Autoimmune encephalitis: a missed diagnostic and therapeutic opportunity

Encephalitis is a common clinical problem affecting 5 cases per 100 000 population annually. After exclusion of the usual infective causes, a number of cases remain unexplained. It has been observed that many such cases have an autoimmune basis resulting in disruption of synaptic and ion channel function. This diagnosis should be suspected based on subacute onset, short term memory loss, altered mental status or psychiatric symptoms in combination with new focal neurological deficits, new onset seizures, CSF pleocytosis or MRI features suggestive of encephalitis. As this is a treatable condition, with a good prognosis if recognised early, it is important not to miss the diagnosis.Keywords: Autoimmune encephaliti

Therapeutic lag in multiple sclerosis

© 2021 Izanne Craill RoosMultiple sclerosis is a heterogenous neurological disorder characterised by an interplay between neuroinflammation and neurodegeneration. Treatment decisions are frequently prompted by the presence of disease activity presenting as relapses or progression-of-disability events. Treatment initiation and switch are therefore two critical periods in multiple sclerosis management. There is a delay between treatment initiation and the onset of full clinically manifest effect of therapy, referred to as ‘therapeutic lag’. It has been suggested that not accounting for delayed treatment effects may obscure treatment response in clinical trials of progressive multiple sclerosis. Further exploration of the influence of therapeutic lag and its determinants, however depends on development of a robust method to detect when treatments attain full clinical effect. Similar to therapeutic lag, there is a delay between treatment stop and the return of disease activity. Disease reactivation after treatment cessation has been identified as a risk factor for disability accrual. Understanding of the optimal timing of the start of the next treatment however remains limited. All studies used data from the two largest multiple sclerosis registries: MSBase (multinational) and OFSEP (French). The first study developed, and externally validated, an objective differential-calculus based method to estimate the duration of therapeutic lag for clinical measures of treatment effect. Time to full clinical treatment effect was estimated as 12-30 weeks for relapses and 30-70 weeks for disability progression. The second study applied this method to groups of patients with different clinical and disease characteristics to investigate the determinants of lag duration. Pre-treatment level of disability and annualised rate of relapse were identified as the most important influencers of therapeutic lag. The third study investigated the effect of high and low-efficacy therapy in secondary progressive multiple sclerosis, after accounting for therapeutic lag. High-efficacy therapy was found to be superior to low-efficacy therapy in reducing relapses in patients with episodic inflammatory activity in the two years before starting therapy. High- and low-efficacy therapies however had comparable effectiveness on disability progression. In the fourth study, the focus was shifted from treatment start to the period after treatment cessation. The rate of disease reactivation after the cessation of disease-modifying therapies was explored. Risks of disease reactivation were highest after cessation of anti-trafficking therapies and were reduced by starting a new treatment. On-treatment rates of relapse, age, sex, and level of disability further influenced the risk of disease reactivation. These findings are highly relevant to clinical decision-making in a number of contexts: (i) patients who experience early on-treatment disease activity should be re-evaluated after the lapse of therapeutic lag, (ii) the selection of immunotherapy in patients with active secondary progressive multiple sclerosis should carefully consider the amount of preceding relapsing activity and the risk-vs-benefit ratio, (iii) decisions regarding wash-out durations after discontinuation of disease-modifying therapies should be individualised based on the discontinued therapy and a patient’s clinical profile. Moreover, treatment outcomes in cohorts enriched with patients with higher disability scores should be interpreted with the expected duration of therapeutic lag in sight

Clinico-pathological evaluation of two patients presenting with the neuromyelitis optica syndrome

The discovery of the Aquaporin 4 (AQP4) antibody in patients with neuromyelitis optica (NMO) has expanded clinical spectrum of disorders associated with this antibody. It has also become clear that NMO can be a paraneoplastic manifestation of an underlying malignancy. We report on the pathological changes in the spinal cord in an NMO patient who underwent a biopsy for a suspected spinal tumour. We also present the findings in the testicular tumour of a patient who initially presented with NMO. In the first patient we demonstrate the loss of AQP4 staining and in the latter case we demonstrate the expression of AQP4 by tumour cells.Keywords: Aquaporin 4 antibodies, NMO, paraneoplastic disorde

Correlation of optic neuritis and retinal nerve fibre thickness using optical coherence tomography in a cohort of multiple sclerosis patients

Background: Optical coherence tomography (OCT) is a fast, non-invasive imaging technology that produces 3D, high-resolution images of the retina. Direct visualisation of the retina allows a unique opportunity to study the effects of multiple sclerosis (MS)-associated neurodegeneration on retinal ganglion cells as well as effects of retrobulbar demyelination on axonal and retinal architecture through measurement of retinal nerve fibre layer (RNFL) thickness and total macular volume (TMV). These findings are clinically important as axonal loss is irreversible and correlates with disability. Aim: To determine the role and usefulness of OCT in a local cohort of MS patients. Setting: Neurology Clinic, Inkosi Albert Luthuli Central Hospital, KwaZulu-Natal, South Africa. Methods: Nineteen patients with MS currently being treated with interferon β-1b underwent OCT examination of both eyes. RNFL thickness and macular volume were measured and correlated with clinical disease characteristics, history of optic neuritis and level of disability. Results: Mean RNFL thickness was 77.3 μm with no significant difference in mean RNFL in eyes with a history of optic neuritis (ON) and those without (p = 0.4). Eyes with a history of ON did, however, have significantly thinner RNFL compared with the contralateral eye (p = 0.04). Despite a strong correlation between TMV and RNFL (p = 0.001), a subset of patients with normal RNFL had TMV that was less than 1% of what was expected. There was no correlation between RNFL and disability scores. Conclusion: OCT enables a direct axonal ‘optical biopsy’, for monitoring disease progression and treatment response in MS. RNFL thinning occurs independently of a history of optic neuritis and may represent a chronic optic neuropathy in patients with MS. Keywords: Multiple sclerosis; optical coherence tomograph

The neuromyelitis optica presentation and the aquaporin-4 antibody in HIV-seropositive and seronegative patients in KwaZulu-Natal, South Africa

CITATION: Bhigjee, A. I., et al. 2017. The neuromyelitis optica presentation and the aquaporin-4 antibody in HIV-seropositive and seronegative patients in KwaZulu-Natal, South Africa. Southern African Journal of HIV Medicine, 18(1):a684, doi:10.4102/sajhivmed.v18i1.684.The original publication is available at http://www.sajhivmed.org.za/Background: The association of the anti-aquaporin-4 (AQP-4) water channel antibody with neuromyelitis optica (NMO) syndrome has been described from various parts of the world. There has been no large study describing this association from southern Africa, an HIV endemic area. HIV patients often present with visual disturbance or features of a myelopathy but seldom both either simultaneously or consecutively. We report our experience of NMO in the era of AQP-4 testing in HIV-positive and HIV-negative patients seen in KwaZulu-Natal, South Africa. Methods: A retrospective chart review was undertaken of NMO cases seen from January 2005 to April 2016 in two neurology units serving a population of 7.1 million adults. The clinical, radiological and relevant laboratory data were extracted from the files and analysed. Results: There were 12 HIV-positive patients (mean age 33 years), 9 (75%) were women and all 12 were black patients. Of the 17 HIV-negative patients (mean age 32 years), 15 (88%) were women and 10 (59%) were black people. The clinical features in the two groups ranged from isolated optic neuritis, isolated longitudinally extensive myelitis or combinations. Recurrent attacks were noted in six HIV-positive patients and six HIV-negative patients. The AQP-4 antibody was positive in 4/10 (40%) HIV-positive patients and 11/13 (85%) HIV-negative patients. The radiological changes ranged from longitudinal hyperintense spinal cord lesions and long segment enhancing lesions of the optic nerves. Three patients, all HIV-positive, had tumefactive lesions with incomplete ring enhancement. Conclusion: This study confirms the presence of AQP-4-positive NMO in southern Africa in both HIV-positive and HIV-negative patients. The simultaneous or consecutive occurrence of optic neuritis and myelitis in an HIV-positive patient should alert the clinician to test for the AQP-4 antibody. It is important to recognise this clinical syndrome as specific therapy is available. We further postulate that HIV itself may act as a trigger for an autoimmune process.https://sajhivmed.org.za/index.php/hivmed/article/view/684Publisher's versio

Evaluating the perspective of patients with MS and related conditions on their DMT in relation to the COVID-19 pandemic in one MS centre in Australia

Objective: Patients with Multiple Sclerosis (MS) and on disease modifying therapies (DMTs) that can be immunosuppressive or immunomodulatory form a special group where risk of continuation of DMT needs to be taken into account with risk of contracting Covid-19. This concept can pose a degree of anxiety for patients as well as neurologists. We aimed to evaluate patient perspectives regarding the use of Natalizumab and anti-CD20 therapies (Rituximab and Ocrelizumab) in the context of the COVID-19 pandemic. Methods: cross-sectional study conducted via voluntary survey filled in by patients with MS and related disorders receiving their infusional treatment in one MS centre in Australia, exploring their concerns regarding their therapy, their therapy and COVID-19, precautions undertaken in response to the pandemic, and factors impacting their decision-making. Results: 170 patients completed the survey. Of patients on Natalizumab, the majority had either no or mild concern regarding their DMT and COVID-19, and of patients on B-cell depleting therapies, again, the majority had no or mild concern, though a slightly higher proportion had a moderate level of concern. Asked to delineate their concerns, an increased risk of contracting COVID-19 was more commonly conveyed than MS-specific factors or poor outcomes pertaining to COVID-19 if contracted, by patients in both groups. Conversely, being invited to specifically consider the possibility of contracting COVID-19 or experience a relapse of MS, almost half of the cohort rated both of equal of concern. More than half of the cohort were self-isolating more stringently than general government advice and government-related resources followed by information provided by patient's neurologist where the commonest means of information to guide decision making. Conclusions: Whilst a large proportion of patients had some concern regarding the impact of their DMT on COVID-19, whether on their risk of contracting COVID-19 or a theoretical risk for more severe disease, the overall level of concern in most cases was at most mild. Patients on B-cell depleting therapies were more inclined to express a higher level of concern. A similar concern was ascribed to a risk of a relapse or worsening MS symptoms compared to the risk of contracting COVID-19. Such attitudes may underscore a willingness of patients to continue their DMT where benefits outweigh risks during future phases of the COVID-19 pandemic

Multiple Sclerosis Relapses Following Cessation of Fingolimod.

There is growing interest in the issue of disease reactivation in multiple sclerosis following fingolimod cessation. Relatively little is known about modifiers of the risk of post-cessation relapse, including the delay to commencement of new therapy and prior disease activity. We aimed to determine the rate of relapse following cessation of fingolimod and to identify predictors of relapse following cessation. Data were extracted from the MSBase registry in March 2019. Inclusion criteria were (a) clinically definite relapsing multiple sclerosis, (b) treatment with fingolimod for ≥ 12 months, (c) follow-up after cessation for ≥ 12 months, and (d) at least one Expanded Disability Status Scale score recorded in the 12 months before cessation. A total of 685 patients were identified who met criteria. The mean annualised relapse rate was 1.71 (95% CI 1.59, 1.85) in the year prior to fingolimod, 0.50 (95% CI 0.44, 0.55) on fingolimod and 0.43 (95% CI 0.38, 0.49) after fingolimod. Of these, 218 (32%) patients experienced a relapse in the first 12 months. Predictors of a higher relapse rate in the first year were: younger age at fingolimod cessation, higher relapse rate in the year prior to cessation, delaying commencement of new therapy and switching to low-efficacy therapy. Disease reactivation following fingolimod cessation is more common in younger patients, those with greater disease activity prior to cessation and in those who switch to a low-efficacy therapy

Disease-modifying therapies in managing disability worsening in paediatric-onset multiple sclerosis: a longitudinal analysis of global and national registries

Background: High-efficacy disease-modifying therapies have been proven to slow disability accrual in adults with relapsing-remitting multiple sclerosis. However, their impact on disability worsening in paediatric-onset multiple sclerosis, particularly during the early phases, is not well understood. We evaluated how high-efficacy therapies influence transitions across five disability states, ranging from minimal disability to gait impairment and secondary progressive multiple sclerosis, in people with paediatric-onset multiple sclerosis. Methods: Longitudinal data were obtained from the international MSBase registry, containing data from people with multiple sclerosis from 151 centres across 41 countries, and the Italian Multiple Sclerosis and Related Disorders Register, containing data from people with multiple sclerosis from 178 Italian multiple sclerosis centres. People younger than 18 years at the onset of multiple sclerosis symptoms were included, provided they had a confirmed diagnosis of relapsing-remitting multiple sclerosis and at least four Expanded Disability Status Scale (EDSS) scores recorded within 12-month intervals. The primary outcome was the time to change in disability state: minimal disability (EDSS scores 0, 1·0, and 1·5), mild disability (EDSS scores 2·0 and 2·5), moderate disability (EDSS scores 3·0 and 3·5), gait impairment (EDSS scores ≥4·0), and clinician diagnosed secondary progressive multiple sclerosis. A multi-state model was constructed to simulate the natural course of multiple sclerosis, modelling the probabilities of both disability worsening and improvement simultaneously. The impact of high-efficacy disease-modifying therapies (alemtuzumab, cladribine, daclizumab, fingolimod, mitoxantrone, natalizumab, ocrelizumab, rituximab, or autologous haematopoietic stem cell transplantation) and low-efficacy disease-modifying therapies (dimethyl fumarate, glatiramer acetate, interferon beta, or teriflunomide), compared with no treatment, on the course of disability was assessed. Apart from recruitment, individuals with lived experience of multiple sclerosis were not involved in the design and conduct of this study. Findings: A total of 5224 people (3686 [70·6%] female and 1538 [29·4%] male) with mean age at onset of multiple sclerosis 15·24 years (SD 2·52) were included. High-efficacy therapies reduced the hazard of disability worsening across the disability states. The largest reduction (hazard ratio 0·41 [95% CI 0·31-0·53]) was observed in participants who were treated with high-efficacy therapies while in the minimal disability state, compared with those remained untreated. The benefit of high-efficacy therapies declined with increasing disability. Young people with minimal disability who received low-efficacy therapy also experienced a reduced hazard (hazard ratio 0·65 [95% CI 0·54-0·77]) of transitioning to mild disability, in contrast to those who remained untreated. Interpretation: Treatment of paediatric-onset relapsing-remitting multiple sclerosis with high-efficacy therapy substantially reduces the risk of reaching key disability milestones. This reduction in risk is most pronounced among young people with minimal or mild disability when treatment began. Children with relapsing-remitting multiple sclerosis should be treated early with high-efficacy therapy, before developing significant neurological impairments, to better preserve their neurological capacity. Funding: National Health and Medical Research Council, Australia; MSBase Foundation Fellowship; MS Australia Postdoctoral Fellowship