Pseudobulbar affect as a negative prognostic indicator in amyotrophic lateral sclerosis.

OBJECTIVE: To evaluate whether the presence of pseudobulbar affect (PBA) in an early stage of the disease influences survival in a population-based incident cohort of amyotrophic lateral sclerosis (ALS). METHODS: Incident ALS cases, diagnosed according to El Escorial criteria, were enrolled from a prospective population-based registry in Puglia, Southern Italy. The Center for Neurologic Study-Lability Scale (CNS-LS), a self-administered questionnaire, was used to evaluate PBA. Total scores range from 7 to 35. A score ≥13 was used to identify PBA. Cox proportional hazard models were used for survival analysis. The modified C-statistic for censored survival data was used for models' discrimination. RECursive Partitioning and AMalgamation (RECPAM) analysis was used to identify subgroups of patients with different patterns of risk, depending on baseline characteristics. RESULTS: We enrolled 94 sporadic ALS, median age of 64 years (range: 26-80). At the censoring date, 65 of 94 (69.2%), 39 of 60 (65.0%), and 26 of 34 (76.5%) patients reached the outcome (tracheotomy/death), in the whole, non-PBA and in the PBA groups, respectively. Kaplan-Meier survival curves for the two subgroups were not significantly different (log-rank test: 1.3, P = .25). The discrimination ability of a multivariable model with demographic and clinical variables of interest was not improved by adding PBA. In the RECPAM analysis, ALSFRSr and the total score of CNS-LS scale (

Cardiovascular diseases may play a negative role in the prognosis of amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Only a few studies have considered the role of comorbidities in the prognosis of amyotrophic lateral sclerosis (ALS) and have provided conflicting results. METHODS: Our multicentre, retrospective study included patients diagnosed from 1 January 2009 to 31 December 2013 in 13 referral centres for ALS located in 10 Italian regions. Neurologists at these centres collected a detailed phenotypic profile and follow-up data until death in an electronic database. Comorbidities at diagnosis were recorded by main categories and single medical diagnosis, with the aim of investigating their role in ALS prognosis. RESULTS: A total of 2354 incident cases were collected, with a median survival time from onset to death/tracheostomy of 43 months. According to univariate analysis, together with well-known clinical prognostic factors (age at onset, diagnostic delay, site of onset, phenotype, Revised El Escorial Criteria and body mass index at diagnosis), the presence of dementia, hypertension, heart disease, chronic obstructive pulmonary disease, haematological and psychiatric diseases was associated with worse survival. In multivariate analysis, age at onset, diagnostic delay, phenotypes, body mass index at diagnosis, Revised El Escorial Criteria, dementia, hypertension, heart diseases (atrial fibrillation and heart failure) and haematological diseases (disorders of thrombosis and haemostasis) were independent prognostic factors of survival in ALS. CONCLUSIONS: Our large, multicentre study demonstrated that, together with the known clinical factors that are known to be prognostic for ALS survival, hypertension and heart diseases (i.e. atrial fibrillation and heart failure) as well as haematological diseases are independently associated with a shorter survival. Our findings suggest some mechanisms that are possibly involved in disease progression, giving new interesting clues that may be of value for clinical practice and ALS comorbidity management.

Time to generalization and prediction of survival in patients with amyotrophic lateral sclerosis: a retrospective observational study.

BACKGROUND AND PURPOSE: A strong association between time to generalization (TTG), considered as the time of spreading of the clinical signs from spinal or bulbar localization to both, and survival was recently identified in patients with amyotrophic lateral sclerosis (ALS). Thus, TTG may be used as an early to intermediate end-point in survival studies. The aim of the present study was to test TTG as a predictor of survival in ALS. METHODS: This was an observational retrospective study of ALS patients from a tertiary referral centre over a 5-year follow-up period. RESULTS: In 212 ALS patients, TTG was associated with time to death/tracheostomy [R 0.62, 95% confidence interval (CI) 0.53-0.70; P < 0.001]. In a time-to-event analysis, longer TTG resulted in lower risk to reach a composite outcome (death or tracheostomy) both in univariate [hazard ratio (HR) 0.98, 95% CI 0.97-0.99] and multivariate Cox analyses (HR 0.98, 95% CI 0.96-0.99). TTG predicted death/tracheostomy at 4 years (C-statistic 0.58; 95% CI 0.53-0.63) and at 5 years (C-statistic 0.58; 95% CI 0.53-0.62). CONCLUSIONS: Based on the present results from a large clinical cohort, TTG may be used as a new early to intermediate end-point to describe the ALS natural history. TTG may be potentially useful as a new primary outcome measure for clinical trials.

Cerebrospinal fluid neurofilament light chain levels: marker of progression to generalized amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: To evaluate whether cerebrospinal fluid (CSF) neurofilament light chain (NFL) levels could predict the time to generalization (TTG) in amyotrophic lateral sclerosis (ALS). METHODS: Cerebrospinal fluid NFL levels of 37 cases of sporadic ALS were measured and the time of symptom spreading from spinal or bulbar localization to both (TTG) was evaluated in all patients. RESULTS: Kaplan-Meier analysis showed a short TTG in patients with high NFL levels (log-rank test chi-squared = 19.4, P < 0.0001). In a multivariate regression model patients with NFL levels above the median had an eight-fold higher risk of generalization (adjusted hazard ratio 7.9, 95% confidence interval 2.9-21.4, P < 0.0001) compared with those with NFL levels below the median. CONCLUSIONS: This study shows that in sporadic ALS NFL, a marker of neurodegeneration, is correlated with TTG, a clinical intermediate parameter of survivorship.

A novel KIF5A mutation in an Italian family marked by spastic paraparesis and congenital deafness.

Hereditary spastic paraplegia (HSP) includes a group of diseases characterized by progressive spastic weakness of the lower limbs (pure forms) with possible additional signs (complicated forms). The SPG10 form is due to alteration in the kinesin1A gene (KIF5A) that encodes the neuronal kinesin heavy chain, a protein required for the anterograde axonal transport. We performed clinical, neurophysiological and molecular studies in two siblings affected by AD-HSP complicated by deafness. The screening of the KIF5A gene revealed the novel mutation p.Leu259Gln in two affected siblings and in their father with a pure form of HSP.

Elevated cerebrospinal fluid neurofilament light levels in patients with amyotrophic lateral sclerosis: a possible marker of disease severity and progression.

BACKGROUND: To date there are no biomarkers with proven reliability as a measure of disease burden in amyotrophic lateral sclerosis (ALS). The aim of our study is to assess the neurofilament light chain (NFL) in cerebrospinal fluid (CSF) samples as a measure of disease activity and progression in ALS. METHODS: Thirty-seven consecutive patients with ALS, 25 with chronic inflammatory demyelinating polyneuropathy and 21 with other neurodegenerative diseases were evaluated. CSF NFL levels were assayed by two-site solid-phase sandwich ELISA. In patients with ALS, neurological status was assessed by the revised ALS Functional Rating Scale (ALSFRS-r) and the Medical Research Council scale, and the progression of the disease was evaluated using the 'diagnostic delay' and the 'progression rate'. RESULTS: Cerebrospinal fluid NFL levels were higher in ALS cases than in controls (P < 0.0001). Using receiver operating curve analysis, an optimal NFL cut-off of 1981 ng/l discriminated between patients with ALS and neurological controls, with a sensitivity of 78.4% and specificity of 72.5%. Multivariate logistic regression confirmed the association between CSF NFL levels and the presence of ALS (age and sex adjusted odds ratio for ALS 8.9; 95% CI 3.1-25.8; P < 0.0001). In ALS, CSF NFL negatively correlated with the diagnostic delay (P < 0.0001) and the ALSFRS-r (P = 0.014) and positively with the progression rate (P < 0.0001). CONCLUSIONS: High CSF NFL levels were found in patients with ALS, reflecting the burden of neurodegeneration. The significant relation between CSF NFL levels and disease progression suggests that NFL may be a useful marker of disease activity and progression in ALS.

Elevated plasma homocysteine levels in patients with amyotrophic lateral sclerosis.

BACKGROUND: Both in vitro and in vivo studies indicate that homocysteine (Hcy) may be directly involved in the damage of motor neurons and in several pathways implicated in amyotrophic lateral sclerosis (ALS) pathogenesis. OBJECTIVE: To determine whether plasma Hcy levels were higher in ALS patients than healthy controls and to examine the relationship between Hcy levels and clinical ALS phenotypes. METHODS: In a cross-sectional study, we compared Hcy, B(12), and folate levels in 62 patients with ALS and 88 age- and sex-matched controls recruited as outpatients in a tertiary clinical center. RESULTS: Patients with ALS had higher median plasma Hcy levels (11.2 [range 5.8 to 46] vs 9.7 [range 4.5 to 15.9] micromol/L; p = 0.0004) and lower folate levels (4.4 [range 1.7 to 22.1] vs 5.8 [range 2.3 to 21.1] ng/mL; p = 0.0003), compared with controls. Multivariate logistic regression revealed a strong direct association between plasma Hcy levels and presence of ALS (odds ratios adjusted for age, sex, and B-vitamin levels comparing the top tertile [Hcy levels >or= 11.6 micromol/L] with the bottom tertile [Hcy levels < 9.2 micromol/L]: 6.4; 95% CI 2.2 to 19.1; p for trend = 0.0008). We also found a trend for higher Hcy levels in patients with shorter interval from symptom onset to diagnosis (ODI; <14 months), compared with patients with longer ODI (>14 months; median Hcy levels 11.8 [range 5.8 to 46] vs 10.1 [range 7.2 to 17.6] micromol/L; p = 0.09). In a multivariate model, Hcy levels strongly correlated with shorter interval onset diagnosis (r(2) = 0.18; p = 0.01). CONCLUSIONS: Plasma homocysteine (Hcy) levels were significantly increased in patients with amyotrophic lateral sclerosis (ALS) compared with healthy controls. ALS cases with shorter time to diagnosis presented higher Hcy levels, suggesting that higher Hcy may be linked to faster progression of the disease.