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Nodding syndrome is an uncommon disorder of childhood onset and unknown cause, presenting with nodding seizures, and which appears to occur exclusively in clusters in sub-Saharan Africa. An endemic pattern of disease was initially described in Tanzania and in Liberia; epidemic occurrences were later reported in South Sudan and northern Uganda. Not the least significant of the many questions remaining about nodding syndrome concerns the common presence or otherwise of neurological features other than seizures—clearly relevant to the core issue of whether this is a focal, primary epileptic disease, or a multi-system CNS disorder, with, in turn implications for its aetiology. We had the opportunity to interview and clinically to examine 57 affected individuals in rural northern Uganda some 10 years after onset. In this observational cross-sectional study, nodding onset was invariably between the ages of 5 and 14, presenting with food-triggered nodding attacks in over 75% of cases; 86% went on to develop other seizure types. In 53 of 57 nodding syndrome individuals (93%), there was a definite history of the child and his or her family having resided in or been fed from an internally displaced person camp for some time prior to the onset of nodding. A half of nodding syndrome sufferers (28/57) had focal neurological abnormalities—mainly pyramidal signs (92%), often asymmetric, some with extrapyramidal abnormalities. Many individuals (28/57) were severely functionally disabled, ranging from ‘sometimes can dig’ to ‘can do nothing at home’ or ‘cannot even feed herself’. Such sufferers tended more frequently to have significant burns, and clear cognitive impairment. We conclude that nodding syndrome is a unique multisystem CNS disorder of childhood onset and then slow progression over several years often followed by spontaneous stabilisation, consistent with an underlying self-limiting neurodegenerative process. We discuss the possibility that this might be triggered by food-related mycotoxins, within a fixed window of CNS vulnerability during childhood.

Clinical trial populations do not fully reflect routine practice. The power of routinely collected data to inform clinical practice is increasingly recognised.The OPTIMISE:MS pharmacovigilance study is a prospective, pragmatic observational study, conducted across 13 UK MS centres. Data were collected at the time of routine clinical visits. The first participant was recruited on 24th May 2019; data were extracted on 11th November 2021.2112 participants were included (median age 44.0 years; 1570 (72%) female; 1981 (94%) relapsing-remitting MS). 639 (30%) were untreated at study entry, 205 (10%) taking interferon beta/copaxone, 1004 (47%) second/third generation DMT first line and 264 (13%) had escalated from a platform DMT. 342 clinical events were reported, of which 108 infections. There was an increased risk of adverse events in people taking second/third generation DMT (RR 3.45, 95%CI 1.57-7.60, p0.01 vs no DMT). Unadjusted Poisson regression demonstrated increased incident adverse events in people taking natalizumab (IRR 5.28, 95%CI 1.41-19.74, p0.05), ocrelizumab (IRR 3.24, 95%CI 1.22-8.62, p0.05), and GA biosimilar (Brabio) (IRR 4.89, 95%CI 1.31-18.21, p0.05) vs no DMT.Routinely collected healthcare data can be used to evaluate DMT safety in people with MS. These data highlight the potential of pragmatic studies to guide understanding of risks and benefits associated with DMT.

IntroductionOxidative stress is implicated in the pathophysiology of multiple sclerosis (MS). To investigate their potential as MS biomarkers, we compared plasma levels of two master regulators of antioxidant processes nuclear factor erythroid 2 related factor 2 (Nrf2) and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α), as well as downstream antioxidant enzymes superoxide dismutase 1 (SOD1) and catalase.MethodsPlasma levels of Nrf2, PGC1α and SOD1 were measured using enzyme-linked immunosorbent assay (ELISA). Plasma catalase levels were measured using a catalase activity assay. The results were analysed using a multiple regression model.ResultsPlasma PGC1α concentrations were higher in people with MS compared to controls and lower in patients with primary progressive MS than those with relapsing remitting MS. Plasma Nrf2 levels were increased in those on disease modifying therapy with Dimethyl fumarate, which was most pronounced 6 weeks post-initiation. Plasma Nrf2 levels fell in patients commencing Ocrelizumab. Plasma catalase activity was higher in patients with MS when compared to control, and higher in patients with progressive MS phenotypes. No statistically significant changes in plasma SOD1 levels were observed.ConclusionsOur findings support further investigation of the potential for plasma PGC1α, Nrf2 and catalase as disease biomarkers in MS.

Abstract Background Sexual and gender-based violence (SGBV), including rape and child sexual abuse, remains a significant challenge in post-conflict northern Uganda, including within refugee settlements. Many victims have never sought help from health-related services. Consequently, the scale of the problem is unknown, and SGBV victims’ injuries, both psychological and physical, remain undetected and unaddressed. We hypothesized that health workers in rural Reproductive Health Services could provide a valuable resource for SGBV screening and subsequent referral for support. Methods Our project had three elements. First, Reproductive Health Service workers were trained in the knowledge and skills needed to screen for and identify women who had experienced SGBV, using a questionnaire-based approach. Second, the screening questionnaire was used by reproductive health workers over a 3-month period, and the data analysed to explore the scale and nature of the problem. Third, victims detected were offered referral as appropriate to hospital services and/or the ActionAid SURGE (Strengthening Uganda’s Response to Gender Equality) shelter in Gulu. Results 1656 women were screened. 778 (47%) had a history of SGBV, including 123 victims of rape and 505 victims of non-sexual violence. 1,254 (76%) had been directly or indirectly affected by conflict experiences; 1066 had lived in IDP camps. 145 (9%) were referred at their request to Gulu SGBV Shelter under SURGE. Of these, 25 attended the shelter and received assistance, and a further 20 received telephone counselling. Conclusion Undetected SGBV remains a problem in post-conflict northern Uganda. Reproductive Health Service workers, following specific training, can effectively screen for and identify otherwise unreported and unassisted cases of SGBV. Future work will explore scaling up to include screening in hospital A&E departments, incorporate approaches to screening for male victims, and the impact of taking both screening and support services to rural communities through local clinics with mobile teams.

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory central nervous system disorder characterized by acute or subacute onset of multifocal neurologic deficits with headache and impaired conscious level. Acute haemorrhagic leuoko-encephalitis (AHEM) is a more sever, often fatal variant. These disorders often follows a viral illness or vaccination, and are usually monophasic, though (probably more commonly in childhood) a multiphasic variant of ADEM is recognized. Because of the relative non-specificity of the clinical presentation (a sub-acute encephalopathy with focal signs), the differential diagnosis is wide; and distinction from the first episode of relapsing-remitting multiple sclerosis can occasionally be difficult. Here the clinical and investigational features of these disorders and their treatment are discussed.

Oligodendrocytes, derived from stem cell precursors which arise in subventricular zones of the developing central nervous system, have as their specialist role the synthesis and maintenance of myelin. Astrocytes contribute to the cellular architecture of the central nervous system and act as a source of growth factors and cytokines; microglia are bone-marrow derived macrophages which function as primary immunocompetent cells in the central nervous system. Myelination depends on the establishment of stable relationships between each differentiated oligodendrocyte and short segments of several neighbouring axons. There is growing evidence, especially from studies of glial cell implantation, that oligodendrocyte precursors persist in the adult nervous system and provide a limited capacity for the restoration of structure and function in myelinated pathways damaged by injury or disease.

The extraordinary expansion in the field of neuroimmunology witnessed in the last decade is not just in the number of neurological disorders now considered to have an immune basis, nor the depth of understanding of disorders long known to be ‘neuroimmune’. Nor is it in the number of antibodies discovered and now testable, nor in the range of new immune suppressant or modifying treatments now emerging or already available. It is of course all of these things, but it is also more than the sum of these parts. What we are currently privileged to witness is the coming together of immunological understanding, the neurobiology of disease, and rational immune therapy, or at least the beginning of this process. To take one isolated example, neurogenetics and neurophysiology taught us about the clinical consequences of channel disruption; laboratory-based neuroimmunology showed antibodies to be capable of producing comparable acquired disease; and it seems likely that specific anti-B-cell humanized monoclonal antibodies offer the therapeutic potential to remove these channel-disrupting antibodies. Neither of these steps could be described in the last edition, and one can imagine similar dramatic changes will emerge before the next.

That part of the clinical interface between neurology and general medicine occupied by inflammatory and immunological diseases is neither small nor medically trivial. Neurologists readily accept the challenges of ‘primary’ immune diseases of the nervous system: these tend to be focussed on one particular target such as oligodendrocytes or the neuro-muscular junction present in predictable ways, and are amenable as a rule to rational, methodological diagnosis, and occasionally even treatment. This is proper neurology.‘Secondary’ neurological involvement in diseases mainly considered systemic inflammatory conditions—for example, SLE, sarcoidosis, vasculitis, and Behçet’s—is a rather different matter. It may be difficult enough to secure such a diagnosis even when systemic disease has previously been diagnosed and new neurological features need to be differentiated from iatrogenic disease, particularly drug side effects or the consequences of immune suppression. But all the diseases mentioned may present with and confine themselves wholly to the nervous system; they may mimic one another, and pursue erratic and unpredictable clinical courses. In central nervous system disease, diagnosis by tissue biopsy is potentially hazardous and unattractive. Few neurologists enjoy excesses of confidence or expertise when faced with such clinical problems: the cautious diagnostician is perplexed, and the evidence-based neuroprescriber confounded. Unsurprisingly, great variations in approaches to diagnosis and management are seen (Scolding et al. 2002b).But rheumatologically inclined general, renal or respiratory physicians, comfortable when managing inflammation affecting their system or indeed other parts of the body designed to support the nervous system, are generally also ill at ease when faced with neurological features whose differential diagnosis may be large, particularly given the near universal diagnostic non-specificity of either imaging or CSF analysis.Here then is the subject material for this chapter: the diagnosis and management of central nervous system involvement in inflammatory and immunological systemic diseases (Scolding 1999a). In not one of these neurological conditions has a single controlled therapeutic trial been reported, and much that is published on these conditions is misleading or inaccurate. And yet the frequency with which the diagnosis is only confirmed or even first emerges at autopsy bears stark witness to both the severity and evasiveness of these disorders.

This chapter describes the many methods that can be used to investigate neurological disorders. The application and suitability for specific disorder types are outlined, as are contraindications for use. Methods of imaging the central nervous system include computed tomography (CT) imaging, several magnetic resonance (MR) scanning methods, Single photon emission computed tomography (SPECT) and Positron Emission Tomography (PET). Invasive (angiography) and non-invasive methods of imaging the cerebral circulation are also outlined.The standard method of recording electrical activity of the brain is the electroencephalogram (EEG), which is heavily used in epilepsy to investigate regions of epileptogenesis.Other investigations described include evoked potentials, nerve conduction and electromyography studies, the examination of cerebrospinal fluid and the diagnostic use of neurological autoantibodies. Finally, neurogenetics, neuropsychological assessment and the assessment of treatments by randomized trials are discussed.

Inflammation is known to cause significant neuronal damage and axonal injury in many neurological disorders. Among the range of inflammatory mediators, nitric oxide is a potent neurotoxic agent. Recent evidence has suggested that cellular peroxisomes may be important in protecting neurons from inflammatory damage. To assess the influence of peroxisomal activation on nitric oxide-mediated neurotoxicity, we investigated the effects of the peroxisomal proliferator-activated receptor (PPAR)-α agonist fenofibrate on cortical neurons exposed to a nitric oxide donor or co-cultured with activated microglia. Fenofibrate protected neurons and axons against both nitric oxide donor-induced and microglia-derived nitric oxide-induced toxicity. Moreover, cortical neurons treated with this compound showed a significant increase in gene expression of ABCD3 (the gene encoding for peroxisomal membrane protein-70), with a concomitant increase in protein levels of PPAR-α and catalase, which was associated with a functional increase in the activity of this enzyme. Collectively, these observations provide evidence that modulation of PPAR-α activity and peroxisomal function by fenofibrate attenuates nitric oxide-mediated neuronal and axonal damage, suggesting a new therapeutic approach to protect against neurodegenerative changes associated with neuroinflammation.

Primary neuroimmune disorders such as multiple sclerosis or the Guillain–Barré syndrome are well recognized (and described elsewhere in this section), but there are numerous diverse systemic inflammatory, infective, or immunological disorders that can affect the nervous system. Autoimmune rheumatic disorders—(1) Systemic lupus erythematosus—neurological manifestations include headache, acute or subacute encephalopathy, fits, myelitis, strokes and movement disorders (including chorea and other extrapyramidal disorders), ataxia and brainstem abnormalities, cranial and peripheral neuropathies, and psychiatric and cognitive disturbances. Risk of stroke is particularly associated with the lupus anticoagulant and the primary antiphospholipid syndrome. (2) Other conditions—(a) rheumatoid arthritis: mononeuritis, cervical cord compression; (b) Sjögren’s syndrome: sensory neuropathy, myositis, various central nervous system complications; (c) Reiter’s disease: polyneuritis, radiculitis, various central nervous system manifestations....

Case History—A 65 yr old man presenting with poor memory a few months after a surgical admission. Case History—An 80 yr old man presenting with falls, reduced mobility, muscular weakness and peripheral neuropathy. Case History—A 34 yr old woman presenting with twitching of the face and jerking of the legs and arms...

It has been postulated that bone marrow-derived mesenchymal stem cells (MSCs) might be effective treatments for neurodegenerative disorders either by replacement of lost cells by differentiation into functional neural tissue; modulation of the immune system to prevent further neurodegeneration; and/or provision of trophic support for the diseased nervous system. Here we have performed a series of experiments showing that human bone marrow-derived MSCs are able to protect cultured rodent cerebellar neurons, and specifically cells expressing Purkinje cell markers, against either nitric oxide exposure or withdrawal of trophic support via cell-cell contact and/or secretion of soluble factors, or through secretion of soluble factors alone. We have demonstrated that MSCs protect cerebellar neurons against toxic insults via modulation of both the phosphatidylinositol 3-kinase/Akt and MAPK pathways and defined superoxide dismutase 3 as a secreted active antioxidant biomolecule by which MSCs modulate, at least in part, their neuroprotective effect on cerebellar cells in vitro. Together, the results demonstrate new and specific mechanisms by which MSCs promote cerebellar neuronal survival and add further evidence to the concept that MSCs may be potential therapeutic agents for neurological disorders involving the cerebellum.

A variety of therapeutic approaches aimed towards promoting myelin repair in multiple sclerosis and in other demyelinating diseases are now on the brink of clinical implementation. In this article, the extensive experimental studies of the past 2 decades, and in particular the considerable progress made over the last 12 months, will be briefly reviewed. A number of hurdles remain, together with practical and ethical problems which may be more difficult to solve; nevertheless, increasing excitement is apparent in this novel therapeutic field, and the rapid progress emerging from these laboratory based studies justifies a cautious optimism towards the successful translation of remyelination strategies from experimental neurobiology to clinical neurology.

The repair of demyelinated axons in patients with multiple sclerosis using growth factors and/or transplantation of glial cells to augment endogenous remyelination has become a more realistic prospect now that treatments are becoming available which may limit inflammatory processes within the CNS. However, until recently, little progress had been made in extrapolating the considerable experimental data now available concerning the rat glial progenitor- a cell which can be expanded in vitro, and which is then capable of successful remyelination upon transplantation into lesioned areas in the rodent CNS - to human oligodendrocyte biology. We have identified cells in cultures of adult human temporal lobe which are morphologically identical to rat oligodendrocyte progenitors and have an A2B5-+ve immunophenotype; they are negative for galactocerebroside (a marker for oligodendrocytes) and glial fibrillary acidic protein (an astrocyte marker), and also for nestin and vimentin. Like their rodent counterparts, human glial precursors are bipotential in vitro. They exhibit a similar astrocyte-driven proliferative response but, in common with oligodendrocyte progenitors in cultures derived from human embryonic spinal cord, do not divide when exposed to soluble growth factor signals known to be mitogenic for rat progenitors. The identification of a proliferative adult human oligodendrocyte progenitor, present also in tissue print preparations of fresh temporal lobe white matter, is the first step towards developing interventional strategies for promoting repair of demyelinated lesions in patients with multiple sclerosis.

A clever achievement, which despite being flawed, has had unintended beneficial consequences

Adult stem cell populations, notably those which reside in the bone marrow, have been shown to contribute to several neuronal cell types in the rodent and human brain. The observation that circulating bone marrow cells can migrate into the central nervous system and fuse with, in particular, cerebellar Purkinje cells has suggested, at least in part, a potential mechanism behind this process. Experimentally, the incidence of cell fusion in the brain is enhanced with age, radiation exposure, inflammation, chemotherapeutic drugs and even selective damage to the neurons themselves. The presence of cell fusion, shown by detection of increased bi-nucleated neurons, has also been described in a variety of human central nervous system diseases, including both multiple sclerosis and Alzheimer's disease. Accumulating evidence is therefore raising new questions into the biological significance of cell fusion, with the possibility that it represents an important means of cell-mediated neuroprotection or rescue of highly complex neurons that cannot be replaced in adult life. Here, we discuss the evidence behind this phenomenon in the rodent and human brain, with a focus on the subsequent research investigating the physiological mechanisms of cell fusion underlying this process. We also highlight how these studies offer new insights into endogenous neuronal repair, opening new exciting avenues for potential therapeutic interventions against neurodegeneration and brain injury.

Cell-based therapies, including autologous haematopoietic stem cell transplantation, have generated substantial interest as strategies for immune modulation, neuroprotection, or repair of the damaged CNS in multiple sclerosis. Scolding et al. summarise the status of cell-based therapies and make consensus recommendations for future studies and clinical trials., The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials.

Cerebellar ataxia commonly occurs in multiple sclerosis, particularly in chronic progressive disease. Previous reports have highlighted both white matter and grey matter pathological changes within the cerebellum; and demyelination and inflammatory cell infiltrates appear commonly. As Purkinje cell axons are the sole output of the cerebellar cortex, understanding pathologic processes within these cells is crucial to develop strategies to prevent their loss and thus reduce ataxia. We studied pathologic changes occurring within Purkinje cells of the cerebellum. Using immunohistochemic techniques, we found changes in neurofilament phosphorylation states within Purkinje cells, including loss of dephosphorylated neurofilament and increased phosphorylated and hyperphosphorylated neurofilament. We also found Purkinje axonal spheroids and Purkinje cell loss, both of which occurred predominantly within areas of leucocortical demyelination within the cerebellar cortex. These changes have important implications for the study of cerebellar involvement in multiple sclerosis and may help design therapies to reduce the burden of ataxia in the condition.