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.

Cerebral amyloid angiopathy with related inflammation masquerading as crescendo transient ischaemic attacks.

Cerebral amyloid angiopathy with related inflammation (CAA-RI) is an uncommon inflammatory subtype of CAA, with a variety of presentations that can mimic other focal and diffuse neurological disorders. We present a 63-year-old man with recurrent stereotyped focal neurological symptoms, who was initially diagnosed as capsular warning syndrome and treated with antithrombotic therapy. Atypical imaging led to further investigation including a cerebral biopsy, which confirmed CAA-RI; he improved clinically and radiologically with immunosuppression. This case highlights how CAA-RI is often under-recognised and that patients risk receiving inappropriate anticoagulation and delay in starting immunosuppression.

Assessing the long-term effectiveness of interferon-beta and glatiramer acetate in multiple sclerosis: final 10-year results from the UK multiple sclerosis risk-sharing scheme.

BACKGROUND: Because multiple sclerosis (MS) is a chronic disease causing disability over decades, it is crucial to know if the short-term effects of disease-modifying therapies reported in randomised controlled trials reduce long-term disability. This 10-year prospective observational study of disability outcomes (Expanded Disability Status Scale (EDSS) and utility) was set up, in conjunction with a risk-sharing agreement between payers and producers, to investigate this issue. METHODS: The outcomes of the UK treated patients were compared with a modelled untreated control based on the British Columbia MS data set to assess the long-term effectiveness of these treatments. Two complementary analysis models were used: a multilevel model (MLM) and a continuous Markov model. RESULTS: 4862 patients with MS were eligible for the primary analysis (mean and median follow-up times 8.7 and 10 years). EDSS worsening was reduced by 28% (MLM), 7% (Markov) and 24% time-adjusted Markov in the total cohort, and by 31% (MLM) and 14% (Markov) for relapsing remitting patients. The utility worsening was reduced by 23%-24% in the total cohort and by 24%-31% in the RR patients depending on the model used. All sensitivity analyses showed a treatment effect. There was a 4-year (CI 2.7 to 5.3) delay to EDSS 6.0. An apparent waning of treatment effect with time was seen. Subgroup analyses suggested better treatment effects in those treated earlier and with lower EDSS scores. CONCLUSIONS: This study supports a beneficial effect on long-term disability with first-line MS disease-modifying treatments, which is clinically meaningful. However the waning effect noted requires further study.

Incidence and prevalence of NMOSD in Australia and New Zealand.

OBJECTIVES: We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry. BACKGROUND: NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established. METHODS: Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases. RESULTS: NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD. CONCLUSIONS: NMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry.

Therapy-related acute leukaemia with mitoxantrone: four years on, what is the risk and can it be limited?

Therapy-related acute leukaemia (TRAL) is a significant concern, when considering treatment with mitoxantrone for multiple sclerosis (MS). We re-evaluated the literature, identifying all case reports and series of > 50 patients reporting TRAL cases in MS. TRAL was diagnosed in 0.73% of the 12,896 patients identified. Median onset was 22 months following treatment. We calculated a number needed to harm of 137.5 exposed patients, significantly higher than our 2008 analysis. We found that 82.8% of patients were exposed to > 60 mg/m(2) with a relative risk of 1.85 (p = 0.018) compared to < 60 mg/m(2), strongly suggesting a relationship to dose. MS treatment regimens which limit the mitoxantrone dose to < 60 mg/m(2) reduce the risk of TRAL.

A new era in the treatment of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system with a multifactorial aetiology and highly variable natural history. A growing understanding of the immunopathogenesis of the condition has led to an expanding array of therapies for this previously untreatable disease. While a cure for MS remains elusive, the potential to reduce inflammatory disease activity by preventing relapses and minimising disease progression is achievable. The importance of early treatment in minimising long-term disability is increasingly recognised. Most of the newer, more effective therapies are associated with risks and practical problems that necessitate an active management strategy and continuous vigilance. While the initiation of these therapies is likely to remain the responsibility of neurologists, other specialist physicians and general practitioners will be involved in the identification and management of adverse effects.

Role of intravenous immunoglobulin in the treatment of acute relapses of neuromyelitis optica: experience in 10 patients.

Prompt treatment of neuromyelitis optica (NMO) relapses with steroids or plasma exchange (PLEX) often prevents irreversible disability. The objective of this study is to report the use of intravenous immunoglobulins (IVIG) as treatment for acute relapses in NMO. A retrospective review of 10 patients treated with IVIG for acute relapses was conducted. IVIG was used in the majority of cases because of lack of response to steroids with/without PLEX. Improvement was noted in five of 11 (45.5%) events; the remaining had no further worsening. One patient, a 79-year-old woman, had a myocardial infarction seven days after IVIG. IVIG may have a role in treating acute NMO relapses.

Planned dose reduction of ocrelizumab in relapsing-remitting multiple sclerosis: a single-centre observational study.

Background: Ocrelizumab, a humanised anti-CD20 monoclonal, is a highly effective treatment for relapsing-remitting multiple sclerosis (RRMS). The long-term safety of B-cell depletion in RRMS, however, is uncertain and there are no data on dose reduction of ocrelizumab as a risk mitigation strategy. This study aimed to evaluate the effectiveness and safety of reducing ocrelizumab dose from 600 to 300 mg in patients with RRMS. Method: Data were collected through the Townsville neurology service. Following the standard randomised controlled trial regimen of 600 mg every 6 months for 2 years, sequential patients consented to dose reduction to 300 mg every 6 months. Patients were included if they were diagnosed with RRMS and received at least one reduced dose of ocrelizumab. Relapse, disability progression, new MRI lesions, CD19+ cell counts and immunoglobulin concentrations were analysed. Results: A total of 35 patients, treated with 177 full and 107 reduced doses, were included. The mean follow-up on reduced dose was 17 (1-31) months. We observed no relapses or new MRI activity in the cohort receiving the reduced dose, accompanied by persistent CD19+B cell depletion (≤0.05×109/L). Mean IgG, IgA and IgM levels remained stable throughout the study. No new safety concerns arose. Conclusions: In this single-centre observational study, dose reduction of ocrelizumab from 600 to 300 mg every 6 months after 2 years appeared to maintain efficacy in terms of new inflammatory disease activity. A randomised trial may be warranted to confirm this and explore the impact of dose reduction on long-term safety.

Immunoglobulin G1 and immunoglobulin G4 antibodies in multiple sclerosis patients treated with IFNß interact with the endogenous cytokine and activate complement.

A subset of patients with relapsing-remitting multiple sclerosis (RRMS) on therapy with interferon beta (IFNß) develop neutralising anti-drug antibodies (ADA) resulting in reduced, or loss of, therapeutic efficacy. The aims were to characterise the relative contributions of anti-IFNß antibody isotypes to drug neutralising activity, ability of these antibodies to cross-react with endogenous IFNß, to form immune complexes and activate complement. IFNß-specific ADA were measured in plasma from RRMS patients treated with IFNß1a (Rebif(®)). Neutralisation of endogenous and therapeutic IFNß by ADA was determined by IFNß bioassay. IFNß-ADA profile was predominantly comprised of IgG1 and IgG4 antibody isotypes. The contribution of IgG4-ADA towards neutralising activity was found to be minimal. Neutralising IFNß-ADA blocks endogenous IFNß activity. ADA interaction with therapeutic IFNß results in immune complex formation and complement activation. In summary, IgG1 and IgG4 IFNß-ADA have the ability to neutralise therapeutic and endogenous protein and to activate complement.

Neuropathic pruritus (itch) in neuromyelitis optica.

BACKGROUND: Neuropathic pruritus (itch) is an uncommon, but well described, symptom in neurology. There are itch-specific neurons in the dorsal horn of the spinal cord. We noted excessive pruritus in patients with neuromyelitis optica (NMO). OBJECTIVE: We aimed to explore the characteristics of pruritus in NMO patients. METHODS: We reviewed case records of a well-defined cohort of 45 serial aquaporin-4 antibody-positive patients visiting the national NMO service. All patients were interviewed. RESULTS: Of the 45 antibody-positive NMO patients, 44 had myelitis and 12 of those 44 (27.3%) patients reported pruritus within a week of other symptoms of transverse myelitis with central cord involvement. In three patients, pruritus was the first symptom of a relapse, while in one case, pruritus was the very first symptom of the index episode of NMO. CONCLUSION: Neuropathic pruritus seems to be a common, but under-recognised symptom of myelitis associated with NMO.

Prognostic factors and disease course in aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan.

Neuromyelitis optica and neuromyelitis optica spectrum disorders have been recently associated with the disease-specific autoantibody aquaporin-4, thought to be pathogenic. Identifying this antibody has allowed the clinical phenotype to be broadened. It is clear that some patients with similar clinical features do not have this antibody and may have a different condition with different outcomes and prognosis. Previous clinical neuromyelitis optica and neuromyelitis optica spectrum disorder studies have included such patients. We investigated clinical outcomes and prognostic characteristics of 106 aquaporin-4 antibody-seropositive patients from the UK and Japan. We looked at predictors of disability outcomes, namely visual disability (permanent bilateral visual loss with visual acuity of <6/36 in the best eye), motor disability (permanent inability to walk further than 100 m unaided), wheelchair dependence and mortality. Data were collected largely retrospectively through review of case records. After median disease duration of 75 months, 18% had developed permanent bilateral visual disability, 34% permanent motor disability, 23% had become wheelchair dependent and 9% had died. Age at disease onset appeared to be an important predictor of disability type. Young-onset patients in the UK, but not the Japanese cohort, commonly presenting with optic neuritis, had a high risk of visual disability while older patients in both cohorts had a high risk of motor disability, regardless of their onset symptom. Genetic factors also appeared important. The UK cohort seemed to have more severe disease than the Japanese cohort, with more severe onset attacks, a higher relapse frequency and greater disability at follow-up, despite earlier immunosuppression. Moreover, within the UK cohort, there were important differences between ethnic groups, with Afro-Caribbean patients having a younger age at disease onset, more brain and multifocal attacks and higher likelihood of visual disability than Caucasian patients. Thus, age at disease onset and genetic factors are both likely to be important in determining clinical outcomes in aquaporin-4 disease. This has important implications for interpreting clinical neuromyelitis optica and neuromyelitis optica spectrum disorder studies, since clinical features and outcomes appear not to be generic across populations and may need to be tailored to individual groups. These factors need to be explored further in future prospective neuromyelitis optica and neuromyelitis optica spectrum disorder studies.

Susac syndrome: a case report with initial presentation of incomplete bitemporal hemianopia.

Susac syndrome (SS) is a rare microangiopathy affecting the precapillary arterioles of the brain, inner ear, and retina. We present a novel case of SS, presenting as acute incomplete bitemporal field loss in addition to temporally spaced neurological and vestibulocochlear symptoms. A 39-year-old female was referred to the ophthalmology clinic with acute incomplete bitemporal hemianopia and worsening hemicrania. History revealed progressive hearing loss, subjective short-term memory impairment, and vertigo temporally spaced over the preceding 12 months. Magnetic resonance brain revealed multiple small colosal lesions and liner 'spoke' lesions. Fundus fluorescein angiography revealed multiple branch retinal artery occlusions in the right eye. Audiometry confirmed bilateral sensorineural hearing loss. Treatment included intravenous corticosteroids and rituximab. This case highlights the importance of early consideration and evaluation of SS in individuals presenting with atypical ocular disturbances, where no clear cause can be elicited, in order to limit the sequelae of disease.

Longitudinal epidemiology of multiple sclerosis in Townsville, Queensland, Australia, 2012-2022.

BACKGROUND: Townsville (population=195,564, latitude=19.3°S) is the largest city in the Northern Queensland region of Australia, an area previously defined as a low/medium-prevalence zone for multiple sclerosis (MS). However, the epidemiology of MS in this region since 1981 is unknown. AIMS: To assess the 2012 to 2022 epidemiology of MS in Townsville. METHODS: Demographic/clinical data extracted from medical records of MS cases identified by public and private clinicians. Prevalence, and incidence and mortality rates estimated for 2012 and 2022 and age-standardised to the 2022 Australian population. Differences in estimates assessed by Poisson regression. RESULTS: Females and relapsing-remitting MS comprised most cases. The 2012 prevalence was 45.0/100,000 (50.4/100,000 age-standardised, F/M sex ratio=2.0). Prevalence increased by 188% in 2022, with a crude prevalence of 86.9/100,000 (91.7/100,000 age-standardised, F/M sex ratio=2.7). 2012-22 MS onset incidence rate was 3.8/100,000 person-years (age-standardised 3.5/100,000, F/M sex ratio=2.7). Mean age increased from 49.4 to 57.3 years. Age-standardised mortality rate was 0.9/100,000 person-years, with standardised mortality ratio=1.0. DISCUSSION: These results show that Townsville is a high-frequency region for MS, with prevalence and incidence on par with that seen at higher latitudes in Australia. These results have implications for clinical practice in the region and for organisational resource allocation.

Adult-onset spinocerebellar ataxia syndromes due to MTATP6 mutations.

BACKGROUND: Spinocerebellar ataxia syndromes presenting in adulthood have a broad range of causes, and despite extensive investigation remain undiagnosed in up to ∼50% cases. Mutations in the mitochondrially encoded MTATP6 gene typically cause infantile-onset Leigh syndrome and, occasionally, have onset later in childhood. The authors report two families with onset of ataxia in adulthood (with pyramidal dysfunction and/or peripheral neuropathy variably present), who are clinically indistinguishable from other spinocerebellar ataxia patients. METHODS: Genetic screening study of the MTATP6 gene in 64 pedigrees with unexplained ataxia, and case series of two families who had MTATP6 mutations. RESULTS: Three pedigrees had mutations in MTATP6, two of which have not been reported previously and are detailed in this report. These families had the m.9185T>C and m.9035T>C mutations, respectively, which have not previously been associated with adult-onset cerebellar syndromes. Other investigations including muscle biopsy and respiratory chain enzyme activity were non-specific or normal. CONCLUSIONS: MTATP6 sequencing should be considered in the workup of undiagnosed ataxia, even if other investigations do not suggest a mitochondrial DNA disorder.

Genetic variations within the OPA1 gene are not associated with neuromyelitis optica.

Neuromyelitis optica (NMO) is an idiopathic demyelinating disease which predominantly affects the optic nerve and spinal cord. Multiplex NMO pedigrees have been reported but the genetic risk factors conferring this increased familial susceptibility have not yet been determined. OPA1 mutations have recently been identified in families with progressive visual failure and spastic paraparesis, raising the possibility that OPA1 genetic variants could contribute to the aetiology of NMO. We therefore screened for OPA1 in 32 patients with NMO. No pathogenic mutations were found, and none of the 13 single-nucleotide polymorphisms identified were associated with an increased risk of developing NMO.

Low vitamin D levels do not predict risk of autoimmune disease following alemtuzumab treatment for multiple sclerosis.

Alemtuzumab is a highly effective treatment for multiple sclerosis (MS) and the treatment strategy of two cycles 12 months apart has a lot of appeal to patients. Widespread use of alemtuzumab has been tempered by treatment emergent autoimmunity which is seen in approximately one-third of patients in the 5 years after treatment. It has been postulated that relative vitamin D deficiency may be a causative factor in this setting. We have conducted a retrospective case-control study looking at the association of vitamin D and other potentially relevant clinical factors on the likelihood of treatment emergent autoimmune disease following alemtuzumab. Occurrence of autoimmunity was monitored for clinically and through the Bloodwatch® monitoring program. Clinical data and vitamin D levels obtained as part of routine clinical practice were recorded. Vitamin D levels were seasonally adjusted. Only cases with complete data were included. Univariable and multivariable Cox proportional hazards analyses were performed. There were 113 patients treated with alemtuzumab for whom there was complete data. Median follow up was 4.4 years. Risk of autoimmune disease was not associated with lower vitamin D levels. Risk of autoimmune disease was associated with female sex (HR 3.5) and with higher EDSS score at treatment. The association with EDSS was lost when analysis was restricted to those with 4 or more years of follow up. These data do not support a role for vitamin D supplementation in the prevention of autoimmune disease following alemtuzumab. Males have a lower risk of autoimmunity following alemtuzumab.

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.

MRI Patterns Distinguish AQP4 Antibody Positive Neuromyelitis Optica Spectrum Disorder From Multiple Sclerosis.

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), "bright spotty" (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS.

The Multiple Sclerosis Severity Score: associations with MC1R single nucleotide polymorphisms and host response to ultraviolet radiation.

BACKGROUND: Multiple sclerosis outcome may be influenced by ultraviolet radiation and vitamin D synthesis, suggesting skin type and genes determining this phenotype are candidates for disability. However, though associations between melanocortin 1 receptor (MC1R) single nucleotide polymorphisms and disability are reported, some data are incompatible with their expected influence on skin type. OBJECTIVE: Determine which MC1R single nucleotide polymorphisms affect disability and establish if ultraviolet radiation modifies such associations. METHODS: We studied using linear regression in 525 cases, associations of the Multiple Sclerosis Severity Score (MSSS) with skin type, gender, ultraviolet radiation exposure and six MC1R single nucleotide polymorphisms (rs1805005, rs1805006, rs2228479, rs1805007, rs1805008, rs1805009). RESULTS: CG(294) with GG(294) genotypes (rs1805009) (coefficient = -1.44, 95% CI -2.30, -0.59, mean MSSS +/- SD = 4.33 +/- 2.87) and AC(84) (rs1805006) (coefficient = 1.62, 95% CI 0.17, 3.06, mean MSSS = 7.62 +/- 2.43) were associated with MSSS. Associations with Asp294His were found in those with skin types 1/2 and 3/4, and cases stratified by ultraviolet radiation exposure. However, they were seen only in cases with a history of childhood sunburn and not in those without sunburn. We found no significant associations between exposure parameters and MSSS. CONCLUSIONS: Multiple sclerosis outcome is influenced by interactions between host response to ultraviolet radiation and MC1R single nucleotide polymorphisms. The influence of the single nucleotide polymorphisms appears distinct from their association with skin type.