Objective Nearly 60% of migraine patients treated with monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway experience a ≥ 50% reduction in monthly migraine days (MMD) at 12 weeks compared to baseline (responders) . However, approximately half of the patients not responding to anti-CGRP mAbs ≤ 12 weeks do respond ≤ 24 weeks ( late responders) . We assessed frequency and characteristics of patients responding to anti-CGRP mAbs only > 24 weeks ( ultra-late responders ). Methods In this multicenter ( n = 16), prospective, observational, real-life study, we enrolled all consecutive adults affected by high-frequency episodic migraine (HFEM: ≥ 8 days/month) or chronic migraine (CM), with ≥ 3 prior therapeutic failures, treated with any anti-CGRP mAbs for ≥ 48 weeks. We defined responders patients with a ≥ 50% response rate ≤ 12 weeks, late responders those with a ≥ 50% response rate ≤ 24 weeks, and ultra-late responders those achieving a ≥ 50% response only > 24 weeks. Results A total of 572 migraine patients completed ≥ 48 weeks of anti-CGRP mAbs treatment. Responders accounted for 60.5% (346/572), late responders for 15% (86/572), and ultra-late responders for 15.7% (90/572). Among ultra-late responders , 7.3% (42/572) maintained the ≥ 50% response rate across all subsequent time intervals (weeks 28, 32, 36, 40, 44, and 48) and were considered persistent ultra-late responders , while 8.4% (48/572) missed the ≥ 50% response rate at ≥ 1 subsequent time interval and were classified as fluctuating ultra-late responders . Fifty patients (8.7%) did not respond at any time interval ≤ 48 weeks. Ultra-late responders differed from responders for higher BMI ( p = 0.033), longer duration of medication overuse ( p < 0.001), lower NRS ( p = 0.017) and HIT-6 scores ( p = 0.002), higher frequency of dopaminergic symptoms ( p = 0.002), less common unilateral pain—either alone ( p = 0.010) or in combination with UAS ( p = 0.023), allodynia ( p = 0.043), or UAS and allodynia ( p = 0.012)—a higher number of comorbidities ( p = 0.012), psychiatric comorbidities ( p = 0.010) and a higher proportion of patients with ≥ 1 comorbidity ( p = 0.020). Conclusion Two-thirds of patients not responding to anti-CGRP mAbs ≤ 24 weeks do respond later, while non-responders ≤ 48 weeks are quite rare (8.7%). These findings suggest to rethink the duration of migraine prophylaxis and the definition of resistant and refractory migraine, currently based on the response after 2–3 months of treatment.

To investigate in real-life the conversion from chronic migraine (CM) to episodic migraine (EM), specifically to EM with High-Frequency (HFEM: 8–14 monthly migraine days, MMDs), Medium-Frequency (MFEM, 4–7 MMDs), and Low-Frequency EM (LFEM, 0–3 MMDs), and its persistence during 1 year of treatment with galcanezumab. Consecutive CM patients treated with galcanezumab completing 1 year of observation were enrolled. We collected data on MMDs, pain intensity (Numeric Rating Scale, NRS score), and monthly acute medication intake (MAMI) from baseline (V1) to the 12-month visit (V12). Of the 155 enrolled patients, 116 (around 75%) reverted to EM at every visit and 81 (52.3%) for the entire 1-year treatment. Patients with older onset age (p = 0.010) and fewer baseline MMDs (p = 0.005) reverted more frequently to EM. At V12, 83 participants (53.5%) presented MFEM or LFEM. Patients reverted to MFEM or LFEM for 7 months (25th 1, 75th 11). The medication overuse discontinuation rate at V12 was 82.8% and occurred for 11 months (25th 8, 75th 12). From baseline to V12, the MAMI decreased by 17 symptomatic drugs (p < 0.000001) while the NRS score reduced by almost 2 points (p < 0.000001). A consistent transition to EM for the entire treatment year was observed in 81 (52.3%) patients. The 1-year GARLIT experience suggests that more than half of CM patients treated with galcanezumab persistently reverted to EM in real life. ClinicalTrials.gov NCT04803513.

BACKGROUND AND PURPOSE:We evaluated the clinical and neurophysiological efficacy of rituximab (RTX) in a neurophysiologically homogeneous group of patients with monoclonal gammopathy and immunoglobulin M (IgM) anti-myelin-associated glycoprotein antibody (anti-MAG) demyelinating polyneuropathy.METHODS:Twenty three anti-MAG-positive polyneuropathic patients were prospectively evaluated before and for 2 years after treatment with RTX 375 mg/m2 . The Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale (INCAT-ds), modified INCAT sensory score (mISS), Medical Research Council sum score, Patients' Global Impression of Change scale were used, IgM levels were assessed and extensive electrophysiological examinations were performed before (T0) and 1 year (T1) and 2 years (T2) after RTX treatment.RESULTS:At T1 and T2 there was a significant reduction from T0 both in mISS and in INCAT-ds, with a p value < 0.001 in the inferential Friedman's test overall analysis. Ulnar nerve Terminal Latency Index and distal motor latency significantly changed from T0 to T1 and in the overall analysis (p = 0.001 and p = 0.002), and ulnar nerve sensory nerve action potential (SNAP) amplitude was significantly increased at T2 from T1, with a p value < 0.001 in the overall analysis. Analysis of the receiver-operating characteristic curves showed that a 41.8% increase in SNAP amplitude in the ulnar nerve at T2 from T0 was a fair predictor of a mISS reduction of ≥2 points (area under the curve 0.85; p = 0.005; sensitivity: 90.9%, specificity: 83.3%).CONCLUSIONS:This study suggests that RTX is effective in patients with clinically active demyelinating anti-MAG neuropathy over 2 years of follow-up, and that some neurophysiological variables might be useful for monitoring this efficacy.

Migraine is the most common primary headache, characterized by a high life and socio- economic burden of disease, with a complex and intriguing pathophysiology: changes in cortical excitability, neurovascular inflammation and endothelial dysfunction, the last linking migraine to cardiovascular risk and comorbidities. Moderate endurance exercise is recommended in prevention of cardiovascular disease, improving cardiorespiratory and muscular fitness, mood and cognitive functions too. Multiple levels of evidence support a role of aerobic exercise in migraine prevention and treatment: exertion reduces pain intensity, frequency, duration of attacks, and medication use; moreover, lower cardiovascular fitness levels increase the lifetime risk of developing migraine. Different biochemical mediators are involved both in physical exertion and in migraine, as serotonin, acetylcholine, and endogenous opioids, playing a crucial role in pain- modulation and inhibition pathways, leading to analgesia. Despite many positive effects, exercise could be harmful, due to predisposing factors as the disfunction of the exercise-induced analgesia, together with other exercise-related factors (short warm up, incorrect rest phases, excessive training) and common migraine triggers. Furthermore, primary exercise headache and other sport headaches, often migraine-like, have been accurately described. In conclusion, aerobic exercise can be a useful tool for migraine therapy; otherwise, exceeding in exercise could lead to a harmful effect with a worsening of pain perception, sometimes acting as a trigger for migraine or migraine-like headaches. Additional studies are needed to better understand the most suitable way of performing exercise, to increase patients' compliance and to gain the maximum beneficial effect.

A rapid response to preventive therapy is of pivotal importance in severely disabled patients with chronic migraine (CM) and diverse preventive treatment failures. This prospective, observational, multicenter real‐life study aimed at investigating the effectiveness of galcanezumab in the first 3 months of treatment of CM patients at 14 Italian headache centers.

Merkel cell carcinoma (MCC) is a rare aggressive skin cancer, the incidence of which is increasing rapidly (1). Various paraneoplastic syndromes have been associated with MCC, due to its neuroendocrine nature, and these could be the first manifestations of cancer (2-7). We report here a case of a patient whose diagnosis of MCC with unknown primary was made following the identification of 2 uncommon neurological disorders. This case report highlights the complexity of paraneoplastic syndrome associated with MCC and the importance of a multidisciplinary approach.

Waldenström Macroglobulinemia (WM) is defined by the presence of an indolent lymphoplasmacytic lymphoma (LPL) (monoclonal lymphocytes, lymphoplasmacytes and plasma cells (PC) in the bone marrow (BM)) and monoclonal IgM protein secretion.1,2 Therefore, a BM biopsy showing LPL infiltration is currently essential to define WM; nevertheless, sometimes the pathological diagnosis can be troublesome: actually, the prevalence of monoclonal PC might suggest a diagnosis of multiple myeloma (MM), while in other cases, when small lymphocyte infiltration is predominant, the differentiation with other lymphomas can represent a challenge, both at morphologic and at immunophenotypic exam. In addition, the BM biopsy is a rather invasive surgical procedure and might represent a diagnostic limitation, in particular when dealing with elderly or unfit patients. Moreover, both the risk of relapse and the sensitivity to novel drugs are still difficult to predict in WM. Finally, some particular IgM-associated conditions (eg, demyelinating polyneuropathy) are still not well characterized. Recently, a novel method to detect in different tissues the MYD88L265P mutation,3,4 a hallmark of WM, has been described: the droplet digital PCR (ddPCR) assay.5 In this paper clinical reports of useful applications of this sensitive and reliable tool in daily practice are described, in a question & answer form. Might MYD88 be useful for non-invasive differential diagnosis of WM vs IgM-MM? MB, a 62 years-old male, presented with fatigue, dyspnea, headache and tinnitus. Blood exams revealed mild anemia (Hb 11.5 g/dl), an IgM value of 6334 mg/dl and an IgMk M-component (MC) of 3410 mg/dl, so a BM biopsy was performed (Fig. 1A–C). An excess of clonal PCs (nearly 60%) was found, at first suggesting the diagnosis of IgM-MM, while immunophenotype reported indolent B lymphoma infiltration. Interestingly, the clonal PCs did not present the chromosomal translocations typical of MM by fluorescent in situ hybridization (FISH); finally, ddPCR on BM, PB and plasma were positive for the MYD88L265P mutation and a diagnosis of WM was established. The patient then started dexamethasone-rituximab-cyclophosphamide (DRC) treatment preceded by plasmapheresis, achieving partial remission (PR).Figure 1: BM biopsy showing nuomerous lymphoplasmacytic cells (A) that are CD20+ (B) and CD138- (C). BM biopsy showing a diffuse small cell population (D) positive for CD20 (E) and k light chain (F), negative for λ light chain (G).Comment Most of PC dyscrasias are attributable to MM, however, there are some exceptions: an IgG MC can be also attributable to rare cases of IgG-LPL or other indolent lymphomas, and similarly, some cases of IgM MC are due to aggressive IgM-MM and not to WM. In particular, because of its LPL-like pathological and phenotypical features, IgM-MM can be often mistaken for WM; however, as reported also by Treon et al,6 these cases are MYD88 wild-type. So, in this setting, when laboratory findings seem discordant, or the BM biopsy is uncertain or not available, the non-invasive MYD88 evaluation can support the differential diagnosis. Might MYD88 be useful to refine the diagnosis of B-cell lymphoma? AL, a 68-years-old male, presented with multiple lymphadenopathies and an IgMk MC at 680 mg/dl. The cervical lymph node biopsy was inconclusive, showing diffused small B-cell lymphoma CD20+, CD10+, BCL2+, IgD+, CD23+/−, with uncertain differential diagnosis between diffuse follicle center and marginal zone lymphoma, MZL. The BM biopsy revealed a small B-cell population with secretory differentiation and clonal IgMk lymphoplasmacytic population (20%) (Fig. 1D–G). The MYD88L265P detection by ddPCR in BM and plasma finally supported the diagnosis of WM, so the patient underwent a DRC therapy, achieving complete remission. Comment The differential diagnosis of small cell lymphomas with a diffuse pattern can be troublesome. Both the lymph node and the BM biopsy can be inconclusive, even after extensive flow cytometric and immunohistochemical characterization. Therefore, the availability of a sensitive and non-invasive tool, as the ddPCR MYD88L265P assay, might help in choosing the most appropriate therapy. Might MYD88 be used as a non-invasive marker to early identify WM relapse? GT, a 76-years-old female patient, was diagnosed with symptomatic WM and underwent a cyclophosphamide-vincristine-prednisone (CVP) therapy, obtaining PR. Four years later, a mild but progressive increase of IgM value was observed (2489 mg/dl), concurrently with anemia and worsening of general conditions. The patient received R-Bendamustine therapy, again achieving PR. Two years later, the patient presented with fatigue and weight loss, without worsening of blood exams (Hb 12.6 g/dl, IgM 1069 mg/dl); nevertheless, after 6 months, the appearance of pancytopenia and splenomegaly (in absence of IgM increase) suggested to repeat the BM biopsy, with a final diagnosis of progressive WM. A retrospective study of the MYD88L265P mutation on PB by ddPCR showed rising values several months before the insurgence of symptoms (Fig. 2A).Figure 2: Comparison between MYD88 L265P , hemoglobin, and IgM values during the follow-up (A). MYD88L265P levels in BM, PB and cell-free DNA (cfDNA) from diagnosis to the present (B).Comment In pre-treated WM patients, the appearance of cytopenia may be due to different causes (eg, chronic blood loss anemia, myelodisplastic syndrome, acute leukemia), rather than directly related to relapsing disease.7 Moreover, a depletion of the secretory fraction often occurs in heavily treated patients, as well as an isolated IgM suppression may occur independently of cytotoreduction when using mTOR and BTK inhibitors,8 leading to discordant serological/histological results. Therefore, the mere IgM levels are not sufficiently reliable for relapse prediction. Actually, BM biopsy is essential to differentiate among these conditions, but non-invasive evaluation of the MYD88 mutation might act as a diagnostic support. Might MYD88 monitoring be used as an early response predictor to describe the activity of new treatments? DM, a 43-years-old male, in 1997 was diagnosed with symptomatic WM and underwent high dose sequential (HDS) therapy followed by autologous stem cell transplantation. After 5 years, a slow but progressive increase of the MC was observed, leading to large lymphadenopathies and massive BM infiltration 9 years later. Therefore, a rituximab-citarabine-bortezomib therapy was started, resulting in PR. Again, after 3 years, an increase of the abdominal lymphadenopathies was observed, with anemia and rising MC: the patient started ibrutinib therapy, with complete resolution of anemia, MC reduction >50%, lymphadenopathies stability. The patient is now in good health and has been on ibrutinib treatment for 30 months. A retrospective analysis of the MYD88L265P levels in BM by ddPCR showed persistent positivity during the follow-up, with a transient, deep reduction after the bortezomib-containing therapy and a slighter but constant decrease during ibrutinib (detectable in PB and plasma, too) (Fig. 2B). Comment Although WM is traditionally managed as an indolent and constantly relapsing disease, modern chemo-immunotherapies containing rituximab, bendamustine, bortezomib, as well as the new drugs carfilzomib and venetoclax9,10,11 resulted in major cytoreduction. Therefore, MRD analysis might provide a more accurate evaluation of the efficacy of novel treatments, rather than the simple clinical response. Actually, MYD88L265P ddPCR assay can overcome the limited feasibility of the IGH-based approach,5,12 providing a stable molecular marker virtually to all WM patients. Moreover, the data on cell-free DNA (cfDNA) seem to nicely reflect the BM status, thus representing a non-invasive alternative for MRD detection. Nevertheless, the role of MRD in WM is not as well characterized as it is in other indolent lymphomas, so far, and its clinical impact is still under evaluation.13 Might ddPCR be useful to identify MYD88 mutation in pre-treated patients? LF, a 62-years-old male, presented with diffused lymphadenopathy and anemia (Hb 10.9 g/dl). The serum protein electrophoresis showed a MC of 1585 mg/dl (IgM value 2730 mg/dl), so lymph node and BM biopsy were performed and a diagnosis of WM was made. The MYD88L265P screening by ddPCR was positive on BM. The patient underwent a DRC therapy, but at the end of treatment the CT scan revealed a SD, along with no serological response (IgM 2438 mg/dl); actually, MYD88L265P resulted negative on PB, but still positive on plasma. Finally, the patient was referred to bendamustine-rituximab-bortezomib (BRB)12 experimental therapy. Comment In patients pre-treated with rituximab, non-invasive MYD88L265P evaluation in PB is not reliable because of the high rate of false negative results,5 likely due to the high clearance of circulating lymphoma cells. Therefore, BM or plasma analysis is advisable in pre-treated cases to identify the mutation. Actually, in paired analysis the median mutational load in PB samples is 1 log lower, compared to BM; conversely, between BM and plasma-cfDNA no statistically significant differences were reported.5 Moreover, a similar underestimation of MYD88L265P was described in PB samples of pre-treated vs rituximab-naïve patients, both in terms of mutational detection rates (about 40% of false negatives) and of median quantitative burden (about 1 log lower).5 This clue is particularly relevant when MYD88 mutational status is investigated as response predictor to targeted therapies, such as to prescribe BTK-inhibitors vs a different relapse treatment.14 Might MYD88 be useful to supplement the diagnosis of anti-mag polyneuropathy? DF, a 54-years-old male, presented with lower limbs paresthesia. An electroneurography (ENG) showed the presence of a demyelinating polyneuropathy. The evaluation for anti-myelin-associated glycoprotein antibodies (MAG) resulted positive and the IgM value was 307 mg/dl (no MC at protein electrophoresis nor at immunofixation). A BM biopsy revealed the presence of a LPL, and the MYD88L265P screening by ddPCR was positive on BM, PB and plasma. Based on the presence of LPL and a progressive anti-MAG polyneuropathy, the patient underwent 4 rituximab infusions. At the end of therapy, the IgM value was 175 mg/dl, the MYD88 screening was negative on PB and plasma (BM biopsy was not repeated) and the ENG revealed a clear reduction of the demyelinization signs. Comment Anti-MAG demyelinating polyneuropathy is a rare, disabling and still under-characterized disease that can be associated either to WM/LPL or to IgM-MGUS. The prevalence of MYD88L265P mutations in anti-MAG neuropathy patients has been recently shown to be comparable to those observed in WM and MGUS control groups. Since there is actually no consensus on the optimal treatment strategy for anti-MAG neuropathies, detecting MYD88L265P mutation even in non-invasive tissues might help to reveal a smoldering WM, identifying patients for which rituximab treatment may be of benefit.15,16,17 In conclusion, the ddPCR MYD88L265P assay might have several clinical applications (Fig. 3): 1) driving the differential diagnosis with IgM-MM and small lymphocytes, Ig-secreting disorders; 2) easy-to use molecular marker for MRD, particularly to measure the efficacy of new drugs; 3) predictive biomarker of response to ibrutinib treatment; 4) supporting the diagnosis of WM as underlying disease for rare IgM-related disorders (eg, anti-MAG polyneuropathy). Figure 3: Clinical applications of the ddPCR MYD88 L265P assay in WM.The ddPCR MYD88L265P assay also presents important advantages compared to other available techniques (as qPCR or NGS): actually, it is non-invasive, cheap, fast, easily applicable to clinical routine and clinical trials, standardizable and promptly scalable to other mutations of interest (eg, CXCR4). Therefore, this assay is rapidly finding its role both for mutational screening and for MRD monitoring in ongoing (BRB, EudraCT Number: 2013-005129-22 and BIO_WM, ID: NCT03521516) and future (ECWM-2, EudraCT Number: 2017-004362-95) clinical trials.

OBJECTIVE:To assess the prognostic influence of pre-morbid type 2 diabetes mellitus, arterial hypertension and cardiovascular (CV) risk profile on ALS phenotype and outcome in a population-based cohort of Italian patients.METHODS:A total of 650 ALS patients from the Piemonte/Valle d'Aosta Register for ALS, incident in the 2007-2011 period, were recruited. Information about premorbid presence of type 2 diabetes mellitus, arterial hypertension was collected at the time of diagnosis. Patients' CV risk profile was calculated according to the Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice (JBS2).RESULTS:At the univariate analysis, the presence of pre-morbid arterial hypertension was associated with a higher age at onset of ALS and a shorter survival, and patients with a high CV risk profile had a worse prognosis than those with a low CV risk profile. The Cox multivariable analysis did not confirm such findings. Type 2 diabetes mellitus did not modify either the phenotype or the prognosis of ALS patients.CONCLUSIONS:This study performed on a large population-based cohort of ALS patients has demonstrated that arterial hypertension, type 2 diabetes and CV risk factors, calculated using the Framingham equation, do not influence ALS phenotype and prognosis.

INTRODUCTION:In the brain, the chemokine (C-X3-C motif) receptor 1 (1CX3CR1) gene is expressed only by microglia, where it acts as a key mediator of the neuron-microglia interactions. We assessed whether the 2 common polymorphisms of the CX3CR1 gene (V249I and T280M) modify amyotrophic lateral sclerosis (ALS) phenotype. METHODS:The study included 755 ALS patients diagnosed in Piemonte between 2007 and 2012 and 369 age-matched and sex-matched controls, all genotyped with the same chips. RESULTS:Neither of the variants was associated with an increased risk of ALS. Patients with the V249I V/V genotype had a 6-month-shorter survival than those with I/I or V/I genotypes (dominant model, P = 0.018). The T280M genotype showed a significant difference among the 3 genotypes (additive model, P = 0.036). Cox multivariable analysis confirmed these findings. DISCUSSION:We found that common variants of the CX3CR1 gene influence ALS survival. Our data provide further evidence for the role of neuroinflammation in ALS. Muscle Nerve 57: 212-216, 2018.

Importance This study reports the long-term epidemiologic trends of amyotrophic lateral sclerosis (ALS) based on a prospective register. Objective To examine the 20-year epidemiologic trends of ALS in the Piemonte and Valle d'Aosta regions of Italy. Design, Setting, and Participants The Piemonte and Valle d'Aosta Register for ALS (PARALS) is an epidemiologic prospective register that covers 2 Italian regions (population of 4 476 931 inhabitants according to the 2011 census) from January 1, 1995, through December 31, 2014. Case ascertainment is based on multiple sources (neurologic departments, hospital discharge archives, and mortality records). Incidence rates are age and sex standardized for the Italian population of the 2011 census. Age-period-cohort (APC) analysis was performed using a Poisson regression model. Main Outcomes and Measures The primary study outcomes were long-term incidence and prevalence rates of ALS using a prospective design and their determinants. Results During the study period, a total of 2702 patients (mean [SD] age at onset, 65.7 [11.1] years; 1246 [46.1%] female and 1456 [53.9%] male) received a diagnosis of ALS between 1995 and 2014, corresponding to a crude annual incidence rate of 3.03 per 100 000 population (95% CI, 2.85-3.23) and an adjusted incidence rate of 2.78 per 100 000 population (95% CI, 2.57-2.96). The age-adjusted incidence rate increased in the 2 decades of the study (1995-2004: 2.66; 95% CI, 2.50-2.83; 2005-2014: 2.89; 95% CI, 2.71-3.07;P = .04), mostly in women. The adjusted rate ratio of men to women decreased from 1.27:1 (1995-2004) to 1.17:1 (2005-2014). The analysis of deviance for the APC regression models indicated that the drift variable is relevant in explaining the variation of ALS incidence rates over time in the overall population (change in deviance, 4.6553;P = .03) and in women (change in deviance, 3.8821;P = .05) but not in men (change in deviance, 0.77215;P = .38). A total of 479 patients with ALS were alive and had not undergone tracheostomy at the prevalence day (December 31, 2014), corresponding to a crude prevalence rate of 10.54 per 100 000 population (95% CI, 9.64-11.52). Conclusions and Relevance During the 1995 to 2014 period, the crude and adjusted incidences of ALS increased in Piemonte and Valle d'Aosta, mostly in women. The APC model revealed that the increase of ALS incidence is attributable to a birth cohort effect in women, with a peak in the 1930 cohort. The different increase of ALS incidence in men and women points to an effect of exogenous factors with a differential effect on the 2 sexes, acting on a genetic background.

Objective To assess the prognostic influence of premorbid smoking habits and vascular risk profile on amyotrophic lateral sclerosis (ALS) phenotype and outcome in a population-based cohort of Italian patients. Methods A total of 650 patients with ALS from the Piemonte/Valle d'Aosta Register for ALS, incident in the 2007–2011 period, were recruited. Information about premorbid cigarette smoking habits and chronic obstructive pulmonary disease (COPD) were collected at the time of diagnosis. Results Current smokers had a significantly shorter median survival (1.9 years, IQR 1.2–3.4) compared with former (2.3 years, IQR 1.5–4.2) and never smokers (2.7 years, IQR 1.8–4.6) (p=0.001). Also COPD adversely influenced patients’ prognosis. Both smoking habits and CODP were retained in Cox multivariable model. Conclusions This study has demonstrated in a large population-based cohort of patients with ALS that cigarette smoking is an independent negative prognostic factor for survival, with a dose–response gradient. Its effect is not related to the presence of COPD or to respiratory status at time of diagnosis. The understanding of the mechanisms, either genetic or epigenetic, through which exogenous factors influence disease phenotype is of major importance towards a more focused approach to cure ALS.

Objective. To assess the role of AH and DM on ALS phenotype and prognosis in a population-based series. Background. Several studies have assessed vascular risk factors in ALS. It has been reported that pre-morbid AH shortens the survival in ALS patients while diabetes mellitus type II (DM) delays the onset of motor symptoms. Design/Methods. The study has been performed on ALS patients incident in the 2007-2011 in Piemonte region. The 712 patients incident in the examined period were included in the study (323 women and 389 men, mean age at onset 66.7 years [SD 10.7]). Results. Of the 712 patients, 314 (44.1[percnt]) had AH for at least 2 years before the onset of ALS, and 68 (9.6[percnt]) had DM. Patients with AH were significantly older than those with normal arterial pressure (men, 68.4 [9.0] vs. 64.8 [11.4]; women 70.4 [8.5] vs. 64.0 [11.6]; p=0.0001 for both comparisons). Pre-morbid AH or DM did not influence the site of onset of ALS (bulbar vs. spinal). The mean age at onset did not differ between patients with and without DM (men, 67.9 [8.8] vs. 66.1 [10.8]; women, 68.7 [8.7] vs. 66.9 [10.9]; p=n.s. for both comparisons). Survival from onset was reduced in women (p=0.05) but not in men with AH, and was not affected by the presence of DM in both genders. Conclusions. In this epidemiological series, the presence of pre-morbid AH or DM did not influence the phenotype and the survival of ALS patients. Funding. Italian Ministry of Health (RF-2010-2309849), Joint Programme Neurodegenerative Disease Research (Sophia Project), European Community’s Health Seventh Framework Programme (grant 259867), Fondazione Vialli e Mauro. Disclosure: Dr. Calvo has nothing to disclose. Dr. Moglia has nothing to disclose. Dr. Canosa has nothing to disclose. Dr. Bertuzzo has nothing to disclose. Dr. Galmozzi has nothing to disclose. Dr. Cugnasco has nothing to disclose. Dr. Clerico has nothing to disclose. Dr. De Mercanti has nothing to disclose. Dr. Bersano has nothing to disclose. Dr. Cammarosano has nothing to disclose. Dr. Ilardi has nothing to disclose. Dr. Manera has nothing to disclose. Dr. Sideri has nothing to disclose. Dr. Marinou has nothing to disclose. Dr. Bottacchi has nothing to disclose. Dr. Pisano has nothing to disclose. Dr. Cantello has nothing to disclose. Dr. Mazzini has nothing to disclose. Dr. Mora has nothing to disclose. Adriano Chio serves on a scientific advisory board for Biogen Idec, Cytokinetics and Italfamaco,

April 21, 2015April 6, 2015Free AccessAdvance directives and palliative care in ALS patients. The Piedmont and Valle d’Aosta register experience (I8-5D)Andrea Calvo, Umberto Manera, Antonio Canosa, Davide Bertuzzo, Stefania Cammarosano, Cristina Moglia, Antonio Ilardi, and Adriano ChioAuthors Info & AffiliationsApril 6, 2015 issue84 (14_supplement)https://doi.org/10.1212/WNL.84.14_supplement.I8-5D Letters to the Editor