Oral corticosteroid dosage and taper duration at onset in myelin oligodendrocyte glycoprotein antibody-associated disease influences time to first relapse.

BACKGROUND: We sought to identify an optimal oral corticosteroid regimen at the onset of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), which would delay time to first relapse while minimising cumulative corticosteroid exposure. METHODS: In a retrospective multicentre cohort study, Cox proportional hazards models examined the relationship between corticosteroid course as a time-varying covariate and time to first relapse. Simon-Makuch and Kaplan-Meier plots identified an optimal dosing strategy. RESULTS: We evaluated 109 patients (62 female, 57%; 41 paediatric, 38%; median age at onset 26 years, (IQR 8-38); median follow-up 6.2 years (IQR 2.6-9.6)). 76/109 (70%) experienced a relapse (median time to first relapse 13.7 months; 95% CI 8.2 to 37.9). In a multivariable model, higher doses of oral prednisone delayed time to first relapse with an effect estimate of 3.7% (95% CI 0.8% to 6.6%; p=0.014) reduced hazard of relapse for every 1 mg/day dose increment. There was evidence of reduced hazard of relapse for patients dosed ≥12.5 mg/day (HR 0.21, 95% CI 0.07 to 0.6; p=0.0036), corresponding to a 79% reduction in relapse risk. There was evidence of reduced hazard of relapse for those dosed ≥12.5 mg/day for at least 3 months (HR 0.12, 95% CI 0.03 to 0.44; p=0.0012), corresponding to an 88% reduction in relapse risk compared with those never treated in this range. No patient with this recommended dosing at onset experienced a Common Terminology Criteria for Adverse Events grade >3 adverse effect. CONCLUSIONS: The optimal dose of 12.5 mg of prednisone daily in adults (0.16 mg/kg/day for children) for a minimum of 3 months at the onset of MOGAD delays time to first relapse.

Longitudinal enlargement of choroid plexus is associated with chronic lesion expansion and neurodegeneration in RRMS patients.

BACKGROUND AND OBJECTIVE: We explored dynamic changes in the choroid plexus (CP) in patients with relapsing-remitting multiple sclerosis (RRMS) and assessed its relationship with chronic lesion expansion and atrophy in various brain compartments. METHODS: Fifty-seven RRMS patients were annually assessed for a minimum of 48 months with 3D FLAIR, pre- and post-contrast 3D T1 and diffusion-weighted magnetic resonance imaging (MRI). The CP was manually segmented at baseline and last follow-up. RESULTS: The volume of CP significantly increased by 1.4% annually. However, the extent of CP enlargement varied considerably among individuals (ranging from -3.6 to 150.8 mm3 or -0.2% to 6.3%). The magnitude of CP enlargement significantly correlated with central (r = 0.70, p < 0.001) and total brain atrophy (r = -0.57, p < 0.001), white (r = -0.61, p < 0.001) and deep grey matter atrophy (r = -0.60, p < 0.001). Progressive CP enlargement was significantly associated with the volume and extent of chronic lesion expansion (r = 0.60, p < 0.001), but not with the number or volume of new lesions. CONCLUSION: This study provides evidence of progressive CP enlargement in patients with RRMS. Our findings also demonstrate that enlargement of the CP volume is linked to the expansion of chronic lesions and neurodegeneration of periventricular white and grey matter in RRMS patients.

The MOG antibody non-P42 epitope is predictive of a relapsing course in MOG antibody-associated disease.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) IgG seropositivity is a prerequisite for MOG antibody-associated disease (MOGAD) diagnosis. While a significant proportion of patients experience a relapsing disease, there is currently no biomarker predictive of disease course. We aim to determine whether MOG-IgG epitopes can predict a relapsing course in MOGAD patients. METHODS: MOG-IgG-seropositive confirmed adult MOGAD patients were included (n=202). Serum MOG-IgG and epitope binding were determined by validated flow cytometry live cell-based assays. Associations between epitopes, disease course, clinical phenotype, Expanded Disability Status Scale and Visual Functional System Score at onset and last review were evaluated. RESULTS: Of 202 MOGAD patients, 150 (74%) patients had MOG-IgG that recognised the immunodominant proline42 (P42) epitope and 115 (57%) recognised histidine103/serine104 (H103/S104). Fifty-two (26%) patients had non-P42 MOG-IgG and showed an increased risk of a relapsing course (HR 1.7; 95% CI 1.15 to 2.60, p=0.009). Relapse-freedom was shorter in patients with non-P42 MOG-IgG (p=0.0079). Non-P42 MOG-IgG epitope status remained unchanged from onset throughout the disease course and was a strong predictor of a relapsing course in patients with unilateral optic neuritis (HR 2.7, 95% CI 1.06 to 6.98, p=0.038), with high specificity (95%, 95% CI 77% to 100%) and positive predictive value (85%, 95% CI 45% to 98%). CONCLUSIONS: Non-P42 MOG-IgG predicts a relapsing course in a significant subgroup of MOGAD patients. Patients with unilateral optic neuritis, the most frequent MOGAD phenotype, can reliably be tested at onset, regardless of age and sex. Early detection and specialised management in these patients could minimise disability and improve long-term outcomes.

Choroid plexus volume is enlarged in clinically isolated syndrome patients with optic neuritis.

OBJECTIVES: We investigated choroid plexus (CP) volume in patients presenting with optic neuritis (ON) as a clinically isolated syndrome (CIS), compared to a cohort with established relapsing-remitting multiple sclerosis (RRMS) and healthy controls (HCs). METHODS: Three-dimensional (3D) T1, T2-FLAIR and diffusion-weighted sequences were acquired from 44 ON CIS patients at baseline, 1, 3, 6 and 12 months after the onset of ON. Fifty RRMS patients and 50 HCs were also included for comparison. RESULTS: CP volumes was larger in both ON CIS and RRMS groups compared to HCs, but not significantly different between ON CIS and RRMS patients (analysis of covariance (ANCOVA) adjusted for multiple comparisons). Twenty-three ON CIS patients who converted to clinically definite MS (MS) demonstrated CP volume similar to RRMS patients, but significantly larger compared to HCs. In this sub-group, CP volume was not associated with the severity of optic nerve inflammation or long-term axonal loss, not with brain lesion load. A transient increase of CP volume was observed following an occurrence of new MS lesions on brain magnetic resonance imaging (MRI). INTERPRETATION: Enlarged CP can be observed very early in a disease. It transiently reacts to acute inflammation, but not associated with the degree of tissue destruction.

Progressive loss of hearing and balance in superficial siderosis due to occult spinal dural defects.

PURPOSE: Superficial siderosis, a progressive, debilitating, neurological disease, often presents with bilateral impairment of auditory and vestibular function. We highlight that superficial siderosis is often due to a repairable spinal dural defect of the type that can also cause spontaneous intracranial hypotension. METHODS: Retrospective chart review of five patients presenting with moderate to severe, progressive bilateral sensorineural hearing loss as well as vestibular loss. All patients had developed superficial siderosis from spinal dural defects: three after trauma, one after spinal surgery and one from a thoracic discogenic microspur. RESULTS: The diagnosis was made late in all five patients; despite surgical repair in four, hearing and vestibular loss failed to improve. CONCLUSIONS: In patients presenting with progressive bilateral sensorineural hearing loss, superficial siderosis should be considered as a possible cause. If these patients also have bilateral vestibular loss, cerebellar impairment and anosmia, then the diagnosis is likely and the inevitable disease progress might be halted by finding and repairing the spinal dural defect.

Choroid plexus volume in multiple sclerosis predicts expansion of chronic lesions and brain atrophy.

OBJECTIVES: Recent studies suggested that the expansion of long-standing multiple sclerosis (MS) lesions and an enlargement of choroid plexus may be linked to chronic inflammation and microglial activation. We investigated the potential association between plexus volume and subsequent lesion expansion in patients with relapsing-remitting MS. METHODS: Pre- and post-gadolinium 3D-T1, 3D FLAIR and diffusion tensor images were acquired from 49 patients. Choroid plexus (CP) volume (normalised by Total Intracranial Volume, TIV) and lesion activity were analysed between baseline and 48 months. In addition, plexus volume was measured in 40 healthy controls of similar age and gender. RESULTS: Baseline CP/TIV ratio was significantly larger in RRMS patients compared to normal controls (p < 0.001). CP/TIV ratio remained stable in RRMS patients during follow-up period. There was a strong correlation between baseline CP/TIV ratio and subsequent rate of chronic lesion expansion (p < 0.001), which was stronger in close proximity to CSF. A cut-off of 98 × 10-5 CP/TIV ratio predicted future lesion expansion with a sensitivity of 85% and specificity of 76%. CP/TIV ratio larger than a cut-off was associated with >8-fold increased risk of chronic lesion expansion. Baseline CP/TIV ratio was also associated with change in Mean Diffusivity (MD) inside of chronic lesions. Furthermore, baseline CP/TIV ratio significantly correlated with central brain atrophy. There was, however, no correlation between CP/TIV ratio and volume of new lesions. INTERPRETATION: Our data demonstrate that baseline CP/TIV ratio predicts subsequent expansion of chronic periventricular MS lesions and associated tissue damage within and outside of chronic lesions.

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.

Mechanisms of central brain atrophy in multiple sclerosis.

BACKGROUND: Change in ventricular volume has been suggested as surrogate measure of central brain atrophy (CBA) applicable to the everyday management of multiple sclerosis (MS) patients. OBJECTIVES: We investigated the contribution of inflammatory activity (including the severity of lesional tissue damage) to CBA. METHODS: Fifty patients with relapsing-remitting multiple sclerosis (RRMS) were enrolled. Lesional activity during 4 years of follow-up was analysed using custom-build software, which segmented expanding part of the chronic lesions, new confluent lesions and new free-standing lesions. The degree of lesional tissue damage was assessed by change in mean diffusivity (MD). Volumetric change of lateral ventricles was used to measure CBA. RESULTS: During follow-up, ventricles expanded on average by 12.6% ± 13.7% (mean ± SD). There was a significant increase of total lesion volume, 69.3% of which was due to expansion of chronic lesions. Correlation between volume of combined lesional activity and CBA (r2 = 0.67) increased when lesion volume was adjusted by the degree of tissue damage severity (r2 = 0.81). Regression analysis explained 90% of CBA variability, revealing that chronic lesion expansion was by far the largest contributor to ventricular enlargement. DISCUSSION: CBA is almost entirely explained by the combination of the volume and severity of lesional activity. The expansion of chronic lesions plays a central role in this process.

The expansion and severity of chronic MS lesions follows a periventricular gradient.

BACKGROUND AND OBJECTIVES: Expansion of chronic lesions in multiple sclerosis (MS) patients and recently described cerebrospinal fluid (CSF)-related gradient of tissue damage are linked to microglial activation. The aim of this study was to investigate whether lesion expansion is associated with proximity to ventricular CSF spaces. METHODS: Pre- and post-gadolinium three-dimensional (3D)-T1, 3D FLAIR and diffusion tensor images were acquired from 36 relapsing-remitting MS (RRMS) patients. Lesional activity was analysed between baseline and 48 months at different distances from the CSF using successive 1 mm thick concentric bands radiating from the ventricles. RESULTS: Voxel-based analysis of the rate of lesion expansion demonstrated a clear periventricular gradient decreasing away from the ventricles. This was particularly apparent when lesions of equal diameter were analysed. Periventricular lesional tissue showed higher degree of tissue destruction at baseline that significantly increased during follow-up in bands close to CSF. This longitudinal change was proportional to degree of lesion expansion. Lesion-wise analysis revealed a gradual, centrifugal decrease in the proportion of expanding lesions from the immediate periventricular zone. DISCUSSION: Our data suggest that chronic white matter lesions in close proximity to the ventricles are more destructive, show a higher degree of expansion at the lesion border and accelerated tissue loss in the lesion core.

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.

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.

Response to treatment in NMOSD: the Australasian experience.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is associated with significant morbidity and mortality. Several therapies have been recommended for NMOSD and more recently clinical trials have demonstrated efficacy for three monoclonal antibody therapies. We present a retrospective observational study of treatment response in NMOSD. METHODS: This was a retrospective, unblinded, observational study of treatment efficacy for rituximab and traditional immunosuppressive therapy in patients with AQP4 antibody positive NMOSD. Treatment efficacy was assessed using annualised relapse rates (ARR), time to first relapse and expanded disability status scale (EDSS) scores. RESULTS: Complete relapse and treatment data were available for 43/68 (63%) of AQP4 antibody positive NMOSD cases covering 74 episodes of treatment. In a time to first relapse analysis rituximab showed a risk ratio of 0.23 (95% CI 0.08 - 0.65) when compared with no treatment and there was a non-significant reduction in ARR of 35% compared to pre-treatment. ß-interferon (p = 0.0002) and cyclophosphamide (p = 0.0034) were associated with an increased ARR compared to pre-treatment. Rituximab (median 4.0 [range 0.0 - 7.0]; p = 0.042) and traditional immunosuppressive therapy (median 4.0 [range 0.0 - 8.0]; p = 0.016) were associated with a lower final EDSS compared to ß-interferon (median 6.0 [range 4.0 - 7.5]). CONCLUSIONS: These data provide additional support for the use of rituximab in preference to traditional immunosuppressive agents and MS disease modifying therapies as first line treatment of NMOSD.

Expansion of chronic MS lesions is associated with an increase of radial diffusivity in periplaque white matter.

BACKGROUND: Expansion of chronic multiple sclerosis (MS) lesion is associated with slow-burning inflammation at lesion rim. However, the underlying mechanisms leading to expansion are not fully understood. OBJECTIVE: To investigate the relationship between diffusivity markers of demyelination and axonal loss in perilesional white matter and lesion expansion in relapsing-remitting MS (RRMS). METHODS: T1, FLAIR and diffusion tensor images were acquired from 30 patients. Novel single-streamline technique was used to estimate diffusivity in lesions, perilesional white matter and normal-appearing white matter (NAWM). RESULTS: Significant association was found between baseline periplaque radial diffusivity (RD) and subsequent lesion expansion. Conversely, periplaque axial diffusivity (AD) did not correlate with lesion growth. Baseline RD (but not AD) in periplaque white matter of expanding lesions was significantly higher compared with non-expanding lesions. Correlation between increase of both RD and AD in the periplaque area during follow-up period and lesion expansion was noticeably stronger for RD. Increase of RD in periplaque area was also much higher compared to AD. There was significant increase of AD and RD in the periplaque area of expanding, but not in non-expanding, lesions. CONCLUSION: Periplaque demyelination is likely to be an initial step in a process of lesion expansion and, as such, potentially represents a suitable target for remyelinating therapies.

NMOSD and MS prevalence in the Indigenous populations of Australia and New Zealand.

BACKGROUND: We studied the prevalence of neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) in Indigenous populations of Australia and New Zealand with the aim of assessing potential differences. METHODS: Cases of possible NMOSD and MS were collected from Australia and New Zealand. Clinical details, MR imaging, and serologic results were used to apply 2015 IPND diagnostic criteria for NMOSD and 2010 McDonald criteria for MS. Frequencies of self-determined ethnic ancestry were calculated for confirmed NMOSD, suspected NMOSD, and MS. Prevalence rates for NMOSD and MS according to ancestry were compared. RESULTS: There were 75 cases with NMOSD, 89 with suspected NMSOD, and 101 with MS. NMOSD cases were more likely to have Asian, Indigenous, or Other ancestry compared to suspected NMOSD or MS. There were no differences in the clinical phenotype of NMOSD seen in Indigenous compared to European ancestry populations. Per 100,000, the prevalence estimate for NMOSD in people with Maori ancestry was 1.50 (95% CI 0.52-2.49) which was similar to those with Asian ancestry 1.57 (95% CI 1.15-1.98). NMOSD prevalence in Australian Aboriginal and Torres Strait Islander populations was 0.38 (95% CI 0.00-0.80) per 100,000. CONCLUSION: The prevalence of NMOSD in the Maori population is similar to South East Asian countries, reflecting their historical origins. The prevalence of MS in this group is intermediate between those with South East Asian and European ancestry living in New Zealand. Both NMOSD and particularly MS appear to be uncommon in the Indigenous populations of Australia.

Validation of a Flow Cytometry Live Cell-Based Assay to Detect Myelin Oligodendrocyte Glycoprotein Antibodies for Clinical Diagnostics.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibodies (MOG Ab) are essential in the diagnosis of MOG Ab-associated disease (MOGAD). Live cell-based assays (CBAs) are the gold standard for MOG Ab detection with improved sensitivity and specificity over fixed CBAs. A number of testing centers have used flow cytometry for its high throughput and quantitative utility. Presently, there is increasing demand to translate these research-based methods into an accredited routine diagnostic setting. METHODS: A flow cytometry live CBA was used to detect MOG Ab in patients with demyelination. Serostatuses were compared between a research-based assay and a streamlined diagnostic assay. Inter-laboratory validation of the streamlined assay was performed in an accredited diagnostic laboratory. Further streamlining was performed by introducing a borderline serostatus range and reducing the number of controls used to determine the positivity threshold. RESULTS: High serostatus agreement (98%-100%) was observed between streamlined and research-based assays. Intra- and inter-assay imprecision was improved in the streamlined assay (mean intra- and inter-assay CV = 7.3% and 27.8%, respectively) compared to the research-based assay (mean intra- and inter-assay CV = 11.8% and 33.6%, respectively). Borderline positive and clear positive serostatuses were associated with confirmed phenotypes typical of MOGAD. Compared to using 24 controls, robust serostatus classification was observed when using 13 controls without compromising analytical performance (93%-98.5% agreement). CONCLUSIONS: Flow cytometry live CBAs show robust utility in determining MOG Ab serostatus. Streamlining and standardizing use of this assay for diagnostics would improve the accuracy and reliability of routine testing to aid diagnosis and treatment of patients with demyelination.

Eculizumab in Asian patients with anti-aquaporin-IgG-positive neuromyelitis optica spectrum disorder: A subgroup analysis from the randomized phase 3 PREVENT trial and its open-label extension.

Background Eculizumab, a terminal complement inhibitor, significantly reduced the risk of relapse compared with placebo in patients with anti-aquaporin-4 immunoglobulin G-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) in the PREVENT trial. We report efficacy and safety analyses in Asian patients in PREVENT and its open-label extension (OLE). Methods PREVENT was a double-blind, randomized, phase 3 trial. Patients with AQP4+ NMOSD were randomly assigned (2:1) to receive intravenous eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo. Patients who completed PREVENT could receive eculizumab in an OLE. Analyses were performed in a prespecified subgroup of Asian patients. Results Of 143 patients enrolled, 52 (36.4%) were included in the Asian subgroup (eculizumab, n = 37; placebo, n = 15); 45 Asian patients received eculizumab in the OLE. Most Asian patients (86.5%) received concomitant immunosuppressive therapy. During PREVENT, one adjudicated relapse occurred in patients receiving eculizumab and six occurred in patients receiving placebo in the Asian subgroup (hazard ratio, 0.05; 95% confidence interval: 0.01-0.35; p = 0.0002). An estimated 95.2% of Asian patients remained relapse-free after 144 weeks of eculizumab treatment. Upper respiratory tract infections, headache, and nasopharyngitis were the most common adverse events with eculizumab in the Asian subgroup. Conclusion Eculizumab reduces the risk of relapse in Asian patients with AQP4+ NMOSD, with a benefit-risk profile similar to the overall PREVENT population. The benefits of eculizumab were maintained during long-term therapy. Clinical trial registration ClinicalTrials.gov identifiers: NCT01892345 (PREVENT); NCT02003144 (open-label extension).

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.

Nerve biopsy: Current indications and decision tools.

After initial investigation of patients presenting with symptoms suggestive of neuropathy, a clinical decision is made for a minority of patients to undergo further assessment with nerve biopsy. Many nerve biopsies do not demonstrate a definitive pathological diagnosis and there is considerable cost and morbidity associated with the procedure. This highlights the need for appropriate selection of patients, nerves and neuropathology techniques. Additionally, concomitant muscle and skin biopsies may improve the diagnostic yield in some cases. Several advances have been made in diagnostics in recent years, particularly in genomics. The indications for nerve biopsy have consequently changed over time. This review explores the current indications for nerve biopsies and some of the issues surrounding its use. Also included are comments on alternative diagnostic modalities that may help to supplant or reduce the use of nerve biopsy as a diagnostic test. These primarily include extraneural biopsy and neuroimaging techniques such as magnetic resonance neurography and nerve ultrasound. Finally, we propose an algorithm to assist in deciding when to perform nerve biopsies.

Interferon-ß Is Less Effective Than Other Drugs in Controlling the Rate of Retinal Ganglion Cell Loss in MS.

OBJECTIVE: To investigate the association between disease-modifying therapies (DMTs) and the rate of progressive retinal ganglion cell (RGC) and nerve fiber loss in MS. METHODS: One hundred five relapsing-remitting patients with MS were followed annually for a median of 4.0 years using optical coherence tomography. Twenty-five healthy subjects were also included as normal controls. The rates of global peripapillary retinal nerve fiber layer (pRNFL), temporal RNFL (tRNFL), and ganglion cell inner plexiform layer (GCIPL) thinning were analyzed according to DMT type using a linear mixed-effects model. Optic radiation lesion volume was measured on brain MRI and included as a covariate to minimize the effects of retrograde transsynaptic degeneration. RESULTS: The annual rates of RNFL and GCIPL thinning were higher in patients treated with "platform" therapies (interferon-ß and glatiramer acetate) compared with DMTs of higher clinical efficacy (including fingolimod, dimethyl fumarate, natalizumab, alemtuzumab, rituximab, and ocrelizumab) (difference = -0.22 µm/y, p = 0.02 for pRNFL; difference = -0.34 µm/y, p = 0.009 for tRNFL; and difference = -0.16 µm/y, p = 0.005 for GCIPL). Based on an analysis of individual treatments (interferon-ß, glatiramer acetate, fingolimod, and natalizumab), interferon-ß was associated with inferior RGC preservation, relative to the other drugs. No effect difference was found between glatiramer acetate, fingolimod, and natalizumab. CONCLUSIONS: Progressive loss of RGCs in patients with MS is more pronounced in patients treated with interferon-ß than other DMTs. This finding may have implications for DMT selection in MS. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with MS, treatment with interferon-ß compared with other DMTs leads to a more pronounced rate of retinal ganglion cell loss.

Differentiating axonal loss and demyelination in chronic MS lesions: A novel approach using single streamline diffusivity analysis.

We describe a new single-streamline based approach to analyse diffusivity within chronic MS lesions. We used the proposed method to examine diffusivity profiles in 30 patients with relapsing multiple sclerosis and observed a significant increase of both RD and AD within the lesion core (0.38+/-0.09 µm2/ms and 0.30+/-0.12 µm2/ms respectively, p<0.0001 for both) that gradually and symmetrically diminished away from the lesion. T1-hypointensity derived axonal loss correlated highly with ΔAD (r = 0.82, p<0.0001), but moderately with ΔRD (r = 0.60, p<0.0001). Furthermore, the trendline of the ΔAD vs axonal loss intersected both axes at zero indicating close agreement between two measures in assessing the degree of axonal loss. Conversely, the trendline of the ΔRD function demonstrated a high positive value at the zero level of axonal loss, suggesting that even lesions with preserved axonal content exhibit a significant increase of RD. There was also a significant negative correlation between the level of preferential RD increase (ΔRD-ΔAD) in the lesion core and the degree of axonal damage (r = -0.62, p<0.001), indicating that ΔRD dominates in cases with milder axonal loss. Modelling diffusivity changes in the core of chronic MS lesions based on the direct proportionality of ΔAD with axonal loss and the proposed dual nature of ΔRD yielded results that were strikingly similar to the experimental data. Evaluation of lesions in a sizable cohort of MS patients using the proposed method supports the use of ΔAD as a marker of axonal loss; and the notion that demyelination and axonal loss independently contribute to the increase of RD in chronic MS lesions. The work highlights the importance of selecting appropriate patient cohorts for clinical trials of pro-remyelinating and neuroprotective therapeutics.