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  • The importance of early immunotherapy in patients with faciobrachial dystonic seizures.

    12 February 2018

    Faciobrachial dystonic seizures and limbic encephalitis closely associate with antibodies to leucine-rich glioma-inactivated 1 (LGI1). Here, we describe 103 consecutive patients with faciobrachial dystonic seizures and LGI1 antibodies to understand clinical, therapeutic and serological differences between those with and without cognitive impairment, and to determine whether cessation of faciobrachial dystonic seizures can prevent cognitive impairment. The 22/103 patients without cognitive impairment typically had normal brain MRI, EEGs and serum sodium levels (P < 0.0001). Overall, cessation of faciobrachial dystonic seizures with antiepileptic drugs alone occurred in only 9/89 (10%) patients. By contrast, 51% showed cessation of faciobrachial dystonic seizures 30 days after addition of immunotherapy (P < 0.0001), with earlier cessation in cognitively normal patients (P = 0.038). Indeed, expedited immunotherapy (P = 0.031) and normal cognition (P = 0.0014) also predicted reduced disability at 24 months. Furthermore, of 80 patients with faciobrachial dystonic seizures as their initial feature, 56% developed cognitive impairment after 90 days of active faciobrachial dystonic seizures. Whereas only one patient developed cognitive impairment after cessation of faciobrachial dystonic seizures (P < 0.0001). All patients had IgG4-LGI1 antibodies, but those with cognitive impairment had higher proportions of complement-fixing IgG1 antibodies (P = 0.03). Both subclasses caused LGI1-ADAM22 complex internalization, a potential non-inflammatory epileptogenic mechanism. In summary, faciobrachial dystonic seizures show striking time-sensitive responses to immunotherapy, and their cessation can prevent the development of cognitive impairment.awx323media15681705685001.

  • Movement disorders with neuronal antibodies: syndromic approach, genetic parallels and pathophysiology.

    9 February 2018

    Movement disorders are a prominent and common feature in many autoantibody-associated neurological diseases, a group of potentially treatable conditions that can mimic infectious, metabolic or neurodegenerative disease. Certain movement disorders are likely to associate with certain autoantibodies; for example, the characteristic dyskinesias, chorea and dystonia associated with NMDAR antibodies, stiff person spectrum disorders with GAD, glycine receptor, amphiphysin or DPPX antibodies, specific paroxysmal dystonias with LGI1 antibodies, and cerebellar ataxia with various anti-neuronal antibodies. There are also less-recognized movement disorder presentations of antibody-related disease, and a considerable overlap between the clinical phenotypes and the associated antibody spectra. In this review, we first describe the antibodies associated with each syndrome, highlight distinctive clinical or radiological 'red flags', and suggest a syndromic approach based on the predominant movement disorder presentation, age, and associated features. We then examine the underlying immunopathophysiology, which may guide treatment decisions in these neuroimmunological disorders, and highlight the exceptional interface between neuronal antibodies and neurodegeneration, such as the tauopathy associated with IgLON5 antibodies. Moreover, we elaborate the emerging pathophysiological parallels between genetic movement disorders and immunological conditions, with proteins being either affected by mutations or targeted by autoantibodies. Hereditary hyperekplexia, for example, is caused by mutations of the alpha subunit of the glycine receptor leading to an infantile-onset disorder with exaggerated startle and stiffness, whereas antibodies targeting glycine receptors can induce acquired hyperekplexia. The spectrum of such immunological and genetic analogies also includes cerebellar ataxias and some encephalopathies. Lastly, we discuss how these pathophysiological considerations could reflect on possible future directions regarding antigen-specific immunotherapies or targeting the pathophysiological cascades downstream of the antibody effects.

  • Pharmacological advances for treatment in Duchenne muscular dystrophy.

    31 January 2018

    Duchenne muscular dystrophy (DMD) is a lethal, X-linked muscle-wasting disease caused by lack of dystrophin, essential for muscle fibre integrity. Despite extensive pre-clinical studies, development of an effective treatment has proved challenging. More recently, significant progress has been made with the first drug approval using a genetic approach and the application of pharmacological agents which slow the progression of the disease. Drug development for DMD has mainly used two strategies: (1) the restoration of dystrophin expression or the expression of the compensatory utrophin protein as an efficient surrogate, and (2) the mitigation of secondary downstream pathological mechanisms. This review details current most promising pharmacological approaches and clinical trials aiming to tackle the pathogenesis of this multifaceted disorder.

  • The genetics of circadian rhythms, sleep and health.

    21 December 2017

    Circadian rhythms are 24-h rhythms in physiology and behaviour generated by molecular clocks, which serve to coordinate internal time with the external world. The circadian system is a master regulator of nearly all physiology and its disruption has major consequences on health. Sleep and circadian rhythm disruption (SCRD) is a ubiquitous feature in today's 24/7 society, and studies on shift-workers have shown that SCRD can lead not only to cognitive impairment, but also metabolic syndrome and psychiatric illness including depression (1,2). Mouse models of clock mutants recapitulate these deficits, implicating mechanistic and causal links between SCRD and disease pathophysiology (3-5). Importantly, treating clock disruption reverses and attenuates these adverse health states in animal models (6,7), thus establishing the circadian system as a novel therapeutic target. Significantly, circadian and clock-controlled gene mutations have recently been identified by Genome-Wide Association Studies (GWAS) in the aetiology of sleep, mental health and metabolic disorders. This review will focus upon the genetics of circadian rhythms in sleep and health.

  • Circadian photoreception: From phototransduction to behaviour

    12 December 2017

    © Springer Science+Business Media New York 2014. All rights are reserved. Environmental light is detected by three classes of ocular photoreceptor, the rods and cones of the outer retina and photosensitive retinal ganglion cells (pRGCs) that utilise the photopigment melanopsin. In addition to their endogenous photosensitivity, pRGCs receive indirect inputs from the rods and cones. The primary role of the rods and cones is to collect light information for the construction of a visual image, whilst the pRGCs send direct projections to many regions of the brain to regulate nonimage-forming responses to light, including the entrainment of circadian rhythms. The master circadian pacemaker of mammals resides within the suprachiasmatic nuclei (SCN), and light information is transmitted from the pRGCs via their axonal projections which form the retinohypothalamic tract. Neurones within the SCN respond to retinal illumination with changes in electrical activity showing characteristic fast-transient components at the light transitions and a sustained response throughout light exposure. Until recently it was assumed that the fast-transient responses were driven by the rods and/or cones, via their inputs to the pRGCs, whilst the sustained responses to light were mediated by melanopsin. However, more recent studies show that both transient and sustained responses can be generated in the absence of melanopsin, suggesting a significant level of functional redundancy between photoreceptor classes. Although SCN electrical activity appears normal in melanopsin-deficient mice, these animals show attenuated lightinduced phase-shifting response in behavioural activity. Collectively these findings raise intriguing questions about how different classes of retinal photoreceptor interact to encode nonimage-forming responses to light and suggest that recordings of multiunit activity at the level of the SCN do not entirely mirror the effects of light on circadian behaviour.

  • The Emerging Neurobiology of Bipolar Disorder.

    2 February 2018

    Bipolar disorder (BD) is a leading cause of global disability. Its biological basis is unknown, and its treatment unsatisfactory. Here, we review two recent areas of progress. First, the discovery of risk genes and their implications, with a focus on voltage-gated calcium channels as part of the disease process and as a drug target. Second, facilitated by new technologies, it is increasingly apparent that the bipolar phenotype is more complex and nuanced than simply one of recurring manic and depressive episodes. One such feature is persistent mood instability, and efforts are underway to understand its mechanisms and its therapeutic potential. BD illustrates how psychiatry is being transformed by contemporary neuroscience, genomics, and digital approaches.