EAN guideline on palliative care of people with severe, progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Patients with severe, progressive multiple sclerosis (MS) have complex physical and psychosocial needs, typically over several years. Few treatment options are available to prevent or delay further clinical worsening in this population. The objective was to develop an evidence-based clinical practice guideline for the palliative care of patients with severe, progressive MS. METHODS: This guideline was developed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Formulation of the clinical questions was performed in the Patients-Intervention-Comparator-Outcome format, involving patients, carers and healthcare professionals (HPs). No uniform definition of severe MS exists: in this guideline, constant bilateral support required to walk 20 m without resting (Expanded Disability Status Scale score > 6.0) or higher disability is referred to. When evidence was lacking for this population, recommendations were formulated using indirect evidence or good practice statements were devised. RESULTS: Ten clinical questions were formulated. They encompassed general and specialist palliative care, advance care planning, discussing with HPs the patient's wish to hasten death, symptom management, multidisciplinary rehabilitation, interventions for caregivers and interventions for HPs. A total of 34 recommendations (33 weak, 1 strong) and seven good practice statements were devised. CONCLUSIONS: The provision of home-based palliative care (either general or specialist) is recommended with weak strength for patients with severe, progressive MS. Further research on the integration of palliative care and MS care is needed. Areas that currently lack evidence of efficacy in this population include advance care planning, the management of symptoms such as fatigue and mood problems, and interventions for caregivers and HPs.

Beyond a physical symptom: the importance of psychosocial factors in multiple sclerosis pain.

BACKGROUND AND PURPOSE: Pain affects around two-thirds of people with Multiple Sclerosis (pwMS). Biomedical treatments show limited efficacy. A recently developed cognitive-behavioural model of Multiple Sclerosis (MS) pain suggests several psychosocial factors may worsen pain and related disability. The current study investigated whether psychosocial factors drawn from this model explain significant amounts of the variance in pain severity and interference over and above measures of disease severity and pain subtype. METHODS: Six hundred and twelve pwMS experiencing pain completed a U.K. wide cross-sectional survey including valid and reliable psychometric questionnaires. Hierarchical regressions determined the relative contribution of disease severity and psychosocial factors to predicting pain severity and interference. RESULTS: All psychosocial factors including distress, negative beliefs about pain and its consequences, and avoidance of activity, were related to pain outcomes, explaining a further 24% and 30% of the variance in pain severity and interference after controlling for demographic and disease variables. Findings were similar for neuropathic and non-neuropathic pain subgroups. CONCLUSIONS: All pwMS reported significant pain and associated disability even though over 90% were taking pain medication. Psychosocial factors identified as important in predicting pain severity and, to a greater extent, pain interference are potentially modifiable and may be important treatment targets for both pain subtypes.

Distress improves after mindfulness training for progressive MS: A pilot randomised trial.

BACKGROUND: Mindfulness-based interventions have been shown to effectively reduce anxiety, depression and pain in patients with chronic physical illnesses. OBJECTIVES: We assessed the potential effectiveness and cost-effectiveness of a specially adapted Skype distant-delivered mindfulness intervention, designed to reduce distress for people affected by primary and secondary progressive MS. METHODS: Forty participants were randomly assigned to the eight-week intervention (n = 19) or a waiting-list control group (n = 21). Participants completed standardised questionnaires to measure mood, impact of MS and symptom severity, quality of life and service costs at baseline, post-intervention and three-month follow-up. RESULTS: Distress scores were lower in the intervention group compared with the control group at post-intervention and follow-up (p < 0.05), effect size -0.67 post-intervention and -0.97 at follow-up. Mean scores for pain, fatigue, anxiety, depression and impact of MS were reduced for the mindfulness group compared with control group at post-therapy and follow-up; effect sizes ranged from -0.27 to -0.99 post-intervention and -0.29 to -1.12 at follow-up. There were no differences in quality-adjusted life years, but an 87.4% probability that the intervention saves on service costs and improves outcome. CONCLUSIONS: A mindfulness intervention delivered through Skype video conferences appears accessible, feasible and potentially effective and cost-effective for people with progressive MS.

A 500-kiloton airburst over Chelyabinsk and an enhanced hazard from small impactors.

Most large (over a kilometre in diameter) near-Earth asteroids are now known, but recognition that airbursts (or fireballs resulting from nuclear-weapon-sized detonations of meteoroids in the atmosphere) have the potential to do greater damage than previously thought has shifted an increasing portion of the residual impact risk (the risk of impact from an unknown object) to smaller objects. Above the threshold size of impactor at which the atmosphere absorbs sufficient energy to prevent a ground impact, most of the damage is thought to be caused by the airburst shock wave, but owing to lack of observations this is uncertain. Here we report an analysis of the damage from the airburst of an asteroid about 19 metres (17 to 20 metres) in diameter southeast of Chelyabinsk, Russia, on 15 February 2013, estimated to have an energy equivalent of approximately 500 (±100) kilotons of trinitrotoluene (TNT, where 1 kiloton of TNT = 4.185×10(12) joules). We show that a widely referenced technique of estimating airburst damage does not reproduce the observations, and that the mathematical relations based on the effects of nuclear weapons--almost always used with this technique--overestimate blast damage. This suggests that earlier damage estimates near the threshold impactor size are too high. We performed a global survey of airbursts of a kiloton or more (including Chelyabinsk), and find that the number of impactors with diameters of tens of metres may be an order of magnitude higher than estimates based on other techniques. This suggests a non-equilibrium (if the population were in a long-term collisional steady state the size-frequency distribution would either follow a single power law or there must be a size-dependent bias in other surveys) in the near-Earth asteroid population for objects 10 to 50 metres in diameter, and shifts more of the residual impact risk to these sizes.

Cognitive behaviour therapy for common mental disorders in people with Multiple Sclerosis: A bench marking study.

BACKGROUND: Mental health problems such as depression and anxiety are common in Multiple Sclerosis (MS) and are often under treated. AIMS: This paper reports on the clinical effectiveness of a cognitive behaviour therapy service for common mental disorders in people with MS and compares it to previous randomised controlled trials (RCTs) of cognitive behaviour therapy (CBT) in this population. METHODS: 49 patients were deemed appropriate for CBT and 29 accepted treatment. Assessments were completed at baseline and end of treatment and included the Hospital Anxiety & Depression Scale. Results in the form of a standardized effect of treatment were compared with five previous RCTs. RESULTS: The results from this clinical service indicated statistically significant outcomes with reductions in depression and anxiety. The uncontrolled effect size was large but inferior to those found in published RCTs. CONCLUSIONS: Cognitive behaviour therapy is effective for people with MS in routine clinical practice. Possible limits on effectiveness include more liberal patient selection, lack of specificity in rating scales and heterogeneity of target problems. Given the high rates of distress in this population, routine psychological interventions within neurology services are justifiable. Future research should aim to maximise CBT in such settings.

'Fighting for everything': service experiences of people severely affected by multiple sclerosis.

BACKGROUND: No previous research exists specifically exploring the needs of those people severely affected by multiple sclerosis (MS). METHODS: Semi-structured interviews were conducted with people identified by the referring health or social care professional as being severely affected by their MS and informal carers, in order to explore their perceptions of their illness and care. The data were analysed for themes using the constant comparative approach. RESULTS: The data relate to 32 people severely affected by MS, who identified several broad themes, relating to loss and change, and provision of services and care. In relation to service provision, people with MS (PwMS) and their carers identified two, interlinked themes--a lack of continuity and co-ordination of care, and a lack of information about services, aids and adaptations, welfare benefits and end-of-life issues. A further theme was identified, which underpinned and linked the two other themes, that of ;fighting for everything'--a sense that people had to struggle for their needs to be met. CONCLUSION: There is a need to develop models of care in order to better meet patients and carers needs for information, co-ordination, and to reduce the feeling of struggling to receive services.

Cannabis use in patients with multiple sclerosis.

INTRODUCTION: Little is known about the extent and patterns of cannabis use in people with multiple sclerosis (MS). METHODS: MS patients attending neurology outpatient clinics at two hospitals in London and one in Kent, UK completed a questionnaire. RESULTS: Questionnaires were completed by 254/337 (75%) MS patients. Forty-three per cent had used cannabis at some stage (ever users). Of these, 68% (75/110) had used cannabis to alleviate symptoms of MS (MS-related cannabis use). Forty-six (18%) had used cannabis in the last month (current users), of whom 12% (31/254) had used it for symptom relief. Being married or having a long-term partner, tobacco smokers and increasing disability were independent risk factors for MS-related cannabis use. Compared to patients who could walk unaided, cannabis use was more likely in those who were chair-bound (adjusted OR 2.47; 1.10-5.56) or only able to walk with an aid (adjusted OR 1.56; 0.90-3.60). Pain and spasms were common reasons for cannabis use. Seventy-one per cent of individuals who had never used cannabis said they would try the drug if it were available on prescription. CONCLUSION: A large proportion of MS patients had tried cannabis for symptom control, however current use was small. A subgroup with greater disability appears to derive some symptomatic benefit.

Sleep and fatigue in multiple sclerosis.

Fatigue is common in multiple sclerosis (MS) and is an important cause of disability. However, the cause of fatigue is poorly understood. This study aimed to describe the frequency and pattern of sleep disturbance in a group of outpatients with MS, and to investigate the relationship between sleep disturbance and fatigue. Sixty outpatients with MS completed the Fatigue Severity Scale (FSS) and the Epworth Sleepiness Scale and kept a sleep diary for seven days. Fatigue and excessive daytime sleepiness were common in this group of patients (64 and 32%). Sleep problems on at least two nights per week occurred frequently, including initial insomnia in 42%, middle insomnia in 53% and terminal insomnia in 58%. The reasons cited for different types of insomnia varied, with anxiety and pain/discomfort being the commonest causes of initial insomnia and nocturia the commonest cause of middle insomnia. Middle insomnia was significantly correlated with daytime fatigue, a relationship that remained after controlling for disability. Sleep disturbance is common in MS and is associated with treatable symptoms, including pain and nocturia. Sleep disturbance may be an important factor contributing to fatigue in patients with MS.

Clinical features of headache at altitude: a prospective study.

BACKGROUND: Headache is the most common nervous system complication at altitude; however, there have been few attempts to characterize clinical features of high-altitude headaches (HAH). OBJECTIVE: To measure prospectively the incidence of HAH and to determine its risk factors and characteristics. METHODS: Members of an expedition to Kanchenjunga base camp in Nepal (5,100 m) were prospectively studied. Subjects were interviewed prior to the trip and while trekking recorded headaches experienced at >3,000 m using a structured questionnaire incorporating International Headache Society (IHS) and acute mountain sickness (AMS) criteria. In addition, clinical features of headaches in 19 trekkers in other groups above 3,000 m were recorded using the same questionnaire. RESULTS: Eighty-three percent (50/60) reported at least 1 HAH (median 2, range 0 to 10). Those who developed HAH were younger (p = 0.04); women and persons with headaches in daily life were more likely to report severe headaches (p = 0.03 and p = 0.07). One hundred thirty-eight HAH, experienced by 69 persons, are described. The mean altitude at which headaches occurred was 4,723 m. Twenty-six percent of headaches woke subjects at night or occurred upon awakening. HAH reported by migraineurs were accompanied by more phonophobia (p = 0.008). There were no IHS accompanying symptoms in 44% of headaches or symptoms of AMS in 52% of headaches. CONCLUSIONS: Headaches are a frequent complication of ascent to altitude. Older age appears to offer some protection, whereas headaches were more severe in women and persons with headaches in daily life. There is a wide clinical spectrum, with some suggesting intracranial hypertension. There is a need for evidence-based diagnostic criteria for headaches at altitude.

Multiple sclerosis: Neurofilament light chain antibodies are correlated to cerebral atrophy.

OBJECTIVE: To evaluate markers of axonal damage in CSF and serum of patients with different subtypes of MS in relation to measures of disease progression on MRI. METHODS: In 51 patients with MS (21 relapsing-remitting, 20 secondary progressive, 10 primary progressive), levels of heavy and light neurofilaments (NfH and NfL) and antibodies to neurofilaments (anti-NfL and -NfH) as well as the total immunoglobulin G (IgG) were analyzed. MRI analysis included T2 hyperintense, T1 hypointense, and gadolinium enhancing lesions and markers of cerebral atrophy (ventricular and parenchymal fractions). RESULTS: For the total group, correlations were found between the anti-NfL index and the parenchymal fraction (PF) (r = -0.51, p < 0.001), T2 lesion load (r = 0.41, p < 0.05), ventricular fraction (r = 0.37, p < 0.05), and T1 lesion load (r = 0.37, p < 0.05). For the anti-NfH index, a correlation was found with the PF (r = -0.39, p < 0.05). No correlations were found between the IgG index and MRI measures. CONCLUSIONS: Intrathecal production of anti-NfL antibodies may serve as a marker of tissue damage, particularly axonal loss, in MS.

Patients with progressive multiple sclerosis have elevated antibodies to neurofilament subunit.

OBJECTIVE: The cause of axonal loss, an important contributor to disability in MS, is poorly understood. This study investigated whether progression in MS is associated with CSF antibodies to the 68-kd light neurofilament subunit (NF-L), an axonal cytoskeletal protein, and compared this with antibodies against tubulin and the heavy neurofilament subunit (NF-H). METHODS: IgG to NF-L, tubulin, and NF-H was measured by immunoassay in matched CSF and serum samples from patients with relapsing-remitting MS (RRMS; n = 39), primary progressive MS (PPMS; n = 10), and secondary progressive MS (SPMS; n = 18); patients with other inflammatory (n = 21) and noninflammatory (n = 40) neurologic diseases; and healthy controls (n = 12). Immunocytochemistry was performed to assess antibody binding to human brain sections, and isoelectric focusing with immunoblotting was performed to assess oligoclonal anti-NF-L production. RESULTS: Intrathecal production of anti-NF-L antibodies was significantly elevated in PPMS and SPMS. In contrast, there were no significant differences in CSF levels of antibodies to tubulin or NF-H between the groups. Anti-NF-L, antitubulin, and anti-NF-H levels correlated with the duration of disease before lumbar puncture and Expanded Disability Status Scale levels. Immunocytochemistry demonstrated binding of CSF or serum antibodies to axonal or neuronal components in six of seven RRMS patients, seven of seven PPMS patients, and eight of 10 SPMS patients tested. Isoelectric focusing demonstrated independent CSF oligoclonal bands reactive with NF-L in six of 13 specimens tested. CONCLUSIONS: Anti-NF-L antibodies seem to be raised in progressive MS and may serve as a marker for axonal loss and disease progression. They may contribute to axonal loss and the accumulation of disability.

Meningococcal disease in South African goldmines--epidemiology and strategies for control.

OBJECTIVES: To describe the epidemiology of meningococcal disease in South African goldmines and to suggest strategies for the prevention and control of further outbreaks. DESIGN: We prospectively investigated a meningococcal outbreak that occurred in 1996 and describe the control measures that were implemented. In addition, we conducted a retrospective analysis of routinely collected data on meningococcal disease in these mines from 1972 to 1996. SETTING: Four goldmines in Gauteng, employing 30,000 workers who live in hostels. SUBJECTS: All cases of meningococcal disease at the mine hospital. RESULTS: Between 1972 and 1976, 588 cases were diagnosed, with peaks in 1972 (203 cases, 727/100,000) and 1975 (147 cases, 564/100,000). Since 1978 less than 5 cases have been reported in most years, but smaller outbreaks occurred in 1990 (30 cases, 89/100,000) and 1996 (14 cases, 50/100,000). The 1996 outbreak (group A, clone I-1) was part of a larger outbreak in Gauteng that originated in Mozambique and began in one mine in July 1996, after which a mass vaccination campaign was implemented. This was followed by a smaller outbreak among non-vaccinated workers at an adjacent mine. Five patients were new recruits. CONCLUSIONS: Despite a dramatic reduction in meningococcal disease over the last 25 years due mainly to changes in the work force, there are still outbreaks in this community. Those most at risk are young men who are new to the industry. Suggestions for prevention include effective surveillance, routine vaccination of new recruits and a rapid response to outbreaks, with mass vaccination and provision of chemoprophylaxis to close contacts.

Upper limb motor function at 5000 metres: determinants of performance and residual sequelae.

Little is known about the effects of age and symptoms of acute mountain sickness and the potential benefit of short term acclimatisation on fine motor performance at altitude. There is uncertainty about whether time spent at altitude results in permanent neurological sequelae. Nine hole pegboard tests were performed on a group of trekkers at sea level (n=61), after ascending to Kanchenjunga base camp (5100 m; n=46), and 20 weeks after return to sea level (n=43). Comparison of baseline and altitude times showed a mean slowing from 36.2 to 39.0 seconds, a 7. 8% deterioration in performance (p<0.0001), which was greatest in subjects aged 50 years or older (5.04 v 1.93 seconds, p=0.017), those tested within 24 hours of arrival at 5100 m (4.75 seconds, 13. 3% v 0.48 seconds, 1.3% p<0.001), and persons experiencing symptoms of acute mountain sickness (p=0.012), each of which were independent determinants of deterioration. Repeat pegboard testing at sea level after 20 weeks showed no significant change compared with baseline (p=0.68). This confirms the deleterious effects of altitude on fine motor function, emphasises the benefit of acclimatisation, and suggests that older persons and those with symptoms of acute mountain sickness are particularly susceptible. The risk of long term motor dysfunction after exposure to these relatively moderate altitudes seems to be small.

Axonal degeneration in the pathogenesis of multiple sclerosis.

Axonal degeneration plays an important role in the accumulation of disability in patients with multiple sclerosis (MS). Pathological studies have demonstrated axonal damage, particularly in areas of acute inflammation and demyelination, and in chronic lesions. Axonal loss and its progression, which is associated with neurological disability, has also been demonstrated by magnetic resonance imaging (MRI) studies. The mechanisms of axonal loss are uncertain, but may involve axonal degeneration secondary to demyelination, or damage to the axonal cytoskeleton. Inflammatory mediators, including cytokines and proteolytic enzymes may contribute to axonal damage, as may nitric oxide. Axonal destruction may also be due to immune attack directed at axonal components. The realisation that axonal degeneration is a fundamental component of MS that may occur early in the disease course should alter the approach to management and open avenues to a more targeted immunotherapy aimed at reducing the progression of disability.

Electrocardiographic patterns of patients with echocardiographically determined biventricular hypertrophy.

The numerous criteria proposed for the electrocardiographic (ECG) diagnosis of biventricular hypertrophy (BVH) suffer from inadequate correlative data. We used two-dimensional (2D) echocardiography to identify BVH and analyzed the ECG patterns in these patients. The study group had 69 such patients with BVH and the control group had 22 patients with isolated left ventricular hypertrophy (LVH) demonstrated by 2D echocardiography. The electrocardiograms were analyzed for the presence of established criteria used in the diagnosis of LVH and right ventricular hypertrophy (RVH). Of the 69 patients in the study group, 17 (25%) had ECG findings of BVH, 25 (36%) had LVH, and 14 (20%) had RVH. An S wave in V5/V6 of >7 mm was most the frequent finding in the 17 patients with BVH on the electrocardiogram. The sensitivity of ECG criteria for BVH was 24.6%, specificity was 86.4%, and positive predictive value was 85%. This study reemphasizes the difficulty of ECG diagnosis of BVH. The electrocardiogram has a low sensitivity but satisfactory specificity and positive predictive accuracy for BVH.

Effect of long-term beta-blockade on aortic root compliance in patients with Marfan syndrome.

BACKGROUND: This study was undertaken to assess the effect of long-term beta-blockade on the aortic root stiffness index and distensibility in patients with Marfan syndrome. METHODS: Aortic root stiffness index and distensibility were calculated according to the formulas of Stefanadis and Hirai, respectively, with 2-dimensional guided M-mode echocardiogram before and after an average of 26 months of atenolol administration. RESULTS: Twenty-three asymptomatic patients were studied (11 men and 12 women, aged 31 +/- 14.2 years). The follow-up was 4 +/- 2.2 years. The dose of atenolol was individualized (mean 43.5 +/- 21.6 mg/d). Heart rate decreased from 79 +/- 9 beats/min to 64 +/- 9 beats/min (P =. 01), and systolic blood pressure decreased from 124 +/- 13 mm Hg to 114 +/- 2 mm Hg (P =.01). Distensibility increased from 1.85 +/- 0. 70 x 10(-6) cm2/dynes-1 to 2.21 +/- 0.76 x 10-6 cm2/dynes-1 (P =.02), and the stiffness index decreased from 9.68 +/- 3.78 to 8.85 +/- 3. 15 ( P =.2). Two groups of responses to treatment were identified. Compared with baseline values 15 (65%) patients who responded to treatment had increased distensibility and decreased stiffness index of the aortic root (P =.05). Eight patients (35%) who did not respond to treatment had no significant change. Body weight >91 kg and baseline end-diastolic aortic root diameter >40 mm were significantly associated with no response (P =.05). Two patients in the nonresponding group had echocardiographic progression of aortic insufficiency. CONCLUSIONS: There was a heterogeneous response in the aortic root elastic properties after long-term treatment with atenolol in asymptomatic patients with Marfan syndrome. Stiffness index and distensibility are more likely to respond when the baseline end-diastolic aortic root diameter is <40 mm.

Meningitis in a community with a high prevalence of tuberculosis and HIV infection.

OBJECTIVES: To evaluate the spectrum of aetiologies, and distinguishing clinical and laboratory features, of meningeal infection in a community with a high prevalence of tuberculosis (TB) and HIV infection. SETTING: A hospital serving mineworkers, originating from rural areas of Southern Africa. DESIGN: Prospective cohort of 60 consecutive lumbar punctures (LPs), performed for suspected meningitis. MEASUREMENTS: Clinical history and examination; concurrent cerebrospinal fluid (CSF) and blood samples; mortality status six months after entry to study. RESULTS: 38 of 57 patients (66.7%) were HIV-1 positive, 59.5% of whom had a CD4 count <200 cells/mm3. Nine patients had tuberculous meningitis (TBM) and two had tuberculomas; four developed disease while on TB therapy. There was one case of multidrug, and two of isoniazid-resistant TBM. There were nine episodes of cryptococcal meningitis (seven patients), nine of aseptic meningitis, two of neurosyphilis and 20 normal LPs, including four with AIDS dementia complex (ADC). Ten patients with meningococcal infection, part of a larger outbreak, were significantly younger (p=0.004). All patients with tuberculous, cryptococcal (most immune-suppressed p<0.001) and aseptic meningitis were HIV-1 positive. Within six months, 19 patients had died. Death was associated with HIV positivity (p=0.004), low CD4 count (p<0.001) and a diagnosis of cryptococcal meningitis, CNS TB or ADC. CONCLUSION: HIV has a major impact on the burden of disease and mortality, with a predominance of opportunistic chronic meningitides, despite a meningococcal outbreak, in this community. Of concern is the development of TBM despite therapy, and the emergence of drug-resistant strains.