Longitudinal stability of JCV antibody index in Natalizumab treated people with multiple sclerosis.

OBJECTIVE: The aim of this study was to evaluate the evolution of JCV index over time in Natalizumab treated people with multiple sclerosis. MATERIALS AND METHODS: We retrospectively reviewed antibody index values from pwMS who were treated with Natalizumab for greater than six months and had at least two antibody results available between 2011 and 2019. Survival analysis was performed on those who were JCV index value negative at baseline to evaluate time to seroconversion. In pwMS who had index values available at 48 and/or 96 months post Natalizumab initiation, t-tests were performed to evaluate change in index over time. RESULTS: 1144 JCV antibody index results were available for 132 pwMS. Median time to seroconversion based on survival analysis was 103 months. Annualised seroconversion rate was 5.8%. Initial antibody index and rate of seroconversion did not differ with regards to age or gender. Antibody index increased significantly over time on treatment for the cohort as a whole, initial antibody index (0.27) to final antibody testing (0.86), t(131)=6.45, p<.0005. There was a significant increase in those with initial positive index value, between first (0.95) and final index (2.14), t(33) = 4.85, p<.0005 over a median of 77 months. CONCLUSIONS: In those who were seronegative at baseline there is a long median duration of treatment with Natalizumab prior to seroconversion. In individuals with positive JCV antibody index at treatment initiation, antibody index increases over time.

Auditing the frequency and the clinical and economic impact of testing for Fabry disease in patients under the age of 70 with a stroke admitted to Saint Vincent's University Hospital over a 6-month period.

BACKGROUND: Fabry disease is an X-linked recessive lysosomal storage disorder that provokes multi-organ morbidity, including early-onset stroke. Worldwide prevalence may be greater than previously estimated, with many experiencing first stroke prior to diagnosis of Fabry disease. AIMS: The aim of this study is to screen a cohort of stroke patients under 70 years of age, evaluating the clinical and economic efficacy of such a broad screening programme for Fabry disease. METHODS: All stroke patients under 70 years of age who were entered into the Saint Vincent's University Hospital stroke database over a 6-month period underwent enzyme analysis and/or genetic testing as appropriate for Fabry disease. Patients' past medical histories were analysed for clinical signs suggestive of Fabry disease. Cost-effectiveness analysis of testing was performed and compared to overall economic impact of young stroke in Ireland. RESULTS: Of 22 patients tested for Fabry disease, no new cases were detected. Few clinical indicators of Fabry disease were identified at the time of testing. CONCLUSION: Broad screening programmes for Fabry disease are highly unlikely to offset the cost of testing. The efficacy of future screening programmes will depend on careful selection of an appropriate patient cohort of young stroke patients with multi-organ morbidity and a positive family history.

Neurosarcoidosis: clinical presentations and changing treatment patterns in an Irish Caucasian population.

BACKGROUND: The clinical manifestations of neurosarcoidosis are highly variable and it should be considered as a potential differential diagnosis in any neurological presentation. AIM: This study was designed to describe the clinical, diagnostic, and treatment patterns and functional outcome in a Caucasian neurosarcoidosis population. DESIGN: A retrospective analysis was performed on prospectively recorded data in patients attending our neurology clinic between 2008 and 2014 with a diagnosis of definite or probable neurosarcoidosis according to Zajiek criteria. METHODS: Detailed clinical features, baseline demographic data, results of investigations, treatment type and duration, and clinical outcomes were collated. RESULTS: Eleven patients were identified (55% men) with mean age 39 years (range 21-63). Four had a prior history of systemic sarcoidosis leading to earlier diagnosis (6.7 vs 13.1 months). Six were found to have evidence of systemic sarcoidosis on further investigation and one was biopsy proven isolated neurosarcoidosis. The commonest site of CNS involvement was the cranial nerves (64%), and headache (45%) was the most frequent presenting symptom. MRI abnormalities included leptomeningeal enhancement, white matter lesions, acute arteritis, spinal cord lesion, and cauda equina enhancement. The commonest CSF finding was raised protein (n = 6) and a lymphocytic pleocytosis (n = 7). Serum ACE was only elevated in three cases. Ten patients were treated with both corticosteroids and steroid-sparing agents 8 of whom went into remission. CONCLUSIONS: This series highlights the diverse nature of neurosarcoidosis. Early introduction of aggressive therapy with corticosteroids and steroid-sparing agents appears to improve clinical outcome.

Expansion of the Spectrum of FLNA Mutations Associated with Melnick-Needles Syndrome.

Melnick-Needles syndrome (MNS) is a rare X-linked bone dysplasia characterised by facial dysmorphology and radiographic abnormalities [Melnick and Needles, 1966;97:39-48]. Previously, all published cases of MNS were associated with only 4 mutations [Robertson et al., 2003;33:487-491; Santos et al., 2010;152A:726-731], all localised within exon 22 of FLNA, the gene encoding the cytoskeletal protein filamin A. Here we report 3 new mutations in FLNA that are associated with MNS. One affected member of the first family with the mutation p.Y1229S presented with a stroke while this patient's daughter, previously known to be affected from a young age, developed multiple sclerosis. A second unrelated patient with a typical phenotype is shown to have the mutation c.1054G>T (p.G352W) within exon 7 of FLNA. A third individual with an atypical presentation but radiological findings very similar to those seen in classic MNS has a deletion likely to affect residues within repeat domain 14. These findings indicate that the mutational spectrum for MNS is wider than previously appreciated and has implications for genetic testing strategies employed to confirm a diagnosis of this rare disorder.

Illness perception and health-related quality of life in multiple sclerosis.

AIMS - A number of physical and psychological factors have been shown to affect health-related quality of life (HRQoL) in patients with multiple sclerosis (MS). Among these, the role of illness perceptions has not been established as an independent factor. This study, the first of its kind in an Australian population, aimed to use a large sample to determine the relative importance of individual factors to each domain of HRQoL, in particular the role of illness perception. MATERIALS AND METHODS - 580 patients with confirmed MS were assessed cross sectionally in a designated research clinic to determine the relative impact of physical factors (illness severity, duration, age, fatigue and pain) and psychological factors (mood, cognition and illness representations) on each domain of the SF-36. RESULTS - Categorical regression analysis showed that a combination of physical and psychological factors predicted 38-71% of variance in HRQoL. Illness perception was shown to have an independent effect on HRQoL in MS. The Extended Disability Status Scale was a significant determinant in all domains except for mental health. Depression was less prevalent than anxiety, but had a greater effect on function. CONCLUSION - Illness perception is an independent factor contributing to HRQoL in people with MS. Individual domains of HRQoL are associated with different patterns of physical and psychological factors. In the domains of role and social function, activities most highly valued by patients with MS, depression, anxiety, fatigue and illness perceptions are key determinants, all of which have the potential to be improved through specific interventions.

Neurology of Fabry disease.

BACKGROUND: Fabry disease has diverse neurological manifestations, many of which influence morbidity and quality of life. AIMS: The aim of the study was to document the clinical and subclinical neurological manifestations in a cohort of Australian patients with Fabry disease, using multiple clinical tools and a multidisciplinary approach. METHODS: Participants completed focused questionnaires and underwent clinical neurological examination, Neurocognitive testing using Mini Mental State Examination and Neuropsychiatry Unit Cognitive Screen, Quantitative Sensory Testing (QST), autonomic assessment using RR interval variation, intracranial magnetic resonance imaging (MRI) and audiology. In subsets of patients who had previously undergone QST and/or prospective serial quality-of-life assessments over the previous 5 years, results before and after enzyme replacement therapy were compared. RESULTS: Twenty hemizygotes and two heterozygotes were recruited. The age (mean +/- standard deviation (SD)) of male participants was 40.4 +/- 11.9 years (range 20-62 years); the women were aged between 20 and 56 years. Increasing age was strongly associated with increasing neurological disability. Clinical peripheral neuropathy predominantly affected thermal sensation in all patients, with variable involvement of pinprick and light touch. QST confirmed these findings. Clinical cerebellar tests were commonly abnormal: this has not been previously reported in the absence of symptomatic cerebrovascular disease. There was hearing loss was in 90% of patients and no patient older than 44 years had normal hearing. MRI lesion prevalence increased with age. Despite neurological complications being common, formal cognitive testing was basically normal. QST thresholds for pain showed a significant change after enzyme replacement therapy. CONCLUSIONS: Neurological complications in Fabry disease are common, complex and may be devastating. All patients studied had neurological involvement, with protean and diverse manifestations.

Variant Creutzfeldt-Jakob disease: first two indigenous cases in Republic of Ireland. Case report and perspective.

The first two cases of indigenous variant Creutzfeldt-Jakob disease (vCJD) in the Republic of Ireland are reported in two men, neither of whom had lived outside Ireland. Both diagnoses were made ante-mortem based on clinical presentation, brain imaging, positive 14-3-3 protein in one case, and tonsillar biopsy. We discuss some of the clinical aspects of vCJD and the significance of these cases in the Irish context.

Intermittent claudication -- atypical presentation, diagnosis and treatment.

A unique case of a man with Fabry's disease and associated small vessel vasculopathy manifesting as recurrent episodes of intermittent claudication is described. The case highlights the concept that microvascular involvement due to local accumulation of glycosphingolipid in the smooth muscle fibres of vessel walls may be responsible for claudicant symptoms in such patients rather than the more classical macrovascular insufficiency.

Cladribine followed by autologous stem-cell transplantation in progressive multiple sclerosis.

We studied the safety of autologous peripheral blood stem-cell transplantation (PBSCT) in four patients with progressive multiple sclerosis. Clinical and magnetic resonance imaging outcomes were secondary end-points. Cladribine administration preceded filgrastim-primed PBSC collection, aiming for lymphocyte depletion. Conditioning was with antithymocyte globulin and cyclophosphamide. The procedure was well tolerated, but without obvious clinical benefit. The study was terminated when other therapeutic options with lower morbidity became available.

Infundibulohypophysitis in a man presenting with diabetes insipidus and cavernous sinus involvement.

Infundibulohypophysitis is an unusual inflammatory condition that affects the infundibulum, the pituitary stalk, and the neurohypophysis and may be part of a range that includes lymphocytic hypophysitis. Lymphocytic hypophysitis occurs mainly in women and most often presents in the later stages of pregnancy. Infundibulohypophysitis usually presents with diabetes insipidus and the cause remains unclear. The case of a 46 year old man with a 12 week history of polyuria and polydipsia is reported. Cranial diabetes insipidus was diagnosed on the basis of a water deprivation test. Initial cranial and pituitary imaging studies were normal. He subsequently developed symptoms of panhypopituitism over a period of 6-9 months and then, more acutely, developed diplopia secondary to a fourth nerve palsy. Further brain imaging studies disclosed an enhancing pituitary stalk and a left cavernous sinus lesion. An initial trial of immunosuppressive treatment did not help symptoms significantly. The diagnosis of infundibulohypophysitis was made on histological evidence. The patient was treated with prednisolone and methotrexate. At 9 months he is well, without symptoms, and the radiological abnormalities have resolved.

Postpartum pituitary hypophysitis.

The case of a young woman who developed lymphocytic hypophysitis 2 weeks after delivery of a healthy baby is reported. The patient presented with clinical features suggestive of a pituitary mass lesion, but surgery was avoided when other clinical and radiologic features were considered. The patient recovered with steroid treatment only. We review the literature on this increasingly recognized condition and argue that medical management may be more suitable than previously thought.

The effect of anti-alpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group.

OBJECTIVE: To determine the effect of humanized monoclonal antibody against alpha4 integrin (reactive with alpha4beta1 integrin or very-late antigen-4) on MRI lesion activity in MS. METHODS: A randomized, double-blind, placebo-controlled trial in 72 patients with active relapsing-remitting and secondary progressive MS was performed. Each patient received two IV infusions of anti-alpha4 integrin antibody (natalizumab; Antegren) or placebo 4 weeks apart and was followed up for 24 weeks with serial MRI and clinical assessment. RESULTS: The treated group exhibited significantly fewer new active lesions (mean 1.8 versus 3.6 per patient) and new enhancing lesions (mean 1.6 versus 3.3 per patient) than the placebo group over the first 12 weeks. There was no significant difference in the number of new active or new enhancing lesions in the second 12 weeks of the study. The number of baseline-enhancing lesions (i.e., lesions that enhanced on the baseline scan) that continued to enhance 4 weeks following the first treatment was not significantly different between the two groups. The number of patients with acute MS exacerbations was not significantly different in the two groups during the first 12 weeks (9 in the treated group versus 10 in placebo) but was higher in the treatment group in the second 12 weeks (14 versus 3; p = 0.005). The study was not, however, designed to look definitively at the effect of treatment on relapse rate. Treatment was well tolerated. CONCLUSIONS: Short-term treatment with monoclonal antibody against alpha4 integrin results in a significant reduction in the number of new active lesions on MRI. Further studies will be required to determine the longer term effect of this treatment on MRI and clinical outcomes.