COVID-19-associated Guillain-Barré syndrome in the early pandemic experience in Lombardia (Italy).

OBJECTIVE: To estimate the incidence and describe clinical characteristics and outcome of GBS in COVID-19 patients (COVID19-GBS) in one of the most hit regions during the first pandemic wave, Lombardia. METHODS: Adult patients admitted to 20 Neurological Units between 1/3-30/4/2020 with COVID19-GBS were included as part of a multi-center study organized by the Italian society of Hospital Neuroscience (SNO). RESULTS: Thirty-eight COVID19-GBS patients had a mean age of 60.7 years and male frequency of 86.8%. CSF albuminocytological dissociation was detected in 71.4%, and PCR for SARS-CoV-2 was negative in 19 tested patients. Based on neurophysiology, 81.8% of patients had a diagnosis of AIDP, 12.1% of AMSAN, and 6.1% of AMAN. The course was favorable in 76.3% of patients, stable in 10.5%, while 13.2% worsened, of which 3 died. The estimated occurrence rate in Lombardia ranges from 0.5 to 0.05 GBS cases per 1000 COVID-19 infections depending on whether you consider positive cases or estimated seropositive cases. When we compared GBS cases with the pre-pandemic period, we found a reduction of cases from 165 to 135 cases in the 2-month study period in Lombardia. CONCLUSIONS: We detected an increased incidence of GBS in COVID-19 patients which can reflect a higher risk of GBS in COVID-19 patients and a reduction of GBS events during the pandemic period possibly due to a lower spread of more common respiratory infectious diseases determined by an increased use of preventive measures.

Guillain-Barré syndrome and COVID-19: A 1-year observational multicenter study.

BACKGROUND AND PURPOSE: Many single cases and small series of Guillain-Barré syndrome (GBS) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were reported during the coronavirus disease 19 (COVID-19) outbreak worldwide. However, the debate regarding the possible role of infection in causing GBS is still ongoing. This multicenter study aimed to evaluate epidemiological and clinical findings of GBS diagnosed during the COVID-19 pandemic in northeastern Italy in order to further investigate the possible association between GBS and COVID-19. METHODS: Guillain-Barré syndrome cases diagnosed in 14 referral hospitals from northern Italy between March 2020 and March 2021 were collected and divided into COVID-19-positive and COVID-19-negative. As a control population, GBS patients diagnosed in the same hospitals from January 2019 to February 2020 were considered. RESULTS: The estimated incidence of GBS in 2020 was 1.41 cases per 100,000 persons/year (95% confidence interval 1.18-1.68) versus 0.89 cases per 100,000 persons/year (95% confidence interval 0.71-1.11) in 2019. The cumulative incidence of GBS increased by 59% in the period March 2020-March 2021 and, most importantly, COVID-19-positive GBS patients represented about 50% of the total GBS cases with most of them occurring during the two first pandemic waves in spring and autumn 2020. COVID-19-negative GBS cases from March 2020 to March 2021 declined by 22% compared to February 2019-February 2020. CONCLUSIONS: Other than showing an increase of GBS in northern Italy in the "COVID-19 era" compared to the previous year, this study emphasizes how GBS cases related to COVID-19 represent a significant part of the total, thus suggesting a relation between COVID-19 and GBS.

Guillain-Barré syndrome and COVID-19: an observational multicentre study from two Italian hotspot regions.

OBJECTIVE: Single cases and small series of Guillain-Barré syndrome (GBS) have been reported during the SARS-CoV-2 outbreak worldwide. We evaluated incidence and clinical features of GBS in a cohort of patients from two regions of northern Italy with the highest number of patients with COVID-19. METHODS: GBS cases diagnosed in 12 referral hospitals from Lombardy and Veneto in March and April 2020 were retrospectively collected. As a control population, GBS diagnosed in March and April 2019 in the same hospitals were considered. RESULTS: Incidence of GBS in March and April 2020 was 0.202/100 000/month (estimated rate 2.43/100 000/year) vs 0.077/100 000/month (estimated rate 0.93/100 000/year) in the same months of 2019 with a 2.6-fold increase. Estimated incidence of GBS in COVID-19-positive patients was 47.9/100 000 and in the COVID-19-positive hospitalised patients was 236/100 000. COVID-19-positive patients with GBS, when compared with COVID-19-negative subjects, showed lower MRC sum score (26.3±18.3 vs 41.4±14.8, p=0.006), higher frequency of demyelinating subtype (76.6% vs 35.3%, p=0.011), more frequent low blood pressure (50% vs 11.8%, p=0.017) and higher rate of admission to intensive care unit (66.6% vs 17.6%, p=0.002). CONCLUSIONS: This study shows an increased incidence of GBS during the COVID-19 outbreak in northern Italy, supporting a pathogenic link. COVID-19-associated GBS is predominantly demyelinating and seems to be more severe than non-COVID-19 GBS, although it is likely that in some patients the systemic impairment due to COVID-19 might have contributed to the severity of the whole clinical picture.

Determinants of therapy switch in multiple sclerosis treatment-naïve patients: A real-life study.

BACKGROUND: With many options now available, first therapy choice is challenging in multiple sclerosis (MS) and depends mainly on neurologist and patient preferences. OBJECTIVES: To identify prognostic factors for early switch after first therapy choice. METHODS: Newly diagnosed relapsing-remitting MS patients from 24 Italian centers were included. We evaluated the association of baseline demographics, clinical, and magnetic resonance imaging (MRI) data to the switch probability for lack of efficacy or intolerance/safety with a multivariate Cox analysis and estimated switch rates by competing risks models. RESULTS: We enrolled 3025 patients. The overall switch frequency was 48% after 3 years. Switch risk for lack of efficacy was lower with fingolimod (hazard ratio (HR) = 0.50; p = 0.009), natalizumab (HR = 0.13; p < 0.001), dimethyl-fumarate (HR = 0.60; p = 0.037), teriflunomide (HR = 0.21; p = 0.031) as compared to interferons. Younger age (HR = 0.96; p < 0.001), diagnosis delay (HR = 1.23; p = 0.021), higher baseline Expanded Disability Status Scale (HR = 1.17; p = 0.001), and spinal cord lesions (HR = 1.46; p = 0.001) were independently associated with higher inefficacy switch rates. We found lower switch for intolerance/safety with glatiramer acetate (HR = 0.61; p = 0.001), fingolimod (HR = 0.35; p = 0.002), and dimethyl-fumarate (HR = 0.57; p = 0.022) as compared to interferons, while it increased with natalizumab (HR = 1.43; p = 0.022). Comorbidities were associated with intolerance switch (HR = 1.28; p = 0.047). CONCLUSION: Several factors are associated with higher switch risk in patients starting a first-line therapy and could be integrated in the decision-making process of first treatment choice.

TREX1 C-terminal frameshift mutations in the systemic variant of retinal vasculopathy with cerebral leukodystrophy.

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult-onset disorder caused by C-terminal heterozygous frameshift (fs) mutations in the human 3'-5' DNA exonuclease TREX1. Hereditary systemic angiopathy (HSA) is considered a variant of RVCL with systemic involvement of unknown genetic cause, described in a unique family so far. Here we describe the second case of RVCL with systemic involvement, characterized by cerebral calcifications and pseudotumoral lesions, retinopathy, osteonecrosis, renal and hepatic failure. The genetic screening of TREX1 in this patient revealed the novel heterozygous T270fs mutation on the C-terminal region. On the same gene, we found the V235fs mutation, formerly shown in RVCL, in one patient previously reported with HSA. These mutations lead to important alterations of the C-terminal of the protein, with the loss of the transmembrane helix (T270fs) and the insertion of a premature stop codon, resulting in a truncated protein (V235fs). Functional analysis of T270fs-mutated fibroblasts showed a prevalent localization of the protein in the cytosol, rather than in the perinuclear region. RVCL with systemic involvement is an extremely rare condition, whose diagnosis is complex due to multiorgan manifestations, unusual radiological and histopathological findings, not easily attributable to a single disease. It should be suspected in young adults with systemic microangiopathy involving retina, liver, kidney, bones and brain. Here we confirm the causative role played by TREX1 autosomal dominant fs mutations disrupting the C-terminal of the protein, providing a model for the study of stroke in young adults.

Early predictors of oxaliplatin-induced cumulative neuropathy in colorectal cancer patients.

OBJECTIVES: Peripheral neuropathy ranks among the most common dose-limiting and disabling side-effect of oxaliplatin (OXA)-based chemotherapy. The aim of this prospective, multicentre study was to define early clinical and neurophysiological markers that may help to identify patients at risk of developing severe, treatment emergent, cumulative OXA-induced peripheral neuropathy (OXAIPN). METHODS: 200 colorectal cancer patients, scheduled to receive OXA-based chemotherapy, were prospectively followed. Detailed neurological assessment employing the clinical Total Neuropathy Score (TNSc), oncological rating scales (National Common Institute-Common Toxicity Criteria V.3) and nerve conduction studies (NCS) were performed at baseline, mid-treatment and at the end of chemotherapy. Symptoms of OXA-induced acute neurotoxicity were systematically recorded. RESULTS: According to TNSc, 36 (18%) patients developed grade 3 OXAIPN. These patients were predominantly men (p=0.005), presented a significant decrease in all NCS (p<0.001), reported more acute neuropathic symptoms (p<0.001) and received higher OXA cumulative dose (p=0.003). Multivariate analysis showed that three variables obtained at intermediate follow-up, namely, the number of acute symptoms (OR 1.9; CI 95% 1.2 to 3.2; p=0.012) and the >30% decrease in sensory nerve action potential amplitude from the baseline value in radial (OR 41.4; CI 95% 4.98 to 343.1; p=0.001) and dorsal sural nerves (OR 24.96; CI 95% 2.6 to 239.4; p=0.005) were independently associated with the risk of developing severe OXAIPN. CONCLUSIONS: High-grade OXA neurotoxicity can be predicted by clinical and neurophysiological information obtained at mid-treatment. Neurological assessment of acute neuropathy symptoms and radial and dorsal sural nerves NCS should be carefully monitored to predict and hopefully prevent the induction of severe OXAIPN.

Long-term course of oxaliplatin-induced polyneuropathy: a prospective 2-year follow-up study.

This prospective study sought to identify the potential reversibility of oxaliplatin-induced peripheral neuropathy (OXAIPN) by following-up its long-term course 2 years after discontinuation of oxaliplatin (OXA)-based chemotherapy. Participants were 91 colorectal cancer patients treated with OXA-based chemotherapy. Neurological assessment, clinical Total Neuropathy Score© (TNSc©) and nerve conduction studies were performed at baseline (T0), the end of chemotherapy (T1) and 2 years (T2) after discontinuation of chemotherapy. A total of 73 of 91 (80%) patients experienced OXAIPN at T1. At a median follow-up of 25 months, persistence of chronic OXAIPN was present in 61 of 73 patients (84%) and complete resolution was present in 12 patients (17%). Longitudinal comparison of TNSc© values between T1 and T2 revealed that the overall severity of OXAIPN in those 61 patients significantly decreased over time. Median TNSc© values were nine (range: 2-15) at T1 vs. four (range: 2-12) at T2 (P < 0.001). Likewise, sensory nerve conduction measures at T2 significantly improved in all sensory nerves tested, compared with T1. Severity of OXAIPN at T2 was significantly associated (P < 0.001) with high severity of OXAIPN at T1. In conclusion, persistence of OXAIPN beyond 2 years after finishing chemotherapy is common. Clinical and neurophysiological improvement is observed, although recovery is often incomplete.

Correspondence between neurophysiological and clinical measurements of chemotherapy-induced peripheral neuropathy: secondary analysis of data from the CI-PeriNomS study.

Chemotherapy-induced peripheral neuropathy (CIPN) lacks standardized clinical measurement. The objective of the current secondary analysis was to examine data from the CIPN Outcomes Standardization (CI-PeriNomS) study for associations between clinical examinations and neurophysiological abnormalities. Logistic regression estimated the strength of associations of vibration, pin, and monofilament examinations with lower limb sensory and motor amplitudes. Examinations were classified as normal (0), moderately abnormal (1), or severely abnormal (2). Among 218 participants, those with class 1 upper extremity (UE) and classes 1 or 2 lower extremity (LE) monofilament abnormality were 2.79 (95% confidence interval [CI]: 1.28-6.07), 3.49 (95%CI: 1.61-7.55), and 4.42 (95%CI: 1.35-14.46) times more likely to have abnormal sural nerve amplitudes, respectively, compared to individuals with normal examinations. Likewise, those with class 2 UE and classes 1 or 2 LE vibration abnormality were 8.65 (95%CI: 1.81-41.42), 2.54 (95%CI: 1.19-5.41), and 7.47 (95%CI: 2.49-22.40) times more likely to have abnormal sural nerve amplitudes, respectively, compared to participants with normal examinations. Abnormalities in vibration and monofilament examinations are associated with abnormal sural nerve amplitudes and are useful in identifying CIPN.

Neurophysiological examination of dorsal sural nerve.

INTRODUCTION: Nerve conduction study of the dorsal sural nerve (DSN) has been reported to be a sensitive method for early detection of peripheral neuropathies. However, normal reference values are scarce and vary greatly among the different studies. METHODS: A comprehensive neurophysiological study, including nerve conduction velocity (NCV) and sensory nerve action potential (SNAP) recording, was performed in 294 healthy subjects (21-86 years) with no evidence of neuropathy. RESULTS: The amplitude of the DSN SNAP ranged from 2.50 to 15.90 µV, and NCV ranged from 28.9 to 52.8 m/s. A significant age-related decrease in DSN SNAP amplitude and NCV was observed. The mean ratio of sural NCV to DSN NCV was 1.33 ± 0.19, and the mean ratio of sural nerve SNAP amplitude to DSN SNAP amplitude was 3.17 ± 1.33. CONCLUSION: These normative data of the DSN might be used as reference values for the study of this very distal peripheral nerve.

Chemotherapy-induced peripheral neurotoxicity can be misdiagnosed by the National Cancer Institute Common Toxicity scale.

The assessment of chemotherapy-induced peripheral neurotoxicity (CIPN) is still uncertain as several of the most frequently used scales do not rely on a formal neurological evaluation and depend on patients' reports and examiners' interpretations. The aim of this study was to compare the assessment of CIPN using the National Cancer Institute Common Toxicity Criteria (NCI-CTC) scale and a formal neurological assessment scored with the Total Neuropathy Score (TNS, i.e., a composite scale designed to grade the impairment in neuropathy patients) to identify possible discrepancies in the diagnosis. In this prospective study, 155 patients treated with cisplatin/carboplatin or with paclitaxel/docetaxel and CIPN were examined in a collaborative oncological/neurological multi-center trial using the NCI-CTC scale and the TNS; the results were then extensively compared. We evidenced that the TNS allows possible misdiagnosed neuropathies to be revealed. In fact, the NCI-CTC evaluation performed by experienced examiners overestimated the occurrence of motor neuropathy, possibly because of the presence of confounding factors (e.g., fatigue, depression, cachexia), which might be difficult to be ruled out without a formal neurological examination. This study strongly indicates that a more formal neurological assessment of patients with CIPN than that achievable with the common toxicity scales (e.g., NCI-CTC) is advisable.

Chemotherapy-induced neuropathy.

OPINION STATEMENT: Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most severe and unpredictable side effects of modern anticancer treatment. In recent years, a clear understanding of the importance of an integrated approach to CIPN has become evident, and efforts are increasing to better characterize its features and to identify more accurate methods to report and grade its occurrence. The clinically relevant impact of CIPN on cancer patients has been known for a long time, but knowledge of its pathogenetic aspects is still very limited. This incomplete knowledge is one of the major limitations in identifying targets for evidence-based neuroprotective strategies. Nevertheless, several studies have been devoted to the prevention or at least the effective treatment of symptoms secondary to peripheral nerve damage and to the early identification of patients at high risk of developing severe CIPN. Unfortunately, none of these studies has been successful and the optimal management of CIPN patients is still an unmet clinical need. Therefore, the modification of chemotherapy is currently the only available approach to limit the severity of neuropathy in the vast majority of patients. The indications for treatment modification are not universally accepted and they can differ among the various drugs. Generally, treatment modification should be considered as soon as symptoms and signs impair the daily life activities of the patient, but the possibility of a delayed worsening of CIPN after treatment withdrawal ("coasting") should always be considered, and delay of modification decisions should be avoided.

Electrophysiological features of acute inflammatory demyelinating polyneuropathy associated with SARS-CoV-2 infection.

OBJECTIVE: To assess whether patients with acute inflammatory demyelinating polyneuropathy (AIDP) associated with SARS-CoV-2 show characteristic electrophysiological features. METHODS: Clinical and electrophysiological findings of 24 patients with SARS-CoV-2 infection and AIDP (S-AIDP) and of 48 control AIDP (C-AIDP) without SARS-CoV-2 infection were compared. RESULTS: S-AIDP patients more frequently developed respiratory failure (83.3% vs. 25%, P=0.000) and required intensive care unit (ICU) hospitalization (58.3% vs. 31.3%, P=0.000). In C-AIDP, distal motor latencies (DMLs) were more frequently prolonged (70.9% vs. 26.2%, P=0.000) whereas in S-AIDP distal compound muscle action potential (dCMAP) durations were more frequently increased (49.5% vs. 32.4%, P=0.002) and F waves were more often absent (45.6% vs. 31.8%, P=0.011). Presence of nerves with increased dCMAP duration and normal or slightly prolonged DML was elevenfold higher in S-AIDP (31.1% vs. 2.8%, P=0.000);11 S-AIDP patients showed this pattern in 2 nerves. CONCLUSION: Increased dCMAP duration, thought to be a marker of acquired demyelination, can also be oserved in critical illness myopathy. In S-AIDP patients, an increased dCMAP duration dissociated from prolonged DML, suggests additional muscle fiber conduction slowing, possibly due to a COVID-19-related hyperinflammatory state. Absent F waves, at least in some S-AIDP patients, may reflect α-motor neuron hypoexcitability because of immobilization during the ICU stay. These features should be considered in the electrodiagnosis of SARS-CoV-2 patients with weakness, to avoid misdiagnosis.

Neurologic manifestations in 1760 COVID-19 patients admitted to Papa Giovanni XXIII Hospital, Bergamo, Italy.

OBJECTIVES: Evidences from either small series or spontaneous reporting are accumulating that SARS-CoV-2 involves the Nervous Systems. The aim of this study is to provide an extensive overview on the major neurological complications in a large cohort of COVID-19 patients. METHODS: Retrospective, observational analysis on all COVID-19 patients admitted from February 23rd to April 30th, 2020 to ASST Papa Giovanni XXIII, Bergamo, Italy for whom a neurological consultation/neurophysiological assessment/neuroradiologic investigation was requested. Each identified neurologic complication was then classified into main neurologic categories. RESULTS: Of 1760 COVID-19 patients, 137 presented neurologic manifestations that manifested after COVID-19 symptoms in 98 pts and was the presenting symptom in 39. Neurological manifestations were classified as: (a) cerebrovascular disease [53 pts (38.7%)] including 37 ischemic and 11 haemorrhagic strokes, 4 transient ischemic attacks, 1 cerebral venous thrombosis; (b) peripheral nervous system diseases [31 (22.6%)] including 17 Guillain-Barrè syndromes; (c) altered mental status [49 (35.8%)] including one necrotizing encephalitis and 2 cases with RT-PCR detection of SARS-Cov-2 RNA in CSF; (d) miscellaneous disorders, among whom 2 patients with myelopathy associated with Ab anti-SARS-CoV-2 in CSF. Patients with peripheral nervous system involvement had more frequently severe ARDS compared to patients with cerebrovascular disease (87.1% vs 42%; difference = 45.1% 95% CI 42.0-48.2; χ2= 14.306; p < 0.0002) and with altered mental status (87.1% vs 55.6%; difference = 31.5% 95% CI 27.5-37.5%; χ2= 7.055; p < 0.01). CONCLUSION: This study confirms that involvement of nervous system is common in SARS-CoV-2 infection and offers clinicians useful information for prevention and prompt identification in order to set the adequate therapeutic strategies.

Predictive Value of Preoperative and Intraoperative Neurophysiology in Evaluating Long-term Facial Function Outcome in Acoustic Neuroma Surgery.

OBJECTIVE: To determine the role of neurophysiological preoperative and intraoperative parameters in providing prognostic information regarding facial nerve (FN) function at 1 year after translabyrinthine acoustic neuroma (AN) resection surgery. STUDY DESIGN: Prospective observational study in a tertiary referral center. Patients treated via translabyrinthine surgical approach for sporadic AN microresection between December 2015 and 2018. METHODS: Patients underwent preoperative (electroneurography-ENG, electromyography-EMG, and Blink Reflex-BR) and intraoperative (FN motor action potential-MAP and continuous EMG traces) neurophysiological studies. FN function was graded postoperatively at 1 year using House-Brackmann Scoring System. RESULTS: Sixty-two patients were included in the analysis. Mean age was 53±10 years and average tumor diameter was 23 ±â€Š9 mm. At 1 year a normal facial function was observed in 68% of patients. In the univariate analysis a pathologic BR, low FN MAP values and ratios, and the presence of pathological neurotonic tracing (A-trains) on continuous EMG were associated with a poor facial nerve function outcome at 1 year postoperatively. Pathological preoperative BR testing and intraoperative A-trains showed a statistical significance also in the multivariable analysis, regardless of tumor size. CONCLUSIONS: Preoperative pathological BR testing and A-train activity on intraoperative EMG are correlated with poor FN outcomes at 1 year postoperative. This may provide important prognostic information to both patients and treating neuro-otologists. In the future this may guide preoperative and postoperative patient counselling and possibly optimize timing of facial nerve reanimation in selected patients.

Cladribine vs other drugs in MS: Merging randomized trial with real-life data.

OBJECTIVE: Cladribine tablets were tested against placebo in randomized controlled trials (RCTs). In this study, the effectiveness of cladribine vs other approved drugs in patients with relapsing-remitting MS (RRMS) was compared by matching RCT to observational data. METHODS: Data from the pivotal trial assessing cladribine tablets vs placebo (CLARITY) were propensity score matched to data from the Italian multicenter database i-MuST. This database included 3,150 patients diagnosed between 2010 and 2018 at 24 Italian MS centers who started a disease-modifying drug. The annualized relapse rate (ARR) over 2 years from treatment start and the 24-week confirmed disability progression were compared between patients treated with cladribine and other approved drugs (interferon, glatiramer acetate, fingolimod, natalizumab, and dimethyl fumarate), with comparisons with placebo as a reference. Treatment effects were estimated by the inverse probability weighting negative binomial regression model for ARR and Cox model for disability progression. The treatment effect has also been evaluated according to baseline disease activity. RESULTS: All weighted baseline characteristics were well balanced between groups. All drugs tested had an effect vs placebo close to that detected in the RCT. Patients treated with cladribine had a significantly lower ARR compared with interferon (relapse ratio [RR] = 0.48; p < 0.001), glatiramer acetate (RR = 0.49; p < 0.001), and dimethyl fumarate (RR = 0.6; p = 0.001); a similar ARR to that with fingolimod (RR = 0.74; p = 0.24); and a significantly higher ARR than natalizumab (RR = 2.13; p = 0.014), confirming results obtained by indirect treatment comparisons from RCTs (network meta-analyses). The relative effect of cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years) was higher in patients with high disease activity vs all treatments except fingolimod and natalizumab. Effects on disability progression were largely nonsignificant, probably due to lack of power for such analysis. CONCLUSION: In patients with RRMS, cladribine tablets showed lower ARR compared with matched patients who started interferon, glatiramer acetate, or dimethyl fumarate; was similar to fingolimod; and was higher than natalizumab. The beneficial effect of cladribine tablets was generally amplified in the subgroup of patients with high disease activity. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with RRMS, cladribine-treated patients had lower ARR compared with interferon, glatiramer acetate, or dimethyl fumarate; similar ARR compared with fingolimod; and higher ARR compared with natalizumab.

First therapy choice in newly diagnosed Multiple Sclerosis patients: A multicenter Italian study.

BACKGROUND: The approval of an increasing number of disease modifying drugs for the treatment of Multiple Sclerosis (MS) creates new challenges for patients and clinicians on the first treatment choice. The main aim of this study was to assess factors impacting first therapy choice in a large Italian MS cohort. METHODS: Newly diagnosed relapsing-remitting (RR) MS patients (2010-2018) followed in 24 Italian MS centres were included in the study. We evaluated the association of baseline demographics, clinical and MRI characteristics to the first treatment choice by logistic regression models applied to pre-defined binary alternatives: dimethyl fumarate vs injectables (interferon and glatiramer acetate), teriflunomide vs injectables, fingolimod vs dimethyl fumarate and fingolimod vs natalizumab. RESULTS: We enrolled 3025 patients in the period between January 2010 and June 2018. Relapses in the previous year (OR = 2.75; p = 0.001), presence of spinal cord lesions (OR = 1.80; p = 0.002) and higher number (>9) of T2 lesions on the baseline brain MRI scan (OR = 1.65; p = 0.022) were the factors associated to dimethyl fumarate choice as first therapy vs an injectable drug. Older age (OR = 1.06; p < 0.001), male sex (OR = 2.29; p = 0.001) and higher EDSS (OR = 1.36; p < 0.001) were the factors associated with the choice of teriflunomide vs injectables. In more recent years, dimethyl fumarate (OR = 3.23; p < 0.001) and teriflunomide (OR = 2.53; p < 0.001) were chosen more frequently than injectables therapies. The main determinant for the choice of fingolimod as compared with dimethyl fumarate was a higher EDSS (OR = 1.56; p = 0.001), while there was a weak association with a longer disease duration (p = 0.068) and a longer time from onset to diagnosis (p = 0.085). Compared to fingolimod, natalizumab was preferred in patients with a younger age (OR = 0.95; p = 0.003) and higher EDSS (OR = 1.45; p = 0.007) and a shorter disease duration (OR = 0.52; p = 0.076). CONCLUSION: Many factors guided therapeutic decision for our Italian cohort of MS patients; they are mainly related to MS disease activity, baseline EDSS, disease duration and age.

Role of a pre-existing neuropathy on the course of bortezomib-induced peripheral neurotoxicity.

We investigated a series of bortezomib-treated patients and correlated the course of bortezomib-induced peripheral neurotoxicity with the presence or absence of peripheral neuropathy at baseline. Forty-eight patients were examined with the total neuropathy score reduced version (TNSr), visual analogue score (VAS) for pain, and nerve conduction studies at baseline and after two and four cycles of chemotherapy. Twenty-three patients had a baseline TNSr = 0-2, and 25 patients had a baseline TNSr >2 (median = 6, range 3-13). The course of bortezomib-induced peripheral neurotoxicity was generally more severe in those patients with the highest baseline TNSr. However, among those subjects with a normal baseline TNSr, two patients developed a clinically relevant peripheral neuropathy with a marked increase in TNSr as early as after two cycles of bortezomib treatment (TNSr = 10 and 15, respectively), while after four cycles, three other patients with normal baseline TNSr had a TNSr of 11, 12, and 13. VAS reporting confirmed that painful neuropathy is frequent after bortezomib administration. Our results indicate that the course of bortezomib-induced peripheral neurotoxicity can be severe in subjects with normal neurological examination at baseline, and therefore, careful monitoring during treatment is suggested in these patients.

Pathophysiology, assessment and management of multiple sclerosis fatigue: an update.

INTRODUCTION: Fatigue is one of the most common symptoms associated with multiple sclerosis, affecting almost 80% of patients with 55% of them reporting it as one of the worst symptoms experienced, often independently of the level of disability. Areas covered: We review the main pathophysiological hypothesis, fatigue assessment scales, and its management. Expert commentary: Fatigue pathophysiology is complex and is often influenced by other secondary but relevant factors (e.g. psychological disturbances, musculoskeletal problems, sleep disorders and medication side effects) which may vary over time. Both peripheral and central mechanisms are implicated. The large heterogeneity of the assessment scales, which were used in the therapeutic trials, is partially responsible for the uncertainty of their results. To date, the best therapeutic approach seems to be from a multidisciplinary management involving exercise, rehabilitation and education in conjunction with medication.