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.

Monocytes of patients with amyotrophic lateral sclerosis linked to gene mutations display altered TDP-43 subcellular distribution.

AIMS: Cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 (TDP-43) is an early determinant of motor neuron degeneration in most amyotrophic lateral sclerosis (ALS) cases. We previously disclosed this accumulation in circulating lymphomonocytes (CLM) of ALS patients with mutant TARDBP, the TDP-43-coding gene, as well as of a healthy individual carrying the parental TARDBP mutation. Here, we investigate TDP-43 subcellular localization in CLM and in the constituent cells, lymphocytes and monocytes, of patients with various ALS-linked mutant genes. METHODS: TDP-43 subcellular localization was analysed with western immunoblotting and immunocytofluorescence in CLM of healthy controls (n = 10), patients with mutant TARDBP (n = 4, 1 homozygous), valosin-containing protein (VCP; n = 2), fused in sarcoma/translocated in liposarcoma (FUS; n = 2), Cu/Zn superoxide dismutase 1 (SOD1; n = 6), chromosome 9 open reading frame 72 (C9ORF72; n = 4), without mutations (n = 5) and neurologically unaffected subjects with mutant TARDBP (n = 2). RESULTS: TDP-43 cytoplasmic accumulation was found (P < 0.05 vs. controls) in CLM of patients with mutant TARDBP or VCP, but not FUS, in line with TDP-43 subcellular localization described for motor neurons of corresponding groups. Accumulation also characterized CLM of the healthy individuals with mutant TARDBP and of some patients with mutant SOD1 or C9ORF72. In 5 patients, belonging to categories described to carry TDP-43 mislocalization in motor neurons (3 C9ORF72, 1 TARDBP and 1 without mutations), TDP-43 cytoplasmic accumulation was not detected in CLM or in lymphocytes but was in monocytes. CONCLUSIONS: In ALS forms characterized by TDP-43 mislocalization in motor neurons, monocytes display this alteration, even when not manifest in CLM. Monocytes may be used to support diagnosis, as well as to identify subjects at risk, of ALS and to develop/monitor targeted treatments.

Amyotrophic lateral sclerosis: a comparison of two staging systems in a population-based study.

BACKGROUND AND PURPOSE: To compare two recently developed staging systems for amyotrophic lateral sclerosis (ALS) [King's College and Milano-Torino staging (MITOS) systems] in an incident, population-based cohort of patients with ALS. METHODS: Since 2009, a prospective registry has been recording all incident cases of ALS in the Emilia Romagna region in Italy. For each patient, detailed clinical information, including the ALS functional rating scale score, is collected at each follow-up. RESULTS: Our study on 545 incident cases confirmed that King's College stages occurred at predictable times and were quite evenly spaced out throughout the disease course (occurring at approximately 40%, 60% and 80% of the disease course), whereas MITOS stages were mostly skewed towards later phases of the disease. In the King's College system there was a decrease in survival and an increase in deaths with escalating stages, whereas in the MITOS system survival curves pertaining to intermediate stages overlapped and the number of deaths was fairly homogenous throughout most stages. CONCLUSIONS: The King's College staging system had a higher homogeneity (i.e. smaller differences in survival among patients in the same stage) and a higher discriminatory ability (i.e. greater differences in survival among patients in different stages), being more suitable for individualized prognosis and for measuring efficacy of therapeutic interventions.

No evidence of cardiomyopathy in spinal and bulbar muscular atrophy.

OBJECTIVES: Spinal and bulbar muscular atrophy (SBMA) is a lower motor neuron disease caused by a CAG repeat expansion within the androgen receptor (AR) gene. Toxic nuclear accumulation of mutant AR has been observed in tissues other than nervous system including cardiac muscle. Moreover, CAG polymorphism length within AR has been associated with an increased risk of heart disease. MATERIALS AND METHODS: To test the hypothesis of the presence of cardiomyopathy in SBMA, a full cardiac protocol was applied to 25 SBMA patients. RESULTS: Patients' age ranged between 32 and 75 years. Cardiologic examination, 12-lead ECG, and echocardiography showed no abnormalities other than those consistent with hypertensive heart disease. One patient showed frequent supraventricular premature beats in absence of other significant arrhythmias at the 24-h ECG Holter. CONCLUSIONS: Our findings do not support the hypothesis of a primary cardiomyopathy in SBMA.

Environmental risk factors for amyotrophic lateral sclerosis: methodological issues in epidemiologic studies.

The exact role of environmental risk factors in the etiology of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) is still unknown. Their hypothetical contribution ranges from a minimal impact to a major role. Among the environmental factors strictu sensu (i.e., not life-style factors) suspected to play a role in ALS etiology, we consider pesticides, the metalloid selenium, some heavy metals, magnetic fields and cyanobacteria. However, the possibility exists that these factors exert their activity only in genetically susceptible persons and only after long-term exposures, thus further hampering epidemiologic studies. The recent availability of powerful tools such as population-based ALS registries for case ascertainment and clustering detection, and of environmental modeling techniques and of geographical information systems, may yield unique opportunities for offering insight into the etiology of the disease.

Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose-finding trial.

BACKGROUND: A neuroprotective effect of lithium in amyotrophic lateral sclerosis (ALS) has been recently reported. We performed a multicenter trial with lithium carbonate to assess its tolerability, safety, and efficacy in patients with ALS, comparing 2 different target blood levels (0.4-0.8 mEq/L, therapeutic group [TG], vs 0.2-0.4 mEq/L, subtherapeutic group [STG]). METHODS: The study was a multicenter, single-blind, randomized, dose-finding trial, conducted from May 2008 to November 2009 in 21 Italian ALS centers. The trial was registered with the public database of the Italian Agency for Drugs (http://oss-sper-clin.agenziafarmaco.it/) (EudraCT number 2008-001094-15). RESULTS: As of October 2009, a total of 171 patients had been enrolled, 87 randomized to the TG and 84 to the STG. The interim data analysis, performed per protocol, showed that 117 patients (68.4%) discontinued the study because of death/tracheotomy/severe disability, adverse events (AEs)/serious AEs (SAEs), or lack of efficacy. The Data Monitoring Committee recommended stopping the trial on November 2, 2009. CONCLUSIONS: Lithium was not well-tolerated in this cohort of patients with ALS, even at subtherapeutic doses. The 2 doses were equivalent in terms of survival/severe disability and functional data. The relatively high frequency of AEs/SAEs and the reduced tolerability of lithium raised serious doubts about its safety in ALS. CLASSIFICATION OF EVIDENCE: The study provides Class II evidence that therapeutic (0.4-0.8 mEq/L) vs subtherapeutic (0.2-0.4 mEq/L) lithium carbonate did not differ in the primary outcome of efficacy (survival/loss of autonomy) in ALS. Both target levels led to dropouts in more than 30% of participants due to patient-perceived lack of efficacy and AEs.

Primary progressive multiple sclerosis and generalized myasthenia gravis: an uncommon association.

The co-occurrence of myasthenia gravis (MG) and multiple sclerosis (MS) is rare, and in all the described cases MS had a relapsing-remitting course and the diseases had a benign clinical evolution. We describe herewith a patient with primary progressive MS (PPMS) and generalized MG with severe clinical course. This is the first report on a case of PPMS associated to MG. Studies on the histology and pathogenesis show that neurodegeneration is predominant over inflammation in PPMS, even if cellular and humoral immune-mediated mechanisms are thought to maintain a crucial importance in the development and progression of this form of disease. In the present case, the detection of cerebrospinal fluid IgM oligoclonal bands support the hypothesis of a possible role of antibody-mediated immunity in PPMS and suggest that humoral immunity may take part in the concomitant development of both MS and MG.

Wernicke encephalopathy: MR findings at clinical presentation in twenty-six alcoholic and nonalcoholic patients.

BACKGROUND AND PURPOSE: Wernicke encephalopathy is a severe neurologic disorder that results from a dietary vitamin B1 deficiency. It is characterized by changes in consciousness, ocular abnormalities, and ataxia. This study was undertaken to analyze and compare findings on MR imaging and neurologic symptoms at clinical presentations of patients with Wernicke encephalopathy with and without a history of alcohol abuse. MATERIALS AND METHODS: A multicenter study group retrospectively reviewed MR brain imaging findings, clinical histories, and presentations of 26 patients (14 female, 12 male) diagnosed between 1999 and 2006 with Wernicke encephalopathy. The age range was 6-81 years (mean age, 46 .6+/-19 years). RESULTS: Fifty percent of the patients had a history of alcohol abuse, and 50% had no history of alcohol abuse. Eighty percent showed changes in consciousness, 77% had ocular symptoms, and 54% had ataxia. Only 38% of the patients showed the classic triad of the disease at clinical presentation. At MR examination, 85% of the patients showed symmetric lesions in the medial thalami and the periventricular region of the third ventricle, 65% in the periaqueductal area, 58% in the mamillary bodies, 38% in the tectal plate, and 8% in the dorsal medulla. Contrast enhancement of the mamillary bodies was statistically positively correlated with the alcohol abuse group. CONCLUSIONS: Our study confirms the usefulness of MR in reaching a prompt diagnosis of Wernicke encephalopathy to avoid irreversible damage to brain tissue. Contrast enhancement in the mamillary bodies is a typical finding of the disease in the alcoholic population.

Bilateral posterior medullary and cervical stroke: a case report.

Spinal strokes are often localised in the anterior spinal artery territory, whereas an involvement of the posterior spinal arteries (PSA) is uncommon, and usually unilateral. Bilateral PSA stroke is exceptional. A 70-year-old woman, after a mild head trauma, presented with cervical pain, left hypoaesthesia and sensitive ataxia, which then extended to the right hemibody, including face. A Doppler ultrasound showed an only systolic flow signal in the left vertebral artery (VA). MR showed a bilateral infarction extending from the posterior medulla oblongata to C4 and a left hypoplasic VA with lack of visualisation of the V3 segment. This case was peculiar, implying a bilateral stroke in the PSA territory, possibly related to a left VA dissection, and in the presence of a dominant PSA, originating from the hypoplasic VA and of hyposupply of posterior radiculomedullary arteries and anastomoses.

Monofocal acute large demyelinating lesion mimicking brain glioma.

We report the case of a 34-year-old woman with clinical, neuroradiological and intraoperative histological findings, suggesting a low-grade astrocytic tumour. The demyelinating nature of the lesion was established through biopsy only after neurosurgery. The lesion size, in fact, greatly exceeded that of the perivenous demyelination seen in typical multiple sclerosis (MS) and tended to present as a space-occupying mass. This case underlines the importance of considering demyelinating isolated lesions in the differential diagnosis of a brain mass. Since misdiagnosis can result in unwarranted and aggressive therapy, it is critical for the neurologist to be aware of this serious diagnostic pitfall.