Epstein-Barr virus associated CNS lymphoproliferative disorder after long-term immunosuppression.

The incidence of Epstein-Barr virus (EBV)associated lymphoproliferative disorders has increased with greater use of immunomodulatory therapies. We present a woman who developed subacute cognitive decline and unilateral weakness while taking long-term mycophenolate mofetil for granulomatosis with polyangiitis; her postmortem brain histopathology confirmed an EBV-driven lymphoproliferative disorder. Clinicians must have a high index of suspicion for EBV-driven lymphoma in people taking long-term immunosuppression who develop new neurological problems. We review the role of mycophenolate mofetil in EBV-driven lymphoproliferative disorders, and discuss checking EBV status in all patients starting immunosuppression and in older people already taking immunosuppression.

Long QT syndrome masquerading as epilepsy.

The diagnosis of epilepsy is incorrect in up to 20% of cases so should be revisited if attacks are not responding to treatment. We present a case of long QT syndrome that remained undiagnosed in the epilepsy clinic for 15 years until a near-fatal arrhythmia revealed the diagnosis and allowed effective treatment of her attacks. We hope this near miss raises awareness of long QT syndrome as a potentially fatal, rare but treatable condition that neurologists must consider in people with a label of refractory epilepsy. We provide practical pointers to increase the chance of early diagnosis and explore the impact of a late diagnosis for the patient and her family.

Brivaracetam in adults with drug-resistant epilepsy and psychiatric comorbidities.

This is a case series of 25 patients with drug-resistant epilepsy and psychiatric comorbidities who started on brivaracetam (BRV) at St George's University Hospitals and Frimley Health in London. Median BRV dose was 150 mg for a median follow-up period of 8 months. Twenty had focal epilepsy, four had generalized epilepsies, and one had unclassified epilepsy; 76% had mood disorders (either depression or bipolar disorder), 12% intellectual disabilities with autism spectrum disorder and challenging behavior, and 12% psychoses. Forty percent of patients presented at least 50% seizure reduction, but none of them became seizure-free. A total of 44% of patients discontinued BRV, 20% because of adverse events, 20% because of inefficacy, and 4% because of both. Depression was reported by 8%, aggressive behavior by 8%, while 4% reported both. A total of 91.6% had received levetiracetam (LEV) before, in whom LEV was discontinued because of psychiatric adverse events (PAEs) in half. Seventy-seven percent of patients who developed PAEs with LEV did not do so on BRV suggesting that BRV is better tolerated than LEV in complex patients with psychiatric comorbidities and that the synaptic vesicle glycoprotein 2A (SV2A) protein modulation is unlikely to be implicated in LEV-related PAEs.

Acute neurology simulation training.

Acute neurology is the neurological care that a patient receives in an emergency or urgent care situation. This can be adapted successfully to training in a simulation where learners are immersed in realistic scenarios in a safe, controlled and reproducible environment. In addition to teaching important technical skills that improve knowledge of the diagnosis and management of acute neurology, the simulation laboratory provides a valuable setting to improve human factors and non-technical skills, such as teamwork and leadership. Simulations are best conducted in a multiprofessional group with scenarios that allow different team members (nurses, physician associates, core medical and specialist trainees) to participate in their actual role. These training sessions require clear learning objectives, and involve designing the scenarios, running the session and ending with a structured debriefing to consolidate learning. The ultimate aim is to improve the team's effectiveness to deliver safe acute neurological care in the emergency department and on the wards.

Erratum: Author Correction: Using a smartphone-based self-management platform to support medication adherence and clinical consultation in Parkinson's disease.

[This corrects the article DOI: 10.1038/s41531-016-0003-z.].

Using a smartphone-based self-management platform to support medication adherence and clinical consultation in Parkinson's disease.

The progressive nature of Parkinson's disease, its complex treatment regimens and the high rates of comorbid conditions make self-management and treatment adherence a challenge. Clinicians have limited face-to-face consultation time with Parkinson's disease patients, making it difficult to comprehensively address non-adherence. Here we share the results from a multi-centre (seven centres) randomised controlled trial conducted in England and Scotland to assess the impact of using a smartphone-based Parkinson's tracker app to promote patient self-management, enhance treatment adherence and quality of clinical consultation. Eligible Parkinson's disease patients were randomised using a 1:1 ratio according to a computer-generated random sequence, stratified by centre and using blocks of variable size, to intervention Parkinson's Tracker App or control (Treatment as Usual). Primary outcome was the self-reported score of adherence to treatment (Morisky medication adherence scale -8) at 16 weeks. Secondary outcomes were Quality of Life (Parkinson's disease questionnaire -39), quality of consultation for Parkinson's disease patients (Patient-centred questionnaire for Parkinson's disease), impact on non-motor symptoms (Non-motor symptoms questionnaire), depression and anxiety (Hospital anxiety and depression scale) and beliefs about medication (Beliefs about Medication Questionnaire) at 16 weeks. Primary and secondary endpoints were analysed using a generalised linear model with treatment as the fixed effect and baseline measurement as the covariate. 158 patients completed the study (Parkinson's tracker app = 68 and TAU = 90). At 16 weeks Parkinson's tracker app significantly improved adherence, compared to treatment as usual (mean difference: 0.39, 95%CI 0.04-0.74; p = 0.0304) with no confounding effects of gender, number of comorbidities and age. Among secondary outcomes, Parkinson's tracker app significantly improved patients' perception of quality of consultation (0.15, 95% CI 0.03 to 0.27; p = 0.0110). The change in non-motor symptoms was -0.82 (95% CI -1.75 to 0.10; p = 0.0822). 72% of participants in the Parkinson's tracker app group continued to use and engage with the application throughout the 16-week trial period. The Parkinson's tracker app can be an effective and novel way of enhancing self-reported medication adherence and quality of clinical consultation by supporting self-management in Parkinson's disease in patients owning smartphones. Further work is recommended to determine whether the benefits of the intervention are maintained beyond the 16 week study period.

Leprosy in a patient infected with HIV.

A 60-year-old Nigerian man, who had lived in Europe for 30 years but had returned home frequently, presented with right frontalis muscle weakness and right ulnar nerve palsy, without skin lesions. Neurophysiology showed a generalised neuropathy with demyelinating features. Blood tests were positive for HIV, with a normal CD4 count. There was nerve thickening both clinically and on MRI. Nerve biopsy showed chronic endoneuritis and perineuritis (indicating leprosy) without visible mycobacteria. His neuropathy continued to deteriorate (lepra reaction) before starting treatment with WHO multidrug therapy, highly active antiretroviral therapy and corticosteroids. There are 10 new cases of leprosy diagnosed annually in the UK. Coinfection with HIV is rare but paradoxically does not usually adversely affect the outcome of leprosy or change treatment. However, permanent nerve damage in leprosy is common despite optimal therapy. Leprosy should be considered in patients from endemic areas who present with mononeuritis multiplex.

Stress and epilepsy: fact or fiction, and what can we do about it?

People with epilepsy report that stress is their most common trigger for seizures and some believe it caused their epilepsy in the first place. The extensive preclinical, epidemiological and clinical studies examining the link between stress and epilepsy have given confusing results; the clinical studies in particular are fraught with confounders. However stress is clearly bad for health, and we now have substantial preclinical evidence suggesting that chronic stress worsens epilepsy; in selected cases it may even be a causal factor for epilepsy. Healthcare professionals working with people with epilepsy should pay more attention to stress in clinical practice. This review includes some practical advice and guidance for stress screening and management.

Microvascular Non-Arteritic Ocular Motor Nerve Palsies-What We Know and How Should We Treat?

Patients with isolated unilateral pupil-sparing third or isolated fourth or sixth nerve palsies over 50 years are often diagnosed with "microvascular extraocular palsies". This condition and its management provoke divergent opinions. We review the literature and describe the incidence, pathology, clinical presentation, yield of imaging, and management. A retrospective diagnosis of exclusion has little practical use. We suggest a pragmatic approach to diagnosis, investigation, and management from initial presentation.

Human post-mortem synapse proteome integrity screening for proteomic studies of postsynaptic complexes.

BACKGROUND: Synapses are fundamental components of brain circuits and are disrupted in over 100 neurological and psychiatric diseases. The synapse proteome is physically organized into multiprotein complexes and polygenic mutations converge on postsynaptic complexes in schizophrenia, autism and intellectual disability. Directly characterising human synapses and their multiprotein complexes from post-mortem tissue is essential to understanding disease mechanisms. However, multiprotein complexes have not been directly isolated from human synapses and the feasibility of their isolation from post-mortem tissue is unknown. RESULTS: Here we establish a screening assay and criteria to identify post-mortem brain samples containing well-preserved synapse proteomes, revealing that neocortex samples are best preserved. We also develop a rapid method for the isolation of synapse proteomes from human brain, allowing large numbers of post-mortem samples to be processed in a short time frame. We perform the first purification and proteomic mass spectrometry analysis of MAGUK Associated Signalling Complexes (MASC) from neurosurgical and post-mortem tissue and find genetic evidence for their involvement in over seventy human brain diseases. CONCLUSIONS: We have demonstrated that synaptic proteome integrity can be rapidly assessed from human post-mortem brain samples prior to its analysis with sophisticated proteomic methods. We have also shown that proteomics of synapse multiprotein complexes from well preserved post-mortem tissue is possible, obtaining structures highly similar to those isolated from biopsy tissue. Finally we have shown that MASC from human synapses are involved with over seventy brain disorders. These findings should have wide application in understanding the synaptic basis of psychiatric and other mental disorders.

Smartphone- and internet-assisted self-management and adherence tools to manage Parkinson's disease (SMART-PD): study protocol for a randomised controlled trial (v7; 15 August 2014).

BACKGROUND: Nonadherence to treatment leads to suboptimal treatment outcomes and enormous costs to the economy. This is especially important in Parkinson's disease (PD). The progressive nature of the degenerative process, the complex treatment regimens and the high rates of comorbid conditions make treatment adherence in PD a challenge. Clinicians have limited face-to-face consultation time with PD patients, making it difficult to comprehensively address non-adherence. The rapid growth of digital technologies provides an opportunity to improve adherence and the quality of decision-making during consultation. The aim of this randomised controlled trial (RCT) is to evaluate the impact of using a smartphone and web applications to promote patient self-management as a tool to increase treatment adherence and working with the data collected to enhance the quality of clinical consultation. METHODS/DESIGN: A 4-month multicentre RCT with 222 patients will be conducted to compare use of a smartphone- and internet-enabled Parkinson's tracker smartphone app with treatment as usual for patients with PD and/or their carers. The study investigators will compare the two groups immediately after intervention. Seven centres across England (6) and Scotland (1) will be involved. The primary objective of this trial is to assess whether patients with PD who use the app show improved medication adherence compared to those receiving treatment as usual alone. The secondary objectives are to investigate whether patients who receive the app and those who receive treatment as usual differ in terms of quality of life, quality of clinical consultation, overall disease state and activities of daily living. We also aim to investigate the experience of those receiving the intervention by conducting qualitative interviews with a sample of participants and clinicians, which will be administered by independent researchers. TRIAL REGISTRATION: ISRCTN45824264 (registered 5 November 2013).

Localization of bilateral auditory hallucinations and correlation to imaging in posterior circulation stroke.

Hearing disturbances are not commonly reported in stroke or transient ischemic attack. We describe a case of a 60-year-old man with fluctuating brainstem ischemia with basilar artery thrombosis where the patient has consistently described hearing "white noise," bilaterally becoming progressively louder over 10 minutes that prevented him from hearing surrounding noise including the radio. These episodes were transient and preceded episodes of hemiparesis or reduced conscious level. We correlate this to the sequential imaging findings from the patient. We discuss how this case provides in vivo evidence for localization of auditory hallucinations in the context of the auditory pathways and their blood supply, and review 25 previous cases of auditory hallucinations and possible mechanisms.

Latent cluster analysis of ALS phenotypes identifies prognostically differing groups.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a degenerative disease predominantly affecting motor neurons and manifesting as several different phenotypes. Whether these phenotypes correspond to different underlying disease processes is unknown. We used latent cluster analysis to identify groupings of clinical variables in an objective and unbiased way to improve phenotyping for clinical and research purposes. METHODS: Latent class cluster analysis was applied to a large database consisting of 1467 records of people with ALS, using discrete variables which can be readily determined at the first clinic appointment. The model was tested for clinical relevance by survival analysis of the phenotypic groupings using the Kaplan-Meier method. RESULTS: The best model generated five distinct phenotypic classes that strongly predicted survival (p<0.0001). Eight variables were used for the latent class analysis, but a good estimate of the classification could be obtained using just two variables: site of first symptoms (bulbar or limb) and time from symptom onset to diagnosis (p<0.00001). CONCLUSION: The five phenotypic classes identified using latent cluster analysis can predict prognosis. They could be used to stratify patients recruited into clinical trials and generating more homogeneous disease groups for genetic, proteomic and risk factor research.

New onset diabetes complicated by haemolysis and rhabdomyolysis: a case report and review of the literature.

INTRODUCTION: Previously undiagnosed glucose-6-phosphate dehydrogenase (G6PD) deficiency can be unmasked by a diabetic crisis and both can be associated with rhabdomyolysis. The relationship between diabetes and G6PD deficiency is discussed and the possible triggers for haemolysis as outlined in this case report. The incidence of G6PD deficiency is 10% in African-American males and up to 35% in parts of Africa so an increased awareness of G6PD deficiency is important when treating diabetes in these populations. CASE PRESENTATION: A 54-year-old Kenyan man presented with a 3-day history of reduced appetite, weakness and reduced level of consciousness as a result of a hyperglycaemic diabetic crisis with both hyperosmolarity and ketoacidosis. The patient then developed haemolysis and a raised creatine kinase level. A diagnosis of G6PD deficiency and rhabdomyolysis was made. CONCLUSION: This case highlights the importance of simple laboratory investigations in the early identification of the rarer complications of diabetic crisis such as haemolysis secondary to G6PD deficiency and rhabdomyolysis.

Distribution and synthesis of extracellular matrix proteoglycans, hyaluronan, link proteins and tenascin-R in the rat spinal cord.

Perineuronal nets (PNNs) are dense extracellular matrix (ECM) structures that form around many neuronal cell bodies and dendrites late in development. They contain several chondroitin sulphate proteoglycans (CSPGs), hyaluronan, link proteins and tenascin-R. Their time of appearance correlates with the ending of the critical period for plasticity, and they have been implicated in this process. The distribution of PNNs in the spinal cord was examined using Wisteria floribunda agglutinin lectin and staining for chondroitin sulphate stubs after chondroitinase digestion. Double labelling with the neuronal marker, NeuN, showed that PNNs were present surrounding approximately 30% of motoneurons in the ventral horn, 50% of large interneurons in the intermediate grey and 20% of neurons in the dorsal horn. These PNNs formed in the second week of postnatal development. Immunohistochemical staining demonstrated that the PNNs contain a mixture of CSPGs, hyaluronan, link proteins and tenascin-R. Of the CSPGs, aggrecan was present in all PNNs while neurocan, versican and phosphacan/RPTPbeta were present in some but not all PNNs. In situ hybridization showed that aggrecan and cartilage link protein (CRTL 1) and brain link protein-2 (BRAL 2) are produced by neurons. PNN-bearing neurons express hyaluronan synthase, and this enzyme and phosphacan/RPTPbeta may attach PNNs to the cell surface. During postnatal development the expression of link protein and aggrecan mRNA is up-regulated at the time of PNN formation, and these molecules may therefore trigger their formation.

Characterization of tests of functional recovery after median and ulnar nerve injury and repair in the rat forelimb.

The majority of human peripheral nerve injuries occur in the upper limb but the majority of studies in the rat are performed in the hindlimb. The upper and lower limbs differ in dexterity and control by supraspinal systems, so an upper limb model is a better representation of the common form of human injury. The purpose of this study was to further develop a rat model involving lesions of the median and ulnar nerves. To produce different degrees of misdirection of axons following nerve repair, we studied nerve crush, cut and repair of the two nerves, and cut and repair with crossover. Assessment of functional recovery was performed using a battery of motor and sensory tests: the staircase test, which assesses skilled forepaw reaching; grip strength meter, which assesses grip strength; pawprint analysis, which assesses toe spread and print length; horizontal ladder, which assesses forepaw placement during skilled locomotion; modified Randall-Selitto device and electronic von Frey probes, which assess fine touch; and cold probes, which assess temperature sensation. All tests revealed deficits in forepaw function after nerve injury except the print length and modified Randall-Selitto device. The time course of functional recovery was observed over 15 weeks. The final degree of functional recovery achieved was related to the misdirection of axon regeneration. The tests that most clearly revealed the effects of axon misdirection on function were the skilled paw reaching and grip strength tests. The lesion model and functional tests that we have developed will be useful in testing therapeutic strategies for treating the consequences of inaccurate axon regeneration following peripheral nerve injury in humans.

The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system.

Chondroitin sulfate proteoglycans (CSPGs) consist of a core protein and glycosaminoglycan (GAG) chains. There is enormous structural diversity among CSPGs due to variation in the core protein, the number of GAG chains and the extent and position of sulfation. Most CSPGs are secreted from cells and participate in the formation of the extracellular matrix (ECM). CSPGs are able to interact with various growth-active molecules and this may be important in their mechanism of action. In the normal central nervous system (CNS), CSPGs have a role in development and plasticity during postnatal development and in the adult. Plasticity is greatest in the young, especially during critical periods. CSPGs are crucial components of perineuronal nets (PNNs). PNNs have a role in closure of the critical period and digestion of PNNs allows their re-opening. In the adult, CSPGs play a part in learning and memory and the hypothalamo-neurohypophysial system. CSPGs have an important role in CNS injuries and diseases. After CNS injury, CSPGs are the major inhibitory component of the glial scar. Removal of CSPGs improves axonal regeneration and functional recovery. CSPGs may also be involved in the pathological processes in diseases such as epilepsy, stroke and Alzheimer's disease. Several possible methods of manipulating CSPGs in the CNS have recently been identified. The development of methods to remove CSPGs has considerable therapeutic potential in a number of CNS disorders.

Promoting plasticity in the spinal cord with chondroitinase improves functional recovery after peripheral nerve repair.

Functional recovery after peripheral nerve repair in humans is often disappointing. A major reason for this is the inaccuracy of re-innervation of muscles and sensory structures. We hypothesized that promoting plasticity in the spinal cord, through digestion of chondroitin sulphate proteoglycans (CSPGs) with chondroitinase ABC (ChABC), might allow the CNS to compensate for inaccurate peripheral re-innervation and improve functional recovery. The median and ulnar nerves were injured and repaired to produce three grades of inaccuracy of peripheral re-innervation by (i) crush of both nerves; (ii) correct repair of median to median and ulnar to ulnar; and (iii) crossover of the median and ulnar nerves. Mapping of the motor neuron pool of the flexor carpi radialis muscle showed precise re-innervation after nerve crush, inaccurate regeneration after correct repair, more inaccurate after crossover repair. Recovery of forelimb function, assessed by skilled paw reaching, grip strength and sensory testing varied with accuracy of re-innervation. This was not due to differences in the number of regenerated axons. Single injections of ChABC into the spinal cord led to long-term changes in the extracellular matrix, with hyaluronan and neurocan being removed and not fully replaced after 8 weeks. ChABC treatment produce increased sprouting visualized by MAP1BP staining and improved functional recovery in skilled paw reaching after correct repair and in grip strength after crossover repair. There was no hyperalgesia. Enhanced plasticity in the spinal cord, therefore, allows the CNS to compensate for inaccurate motor and sensory re-innervation of the periphery, and may be a useful adjunct therapy to peripheral nerve repair.