments are widely used to modify the course of neuromyelitis optica spectrum disorder (NMOSD). Despite recent successful Phase 3 trials of several novel NMOSD therapies, limited availability and high cost constrains their clinical use, and rituximab (RTX) remains a core treatment in many centres. Since 2013, the Royal Prince Alfred Hospital Neuroimmunology Clinic (NIC) has regularly measured class-switched memory B-cells (SMB-cells) in the peripheral blood of patients with NMOSD, who have been treated with RTX, in order to guide retreatment intervals. OBJECTIVE: To assess the management and outcomes of the treated patients, and to determine the effect of SMB-cell monitoring in guiding retreatment intervals. METHODS: A retrospective analysis of hospital records, clinic letters and laboratory data was performed. RESULTS: Sixteen patients with NMOSD received individualised rituximab dosing at NIC between 2013 and 2018. Fourteen (87.5%) were aquaporin-4 antibody (AQP4-Ab) positive; 1 (6.25%) was myelin oligodendrocyte glycoprotein antibody (MOG-Ab) positive and 1 (6.25%) was seronegative. After commencement of RTX, individually dosed according to regular measurements of serum SMB-cells, there was a 77.5% reduction in annualised relapse rate over a mean follow-up time of 46.1 months in our recently active NMOSD patients. Their mean retreatment interval was 50.9 weeks. CONCLUSIONS: This study provides real-world evidence supporting individualised rituximab dosing in the treatment of NMOSD.

The neuro-otology of Susac syndrome.

OBJECTIVE: We characterised the clinical and neuro-otological characteristics of patients with Susac syndrome. METHODS: The medical records of 30 patients with Susac syndrome were reviewed for details of their clinical presentation and course, neuro-otological symptoms, investigation results including audiology and vestibular function tests, treatment and outcomes. RESULTS: Our findings demonstrate that 29 of our 30 patients with Susac syndrome developed neuro-otological symptoms such as hearing loss, disequilibrium, tinnitus or vertigo during their disease course. Hearing loss was the most common neuro-otological symptom occurring in 93% of patients. A rising configuration of low-frequency greater than the high-frequency sensorineural hearing loss was the most characteristic finding on audiological testing (37% of reviewed audiograms). Disproportionately poor speech discrimination was identified in 20% of cases, and one case demonstrated a retrocochlear pattern on electrophysiological testing. Four patients required hearing aids and a further two patients required a cochlear implant due to severe hearing loss. Two out of two treated patients had improvements in hearing after the prompt administration of corticosteroids, indicating the potential for recoverable hearing loss if relapses are treated early. Effects on vestibular function were variable in ten patients who were tested, with most showing preservation of function despite significant hearing loss. CONCLUSIONS: Neuro-otological symptoms in Susac syndrome are almost universal. In the correct clinical context, a rising configuration of low to high-frequency sensorineural hearing loss should prompt consideration of Susac syndrome. Treatment of inner ear symptoms in Susac syndrome requires further research as early immunotherapy may be beneficial.

Investigation of tumefactive demyelination is associated with higher economic burden and more adverse events compared with conventional multiple sclerosis.

BACKGROUND: Tumefactive demyelinating lesions occur as part of the spectrum of multiple sclerosis (MS), but can be difficult to distinguish from other large cerebral lesions such as neoplasm or abscess. OBJECTIVES: To estimate the cost associated with diagnostic investigation of patients with tumefactive demyelination (TD), including associated morbidity, and compare this to more typical relapsing-remitting MS. METHODS: Retrospective review of medical records of patients seen between 2013 and 2018 in clinics at the Brain and Mind Centre, Sydney, Australia; a center with tertiary referral expertise in MS. RESULTS: Thirty-one patients with TD and 31 patients with MS were compared. The cost of investigating TD was more than 7.5 times higher per patient than MS ($18,300 vs $2418, p < 0.01). More patients in the TD group were admitted to hospital (22/31 versus 10/31) and ICU admissions only occurred in the TD group (10/22 versus 0/10). Brain biopsy was performed only in the TD group (7 patients), which contributed to cost differences and also accounted for differences in adverse outcomes. CONCLUSION: The cost and morbidity related to investigating TD is higher than in typical MS. Improvements in the diagnosis of TD have the potential to improve health and economic outcomes.

Deep sequencing of circulating exosomal microRNA allows non-invasive glioblastoma diagnosis.

Exosomes are nano-sized extracellular vesicles released by many cells that contain molecules characteristic of their cell of origin, including microRNA. Exosomes released by glioblastoma cross the blood-brain barrier into the peripheral circulation and carry molecular cargo distinct to that of "free-circulating" miRNA. In this pilot study, serum exosomal microRNAs were isolated from glioblastoma (n = 12) patients and analyzed using unbiased deep sequencing. Results were compared to sera from age- and gender-matched healthy controls and to grade II-III (n = 10) glioma patients. Significant differentially expressed microRNAs were identified, and the predictive power of individual and subsets of microRNAs were tested using univariate and multivariate analyses. Additional sera from glioblastoma patients (n = 4) and independent sets of healthy (n = 9) and non-glioma (n = 10) controls were used to further test the specificity and predictive power of this unique exosomal microRNA signature. Twenty-six microRNAs were differentially expressed in serum exosomes from glioblastoma patients relative to healthy controls. Random forest modeling and data partitioning selected seven miRNAs (miR-182-5p, miR-328-3p, miR-339-5p, miR-340-5p, miR-485-3p, miR-486-5p, and miR-543) as the most stable for classifying glioblastoma. Strikingly, within this model, six iterations of these miRNA classifiers could distinguish glioblastoma patients from controls with perfect accuracy. The seven miRNA panel was able to correctly classify all specimens in validation cohorts (n = 23). Also identified were 23 dysregulated miRNAs in IDHMUT gliomas, a partially overlapping yet distinct signature of lower-grade glioma. Serum exosomal miRNA signatures can accurately diagnose glioblastoma preoperatively. miRNA signatures identified are distinct from previously reported "free-circulating" miRNA studies in GBM patients and appear to be superior.

Exosomal microRNA signatures in multiple sclerosis reflect disease status.

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). There is currently no single definitive test for MS. Circulating exosomes represent promising candidate biomarkers for a host of human diseases. Exosomes contain RNA, DNA, and proteins, can cross the blood-brain barrier, and are secreted from almost all cell types including cells of the CNS. We hypothesized that serum exosomal miRNAs could present a useful blood-based assay for MS disease detection and monitoring. Exosome-associated microRNAs in serum samples from MS patients (n = 25) and matched healthy controls (n = 11) were profiled using small RNA next generation sequencing. We identified differentially expressed exosomal miRNAs in both relapsing-remitting MS (RRMS) (miR-15b-5p, miR-451a, miR-30b-5p, miR-342-3p) and progressive MS patient sera (miR-127-3p, miR-370-3p, miR-409-3p, miR-432-5p) in relation to controls. Critically, we identified a group of nine miRNAs (miR-15b-5p, miR-23a-3p, miR-223-3p, miR-374a-5p, miR-30b-5p, miR-433-3p, miR-485-3p, miR-342-3p, miR-432-5p) that distinguished relapsing-remitting from progressive disease. Eight out of nine miRNAs were validated in an independent group (n = 11) of progressive MS cases. This is the first demonstration that microRNAs associated with circulating exosomes are informative biomarkers not only for the diagnosis of MS, but in predicting disease subtype with a high degree of accuracy.

Baló's concentric sclerosis and tumefactive demyelination: a shared immunopathogenesis?

Baló's concentric sclerosis (BCS) and tumefactive demyelination (TD) are considered atypical forms of multiple sclerosis (MS). Baló lesions are characterized by concentric rings corresponding to alternating bands of demyelination and relatively preserved myelin (Hu and Lucchinetti, 2009). Tumefactive lesions are pseudotumoural demyelinating lesions of >2 cm and may have an open ring-enhancing magnetic resonance imaging appearance (Hu and Lucchinetti, 2009; Lucchinetti et al., 2008; Altintas et al., 2012). We present a patient who developed limb weakness and focal seizures secondary to a lesion radiologically and histopathologically consistent with BCS who, six months later, developed a tumefactive demyelinating lesion. This is the first description of BCS and TD occurring in the same patient and is particularly notable because of the lack of any other more typical demyelinating lesions on the MRIs. The nature of BCS and TD in relation to more typical multiple sclerosis is discussed.