Bremner F.D.,National Hospital for Neurology and Neurosurgery
Investigative Ophthalmology and Visual Science | Year: 2012
Purpose. To investigate the correlation between measurements of amplitude (A) and peak velocity (V) of constriction in the pupil light reflex of normal subjects, and to determine the effects of stimulus intensity, pupil size, and age on this relationship. Methods. The pupil response to a variable intensity 1.0 second light stimulus presented under open-loop conditions (Maxwellian optics) was measured using infrared video techniques in 43 healthy subjects aged 20 to 75 years old. Results. In response to the "standard-intensity" light stimulus, mean measurements of A and V were 1.92 mm (SD 0.39) and 5.65 mm/s (SD 1.17), respectively. Over a 4.0 log unit range of stimulus intensities measurements of A and V were seen to co-vary with the data being best fit by the equation V=0.86+2.65A (linear regression coefficient, R = 0.919, P < 0.001). In each subject the regression plot was used to normalize the velocity estimates for A = 1.0 mm; these normalized velocity estimates showed no significant correlation with the starting size of the pupil or the age of the subject. Conclusions. There is a strong linear correlation between amplitude and peak velocity of constriction for the pupil light reflex in normal subjects. This relationship is unaffected by the stimulus intensity, size of the pupil, or age of the subject. Clinicians and researchers must keep this interdependence in mind when drawing inferences from the observed (or measured) speed of the pupillary constriction to light. © 2012 The Association for Research in Vision and Ophthalmology, Inc.
Stevenson V.L.,National Hospital for Neurology and Neurosurgery
Clinical Rehabilitation | Year: 2010
This series of articles for rehabilitation in practice aims to cover a knowledge element of the rehabilitation medicine curriculum. Nevertheless they are intended to be of interest to a multidisciplinary audience. The competency addressed in this article is ĝ€The trainee consistently demonstrates a knowledge of the pathophysiology of various specific impairments including spasticityĝ€™. Spasticity is an extremely common feature of chronic neurological conditions and, if badly managed, it can result in pain, contractures and pressure sores, all of which can impact on function. It is therefore essential that a multidisciplinary management strategy is in place to help the individual manage their particular situation through education with timely access to interventions including instigation of a physical management programme and medication such as baclofen, tizanidine, dantrolene, benzodiazepines and gabapentin. Further treatment options for focal spasticity are botulinum toxin and phenol nerve blocks or intrathecal baclofen or phenol for predominant lower limb spasticity. Ongoing assessment with the use of appropriate outcome measures can both guide choice of treatment and monitor efficacy. © 2010 The Author(s).
Rugg-Gunn F.,National Hospital for Neurology and Neurosurgery
Epilepsia | Year: 2014
Quality of life is directly related to the number and severity of adverse effects, and a successful antiepileptic medication must demonstrate a good balance between efficacy and tolerability. Perampanel is a newly licensed antiepileptic medication for the adjunctive treatment of patients (age 12 and older) with partial epilepsy with or without secondary generalization. Safety endpoints in the three phase III trials (304, 305, and 306) included treatment-emergent adverse events (TEAEs), vital signs, clinical laboratory parameters, and electrocardiography studies (ECGs). The most common adverse drug reactions in patients receiving perampanel were dizziness, somnolence, fatigue, irritability, nausea, and falls. Of particular concern to patients are cognitive and psychiatric side effects. Overall, depression and aggression were reported more frequently in patients taking perampanel, particularly at higher doses, than in patients taking placebo. TEAEs necessitated the withdrawal of perampanel in 99 patients (9.5%) and placebo in 21 patients (4.8%). Typically this was due to dizziness, convulsion, and somnolence. There were no clinically important changes or treatment group differences in vital signs, ECG measures, or biochemical or hematologic parameters. Weight increase of greater than 7% was seen in 14.6% of perampanel-treated patients versus 7.1% of placebo-treated patients. Overall, perampanel appears to be associated with a relatively low incidence of serious adverse effects, particularly at low doses, and the majority of TEAEs were mild or moderate in intensity. The incidence of predictable side effects, such as somnolence and dizziness, is seen more frequently at higher doses. Of importance is the greater rate of psychiatric side effects in patients treated with perampanel, principally, irritability and aggression, than with placebo. However, the rate of serious psychiatric TEAEs was low. © 2014 International League Against Epilepsy.
Lunn M.P.,National Hospital for Neurology and Neurosurgery
Cochrane database of systematic reviews (Online) | Year: 2012
Serum monoclonal anti-myelin-associated glycoprotein antibodies may be pathogenic in some people with immunoglobulin M (IgM) paraprotein and demyelinating neuropathy. Immunotherapies aimed at reducing the level of these antibodies might be expected to be beneficial. This is an update of a review first published in 2003 and previously updated in 2006. To assess the effects of immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated demyelinating peripheral neuropathy. We searched the Cochrane Neuromuscular Disease Group Specialized Register 6 June 2011), CENTRAL (2011, Issue 2), MEDLINE (January 1966 to May 2011) and EMBASE (January 1980 to May 2011) for controlled trials. We also checked bibliographies and contacted authors and experts in the field. We included randomised or quasi-randomised controlled trials involving participants of any age treated with any type of immunotherapy for anti-myelin-associated glycoprotein antibody-associated demyelinating peripheral neuropathy with monoclonal gammopathy of undetermined significance and of any severity.Our primary outcome measure was change in the Neuropathy Impairment Scale or Modified Rankin Scale at six months after randomisation. Secondary outcome measures were: Neuropathy Impairment Scale or the Modified Rankin Score at 12 months after randomisation; 10-metre walk time, subjective clinical scores and electrophysiological parameters at six and 12 months after randomisation; IgM paraprotein levels and anti-myelin-associated glycoprotein antibody titres at six months after randomisation; and adverse effects of treatments. The two authors independently selected studies. Two authors independently assessed the risk of bias in included studies. We identified seven eligible trials (182 participants), which tested intravenous immunoglobulin, alfa interferon alfa-2a, plasma exchange, cyclophosphamide and steroids, and rituximab. Only two trials, of intravenous immunoglobulin (with 33 participants, including 20 with antibodies against myelin-associated glycoprotein), had comparable interventions and outcomes, but both were short-term trials.There were no clinical or statistically significant benefits of the treatments used on the outcomes predefined for this review, but not all the predefined outcomes were used in every included trial. Intravenous immunoglobulin showed a statistical benefit in terms of improvement in Modified Rankin Scale at two weeks and 10-metre walk time at four weeks. Cyclophosphamide failed to show any benefit in the trial's primary outcome, and showed a barely significant benefit in the primary outcome specified here, but some toxic adverse events were identified. A trial of rituximab was of poor methodological quality with a high risk of bias and a further larger study is awaited. Serious adverse events were few in the other trials. There is inadequate reliable evidence from trials of immunotherapies in anti-myelin-associated glycoprotein paraproteinaemic neuropathy to form an evidence base supporting any particular immunotherapy treatment. There is very low quality evidence of benefit from rituximab. Large well designed randomised trials of at least six to 12 months duration are required to assess existing or novel therapies, preferably employing unified, consistent, well designed, responsive and valid outcome measures.
Hughes R.A.,National Hospital for Neurology and Neurosurgery
Cochrane database of systematic reviews (Online) | Year: 2012
Guillain-Barré syndrome (GBS) is an acute paralysing disease caused by inflammation of the peripheral nerves, which corticosteroids would be expected to benefit. To examine the ability of corticosteroids to hasten recovery and reduce the long-term morbidity from GBS. We searched The Cochrane Neuromuscular Disease Group Specialized Register (1 November 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4), CENTRAL (2011, Issue 4), MEDLINE (January 1966 to October 2011) and EMBASE (January 1980 to October 2011). We included randomised controlled trials (RCTs) or quasi-RCTs of any form of corticosteroid or adrenocorticotrophic hormone in GBS. Our primary outcome was change in disability grade on a seven-point scale after four weeks. Secondary outcomes included time from randomisation until recovery of unaided walking, time from randomisation until discontinuation of ventilation (for those ventilated), death, death or disability (inability to walk without aid) after 12 months, relapse, and adverse events. Two authors extracted the data independently. No new trials were discovered in the new searches in June 2009 or November 2011. Six trials with 587 participants provided data for the primary outcome. According to moderate quality evidence, the disability grade change after four weeks in the corticosteroid groups was not significantly different from that in the control groups, mean difference (MD) 0.36 less improvement (95% confidence intervals (CI) 0.16 more to 0.88 less improvement). In four trials of oral corticosteroids with 120 participants in total, there was significantly less improvement after four weeks with corticosteroids than without corticosteroids, MD 0.82 disability grades less improvement (95% CI 0.17 to 1.47). In two trials with a combined total of 467 participants, there was no significant difference, MD 0.17 (95% CI -0.06 to 0.39) of a disability grade more improvement after four weeks with intravenous corticosteroids. According to moderate to high quality evidence, there were no significant differences between the corticosteroid-treated and the control groups in any of the secondary efficacy outcomes. Diabetes was significantly more common and hypertension significantly much less common in the corticosteroid-treated participants. According to moderate quality evidence, corticosteroids given alone do not significantly hasten recovery from GBS or affect the long-term outcome. According to low quality evidence oral corticosteroids delay recovery. Diabetes requiring insulin was significantly more common and hypertension less common with corticosteroids.
Trimble M.,National Hospital for Neurology and Neurosurgery
Epilepsia | Year: 2013
This article supports a view that certain personality disturbances in epilepsy should be viewed as associated with the cerebral abnormalities that also lead to seizures. Herein I discuss two main variants: that related to temporal lobe epilepsy and that associated with juvenile myoclonic epilepsy. In view of its controversial nature, I also comment on the link between aggression and epilepsy. Recommendations for treatment include psychological and social therapies with further advice about the use of antiepileptic drugs (AEDs) and psychotropic medications in these conditions. © Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.
Reddi D.,National Hospital for Neurology and Neurosurgery
Anaesthesia | Year: 2016
Chronic postoperative pain is common. Nerve injury and inflammation promote chronic pain, the risk of which is influenced by patient factors, including psychological characteristics. Interventional trials to prevent chronic postoperative pain have been underpowered with inadequate patient follow-up. Ketamine may reduce chronic postoperative pain, although the optimum treatment duration and dose for different operations have yet to be identified. The evidence for gabapentin and pregabalin is encouraging but weak; further work is needed before these drugs can be recommended for the prevention of chronic pain. Regional techniques reduce the rates of chronic pain after thoracotomy and breast cancer surgery. Nerve-sparing surgical techniques may be of benefit, although nerve injury is not necessary or sufficient for chronic pain to develop. © 2015 The Association of Anaesthetists of Great Britain and Ireland.
Lachmann R.,National Hospital for Neurology and Neurosurgery
Biochemical Society Transactions | Year: 2010
There are over 70 human diseases that are caused by defects in various aspects of lysosomal function. Until 20 years ago, the only specific therapy available for lysosomal storage disorders was allogeneic haemopoietic stem cell transplantation. Over the last two decades, there has been remarkable progress and there are now licensed treatments for seven of these diseases. In some cases, a choice of agents is available. For selected enzyme-deficiency disordes, ERT (enzyme-replacement therapy) has proved to be highly effective. In other cases, ERT has been less impressive, and it seems that it is not possible to efficiently deliver recombinant enzyme to all tissues. These difficulties have led to the development of other small-moleculebased therapies, and a drug for SRT (substrate-reduction therapy) is now licensed and potential chaperone molecules for ERT are in the late stages of clinical development. Nonetheless, there is still significant unmet clinical need, particularly when it comes to treating LSDs which affect the brain. LSDs have led the way in the development of treatment for genetic disorders, and it seems likely that there will be further therapeutic innovations in the future. ©The Authors Journal compilation ©2010 Biochemical Society.
Lachmann R.H.,National Hospital for Neurology and Neurosurgery
Current Opinion in Pediatrics | Year: 2011
PURPOSE OF REVIEW: Enzyme replacement therapy (ERT) for type 1 Gaucher has been highly successful. ERT is now available for other lysosomal storage disorders (LSDs) but none of these highly expensive treatments has had the same efficacy. This review explores why these newer treatments have failed to live up to expectations and how future products might be made more effective. RECENT FINDINGS: In Gaucher, the target cells for ERT are macrophages, which are efficiently accessed by intravenously injected recombinant enzyme. The target tissues in other LSDs receive much lower doses of enzyme and intravenous ERT does not enter the brain at all. Uptake of recombinant enzyme is via the mannose-6-phosphate receptor (M6PR). Recent work has looked at improving the efficiency of enzyme delivery to tissues by altering both the ligand on the infused enzyme and the expression of the M6PR on cells. For delivery to the central nervous system, intrathecal routes of administration have been explored. SUMMARY: Work in tissue culture and in animal models has shown increased efficiency of enzyme delivery and clinical trials of second-generation products and novel delivery systems are now underway. © 2011 Wolters Kluwer Health | Lippincott Williams &Wilkins.
Lunn M.P.,National Hospital for Neurology and Neurosurgery
The Cochrane database of systematic reviews | Year: 2014
Duloxetine is a balanced serotonin and noradrenaline reuptake inhibitor licensed for the treatment of major depressive disorders, urinary stress incontinence and the management of neuropathic pain associated with diabetic peripheral neuropathy. A number of trials have been conducted to investigate the use of duloxetine in neuropathic and nociceptive painful conditions. This is the first update of a review first published in 2010. To assess the benefits and harms of duloxetine for treating painful neuropathy and different types of chronic pain. On 19th November 2013, we searched The Cochrane Neuromuscular Group Specialized Register, CENTRAL, DARE, HTA, NHSEED, MEDLINE, and EMBASE. We searched ClinicalTrials.gov for ongoing trials in April 2013. We also searched the reference lists of identified publications for trials of duloxetine for the treatment of painful peripheral neuropathy or chronic pain. We selected all randomised or quasi-randomised trials of any formulation of duloxetine, used for the treatment of painful peripheral neuropathy or chronic pain in adults. We used standard methodological procedures expected by The Cochrane Collaboration. We identified 18 trials, which included 6407 participants. We found 12 of these studies in the literature search for this update. Eight studies included a total of 2728 participants with painful diabetic neuropathy and six studies involved 2249 participants with fibromyalgia. Three studies included participants with depression and painful physical symptoms and one included participants with central neuropathic pain. Studies were mostly at low risk of bias, although significant drop outs, imputation methods and almost every study being performed or sponsored by the drug manufacturer add to the risk of bias in some domains. Duloxetine at 60 mg daily is effective in treating painful diabetic peripheral neuropathy in the short term, with a risk ratio (RR) for ≥ 50% pain reduction at 12 weeks of 1.73 (95% CI 1.44 to 2.08). The related NNTB is 5 (95% CI 4 to 7). Duloxetine at 60 mg daily is also effective for fibromyalgia over 12 weeks (RR for ≥ 50% reduction in pain 1.57, 95% CI 1.20 to 2.06; NNTB 8, 95% CI 4 to 21) and over 28 weeks (RR 1.58, 95% CI 1.10 to 2.27) as well as for painful physical symptoms in depression (RR 1.37, 95% CI 1.19 to 1.59; NNTB 8, 95% CI 5 to 14). There was no effect on central neuropathic pain in a single, small, high quality trial. In all conditions, adverse events were common in both treatment and placebo arms but more common in the treatment arm, with a dose-dependent effect. Most adverse effects were minor, but 16% of participants stopped the drug due to adverse effects. Serious adverse events were rare. There is adequate amounts of moderate quality evidence from eight studies performed by the manufacturers of duloxetine that doses of 60 mg and 120 mg daily are efficacious for treating pain in diabetic peripheral neuropathy but lower daily doses are not. Further trials are not required. In fibromyalgia, there is lower quality evidence that duloxetine is effective at similar doses to those used in diabetic peripheral neuropathy and with a similar magnitude of effect. The effect in fibromyalgia may be achieved through a greater improvement in mental symptoms than in somatic physical pain. There is low to moderate quality evidence that pain relief is also achieved in pain associated with depressive symptoms, but the NNTB of 8 in fibromyalgia and depression is not an indication of substantial efficacy. More trials (preferably independent investigator led studies) in these indications are required to reach an optimal information size to make convincing determinations of efficacy.Minor side effects are common and more common with duloxetine 60 mg and particularly with 120 mg daily, than 20 mg daily, but serious side effects are rare.Improved direct comparisons of duloxetine with other antidepressants and with other drugs, such as pregabalin, that have already been shown to be efficacious in neuropathic pain would be appropriate. Unbiased economic comparisons would further help decision making, but no high quality study includes economic data.