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IntroductionAlemtuzumab is a highly effective therapy for multiple sclerosis that has a significant, but well-defined adverse event profile. We report cases treated since the commercial release of alemtuzumab at two centres in Queensland with the aim of comparing real-world experience with trial data.MethodsThis was a retrospective case note review of patients treated with alemtuzumab for multiple sclerosis since becoming commercially available in Australia. The two sites were the Gold Coast University Hospital and the Townsville Hospital. Demographic, clinical and MRI data were systematically collected from the available records at each site. De-identified aggregated data were analysed using descriptive statistics (mean (±SD), median (range)) and compared with phase III clinical trial data.Results104 cases treated with alemtuzumab were identified at the two sites. The median age at first treatment was 3817–55 years, slightly older than the trial populations (33 and 35 years) and two-thirds were female. The mean disease duration was 8.4 (±7.0) years, which is longer that seen in the trials (2.1 and 4.5 years). The median number of prior relapses was 31–12 with 1 (0–3) in the prior 2 years. The median number of prior treatments for MS was 1.5. The median follow up was 201–35 months. The median EDSS at time of first treatment was 2 (0–7) and at last follow up was 1.5 (0–7). At last follow up, 24/104 (23%) had improved, 61/104 (58%) were stable and 9/104 (9%) had worsened. Autoimmune adverse events were seen in 18/104 (17%) with autoimmune thyroid disease being the most common (13/104 (13%).ConclusionAlemtuzumab is an effective therapy for MS. Clinical outcomes in a real world setting were similar to those seen in phase III clinical trials. Autoimmune diseases occurred in a similar proportion to those seen in clinical trials.References. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: A randomised controlled phase 3 trial. Lancet2012;380(9856):1819–28.. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: A randomised controlled phase 3 trial. Lancet2012;380(9856):1829–39.

When a patient presents with vivid visual hallucinations, a doctor probably considers common diagnoses such as delirium, dementia, psychoses, or a drug related condition. Charles Bonnet syndrome, however, is a condition characterised by visual hallucinations alongside deteriorating vision, usually in elderly people.1 The correct diagnosis of this distressing but not uncommon condition is of utmost importance, considering the serious implications of the alternative diagnoses. Neighbours brought an 87 year old white widower—who lived alone in a flat—to the medical assessment unit of a district general hospital. They were concerned that he was becoming demented. Apparently he had reported seeing people and animals in his house—including bears and Highland cattle. He verified these statements and said he had been seeing them for the previous six weeks. He had also often seen swarms of flies and blue fish darting across the room. He knew that these visions were not real and they didn't bother him much, but he thought he might be losing his mind. The visions lasted for minutes to hours, and the cattle used to stare at him while quietly munching away at the grass. The visions tended to occur more in the evenings before he switched on the lights. His medical problems included chronic lymphatic leukaemia, which had been in remission for the past five years. He was registered blind and had been diagnosed as having gross bilateral macular degeneration. He had never had hallucinations before. He also had chronic obstructive airways disease and essential hypertension. He had had no other neurological illness and no mental health problems. He did not drink alcohol or smoke. He had …

Background Fever in the returned traveller is a potential medical emergency warranting prompt attention to exclude life-threatening illnesses. However, prolonged evaluation in the emergency department (ED) may not be required for all patients. As a quality improvement initiative, we implemented an algorithm for rapid assessment of febrile travelers (RAFT) in an ambulatory setting. Methods Criteria for RAFT referral include: presentation to the ED, reported fever and travel to the tropics or subtropics within the past year. Exclusion criteria include Plasmodium falciparum malaria, and fulfilment of admission criteria such as unstable vital signs or significant laboratory derangements. We performed a time series analysis preimplementation and postimplementation, with primary outcome of wait time to tropical medicine consultation. Secondary outcomes included number of ED visits averted for repeat malaria testing, and algorithm adherence. Results From February 2014 to December 2015, 154 patients were seen in the RAFT clinic: 68 men and 86 women. Median age was 36 years (range 16–78 years). Mean time to RAFT clinic assessment was 1.2±0.07 days (range 0–4 days) postimplementation, compared to 5.4±1.8 days (range 0–26 days) prior to implementation (p

Distinguishing aquaporin-4-antibody(AQP4-Ab)-negative neuromyelitis optica spectrum disorders (NMOSD) from optico-spinal predominant MS is a clinical challenge with important treatment implications. 12 AQP4-Ab-negative patients presenting to an NMO clinic were selected for having overlapping features of NMO and MS. 27 NMO and MS experts reviewed their case vignettes, including relevant findings. Opinions were categorized for diagnosis (NMO, MS, indeterminate, other) and treatment (MS drugs, immunosuppression, none). The mean proportion of agreement for diagnosis was low (0.51). The majority opinion was divided between NMO versus MS (9 cases), monophasic longitudinally extensive transverse myelitis (LETM) versus NMOSD (1), acute disseminated encephalomyelitis versus NMO (1), and recurrent isolated optic neuritis (ON) versus NMOSD (1). LETM and/or ON with limited recovery even if accompanied by typical MS features (short TM, mild ON, oligoclonal bands), were associated with a low rate of MS diagnoses. TM with short lesions or mild ON did not preclude a diagnosis of NMO. Agreement on treatment was higher (0.64) with immunosuppression being the most common choice not only in patients with NMO but also in those indeterminate between NMO and MS. Experts frequently disagree on the diagnosis of NMO/MS overlapping syndromes. Prospective long-term studies on ultimate diagnosis in this group of patients are needed.

Following guidance from NICE in 2002, the Risk-sharing Scheme (RSS) was established to ensure cost-effective provision of interferon-beta and glatiramer acetate in the UK. The aim was to permit price adjustment should prospectively collected disability data deviate from the predicted course of treated patients modelled from natural history data. The first analysis identified problems with both the modelling and the chosen natural history dataset, resulting in estimations of the treatment effect which lacked validity and were not robust to sensitivity analyses. Guided by a Scientific Advisory Group blinded to subsequent data, a new analysis plan was derived, identifying the British Columbia MS database as a better comparator, and adopting a continuous Markov model with a single covariate. An alternative repeated measures model was developed in parallel. A series of sensitivity analyses were agreed. The predicted course of the RSS cohort on and off treatment has been modelled to 6 years from baseline values using both methods and compared to the observed data. Sensitivity analyses to examine the impact of assumptions in the analysis plan have been performed. The calculated deviation scores demonstrate how the drugs have performed in the real world compared to predictions from the short term randomised trials.

Background Therapy related acute leukaemia (TRAL) is a concern for neurologists and patients when considering treatment with Mitoxantrone for Multiple Sclerosis (MS). In 2008 we performed a literature review to determine the risk of TRAL, the associated mortality and potential relationship to total dose exposure. 1 Four years on, there have inevitably been numerous further reports of TRAL associated with mitoxantrone therapy for MS, and we have therefore re-reviewed the literature to attempt to establish a definitive risk and stratify this according to dose. Methods A literature search was undertaken for relevant articles to identify all reported cases of TRAL in MS and data extracted from cases reporting individual exposure (dose or mg/m 2 ) and timing of TRAL. We also identified all case series of >50 patients, reporting follow-up and complications of treatment with Mitoxantrone in MS and combined this with the 250 cases from the Walton Centre, Liverpool treated since 1997. Results Case series including 12,511 patients were identified; mean dose of Mitoxantrone was 90.1 mg/m 2 (range 12–242 mg/m 2 ). TRAL was diagnosed in 0.72%; with a number needed to harm of 139.2 patients. In 142 TRAL cases sufficient data was available to inform analysis of exposure. Onset was a median of 22 months following treatment (range 1–64). APL was the most common leukaemia subtype (58.0%) and AML second most frequent (35.1%). Thirty-seven of 124 TRAL patients had died (29.8%). Eighty-two percent of cases (n=117) occurred in patients exposed to >60 mg/m, 2 relative risk 1.86 (p=0.018), when comparing cumulative dose 2 against >60 mg/m 2 strongly suggesting a relationship to dose, as is the case with cardiac and reproductive adverse events. Discussion Whilst there remains the potential for publication bias to over-estimate the risk, the current review suggests an incidence of TRAL following Mitoxantrone of 1 in 139, significantly higher than our previous analysis of all available data in 2008. The data further highlights that treatment regimes which limit the cumulative dose to 2 (around 100–120 mg for most patients) will minimise the risk of late leukaemia. It is essential that clinicians and patients are aware of this significant risk before embarking on a highly effective, but potentially life-limiting treatment.

Background: A point mutation in protein tyrosine phosphatase receptor, type c polypeptide (PTPRC) has been associated with familial multiple sclerosis. This CG mutation at position 77 of exon 4 results in altered expression of CD45 isoforms on immune cells. Objective: To study the incidence of PTPRC mutations in subjects with multiple sclerosis in the North West region of the United Kingdom. Methods: Affected and unaffected subjects from five pedigrees with familial multiple sclerosis, 330 non-familial cases of multiple sclerosis, and 197 controls were studied. Genomic DNA was amplified using CD45IE34 and CD45IE44 primers, digested with Mspl, and run on an agarose gel. Polymerase chain reaction products were sequenced to exclude any other mutations. Results: No PTPRC exon 4 genomic mutations were seen in any of the five families. In the non-familial cases the incidence of mutation was 4.1% in 197 controls and 5.1% in 330 multiple sclerosis patients. No significant association was found in this study with this mutation and disease susceptibility, sex, or an extended disability scale score of Conclusions: This candidate does not appear to influence the development of familial multiple sclerosis in this population. The negative result could arise from a type II error owing to the number of families and non-familial cases screened. Alternatively it might suggest that the contribution of the PTPRC mutation depends upon the genetic background.

Background Pruritis (itch) is primarily a dermatologic problem. ‘Neurogenic pruritus’ (NP) has been described in some neurological diseases including MS and in a case with neuromyelitis optica spectrum disorder (NMOSD). Though the physiology of NP is uncertain ascending pathways or central processing could be involved. Aim To assess the characteristics of NP in NMOSD patients. Method Retrospective case note review followed by prospective telephone/clinic interviews of all AQP4 positive patients who attended National NMO clinic after 1 January 2011. Results 14/45 patients reported significant pruritus during the course of NMO and were interviewed. After excluding patients with only optic neuritis or an obvious skin/systemic cause 12 (26.7%) had NP occurring within a median of 3(0–90) months from onset of NMO. The median severity on visual analogue score was 6 (2–9). In three cases pruritus developed at a median of 5 (2–28) days before onset of motor-sensory symptoms of transverse myelitis (TM); most of the remaining patients developed it within 1 month after the onset of TM. A long cervical cord lesion was seen in 9 of 12 cases and correlated well with the dermatomal distribution of NP. Conclusions NP seems to be a common symptom associated with the TM of NMOSD.

Introduction Neuromyelitis optica (NMO) is a severe inflammatory condition causing optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM). Limited forms are called NMO spectrum disorder (NMOSD). Pathogenic aquaporin-4 (AQP4) antibodies are found in most patients with NMO and some with NMOSD. Previous studies have included seronegative patients in their cohorts despite suggestions that they may behave differently. Ethnic differences have not previously been directly studied. Methods We compared the clinical features and early long-term prognostic characteristics of 106 AQP4 antibody positive NMO/NMOSD patients from the UK (n=59) and Japan (n=47). Results Onset age was similar in both cohorts. The majority of both cohorts experienced a relapsing course but relapse rates were higher in the UK cohort. Attacks of LETM resulted in greater disability in the UK cohort. Motor disability was greater in those with late onset disease and in Caucasians, whatever their onset symptom. Visual disability was worse in young onset patients presenting with ON. Early treatment appeared to be associated with reduced visual disability in both cohorts and reduced motor disability only in the Japanese cohort. The small number of males in the UK cohort did worse than females. Conclusion NMO appears to be more severe in Caucasians than in Asians but outcome is also influenced by onset age, gender and treatment.

Objectives To identify clinical features of aquaporin 4 (AQP4) antibody positive optic neuritis (ON) in neuromyelitis optica (NMO) and NMO spectrum disorder (NMOSD) in a UK cohort. Methods We performed a retrospective review of case notes of NMO and NMOSD patients referred to the joint UK National NMO service (based at Liverpool and Oxford) positive for AQP4 antibody by cell based assay between 2006 and 2011. The clinical features, visual acuity, visual perimetry, optical coherence tomography results and visual evoked responses were analysed. Results 50 AQP4 antibody positive patients were identified. The optic neuronopathy was associated with severe sight impairment. However some NMO patients had a mild ON indistinguishable clinically from MS. Patients with isolated longitudinally extensive myelitis (LETM) and AQP4 antibodies did not show subclinical optic nerve abnormalities. Conclusions AQP4 antibody optic neuritis is clinically expressed and generally causes severe optic nerve damage. In those without clinical features the antibodies do not cause asymptomatic evidence of damage unlike in Multiple sclerosis which is commonly associated with subclinical involvement. The factors that influence whether AQP4 antibodies cause ON require elucidating. DoH National Specialised Commissioning Team joint UK Neuromyelitis Optica Service.

Introduction Neuromyelitis optica (NMO) is an inflammatory demyelinating condition, usually causing relapsing optic neuritis and longitudinally extensive transverse myelitis. Patients with limited forms are said to have NMO spectrum disorder (NMOSD). Azathioprine (AZA) is the most commonly used immunosuppressive drug to prevent relapses. However, its effectiveness over prolonged follow-up in larger cohorts is unknown. Aim Aim of this study was to analyse the effectiveness and tolerability of AZA in Aquaporin4 antibody positive NMO/NMOSD patients. Methods We retrospectively reviewed 54 Aquaporin-4 antibody positive NMO/NMOSD patients treated with AZA from two tertiary neurological centres in the UK. Results AZA was the first steroid-sparing drug to be used in 80% patients, 60% of whom were also on prednisolone. Median annualised relapse rates (ARR) pre treatment was 1.59 (0–26). At a median of 2 (1–10) years after starting treatment the median ARR was reduced to 0 (0–4.8), p Conclusion AZA in combination with prednisolone is an effective, cheap and convenient first line drug in NMO. However morbidity and mortality in NMO is high and controlled trials to compare it with other treatments (mycophenolate, mitoxantrone and Rituximab) are needed.

We present a 21-year-old Caucasian female with antibody positive NMO, mis-diagnosed as MS for a period of 5 years. The diagnosis became evident only when bilateral severe optic neuritis occurred shortly after the introduction of Natalizumab. The patient presented in 2005, aged 15, with hemi-sensory symptoms and diplopia, resolving with methylprednisolone. MRI revealed a non-enhancing lesion in the left thalamus. CSF oligoclonal bands were absent. She experienced two further relapses characterised by hemi-sensory disturbance, diplopia and fatigue; again responding to steroids. MRI revealed a new brain stem lesion. A diagnosis of MS was made and she was treated with Interferon. Despite treatment she had two further relapses, brain-stem and spinal, with recovery. Treatment with Mitoxantrone followed by Glatiramer Acetate resulted in a 2-year remission. In 2010 she experienced three further sensory events (MRI spine normal). Treatment with Natalizumab was initiated. She experienced a further spinal event following the second infusion, resolving rapidly with steroids. In April 2011, after six infusions, she presented with rapid onset bilateral optic neuritis to NPL and was found to be Aquaporin-4 antibody positive. Treatment with steroids and plasma exchange resulted in full visual recovery over 6 weeks. She has now been commenced on Azathioprine. The clinical spectrum of NMO is expanding. In “MS” patients experiencing frequent relapses despite escalating therapy, even if attacks are non-disabling, NMO should be considered. Although n=1, this case suggests that Natalizumab may be ineffective in, or indeed exacerbate, NMO.

With the availability of Aquaporin-4 antibodies, patients with relapsing spinal cord and optic nerve syndromes can be classified as NMO spectrum disorders. Despite this, a number of patients remain who have idiopathic optico-spinal demyelination. Though small series of such patients have been reported data on the long-term outcome of these patients is sparse. Methods From 2003 to 2005 cases of non-MS optico-spinal demyelination (ie, optic neuritis, myelitis and brain MRI not suggestive of MS) were reported via the British Neurological Surveillance Unit. Consenting patients and scans were reviewed and cases have been followed-up. Aquaporin-4 antibodies were assayed and patients were classified at 6 years into: NMO/NMO spectrum disorders, MS and optico-spinal demyelination—unclassified (OSD-U). Results Of 128 patients screened, 67 were initially classified as non-MS, optico-spinal demyelination. On follow-up at a median of 3.2 years (0–5.5) 34 patients were diagnosed as NMO (2006 criteria), six patients had been re-classified as MS and 27 patients remained as OSD-U. Relapses in this latter group were limited to optic nerve and spinal cord. Spinal cord lesions did not extend beyond three vertebral bodies, CSF oligoclonal bands were absent in 18/27 (67%) and MRI brain remained normal or atypical for MS on follow-up. Conclusions On follow-up around 20% of patients with optico-spinal demyelinating disorders cannot currently be easily classified. It is possible that idiopathic optico-spinal demyelination is a distinct entity or a sub-group of either MS or NMO. Longer clinical follow with repeat MRI and re-analysis of sera for possible new markers should be informative.

Introduction There is currently no disease modifying therapy for PPMS, which constitutes 10–15% of MS cases. rhEPO is has previously been suggested to have a neuroprotective role in an open label, exploratory study of rhEPO in progressive MS. Methods A pilot randomised controlled trial of rhEPO vs placebo was performed in 21 subjects with PPMS at The Walton Centre, Liverpool. rhEPO (30 000 IU IV) was given weekly for 12 weeks, with follow-up at week 13, 17 and 21. Primary outcome measures were maximum walking distance (MWD) and Expanded Disability Status Scale (EDSS). Results There was a nonsignificant improvement in MWD in the rhEPO arm (p=0.879) although there was no change in EDSS. The rhEPO arm performed significantly worse on MSFC (p=0.042). There was a higher frequency of adverse events in the rhEPO arm, although there were no serious adverse events. Consequently, only two of 11 patients completed the 12 week rhEPO regimen. One patient required venesection due to polycythaemia, and the rhEPO arm showed a significantly higher red cell count, haemoglobin and packed cell volume posttreatment than placebo (p=0.004, 0.004 and 0.024 respectively). Conclusion Despite the large proportion of dose omissions, a nonsignificant improvement in MWD was found, particularly in those receiving the majority of the active treatment. Future trials should address the safety issues highlighted here; alterations in the dosage and treatment regimen may improve the drug9s safety profile.

Alemtuzumab is a anti-CD52 humanised monoclonal antibody shown to be an effective treatment for relapsing multiple sclerosis (MS) in phase II studies but exhibits a unique adverse event profile. In limited follow-up studies development of autoimmune disease has been observed 20–30% of patients. Currently, the exact range and temporal evolution of autoimmune disease following treatment remains unclear but will have important implications for screening and safety monitoring. In this study we analyse prospective clinical and serological data from 225 patients treated with Alemtuzumab for a mean of 40.5 months (range 0.2–93.8). Novel autoimmune disease developed in 22.7%. Thyroid autoimmune disease was most common (17.8%) but a range of other autoimmune diseases including immune thrombocytopenic purpura, anti-GBM disease, neutropoenia, skin disorders and asymptomatic development of novel auto-antibodies was also observed. Risk of autoimmune disease was constant up to 55 months, following which there was a rapid decline, and independent of the number of treatments received or interval of dosage. Whilst established risk factors for autoimmune disease such as sex and age had no impact on autoimmune disease frequency, smoking was identified as a major risk factor with a relative risk of 4.95 for ever smokers. Risk of autoimmune disease in MS following alemtuzumab appears to be time limited and screening will need to continue for at least 5 years posttreatment. Individual risk for autoimmune disease is modified by external factors which should be incorporated within the counselling process prior to treatment.