Prevalence of depression in amyotrophic lateral sclerosis/motor neuron disease: multi-attribute ascertainment and trajectories over 30 months.

Objective: Evidence is equivocal about the prevalence of depression in amyotrophic lateral sclerosis (ALS). This study uses a multi-attribute ascertainment of the prevalence of depression and examines this prevalence over time. Methods: Patients with ALS were recruited into the Trajectories of Outcome in Neurological Conditions (TONiC-ALS) study. Caseness was identified by the Modified-Hospital Anxiety and Depression Scale (M-HADS). In addition, participants provided data on co-morbidities and medication use. A combination of the three was used to derive the estimate for the prevalence of depression, treated or untreated. Longitudinal data were analyzed by trajectory analysis of interval level M-HADS-Depression data. Results: Among 1120 participants, the mean age was 65.0 years (SD 10.7), 60.4% male, and the median duration since diagnosis was 9 months (IQR 4-24). Caseness of probable depression at baseline, defined by M-HADS-Depression, was 6.45% (95%CI: 5.1-8.0). Taken together with antidepressant medication and co-morbidity data, the prevalence of depression was 23.1% (95%CI: 20.7-25.6). Of those with depression, 17.8% were untreated. Trajectory analysis identified three groups, one of which contained the most cases; the level of depression for each group remained almost constant over time. Conclusion: Depression affects almost a quarter of those with ALS, largely confined to a single trajectory group. Prevalence estimates based on screening for current depressive symptoms substantially under-estimate the population experiencing depression. Future prevalence studies should differentiate data based on current symptoms from those including treated patients. Both have their place in assessing depression and the response by the health care system, including medication, depending upon the hypothesis under test.

Measuring coping in people with amyotrophic lateral sclerosis using the Coping Index-ALS: A patient derived, Rasch compliant scale.

OBJECTIVE: The progressively disabling and terminal nature of ALS/MND imposes major coping demands on patients. We wished to improve the psychometric properties of our previously published MND-Coping Scale, so that parametric analyses were valid, and to make it simpler for patients to complete and clinicians to score. METHODS: After a new qualitative analysis of 26 patients with ALS/MND, the draft Coping Index-ALS (CI-ALS) was administered to 465 additional patients, alongside COPE-60, General Perceived Self Efficacy scale, and WHOQOL-BREF. Validity of the CI-ALS was assessed using the Rasch model. External validity was checked against comparator measures. RESULTS: Thirteen centres contributed 465 patients, mean age 64.9 years (SD 10.8), mean disease duration 28.4 months (SD 37.5). The CI-ALS-Self and CI-ALS-Others both satisfied Rasch model expectations and showed invariance across age, gender, marital status and type of onset. Expected correlations were observed with comparator scales. A nomogram is available to convert the raw scores to interval level measures suitable for parametric analysis. CONCLUSIONS: Coping abilities in ALS/MND can now be measured using a simple 21 item self-report measure, offering two subscales with a focus of 'coping by self ' and 'coping with others'. This allows clinicians to identify individuals with poor coping and facilitates research on interventions that may improve coping skills.

Development and validation of Spasticity Index-Amyotrophic Lateral Sclerosis.

OBJECTIVES: Spasticity is a common and disabling feature of amyotrophic lateral sclerosis (ALS). There are currently no validated ALS-specific measures of spasticity. The aim of this study was to develop and use a self-report outcome measure for spasticity in ALS. METHODS: Following semi-structured interviews with 11 ALS patients, a draft scale was administered across ALS clinics in the UK. Internal validity of the scale was examined using the Rasch model. The numerical rating scale (NRS) for spasticity and Leeds Spasticity scale (LSS) were co-administered. The final scale was used in a path model of spasticity and quality of life. RESULTS: A total of 465 patients (mean age 64.7 years (SD 10), 59% male) with ALS participated. Spasticity was reported by 80% of subjects. A pool of 71 items representing main themes of physical symptoms, negative impact and modifying factors was subject to an iterative process of item reduction by Rasch analysis resulting in a 20-item scale-the Spasticity Index for ALS (SI-ALS)-which was unidimensional and free from differential item functioning. Moderate correlations were found with LSS and NRS-spasticity. Incorporating the latent estimate of spasticity into a path model, greater spasticity reduced quality of life and motor function; higher motor function was associated with better quality of life. CONCLUSIONS: The SI-ALS is a disease-specific self-report scale, which provides a robust interval-level measure of spasticity in ALS. Spasticity has a substantial impact on quality of life in ALS.

Creatine kinase enzyme level correlates positively with serum creatinine and lean body mass, and is a prognostic factor for survival in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition for which there is no single diagnostic test or biomarker. The level of the creatine kinase (CK) enzyme in serum may be mild to moderately elevated in some patients with ALS, the precise cause of which and its behaviour with disease progression is unknown. The aim of this study was to examine the usefulness of monitoring CK serially during the ALS disease trajectory and to determine whether CK levels mirror disease progression. METHODS: This was a prospective observational cohort study, using the clinical database of the olesoxime (TRO19622) investigational medicinal product trial. RESULTS: The baseline CK was raised in 52% of the trial participants with the mean CK ± SD being 257 ± 239 U/l. The mean CK was significantly higher in male participants than in female participants (P < 0.001) and amongst participants with limb onset ALS compared to participants with bulbar onset ALS (P < 0.001). There was no significant difference in the CK levels between upper limb and lower limb onset disease (P = 0.746). The CK level co-related positively with serum creatinine and estimated lean body mass but there was no relationship between CK and muscle scores and limb function. A higher CKlog was associated with significantly better survival, even when adjusted for prognostic co-variants (P = 0.013). CONCLUSIONS: The serum CK level seems to be an independent prognostic factor for survival in ALS. The cellular mechanism of CK enzyme suggests that it may be upregulated to provide energy in the face of metabolic stress in ALS.

Lack of unique neuropathology in amyotrophic lateral sclerosis associated with p.K54E angiogenin (ANG) mutation.

AIMS: Five to 10% of cases of amyotrophic lateral sclerosis are familial, with the most common genetic causes being mutations in the C9ORF72, SOD1, TARDBP and FUS genes. Mutations in the angiogenin gene, ANG, have been identified in both familial and sporadic patients in several populations within Europe and North America. The aim of this study was to establish the incidence of ANG mutations in a large cohort of 517 patients from Northern England and establish the neuropathology associated with these cases. METHODS: The single exon ANG gene was amplified, sequenced and analysed for mutations. Pathological examination of brain, spinal cord and skeletal muscle included conventional histology and immunohistochemistry. RESULTS: Mutation screening identified a single sporadic amyotrophic lateral sclerosis case with a p.K54E mutation, which is absent from 278 neurologically normal control samples. The clinical presentation was of limb onset amyotrophic lateral sclerosis, with rapid disease progression and no evidence of cognitive impairment. Neuropathological examination established the presence of characteristic ubiquitinated and TDP-43-positive neuronal and glial inclusions, but no abnormality in the distribution of angiogenin protein. DISCUSSION: There is only one previous report describing the neuropathology in a single case with a p.K17I ANG mutation which highlighted the presence of eosinophilic neuronal intranuclear inclusions in the hippocampus. The absence of this feature in the present case indicates that patients with ANG mutations do not always have pathological changes distinguishable from those of sporadic amyotrophic lateral sclerosis.

Neuro-ophthalmological Complications of Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) can lead to prominent nerve hypertrophy, which can mimic other forms of neuropathy radiologically. Neuro-ophthalmological complications can also occur in CIDP, either at presentation or chronically in the disorder. This can also cause diagnostic difficulties. We report three cases of neuro-ophthalmological complications of CIDP: two cases of papilloedema and one case of proptosis. In all three cases cranial nerve hypertrophy was present. CIDP should be considered in neuro-ophthalmological presentations associated with cranial/spinal nerve root hypertrophy.

Dysfunctional metacognitions in anorexia nervosa.

OBJECTIVE: The aim was to compare women with anorexia nervosa (AN) and without AN in terms of dysfunctional metacognitions. METHOD: 167 Australian women with AN (N=74; mean age 24.3 yrs) and without AN (N=93; mean age 27.3 yrs) completed the Metacognitions Questionnaire-30. RESULTS: Multivariate analyses revealed that relative to controls, AN patients had higher scores on metacognitive dysfunction: they exhibited low confidence in their cognitive competence, reported obsessively monitoring and striving to control their thoughts, and held negative beliefs about the danger of worrying. Furthermore, this was not due to starvation effects. However, patients did not exhibit significantly more positive beliefs about worry than controls once body mass index had been controlled. CONCLUSION: Metacognitive dysfunction may play a key role in the maintenance of AN; therefore, metacognitive therapy may be usefully applied to its treatment.

An evaluation of neurophysiological criteria used in the diagnosis of motor neuron disease.

BACKGROUND: New criteria for the neurophysiological diagnosis of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) were recently proposed at an international symposium in Awaji-shima, Japan. They differ from the accepted revised El-Escorial criteria by considering fasciculation potentials to be evidence of acute denervation. In addition, when assessing diagnostic certainty, the Awaji-shima criteria equate electrodiagnostic evidence of lower motor neuron dysfunction with clinical examination findings. METHODS: A retrospective review of 205 consecutive sets of notes was performed, from patients who underwent neurophysiological assessment for suspected MND. The clinical signs and neurophysiological findings were combined according to the two sets of criteria (revised El-Escorial and Awaji-shima), and the diagnoses reached were compared with the interval diagnosis, to establish the sensitivities and specificities of each protocol. RESULTS: An interval diagnosis of MND was recorded in 107 patients. The sensitivity of the Awaji-shima criteria in reaching a diagnosis of MND was 60.7% and the revised El-Escorial 28%, with a specificity of 95.9% for both criteria. The Awaji-shima criteria increased the sensitivity of diagnosis without affecting the specificity. CONCLUSION: Accepting EMG evidence of fasciculations as evidence of acute denervation increases the diagnostic certainty of MND, and the new criteria allow earlier diagnosis of MND without increasing the false-positive rate.

Clinical features of hereditary spastic paraplegia due to spastin mutation.

BACKGROUND: Mutations in the spastin gene are the commonest cause of hereditary spastic paraparesis (HSP), accounting for up to 40% of autosomal dominant cases. The phenotype associated with HSP due to mutation in the spastin gene (SPG4) tends to be pure HSP. OBJECTIVE: To characterize in more detail the genetic and phenotypic characteristics of SPG4 by examining a large cohort of patients with HSP. METHODS: The authors identified patients who tested positive for spastin mutation using a direct sequencing approach of all exons. RESULTS: The authors identified spastin mutations in 53 patients. Twenty-seven of the mutations identified were novel. The phenotype in the majority of patients was of pure HSP. In one individual, a complicated phenotype with progressive bulbar dysfunction and respiratory insufficiency was observed. Evidence of lower motor neuron dysfunction in a subgroup of SPG4 patients was identified. The missense changes S44L and P45Q were identified in patients with other spastin mutations and seemed to be exerting a phenotype-modifying effect. CONCLUSION: These findings add to the number of spastin mutations identified and demonstrate the importance of screening the whole gene, given the possibility of double mutations and intragenic modifiers. The identification of the complicated phenotypes has important implications for identifying the phenotype of patients in whom spastin screening should be considered. The presence of lower motor neuron dysfunction in a subgroup of SPG4 patients suggests that the cellular dysfunction in SPG4 extends beyond the axonal projections of upper motor neurons and ascending sensory pathways.

Striatal neurones show sustained recovery from severe hypoglycaemic insult.

Glucose deprivation provides a reliable model to investigate cellular responses to metabolic dysfunction, and is reportedly associated with permanent cell death in many paradigms. Consistent with previous studies, primary cultures of rat striatal neurones exposed to 24-h hypoglycaemia showed dramatically decreased sodium 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) metabolism (used as a marker of cell viability) and increased TUNEL staining, suggesting widespread DNA damage typical of apoptotic cell death. Remarkably, restoration of normal glucose levels initiated a sustained recovery in XTT staining, along with a concomitant decrease in TUNEL staining, even after 24 h of hypoglycaemia, suggesting recovery of damaged neurones and repair of nicked DNA. No alterations in the levels of four DNA repair proteins could be detected during hypoglycaemia or recovery. A reduction in intracellular calcium concentration was seen in recovered cells. These data suggest that striatal cells do not die after extended periods of glucose deprivation, but survive in a form of suspended animation, with sufficient energy to maintain membrane potential.

Investigation of mitochondrial function in hereditary spastic paraparesis.

Following the association of hereditary spastic paraparesis (HSP) with mutation in the paraplegin gene (SPG7) and mitochondrial dysfunction, we wished to investigate whether mitochondrial dysfunction might be associated with other forms of HSP. Five cases of HSP caused by mutation in the spastin gene (SPG4) and nine cases with HSP with mutation in the spastin and paraplegin genes excluded (non-SPG4/SPG7), were investigated for mitochondrial dysfunction. Muscle tissue from the HSP groups and a control group was analysed histochemically and spectrophotometrically for mitochondrial dysfunction. A significant decrease in mitochondrial respiratory chain complexes I and IV was demonstrated in the non-SPG4/SPG7 group. No abnormality was detected in the SPG4 group. We therefore conclude that there is evidence for mitochondrial dysfunction in non-SPG4/SPG7 HSP. There is no evidence for mitochondrial dysfunction in the pathogenesis of spastin-related HSP.

Mutation screening of manganese superoxide dismutase in amyotrophic lateral sclerosis.

Seventy-seven cases of ALS were screened for mutations in the manganese superoxide dismutase gene (SOD2). DNA was extracted from CNS tissue and screened using single stranded conformation polymorphism and heteroduplex analysis. No mutations were identified in the entire coding region of the SOD2 gene. The known polymorphism in the mitochondrial targeting sequence was identified. No association was found between this polymorphism and ALS. A further polymorphism was detected in the intronic sequence upstream of exon 4, though no association with ALS was demonstrated. We therefore conclude that mutations in SOD2 do not appear to cause ALS.

Paraplegin gene analysis in hereditary spastic paraparesis (HSP) pedigrees in northeast England.

OBJECTIVE: To identify the frequency and characterize the phenotype of paraplegin mutations in the hereditary spastic paraparesis (HSP) population in the northeast of England. BACKGROUND: HSP is a disorder that shows both clinical and genetic heterogeneity. To date, 13 loci have been associated with an HSP phenotype, with the causative gene having been identified in four of these. Two autosomal genes have been identified, paraplegin and spastin, and two X-linked genes have been identified, L1CAM (cell adhesion molecule) and proteolipid protein. METHODS: Thirty HSP pedigrees from the northeast of England were analyzed for mutation in each of the 17 exons of the paraplegin gene. RESULTS: A single family with a paraplegin mutation was identified in which the paraplegin mutation co-segregates with an HSP phenotype in an apparent dominant manner. The authors also describe frequent polymorphism in the paraplegin gene in both the HSP and control populations. CONCLUSION: Mutations in the paraplegin gene are not a common cause of HSP in the northeast of England. The phenotype of the paraplegin-related HSP family described had several striking features including amyotrophy, raised creatine kinase, sensorimotor peripheral neuropathy, and oxidative phosphorylation defect on muscle biopsy.

Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis.

BACKGROUND: Hereditary spastic paraparesis is a genetically heterogeneous condition. Recently, mutations in the spastin gene were reported in families linked to the common SPG4 locus on chromosome 2p21-22. OBJECTIVES: To study a population of patients with hereditary spastic paraparesis for mutations in the spastin gene (SPG4) on chromosome 2p21-22. METHODS: DNA from 32 patients (12 from families known to be linked to SPG4) was analysed for mutations in the spastin gene by single strand conformational polymorphism analysis and sequencing. All patients were also examined clinically. RESULTS: Thirteen SPG4 mutations were identified, 11 of which are novel. These mutations include missense, nonsense, frameshift, and splice site mutations, the majority of which affect the AAA cassette. We also describe a nucleotide substitution outside this conserved region which appears to behave as a recessive mutation. CONCLUSIONS: Recurrent mutations in the spastin gene are uncommon. This reduces the ease of mutation detection as a part of the diagnostic work up of patients with hereditary spastic paraparesis. Our findings have important implications for the presumed function of spastin and schemes for mutation detection in HSP patients.

Catheter infection. A comparison of two catheter maintenance techniques.

Incidence of catheter-related infections was studied using two techniques: changing catheters over a guide-wire or placing a new catheter at a new site every 3 days. Patients were randomized into two groups: Group 1 (new site) and Group 2 (guide-wire). Of the 105 catheterization sites (20 arterial and 85 central lines) in patients of Group 1, none were considered infected (i.e., having 15 or more colonies at the time of semi-quantitative microbiology analysis and clinical signs of infection at the catheter site). Of the 274 catheterization sites (56 arterial and 218 central) of patients of Group 2, eight (2.9%) were infected (chi 2 = 1.89, p greater than 0.05). Colonization (15 or more cultures without clinical signs of infection) occurred in three of 105 (2.9%) and in four of 274 (1.5%) of the catheterization sites of Groups 1 and 2, respectively (chi 2 = 0.23, p greater than 0.05). Study results indicate no significant difference in infection or colonization rates between the two methods of catheter replacement.