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ALS Patients (als + patient)

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Selected Abstracts

Cerebrospinal fluid and serum antibodies against neurofilaments in patients with amyotrophic lateral sclerosis

EUROPEAN JOURNAL OF NEUROLOGY, Issue 4 2010
L. Fialová
Background:, The aim of the study was to assess autoimmune involvement in amyotrophic lateral sclerosis (ALS). Methods:, We measured IgG antibodies against light (NFL) and medium (NFM) subunits of neurofilaments using ELISA in paired cerebrospinal fluid (CSF) and serum samples from 38 ALS patients and 20 controls. Results:, Serum levels of anti-NFL were higher in ALS patients than in controls (P < 0.005). Serum anti-NFL antibodies and intrathecal anti-NFM antibodies were related to patient disability (serum anti-NFL: P < 0.05; intrathecal anti-NFM: P < 0.05). Anti-NFL levels were significantly correlated with anti-NFM levels in ALS (P < 0.001) and the control group (P < 0.0001) in the CSF, but not in serum. Anti-NFL and anti-NFM antibodies significantly correlated between serum and CSF in the ALS group (anti-NFL: P < 0.0001; anti-NFM: P < 0.001) and in the control group (anti-NFL: P < 0.05; anti-NFM: P < 0.05). Conclusions:, Autoimmune humoral response to neurocytoskeletal proteins is associated with ALS. [source]

Frontal-lobe mediated behavioral dysfunction in amyotrophic lateral sclerosis

EUROPEAN JOURNAL OF NEUROLOGY, Issue 1 2010
M. Witgert
Background:, Cognitive impairment secondary to frontal lobe atrophy exists in 40,60% of Amyotrophic Lateral Sclerosis (ALS) cases. We aimed to determine the prevalence of frontal-lobe mediated behavioral impairment in (ALS) and to ascertain its relationship to cognitive impairment. Methods:, Two-hundred and twenty five patients diagnosed with sporadic ALS were evaluated for behavioral dysfunction using the Frontal Systems Behavior Scale (FrSBe), a validated measure used to examine frontal-lobe mediated behaviors, specifically apathy, executive dysfunction and disinhibition; a total behavior score is also provided. Additionally, a subset of patients also underwent a comprehensive neuropsychological evaluation. Results:, Changes in the total FrSBe scores were observed in 24.4% of the patients and 39.6% of the patients had impairment in at least one behavioral domain with symptoms of Apathy being the most common (31.1%). Cognitively impaired ALS patients had worse total (P = 0.05) and apathy scores (P < 0.01); however, behavioral dysfunction was also present in 16% of the cognitively intact patients. Half of the behaviorally intact patients exhibited cognitive impairment. Significant correlations were observed for performance on certain neuropsychological tests (Animal fluency, Block Design, Logical Memory I and Verbal Series Attention Test) and severity of behavioral dysfunction on certain FrSBe sub scores. Conclusions:, Frontal-lobe mediated behavioral dysfunction appears to be common in ALS. Cognitively impaired ALS patients had greater behavioral dysfunction. Recognition of behavioral and cognitive dysfunction may assist health-care providers and care-givers recognize changes in decision-making capacity and treatment compliance of patients with ALS. [source]

Increased levels of inflammatory chemokines in amyotrophic lateral sclerosis

EUROPEAN JOURNAL OF NEUROLOGY, Issue 6 2009
J. Kuhle
Background and purpose:, Amyotrophic lateral sclerosis (ALS) is classically assumed to be a neurodegenerative disorder. Inflammation has been observed in CNS tissue in ALS patients. We investigated the expression and prognostic relevance of proinflammatory chemokines in ALS. Methods:, We analyzed nine chemokines, eotaxin, eotaxin-3, IL-8, IP-10, MCP-1, MCP-4, macrophage derived chemokine (MDC), macrophage inflammatory protein-1, (MIP-1,), and serum thymus and activation- regulated chemokine (TARC) in serum and cerebrospinal fluid (CSF) of 20 ALS- and 20 non-inflammatory neurological disease (NIND)-patients. Results:, MCP-1 and IL-8 levels in CSF in ALS were significantly higher than in NIND (1304 pg/ml vs. 1055 pg/ml, P = 0.013 and 22.7 pg/ml vs. 18.6 pg/ml, P = 0.035). The expression of MCP-1 and IL-8 were higher in CSF than in serum (P < 0.001). There was a trend towards higher MCP-1 CSF levels in ALS patients with shorter time between first symptoms and diagnosis (r = ,0.407; P = 0.075). Conclusions:, We confirmed previous findings of increased MCP-1 levels in CSF of ALS patients. Furthermore, increased levels of IL-8 in CSF suggest a stimulation of a proinflammatory cytokine cascade after microglia activation. We found a tendency for higher MCP-1 values in patients with a shorter diagnostic delay, who are known to have also a shorter survival. This may suggest an association of higher MCP-1 levels with rapidly progressing disease. [source]

ALS patients request more information about cognitive symptoms

EUROPEAN JOURNAL OF NEUROLOGY, Issue 5 2008
P. Wicks
Background and purpose:, Once thought to impact only voluntary motor function, ALS/Motor neuron disease (MND) is now seen as a multi-system disorder in which a minority of patients experience mild cognitive dysfunction or frontotemporal dementia. Despite clinical guidelines advocating supplying complete information to patients, educational materials on ALS often state that the mind is unaffected. We sought to establish how much patients and caregivers understand about ALS, what they have been told to expect by their physician, and if they would have appreciated more complete information. Methods:, A two-part survey was administered online. An ,ALS quiz' gauged participants' knowledge of physical and psychological aspects of ALS. A second questionnaire assessed which symptoms patients had discussed with their clinician and explored patients' desire to receive information on psychological effects. Results:, A total of 247 ALS patients and 87 caregivers participated. Participants knew less about psychological symptoms than physical ones (72% correct responses versus 82%; paired t(333) = ,5.04, P < 0.001). Patients commonly reported being told by their doctor about physical symptoms such as problems walking (85%) or stiffness/cramps (74%) but not psychological issues like emotional lability (46%) or cognitive change (11%). The majority of patients (62%) and carers (71%) indicated a desire to be informed that cognitive change or dementia might occur. Conclusion:, ALS is a multi-system disorder. However, despite a desire for more information from patients and their carers, healthcare professionals continue to primarily address only the physical consequences of the disease. [source]

ALS patients and caregivers communication preferences and information seeking behaviour

EUROPEAN JOURNAL OF NEUROLOGY, Issue 1 2008
A. Chiň
To evaluate information preferences and information seeking behaviour in ALS patients and caregivers. Sixty ALS patients and caregivers couples were interviewed using a structured questionnaire about the content of diagnosis communication and their information seeking behaviour. The patients (35 men and 25 women) had a mean age of 63.4 years (SD 9.5). The caregivers (21 men and 39 women) had a mean age of 53.3 years (SD 14.9). The overall satisfaction with bad news communication and the impression that the physician had understood their feelings were higher amongst patients. Both parties indicated that the most important aspects to be informed were current researches, disease-modifying therapies and ALS outcome. Approximately 55% of patients and 83.3% of caregivers searched for information from sources outside the healthcare system. The most frequently checked source was internet, although its reliability was rated low. The caring neurologist should better attune the content of communication to patients' and caregivers' preferences, trying to understand what they want to know and encouraging them to make precise questions. Health professionals should be aware that ALS patients and caregivers often use internet to obtain information and should help them to better sort-out and interpret the news they found. [source]

Signs and symptoms at diagnosis of amyotrophic lateral sclerosis: a population-based study in southern Italy

EUROPEAN JOURNAL OF NEUROLOGY, Issue 7 2006
S. Zoccolella
Amyotrophic lateral sclerosis (ALS) diagnostic criteria are used to select patients for clinical trials based on different levels of diagnostic certainty, according to the spread of upper (UMN) and lower motoneuron (LMN) signs in different anatomic regions. However, the clinical presentation of ALS patients is extremely variable and this can delay the time to diagnosis and decrease the likelihood for trial entry. The aims of the study were to describe the signs and symptoms of diagnosis in a population-based incident cohort of ALS cases, using the El Escorial (EEC) and the Revised Airlie Diagnostic Criteria (AHC). The source of the study was a prospective population-based registry established in Puglia, southern Italy, in 1997. The diagnosis and the classification of the cases were based on EEC and AHC. All incident ALS cases during the period 1998,1999 were enrolled and followed up. During the surveillance period, we identified 130 ALS incident cases, and bulbar-ALS represented 20% of our cohort. The highest risk for bulbar onset was among subjects aged >75 years [RR: 20.1, 95% confidence interval (CI) 3.4,118.0] compared with subjects aged <55 years and among females compared with males (Relative risk (RR): 2.75, 95% CI: 1,7.3). The vast majority of patients (72%) referred progressive muscle weakness in the limbs as the presenting symptom. Eighty percent of cases presented contemporary bulbar or spinal involvement; UMN signs in the bulbar region were present in 24% of cases and any motoneuronal sign in thoracic region in only 15% of the cases. In this population-based series, progressive muscle weakness was the most common presenting sign; bulbar onset was associated with advanced age and female sex. UMN signs in the bulbar region and any motoneuronal sign in the thoracic region were observed in 20% of our case series. This may represent the main limitation to show the spread of signs during diagnostic assessment for inclusion in epidemiological studies and clinical trials. [source]

Immunoreactivity of the phosphorylated axonal neurofilament H subunit (pNF-H) in blood of ALS model rodents and ALS patients: evaluation of blood pNF-H as a potential ALS biomarker

JOURNAL OF NEUROCHEMISTRY, Issue 5 2009
Kevin Boylan
Abstract Levels of neurofilament subunits, potential biomarkers of motor axon breakdown, are increased in amyotrophic lateral sclerosis (ALS) patient's CSF but data on blood are not available. We measured blood levels of the phosphorylated axonal form of neurofilament H (pNF-H) by ELISA in transgenic rodent models of superoxide dismutase 1 (SOD1) ALS, and in 20 ALS patients and 20 similar aged controls monthly for 4 months. All symptomatic rodent ALS models showed robust levels of blood pNF-H, while control rodents or mice transgenic for unmutated SOD1 showed no detectable blood pNF-H. Average pNF-H levels in the G93A SOD1 mouse progressively increased from day 74 through death (day ,130). Median blood pNF-H level in ALS patients was 2.8-fold higher than controls (p < 0.001). Median ALSFRS-R declined a median of 0.8 pt/month (p < 0.001); higher baseline pNF-H level appeared to be associated with faster ALSFRS-R decline over 4 months (p = 0.087). The median rate of decline in ALSFRS-R was 1.9 pt/month in patients with baseline pNF-H levels above the median pNF-H value of 0.53 ng/mL; ALSFRS-R declined at a median of 0.6 pt/month in patients below this level. The pNF-H levels were relatively stable month to month in individual patients, raising questions regarding the molecular pathogenesis of ALS. Baseline control human pNF-H levels were higher in men than women and increased minimally over time. These data suggest that blood pNF-H can be used to monitor axonal degeneration in ALS model rodents and support further study of this protein as a potential biomarker of disease prognosis in ALS patients. [source]

NAALADase (GCP II) inhibitors protect in models of amyotrophic lateral sclerosis (ALS)

JOURNAL OF NEUROCHEMISTRY, Issue 2002
A. G. Thomas
Chronic glutamate toxicity is implicated in the pathogenesis of ALS. The neuropeptide N-acetyl-aspartyl glutamate (NAAG) appears to function both as a storage form for glutamate and as a neuromodulator at glutamatergic synapses. Catabolism of NAAG by N-acetylated-,-linked acidic dipeptidase (NAALADase; also termed glutamate carboxypeptidase II), yields N-acetyl aspartate (NAA) and glutamate. Since prior studies demonstrate an up-regulation of NAALADase in motor cortex and increased levels of NAA and glutamate in the CSF of ALS patients, we hypothesized that inhibition of NAALADase could protect against neuronal degeneration in ALS. Neuroprotective effects of two NAALADase inhibitors were assessed. 2-(Phosphonomethyl)pentanedioic acid (2-PMPA) decreased motor neuron loss and prevented loss of choline acetyltransferase (ChAT) activity in an in vitro model of ALS wherein chronic glutamate toxicity was induced by blocking glutamate transport. Gross morphology was preserved in 2-PMPA-treated cultures. In a SOD-1 transgenic mouse model of ALS, oral administration of a structurally different NAALADase inhibitor (GPI 5693) increased survival by 29 days and delayed onset of clinical symptoms by 17 days. Preliminary analysis of spinal cord pathology revealed severe neuronal depletion and astrocytosis with white matter changes in control mice. In mice treated with GPI 5693, normal neuronal populations with modest vacuolar changes were observed. These data suggest that NAALADase inhibition may provide an exciting therapeutic approach to the devastating disease, ALS. [source]

Bioenergetics in the pathogenesis of neurodegeneration

JOURNAL OF NEUROCHEMISTRY, Issue 2001
M. Flint Beal
Evidence implicating both mitochondria and bioenergetics as playing a crucial role in necrotic and apoptotic cell death is rapidly accumulating. Mitochondria are essential in controlling specific apoptosis cell death pathways and they are the major source of free radicals in the cell. Direct evidence for a role of mitochondria in neurodegenerative diseases comes from studies in Friedreich's Ataxia. Mutations in frataxin lead to an accumulation of iron within mitochondria. We found a three-fold increase in a marker of oxidative damage to DNA in the urine of patients with Friedreich's Ataxia. There is evidence for mitochondrial defects in patients with amyotrophic lateral sclerosis (ALS). There are mitochondrial abnormalities in liver biopsies and muscle biopsies from individuals with sporadic ALS. Muscle biopsies have shown reduced complex I activity in patients with sporadic ALS. A study of ALS cybrids showed a significant decrease in complex I activity as well as trends towards reduced complex 3 and 4 activities. We found increased levels of 8-hydroxy-2-deoxyguanosine, a marker of oxidative damage to DNA in the plasma, urine and CSF of sporadic ALS patients and increased numbers of point mutations in mtDNA of ALS spinal cord tissue. There is mitochondrial vacuolization in transgenic mouse models of ALS. We found substantial evidence for mitochondrial dysfunction in Huntington's Disease (HD). In HD postmortem brain tissue, there are significant reductions in complex 2, 3 activity. We also demonstrated increased brain lactate concentrations as well as reduced phosphocreatine to inorganic phosphate ratio in the resting muscle of patients with HD. More recent studies have demonstrated that there is abnormal depolarization of mitochondria of HD lymphoblasts, which directly correlates with CAG repeat length. There are reductions in ATP production in muscle are both presymptomatic and symptomatic HD patients. Transgenic mouse models of HD show significant reductions in N-acetylaspartate concentrations, which precede the onset of neuronal degeneration. We investigated a number of therapeutic interventions in both transgenic mouse models of ALS and HD. In transgenic ALS mice we found that oral administration of creatine dose-dependently extends survival and reduces the neuronal degeneration in the spinal cord. We found modest protection with ginkgo biloba and lipoic acid. In the HD mice we found significant improvement with oral administration of creatine in two different transgenic mouse models. Creatine not only extended survival but it also improved motor performance, delayed weight loss and attenuated striatal atrophy. Creatine significantly attenuated reductions in N-acetylaspartate concentrations as assessed using magnetic resonance spectroscopy. We also found significant neuroprotective effects with dichloroacetate, which stimulates pyruvate dehydrogenase. These findings implicate bioenergetic dysfunction in transgenic mouse models of both ALS and HD, and they suggest several novel therapeutic strategies aimed at energy replenishment. [source]

Diffusion Tensor Tractography-based Analysis of the Pyramidal Tract in Patients with Amyotrophic Lateral Sclerosis

JOURNAL OF NEUROIMAGING, Issue 3 2008
Yoon-Ho Hong MD
ABSTRACT BACKGROUND AND PURPOSE We attempted to measure DTI parameters of the brainstem pyramidal tract using two approaches, ie, simple ROI and tract-specific analyses. Results obtained for healthy subjects and ALS patients were compared. METHODS DTI was performed using a single shot SE-EPI with 25 noncollinear diffusion gradient directions (b= 1000 second/mm2) and with no diffusion gradient on a 3.0-T MR system in 10 ALS patients and in 8 age- and sex-matched normal controls. To delineate the brainstem pyramidal tract, tractography was performed using two ROIs, ie, a seed ROI at the cerebral peduncle (ROI-1) and a target ROI at the lower pons (ROI-2). ROI-1 was subsequently restricted to voxels that contained streamlines in the tract reconstruction, thus creating a sub-ROI. RESULTS Mean fractional anisotropy (FA) and mean diffusivity values were highly reproducible by tract specific analysis, whereas simple ROI analysis yielded larger variabilities between operators. FA values were significantly lower in ALS patients than in normal controls in the tractography-derived sub-ROI (P= .01), but not in the seed or target ROIs. CONCLUSIONS These results suggest, compared with simple ROI analysis, that tract-specific analysis using DTI fiber-tracking is more reliable and sensitive for detecting upper motor neuron pathology in ALS. [source]

Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 3

JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2003
F Terenghi
Intravenous immunoglobulins (IVIg) are successfully used as immunomodulatory therapy in patients with multifocal motor neuropathy (MMN) but their mechanism of action remains unknown. An anti-idiotypic block of pathogenic autoantibodies has been often postulated even if other possible mechanisms, including a modulation of the release of various cytokines, have been proposed. To evaluate the expression of cytokines in patients with MMN and their possible modulation by IVIg, we determined circulating levels of TNF,, INF,, IL2, IL4, IL10, and IL12 by ELISA in serum samples of 17 patients with MMN and compared them with 12 patients with amyotrophic lateral sclerosis (ALS), 12 with multiple sclerosis (MS), 6 with chronic inflammatory demyelinating polyneuropathy (CIDP), 5 with myasthenia gravis (MG) and 12 healthy controls (NS). Comparable levels of INF,, IL2, IL4, IL10 and IL12 were detected in patients' sera and controls. Even if TNF, levels did not differ significantly among patients' groups, they were higher than in any healthy control (mean ± SD 1.2 ± 0.5 pg/ml, range 0.7,2.4 pg/ml), in 12 (70%) MMN patients (mean ± SD 3.6 ± 1.9 pg/ml; range 0.2,7.5 pg/ml), all ALS, 3 MS (25%), 2 CIDP (40%) and 2 MG (40%). We then measured the concentration of TNF, before and after IVIg therapy in 9 MMN and 2 ALS patients. In all but one MMN patients, circulating levels of TNF, slightly increased after treatment with IVIg (mean values 4.3 vs. 7.2 pg/ml) and decreased 3 weeks after therapy while in both ALS patients they decreased or remained unchanged. No detectable level of TNF, was found in IVIg preparation. This study shows that, similarly to what previously reported in other autoimmune neuropathy as GBS and CIDP, TNF, serum levels are slightly increased in MMN but, at odds with what reported in these disease, their concentration tend to increase parallel to clinical improvement after IVIg therapy. Further studies are necessary to clarify the pathogenetic implication of this finding and in particular whether a possible deviation from a presumably Th2 to a Th1 immune response may help explaining the effect of IVIg in MMN. [source]

Pathological gambling amongst Parkinson's disease and ALS patients in an online community (PatientsLikeMe.com),

MOVEMENT DISORDERS, Issue 7 2009
Paul Wicks PhD
Abstract Pathological gambling (PG) has been identified in Parkinson's disease (PD), but such gambling behaviors may also occur in amyotrophic lateral sclerosis (ALS). We sought to estimate the prevalence of PG amongst members of a web-based community, PatientsLikeMe.com. A survey was constructed, consisting of demographic information, the South Oaks Gambling Screen (SOGS), the K-6 measure of distress, and items related to motivation for gambling. Data were obtained from 236 ALS patients and 208 PD patients. Of the PD patients, 13% were classified as problem gamblers compared with 3% of ALS patients (,2 = 14.005, P , 0.001). PD patients reported thoughts about gambling to be more distressing, harder to resist and more outside their control than ALS patients. Thus, the higher prevalence of compulsive behavior in PD may relate to damaged reward pathways or medication rather than to the effects of living with a chronic progressive neurological disorder per se. © 2009 Movement Disorder Society [source]

Modafinil treatment of fatigue in patients with ALS: A placebo-controlled study

MUSCLE AND NERVE, Issue 3 2009
Judith G. Rabkin PhD
Abstract Our objective was to determine whether modafinil alleviates fatigue in patients with amyotrophic lateral sclerosis (ALS). A placebo controlled trial with a 3:1 modafinil:placebo randomization in doses up to 300 mg/day for 4 weeks was followed by 8 weeks of open maintenance treatment. The primary endpoint was the Clinical Global Impressions-Improvement Scale. Secondary endpoints were the Fatigue Severity Scale, Epworth Sleepiness Scale, Beck Depression Inventory, Role Function Scale, and visual analog scales. Analysis of covariance was used to assess change at Week 4. Thirty-two patients were randomized; 29 completed the 4-week trial. In intention to treat (ITT) analysis, the response was 76% for modafinil versus 14% for placebo. In a completer analysis, the modafinil response rate was 86%, and the placebo response rate remained 14%. The number needed to treat was 1.6 (ITT). No medically serious adverse events were reported. Modafinil may be a promising intervention for fatigue in ALS patients. Replication in a larger study is needed. Muscle Nerve 39: 297,303, 2009 [source]

Optimizing measurement of the electrical anisotropy of muscle

MUSCLE AND NERVE, Issue 5 2008
Anne B. Chin BS
Abstract Skeletal muscle is electrically anisotropic, with applied high-frequency electrical current flowing more easily along than across muscle fibers. As an early step in harnessing this characteristic for clinical use, we studied approaches for maximizing the measured anisotropy by varying electrode size and applied current frequency in the tibialis anterior of 10 normal subjects. The results were compared to those from two patients with amyotrophic lateral sclerosis (ALS). Current was applied percutaneously, first parallel and then perpendicular to the major fiber direction of the muscle at frequencies ranging from 20 kHZ to 1 MHZ, using a fixed voltage,electrode length and varying the current,electrode length. The measured anisotropy was most pronounced using the longest length current electrodes and with a 125-kHZ applied frequency for the major outcome parameter phase. In addition, the two ALS patients showed very distinct anisotropic patterns. These results support the belief that, with the appropriate measurement technique, non-invasive assessment of electrical anisotropy of muscle may have useful clinical application. Muscle Nerve, 2008 [source]

Dissociated small hand muscle atrophy in amyotrophic lateral sclerosis: Frequency, extent, and specificity

MUSCLE AND NERVE, Issue 4 2008
Satoshi Kuwabara MD
Abstract Previous studies suggest that in amyotrophic lateral sclerosis (ALS) the abductor pollicis brevis (APB) and first dorsal interosseous (FDI) are more severely involved than abductor digiti minimi (ADM). To elucidate the pattern, frequency, extent, and specificity of such dissociated muscle atrophy in ALS, compound muscle action potentials recorded from APB, FDI, and ADM were analyzed in 77 ALS patients, 171 normal controls, and 196 disease controls. Compared with normal controls, ALS patients had a reduced APB/ADM amplitude ratio (P < 0.001) and FDI/ADM ratio (P < 0.001), whereas patients with other anterior horn diseases showed similar APB/ADM and FDI/ADM ratios to normal values. Decreased APB/ADM ratio was found in 41% of ALS patients, 5% of normal controls, and 4% of disease controls. Prominent muscle atrophy in APB and FDI, with relatively preserved ADM, appears to be specific to ALS. Dissociated hand muscle atrophy presumably reflects part of the pathophysiology and supports the diagnosis of ALS. Muscle Nerve, 2008 [source]

Cortical versus spinal dysfunction in amyotrophic lateral sclerosis

MUSCLE AND NERVE, Issue 5 2006
Shahram Attarian MD
Abstract Little is known about the possible link between cortical and spinal motor neuron dysfunction in amyotrophic lateral sclerosis (ALS). We correlated the characteristics of the responses to transcranial magnetic stimulation (TMS) with the electromechanical properties and firing pattern of single motor units (MUs) tested in nine ALS patients, three patients with Kennedy's disease, and 15 healthy subjects. In Kennedy's disease, 19 of 22 MUs were markedly enlarged with good electromechanical coupling and discharged with great variability. Their excitatory responses increased with MU size. In ALS, 17 of 34 MUs with excitatory responses behaved as in Kennedy's disease. By contrast, 28 MUs with nonsignificant responses showed poor electromechanical coupling and high firing rates, whereas 28 MUs with inhibitory responses showed moderate functional alterations. This result indicates that in ALS as in Kennedy's disease, sprouting of corticospinal axons may occur on surviving motoneurons. A clear relationship exists between the responsiveness of MUs to TMS and their functional state. Muscle Nerve, 2006 [source]

Disease progression in amyotrophic lateral sclerosis: Predictors of survival

MUSCLE AND NERVE, Issue 5 2002
T. Magnus MD
Abstract Predicting the rate of disease progression has become important as trials of new medical treatments for amyotrophic lateral sclerosis (ALS) are planned. Bulbar onset, early impairment of forced vital capacity, and older age have all been associated with shorter survival. We performed a retrospective study to compare survival factors with disease progression in a German ALS population. We analyzed disease progression in 155 patients at intervals of 4 months over a period of 3 years. To evaluate disease progression, the ALS functional rating scale (ALS-FRS), forced vital capacity (FVC%), and a Medical Research Council (MRC) compound score based on a nine-step modified MRC scale were used. We compared age (<55 years vs. ,55 years), different sites of disease onset (bulbar vs. limb), and gender to the rate of disease progression and performed survival analyses. No overall significant difference could be detected when analyzing these subgroups with regard to disease progression. By contrast, significantly longer survival was observed in the younger age group (56 months vs. 38 months, P < 0.0001) and in patients with limb-onset disease (51 months vs. 37 months, P = 0.0002). Using Cox analyses values we found that the declines of ALS-FRS, FVC%, and MRC compound score were predictive of survival (P < 0.0001, P = 0.002, and P = 0.003, respectively). Future studies are needed to clarify whether nonspecific factors including muscle atrophy, dysphagia, and coexisting diseases influence prediction of survival in ALS patients. A more precise set of predictors may help to better stratify patient subgroups for future treatment trials. © 2002 Wiley Periodicals, Inc. Muscle Nerve 25:000,000, 2002 [source]

Activation of STAT3 and inhibitory effects of pioglitazone on STAT3 activity in a mouse model of SOD1-mutated amyotrophic lateral sclerosis

NEUROPATHOLOGY, Issue 4 2010
Noriyuki Shibata
Signal transducer and activator of transcription-3 (STAT3) is a member of the proinflammatory transcription factor STAT family. Several studies have documented implications for neuroinflammation in amyotrophic lateral sclerosis (ALS). We recently demonstrated activation of STAT3 in spinal cords obtained at autopsy from sporadic ALS patients. To determine the involvement of STAT3 and effects of pioglitazone on STAT3 activity in familial ALS with superoxide dismutase-1 (SOD1) mutation, we performed immunoblot and immunohistochemical analyses of the active form of STAT3 (p-STAT3) in spinal cords from mice overexpressing mutant SOD1 (ALS mice) and nontransgenic littermates (control mice). Immunoblot analysis delineated significant increases in nuclear p-STAT3 levels in non-treated ALS mice as compared with pioglitazone-treated ALS mice and non-treated and pioglitazone-treated control mice. Immunohistochemical analysis revealed prominent p-STAT3 accumulations in the nucleus of motor neurons, reactive astrocytes and activated microglia in non-treated ALS mice but not pioglitazone-treated ALS mice and non-treated and pioglitazone-treated control mice. The present results provide in vivo evidence for increased phosphorylative activation and nuclear translocation of STAT3 in motor neurons and glia in mouse motor neuron disease, suggesting a common pathological process between sporadic and SOD1-mutated familial forms of ALS. Moreover, it is likely that pioglitazone may exert inhibitory effects on STAT3-mediated proinflammtory mechanisms in this disease. [source]

Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis,

ANNALS OF NEUROLOGY, Issue 2 2009
Sanne Piepers MD
Objective To determine whether valproic acid (VPA), a histone deacetylase inhibitor that showed antioxidative and antiapoptotic properties and reduced glutamate toxicity in preclinical studies, is safe and effective in amyotrophic lateral sclerosis (ALS) using a sequential trial design. Methods Between April 2005 and January 2007, 163 ALS patients received VPA 1,500mg or placebo daily. Primary end point was survival. Secondary outcome measure was decline of functional status measured by the revised ALS Functional Rating Scale. Analysis was by intention to treat and according to a sequential trial design. This trial was registered with ClinicalTrials.gov (number NCT00136110). Results VPA did not affect survival (cumulative survival probability of 0.72 in the VPA group [standard error (SE), 0.06] vs 0.88 in the placebo group [SE, 0.04] at 12 months, and 0.59 in the VPA group [SE, 0.07] vs 0.68 in the placebo group [SE, 0.08] at 16 months) or the rate of decline of functional status. VPA intake did not cause serious adverse reactions. Interpretation Our finding that VPA, at a dose used in epilepsy, does not show a beneficial effect on survival or disease progression in patients with ALS has implications for future trials with histone deacetylase inhibitors in ALS and other neurodegenerative diseases. The use of a sequential trial design allowed inclusion of only half the number of patients required for a classic trial design and prevented patients from unnecessarily continuing potentially harmful study medication. Ann Neurol 2009;66:227,234 [source]

Familial aggregation of amyotrophic lateral sclerosis,

ANNALS OF NEUROLOGY, Issue 1 2009
Fang Fang MD
Objective To assess the relative risk for amyotrophic lateral sclerosis (ALS) in families of ALS patients. Methods We conducted a cohort study based on the Swedish Multi-Generation Register in 1961 to 2005. Among 6,671 probands (first ALS case in the family), 1,909 full siblings, 13,947 children, and 5,405 spouses were identified (exposed group). Other persons in the Multi-Generation Register, who were siblings, children, or spouses to persons without ALS, served as the reference group. Relative risks for ALS among the exposed group, compared with the reference group, were calculated from Poisson regression models. Concurrence of ALS within twins was assessed in 86,441 twin pairs registered in the Swedish Twin Register. Results Nine cases of ALS were noted among the siblings and 37 cases among the children of the probands, giving a 17-fold risk among the siblings (95% confidence interval, 8.1,30.4) and a 9-fold risk among the children (95% confidence interval, 6.2,12.0), compared with the reference group. Siblings and children had a greater excess risk if the proband was diagnosed at a younger age, and the excess risks decreased with increasing age at diagnosis of the proband (p < 0.001). Spouses had no significantly increased risk (p = 0.27). Two cases were identified among the cotwins of ALS probands, giving a relative risk of 32 (95% confidence interval, 5.2,102.6). Interpretation The siblings and children of ALS patients have an about 10-fold risk for ALS compared with the reference group. The excess risks vary with both age and kinship, indicating a major genetic role in familial ALS. Ann Neurol 2009;66:94,99 [source]

Managing amyotrophic lateral sclerosis: Slowing disease progression and improving patient quality of life,

ANNALS OF NEUROLOGY, Issue S1 2009
Benjamin Rix Brooks MD
It is now possible to slow the disease progression of amyotrophic lateral sclerosis (ALS), but documented improvement in the quality of life of ALS patients has been difficult to quantitate. Putative mechanisms involved in motor neuron degeneration in ALS include oxidative damage, mitochondrial dysfunction, neuroinflammation, growth factor deficiency, and glutamate excitotoxicity. Several pharmacological agents that target these potential targets have demonstrated therapeutic potential in animal models with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Many treatments that have been moderately effective in this animal model have not been successfully translated into effective treatments for humans with ALS. Only the glutamate modulator riluzole has demonstrated efficacy in clinical trials and is approved for treating ALS. Combination treatments may represent a potential therapeutic strategy to more robustly prolong life and preserve function, but only vitamin E with riluzole has been formally studied in clinical trials, and to date, no combination treatments have been found to be more effective than currently available single agents. Ann Neurol 2009;65 (suppl):S17,S23 [source]

Pharmacokinetics of riluzole: evidence for glucuronidation as a major metabolic pathway not associated with UGT1A1 genotype

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2008
H. J. M. van Kan
Abstract Pharmacokinetic studies of riluzole show a large inter-individual variability of the drug's clearance and serum concentrations. Optimizing the individual dosage of riluzole may have the potential to improve the effect of riluzole treatment on survival of patients with amyotrophic lateral sclerosis (ALS). Limited data are available on the in vivo metabolic elimination of riluzole. From in vitro experiments, CYP1A2 seems to be mainly involved in riluzole clearance. However, in vitro studies suggest that formation of riluzole-glucuronide plays a role and may determine the drug's pharmacokinetic variability in patients to some extent. In the current study the formation of riluzole-glucuronide was examined in amyotrophic lateral sclerosis (ALS) patients. It also aimed at relating glucuronidation of riluzole to differential UGT1A1*28 genotypes. The formation of riluzole-glucuronide was confirmed in serum from a group of 14 ALS patients taking riluzole. Riluzole-glucuronide concentrations were positively associated with those of riluzole. In a separate group of 131 ALS patients taking riluzole, the UGT1A1*28 genotype was not associated with trough or peak serum concentrations of riluzole. This study provides evidence that the in vivo metabolic elimination of riluzole in ALS patients involves glucuronidation. The results do not indicate that glucuronidation of riluzole highly contributes to the drug's inter-individual pharmacokinetic variability. Copyright © 2007 John Wiley & Sons, Ltd. [source]

Increased expression of TDP-43 in the skin of amyotrophic lateral sclerosis

ACTA NEUROLOGICA SCANDINAVICA, Issue 5 2010
M. Suzuki
Suzuki M, Mikami H, Watanabe T, Yamano T, Yamazaki T, Nomura M, Yasui K, Ishikawa H, Ono S. Increased expression of TDP-43 in the skin of amyotrophic lateral sclerosis. Acta Neurol Scand: 2010: 122: 367,372. © 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Objectives,,, Transactivation-responsive DNA-binding protein-43 (TDP-43) was indentified as a major component of the ubiquitin-positive inclusions in sporadic amyotrophic lateral sclerosis (ALS). However, there has been no study of TDP-43 in ALS skin. The present study investigates TDP-43 in ALS skin. Materials and methods,,, We made a quantitative immunohistochemical study of the expression of TDP-43 in the skin from 15 patients with ALS and 15 control subjects. Results,,, The proportion of TDP-43-positive (TDP-43+) cells in the epidermis in ALS patients was significantly higher (P < 0.001) than in controls. There was a significant positive relationship (r = 0.62, P < 0.02) between the proportion and duration of illness in ALS patients. The optical density of TDP-43+ cells in the epidermis in ALS patients is markedly stronger (P < 0.001) than in controls. There was a significant positive relation (r = 0.72, P < 0.01) between the immunoreactivity and duration of illness in ALS patients. Conclusions,,, These data suggest that changes of TDP-43 in ALS skin are likely to be related to the disease process and that metabolic alterations of TDP-43 may take place in the skin of patients with ALS. [source]

Causes and place of death in Italian patients with amyotrophic lateral sclerosis

ACTA NEUROLOGICA SCANDINAVICA, Issue 3 2010
R. Spataro
Spataro R, Lo Re M, Piccoli T, Piccoli F, La BellaV. Causes and place of death in Italian patients with amyotrophic lateral sclerosis. Acta Neurol Scand: 122: 217,223. © 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Objectives,,, To determine the causes and place of death in a cohort of Italian patients with amyotrophic lateral sclerosis (ALS). A better understanding of the likely causes of death in ALS might improve the palliative care at the end-of-life, whereas knowing the place of death will help to verify the need for highly specialized care services, e.g. hospice and nursing home. Patients and methods,,, Between 2000 and 2008, 182 ALS patients (onset: spinal, 127; bulbar, 55; M/F: 1.6) were followed in a single ALS Tertiary Centre in Palermo, Sicily, Italy until death. Medical data for each individual patient were recorded in a large database throughout the disease course. Information concerning causes and place of death were obtained by consultation with relatives or the family physician. Results,,, Respiratory failure (terminal respiratory insufficiency, pneumonia) was the most frequent cause of death (81.3%), which included six cases (3.3%) who requested a terminal sedation. Sudden death and death during sleep accounted for by 6.0% and 6.6% of all deaths, respectively. Heart-related causes of death were relatively infrequent in our cohort, accounting for by 7.1% of all deaths (i.e. sudden death: 6.0% and myocardial infarct: 1.1%). Patients (85.2%) died at home. Conclusions,,, The leading cause of death in ALS remains the respiratory failure, followed by the sudden death and death during sleep. Most patients in our cohort died at home, a choice that might be only partially driven by cultural factors. These findings might have a great impact on the development of the advanced and end-of-life palliative care and in the planning of specialized care services, as hospice and nursing home. [source]

Pulmonary function tests and diaphragmatic compound muscle action potential in patients with sporadic amyotrophic lateral sclerosis

ACTA NEUROLOGICA SCANDINAVICA, Issue 6 2010
T. N. Sathyaprabha
Sathyaprabha TN, Pradhan C, Nalini A, Thennarasu K, Raju TR. Pulmonary function tests and diaphragmatic compound muscle action potential in patients with sporadic amyotrophic lateral sclerosis. Acta Neurol Scand: 2010: 121: 400,405. © 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Background,,, Respiratory failure is the primary cause of death in patients with amyotrophic lateral sclerosis (ALS). Diaphragmatic compound muscle action potentials (DCMAP) are valid parameters to assess the respiratory muscle innervation. Aim,,, In this study we propose to establish evidence of pulmonary dysfunction in patients with ALS and its relation to DCMAP parameters among patients with sporadic ALS. Materials and methods,,, Twenty nine patients (M-20, F-9) diagnosed to have sporadic ALS by El. Escorial criteria, without symptoms of pulmonary dysfunction, and able to perform the PFT satisfactorily, were studied. Thirty controls (M-20, F-10) were selected from patient's relatives. Forced vital capacity (FVC), forced expiratory volume in one second (FEV1), peak expiratory flow rate (PEFR) and maximum voluntary ventilation (MVV) were measured by spirometry. Maximum expiratory pressure (MEP) was measured by digital peak pressure monitor. Right phrenic nerve conductions (DCMAP) were performed and the latencies and amplitude of diaphragmatic com-pound action potential (DCMAP) was recorded in controls and ALS patients. Results,,, The mean age of patients was 51.41 ± 10.72 years (37,82) and control was 53.57 ± 8.85 years (30,68). None of the patients had symptoms or clinical evidence of respiratory dysfunction. The FVC, FEV1, PEFR, MVV, MIP and MEP were significantly (P < 0.001) reduced in ALS. The mean DCMAP amplitude was reduced among patients (610 ± 506.231 ,v) as compared to controls (1303.33 ± 584.56, P < 0.001) and mean latency was increased in patients (9.73 ± 2.57 ms) compared to controls (7.69 ± 0.87, P = 0.001). There was significant negative correlation between PFTs and latencies of DCMAP. Amplitude of DCMAP did not correlate with PFTs. Conclusion,,, There is significant negative correlation between DCMAP latencies and PFTs suggesting early loss of myelinated fibres and diaphragmatic dysfunction. DCMAP latencies may be a good indicator of early respiratory muscle involvement and also of disease progression in ALS. [source]

MRI in ALS patients

ACTA NEUROLOGICA SCANDINAVICA, Issue 6 2003
Article first published online: 20 MAY 200
No abstract is available for this article. [source]

The neuromuscular junction microenvironment in extraocular and limb muscles

ACTA OPHTHALMOLOGICA, Issue 2009
F PEDROSA DOMELLOF
Purpose To characterise the components of the neuromuscular junction (NMJ) in normal and pathological extraocular muscles (EOMs) and to assess the dynamics of progressive denervation. Methods Limb and EOM samples from 11 controls,8 ALS patients and from transgenic mice with SOD1 mutations (D90A, G93A) paralleling familiar ALS were processed for immunocytochemistry with antibodies against Schwann cell markers (S-100, p75, GFAP), gangliosides GD1b and GQ1b/GT1a, neurotrophic factors (BDNF, GDNF, NT-3, NT-4) and their receptors, parvalbulmin, nestin, desmin and laminin chains. Results The NMJs of normal EOMs had a different cytoskeleton composition. Differences in the expression of gangliosides GD1b and GQ1b/GT1a, Schwann cell marker S-100, agrin and nestin at the NMJs were noted in the human ALS EOMs. Parvalbumin was absent or scarce in EOM nerve trunks of ALS patients. The analysis of the time aspects of denervation in the animal models is ongoing. Conclusion The human EOMs in late stages of ALS and the EOMs of the transgenic mice show signs of denervation, although these muscles appear remarkably well preserved. High levels of parvalbumin, proposed to be protective for oculomotor neurons in ALS, are not apparent in advanced stages of the disease. The identification of similar endpoints in the EOMs of patients with D90A mutation and the ALS transgenic mice carrying the same mutation indicates that this is a useful model to study the temporal aspects of progressive denervation in the EOMs, to explore aspects of muscle-nerve interplay that protect the EOMs in motoneuron disease and to gain further knowledge useful for the development of selective tools to modulate eye muscle function in the treatment of strabismus. [source]