Direct Oral Anticoagulants and Concomitant Anti-seizure Medications: A Retrospective, Case-Control Study in a Real-World Setting.

PURPOSE: Although prescription of direct oral anticoagulants (DOACs) for epileptic patients on anti-seizure medications (ASMs) is on the increase, international guidelines pose strict restrictions because this may lead to pharmacologic interactions. However, current evidence on their clinical relevance remains scanty. This retrospective, case-control study assessed the frequency of ischemic/hemorrhagic events and epileptic seizures involving DOAC-ASM cotherapy in the real world, compared with DOAC and ASM monotherapy, in age- and gender-matched controls. METHODS: Data on patients who had been prescribed a concomitant DOAC and ASM therapy for at least 6 months were extracted from the database of the Pharmaceutical Service of the Alessandria Province (Italy). After exclusions, the case group included 124 patients, 44 on valproic acid (VPA) and 80 on levetiracetam (LEV) concomitant with a DOAC, and it was compared with the DOAC-control and ASM-control groups. The clinical and laboratory data were extracted from the electronic archives of the hospitals in the same province. FINDINGS: Two (1.6%) ischemic and 2 (1.6%) major hemorrhagic events were observed in the case group. Four (3.2%) ischemic and no hemorrhagic events occurred in the DOAC-control group. There were no statistically significant differences in the ischemic and hemorrhagic events between the case group (patients on concomitant LEV or VPA who were prescribed a DOAC) and the DOAC-control group, and there was no difference in the recurrence rate of epileptic seizures between the case group and the ASM-control group. IMPLICATIONS: Although this study has some limits, mainly the small sample size, our findings indicate that neither LEV nor VPA concomitant treatment significantly affects the effects of DOACs in a real-world setting.

Mind the Metabolic Gap: Bridging Migraine and Alzheimer's disease through Brain Insulin Resistance.

Brain insulin resistance has recently been described as a metabolic abnormality of brain glucose homeostasis that has been proven to downregulate insulin receptors, both in astrocytes and neurons, triggering a reduction in glucose uptake and glycogen synthesis. This condition may generate a mismatch between brain's energy reserve and expenditure, mainly during high metabolic demand, which could be involved in the chronification of migraine and, in the long run, at least in certain subsets of patients, in the prodromic phase of Alzheimer's disease, along a putative metabolic physiopathological continuum. Indeed, the persistent disruption of glucose homeostasis and energy supply to neurons may eventually impair protein folding, an energy-requiring process, promoting pathological changes in Alzheimer's disease, such as amyloid-ß deposition and tau hyperphosphorylation. Hopefully, the "neuroenergetic hypothesis" presented herein will provide further insight on there being a conceivable metabolic bridge between chronic migraine and Alzheimer's disease, elucidating novel potential targets for the prophylactic treatment of both diseases.

Alexithymia Increases Pericranial and Cervical Muscle Tenderness in Women with Migraine.

Background/Objectives: Alexithymia is characterized by a deficit in identifying and communicating feelings. Emerging evidence suggests that alexithymia is highly prevalent in migraine, in a complex interplay with psychiatric comorbidity. Pericranial/cervical muscle tenderness is a remarkable clinical feature in a large proportion of migraine patients. This pilot study aimed at investigating the relationship between alexithymia and pericranial/cervical muscle tenderness in female migraineurs. Methods: A total of 42 female patients fulfilling the diagnostic criteria for migraine were enrolled into this pilot, observational, cross-sectional study after informed consent was obtained. Each patient underwent a psychological assessment to identify any alexithymia by means of TAS-20, anxiety/mood comorbidity (by means of STAI-Y1 STAI-Y2, BDI-II), and migraine-related disability (by means of HIT-6), and a physical cranial/cervical musculoskeletal examination. Palpation of pericranial and cervical muscles was carried out in the standardized manner. A Cumulative Muscle Tenderness (CUM) score (0-6) was calculated for each patient. A multivariate analysis was performed to investigate any association amongst the TAS-20 score, the CUM score, and the following covariates: BDI-II, STAI-Y1, STAI-Y2, and HIT-6 scores, age, disease duration, monthly migraine days, and average head pain intensity in the previous three months. Results: Overall, 35.6% of the sample had alexithymia. The multivariate analysis detected a linear and independent relationship between the TAS-20 and CUM scores, with a statistically significant (p = 0.017) association. Conclusions: This pilot study suggests that alexithymia plays a role in increasing pericranial/cervical muscle tenderness in migraine, independently from psychiatric comorbidity. A novel therapeutical approach, targeting alexithymia, may well reduce muscular tenderness in female migraineurs.

Breakthrough COVID-19 in people with multiple sclerosis on disease modifying treatments: Is it still a severe disease?

INTRODUCTION: Disease modifying treatments (DMTs) for multiple sclerosis (MS) are effective in preventing both relapses and disability progression. Highly effective treatments (HETs) are more effective than platform therapy in preventing confirmed disability progression (CDP), when used early. Infections may complicate HETs administration, and their prevention through vaccination is crucial in order to assure the safety of people with MS (pwMS). The aim of the present study is to describe the effect of MS DMTs on COVID-19 vaccination and the risk of breakthrough infection in a cohort of pwMS. MATERIALS AND METHODS: This is a monocentric retrospective observational study conducted at the MS center of the Guglielmo da Saliceto Hospital in Piacenza, Italy. One hundred and fifty-seven (157) pwMS who received two doses of the SARS-CoV-2 vaccine (with 80.3 % receiving a booster dose) were included in the study. RESULTS: fifty-six pwMS (35.7 %) were females, the mean age was 48.6 (SD: 12.87) years, and 59 (37.6 %) had at least one comorbidity. Twenty-five (15.9 %) breakthrough infections were observed, with 17 (68.0 %) classified as mild and 8 (32.0 %) as moderate. A multivariable linear regression model confirmed that B-cell suppressor DMTs and EDSS were factors associated with the latest antibody titre. Patients treated with B-cell suppressors exhibited a risk almost four times higher for breakthrough infections compared to other patients, with a hazard ratio (HR) of 3.72 (95 % CI: 1.50 - 9.27) (p = 0.005). CONCLUSIONS: B-cell suppressor DMTs are associated with the risk of breakthrough COVID-19 in our cohort, but vaccination fully protected pwMS against severe breakthrough disease.

Psychophysiological and Neurophysiological Correlates of Dropping Objects from Hands in Carpal Tunnel Syndrome.

BACKGROUND: Dropping objects from hands (DOH) is a common symptom of carpal tunnel syndrome (CTS). We evaluated the clinical, neurophysiological, and psychophysiological features of 120 CTS patients to elucidate the DOH pathophysiology. Forty-nine healthy controls were included. METHODS: In the patients, the Boston Carpal Tunnel Questionnaire (BCTQ), the Douleur Neuropathique 4 questions (DN4), and a numeric rating scale for pain (NRS) were evaluated. In patients and controls, we evaluated bilateral median and ulnar motor and sensory nerve conduction studies, cutaneous silent period and cutaneomuscular reflexes (CMR) of the abductor pollicis brevis, cold-detection threshold (CDT) and heat-pain detection threshold (HPT) at the index, little finger, and dorsum of the hand, and vibratory detection threshold at the index and little finger by quantitative sensory testing. RESULTS: CTS with DOH had higher BCTQ, DN4 and NRS, lower median sensory action potential, longer CMR duration, lower CDT and higher HPT at all tested sites than controls and CTS without DOH. Predictive features for DOH were abnormal CDT and HPT at the right index and dorsum (OR: 3.88, p: 0.03) or at the little finger (OR: 3.27, p: 0.04) and a DN4 higher than 4 (OR: 2.16, p < 0.0001). CONCLUSIONS: Thermal hypoesthesia in median and extra-median innervated territories and neuropathic pain are predictive of DOH in CTS.

CT perfusion extended window ischemic core estimation: Bayesian algorithm versus oscillation index singular value decomposition.

BACKGROUND AND PURPOSE: Ischemic core estimation by CT perfusion (CTp) is a diagnostic challenge, mainly because of the intrinsic noise associated with perfusion data. However, an accurate and reliable quantification of the ischemic core is critical in the selection of patients for reperfusion therapies. Our study aimed at assessing the diagnostic accuracy of two different CTp postprocessing algorithms, that is, the Bayesian Method and the oscillation index singular value decomposition (oSVD). METHODS: All the consecutive stroke patients studied in the extended time window (>4.5 hours from stroke onset) by CTp and diffusion-weighted imaging (DWI), between October 2019 and December 2021, were enrolled. The agreement between both algorithms and DWI was assessed by the Bland-Altman plot, Wilcoxon signed-rank test, Spearman's rank correlation coefficient, and the intraclass correlation coefficient (ICC). RESULTS: Twenty-four patients were enrolled (average age: 72 ± 15 years). The average National Institutes of Health Stroke Scale was 14.42 ± 6.75, the median Alberta Stroke Program Early CT score was 8.50 (interquartile range [IQR] = 7.75-9), and median time from stroke onset to neuroimaging was 7.5 hours (IQR = 6.5-8). There was an excellent correlation between DWI and oSVD (ρ = .87, p-value < .001) and DWI and Bayesian algorithm (ρ = .94, p-value < .001). There was a stronger ICC between DWI and Bayesian algorithm (.97, 95% confidence interval [CI]: .92-.99, p-value < .001) than between DWI and oSVD (.59, 95% CI: .26-.8, p-value < .001). DISCUSSION: The agreement between Bayesian algorithm and DWI was greater than between oSVD and DWI in the extended window. The more accurate estimation of the ischemic core offered by the Bayesian algorithm may well play a critical role in the accurate selection of patients for reperfusion therapies.

A checklist-based survey for early mobilization of stroke unit patients in an Italian region.

BACKGROUND: Although early mobilization (EM) is recommended by most guidelines in acute stroke patients, there is a paucity of tools to perform a standardized patient risk assessment prior to EM in stroke units (SUs). OBJECTIVE: This survey aimed at assessing (1) the usefulness of an ad hoc checklist for a standardized approach to EM in SUs and (2) the relationship between EM achieved by this checklist and SU characteristics. METHODS: This survey was carried out in 10 SUs in Piedmont, Italy. The EM checklist was based on 15 "items", including quantitative/qualitative, clinical and management features. RESULTS: A total of 250 completed checklists were assessed. EM, defined as out-of-bed activity within 72 h of admission, was reached by 174 patients (69.6%), according to the checklist. There was a statistically significant association between the admission NIHSS score and EM. Hypotension at mobilization was observed in 29/250 patients (11.6%) and was significantly associated with EM. A total of 6 falls (2.4%) were reported. Nurses were most frequently involved in EM, either alone (40.8%) or with another professional. CONCLUSION: A large percentage of acute stroke patients managed to achieve a safe EM in the SUs that adopted the novel checklist. These results suggest that this checklist may well be a user-friendly, reliable tool to assist SU professionals in deciding whether to mobilize or not, by means of a standardized approach.

A cross-sectional study on the association between Helicobacter pylori infection and headache.

BACKGROUND: The relationship between chronic Helicobacter pylori (HP) infection and headache has been discussed for long; nevertheless, the results of the studies are still contrasting. OBJECTIVE: This cross-sectional study is aimed to investigate a possible association between HP and headache, mainly migraine. METHODS: We screened, by a self-administered questionnaire, the subjects undergoing a breath test or an esophagogastroduodenoscopy. Migraine was diagnosed according to the international criteria. RESULTS: A total of 3914 patients underwent a breath test and 2200 an esophagogastroduodenoscopy at two hospitals, in Piedmont (Italy), in a 5-year period; a total of 1362 questionnaires were included in the study. The mean age of the subjects was 53 years; there were 777 women (57%). HP was detected in 364 (27%) subjects. A total of 702 (51%) subjects suffered from headache: migraine with aura was diagnosed in 176 subjects (176/702, i.e., 25% of the headache group; 176/1362, i.e., 13% of the total population); migraine without aura in 98 subjects (98/702, i.e., 14% of the headache group; 98/1362, i.e., 7% of the total). The logistic regression model did not detect any significant association between HP infection and headache, while a significant association between HP and headache frequency (p =0.009) was found, independently of age, gender, comorbidity, and diagnostic category. CONCLUSION: Our study does not reveal an association between chronic HP infection and migraine. However, since HP is significantly associated with higher headache frequency, a role for HP as a risk factor for headache chronification, possibly underlain by inflammatory mechanisms, may be supposed.

Multiple Sclerosis Treatment in the COVID-19 Era: A Risk-Benefit Approach.

The COVID-19 pandemic poses an ongoing global challenge, and several risk factors make people with multiple sclerosis (pwMS) particularly susceptible to running a severe disease course. Although the literature does report numerous articles on the risk factors for severe COVID-19 and vaccination response in pwMS, there is a scarcity of reviews integrating both these aspects into strategies aimed at minimizing risks. The aim of this review is to describe the risk of vulnerable pwMS exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the issues related to the SARS-CoV-2 vaccine and to evidence possible future strategies in the clinical management of pwMS. The authors searched for papers on severe COVID-19 risk factors, SARS-CoV-2 vaccination and people with multiple sclerosis in support of this narrative literature review. We propose a multilevel strategy aimed at: the evaluation of risk factors for severe COVID-19 in people with multiple sclerosis, identifying the most appropriate vaccination schedule that is safe for people on disease-modifying drugs (DMDs) and a strict follow-up of high-risk people with multiple sclerosis to allow for the prompt administration of monoclonal antibodies to manage COVID-19 risks in this patient population.

Migraine, Brain Glucose Metabolism and the "Neuroenergetic" Hypothesis: A Scoping Review.

Increasing evidence suggests that migraine may be the result of an impaired brain glucose metabolism. Several studies have reported brain mitochondrial dysfunction, impaired brain glucose metabolism and gray matter volume reduction in specific brain areas of migraineurs. Furthermore, peripheral insulin resistance, a condition demonstrated in several studies, may extend to the brain, leading to brain insulin resistance. This condition has been proven to downregulate insulin receptors, both in astrocytes and neurons, triggering a reduction in glucose uptake and glycogen synthesis, mainly during high metabolic demand. This scoping review examines the clinical, epidemiologic and pathophysiologic data supporting the hypothesis that abnormalities in brain glucose metabolism may generate a mismatch between the brain's energy reserve and metabolic expenditure, triggering migraine attacks. Moreover, alteration in glucose homeostasis could generate a chronic brain energy deficit promoting migraine chronification. Lastly, insulin resistance may link migraine with its comorbidities, like obesity, depression, cognitive impairment and cerebrovascular diseases. PERSPECTIVE: Although additional experimental studies are needed to support this novel "neuroenergetic" hypothesis, brain insulin resistance in migraineurs may unravel the pathophysiological mechanisms of the disease, explaining the migraine chronification and connecting migraine with comorbidities. Therefore, this hypothesis could elucidate novel potential approaches for migraine treatment.

Change in the second exteroceptive suppression period of the temporalis muscle during erenumab treatment.

Comparative studies on the second exteroceptive suppression period (ES2) of the masseter or temporalis muscle in migraineurs and controls have provided conflicting results. As the interneurons responsible for ES2 are probably close to the trigeminal nucleus caudalis and receive afferents also from the anti-nociceptive system, the study of ES2 could provide information on neural circuits involved in migraine pathophysiology. The aim of this observational, pilot study was to assess whether erenumab treatment may affect the exteroceptive suppression reflex of the temporalis muscle activity in migraineurs. The exteroceptive suppression reflex of the temporalis muscle activity was previously studied in a small case series of three chronic female migraineurs and after 4 months of beneficial erenumab treatment, administered according to current clinical indications. There was a statistically significant decrease in ES2 latency (p-value 0.039) and duration (p-value 0.030) after treatment. The change observed in the temporalis ES2 during erenumab treatment indicates that ES2 may play some kind of role as a neurophysiological marker and that this monoclonal antibody can modulate the brainstem circuits involved in migraine pathophysiology, at least indirectly. Further studies are required to confirm this intriguing hypothesis.

An integrated approach to the evaluation of patients with asymptomatic or minimally symptomatic hyperCKemia.

INTRODUCTION/AIMS: Currently, there are no straightforward guidelines for the clinical and diagnostic management of hyperCKemia, a frequent and nonspecific presentation in muscle diseases. Therefore, we aimed to describe our diagnostic workflow for evaluating patients with this condition. METHODS: We selected 83 asymptomatic or minimally symptomatic patients with persistent hyperCKemia for participation in this Italian multicenter study. Patients with facial involvement and distal or congenital myopathies were excluded, as were patients with suspected inflammatory myopathies or predominant respiratory or cardiac involvement. All patients underwent a neurological examination and nerve conduction and electromyography studies. The first step of the investigation included a screening for Pompe disease. We then evaluated the patients for myotonic dystrophy type II-related CCTG expansion and excluded patients with copy number variations in the DMD gene. Subsequently, the undiagnosed patients were investigated using a target gene panel that included 20 genes associated with isolated hyperCKemia. RESULTS: Using this approach, we established a definitive diagnosis in one third of the patients. The detection rate was higher in patients with severe hyperCKemia and abnormal electromyographic findings. DISCUSSION: We have described our diagnostic workflow for isolated hyperCKemia, which is based on electrodiagnostic data, biochemical screening, and first-line genetic investigations, followed by successive targeted sequencing panels. Both clinical signs and electromyographic abnormalities are associated with increased diagnostic yields.

Characterization and management of neurological adverse events during immune-checkpoint inhibitors treatment: an Italian multicentric experience.

BACKGROUND: Neurological immune-related adverse events (nirAEs) are rare toxicities of immune-checkpoint inhibitors (ICI). With the increase of ICI oncological indications, their incidence is growing. Their recognition and management remain nevertheless challenging. METHODS: A national, web-based database was built to collect cases of neurological symptoms in patients receiving ICI and not attributable to other causes after an adequate workup. RESULTS: We identified 27 patients who developed nirAEs (20 males, median age 69 years). Patients received anti-PD1/PDL1 (78%), anti-CTLA4 (4%), or both (19%). Most common cancers were melanoma (30%) and non-small cell lung cancer (26%). Peripheral nervous system was mostly affected (78%). Median time to onset was 43.5 days and was shorter for peripheral versus central nervous system toxicities (36 versus 144.5 days, p = 0.045). Common manifestations were myositis (33%), inflammatory polyradiculoneuropathies (33%), and myasthenia gravis (19%), alone or in combination, but the spectrum of diagnoses was broad. Most patients received first-line glucocorticoids (85%) or IVIg (15%). Seven patients (26%) needed second-line treatments. At last follow-up, four (15%) patients were deceased (encephalitis, 1; myositis/myasthenia with concomitant myocarditis, 2; acute polyradiculoneuropathy, 1), while seven (26%) had a complete remission, eight (30%) partial improvement, and six (22%) stable/progressing symptoms. ICI treatment was discontinued in most patients (78%). CONCLUSIONS: Neurological irAEs are rare but potentially fatal. They primarily affect neuromuscular structures but encompass a broad range of presentations. A prompt recognition is mandatory to timely withheld immunotherapy and administrate glucocorticoids. In corticoresistant or severely affected patients, second-line treatments with IVIg or plasmapheresis may result in additional benefit.

Migraine in Chiari 1 Malformation: a cross-sectional, single centre study.

In Chiari 1 Malformation (CM1) the most frequent symptom is exertional headache, but other headache types have been reported, such as migraine. This cross-sectional study is aimed to examine the prevalence of migraine in a group of CM1 headache patients and to compare clinical-demographic characteristics between migraine and non-migraine patients. 427 adults were enrolled at the multidisciplinary Chiari Center in Torino. 230 headache patients were classified, based on radiological criteria. Frequencies (absolute/percentage values) were calculated in the whole sample for: migraine presence (with and without aura), gender, age, radiologic phenotypes and headache clinical characteristics. The association between CM1 diagnosis and headache characteristics (independent variables) and migraine diagnosis (dependent variable) was estimated by logistic regression models. Seventy-eight patients (67 females) out of 230 presenting headache had a migraine (34%), 44/78 (56%) with aura; in 58/78 (74%) migraine was comorbid with secondary headache attributable to CM1. Migraine prevalence in patients with isolated CM1 (52/120, 43.3%) was higher (p = 0.0016) than in all the other patients (26/110, 23.6%). Although migraine was prevalent in females (86%; 6:1 female:male ratio), age classes and gender were not risk factors for migraine at multivariate analysis, while migraine was associated with isolated CM1 phenotype (OR = 2.6). This study shows a high prevalence of migraine in CM1 patients and a significant association between migraine and isolated CM1. In patients with radiological evidence of CM1, particularly in the absence of neurological signs, a careful headache clinical characterization, according to the International Headache Society criteria, may be advised.

Two-year follow-up during fingolimod treatment in a pediatric multiple sclerosis patient still active on first-line treatment.

Treatment of pediatric multiple sclerosis (MS) has been increasingly debated in the last few years due to limited knowledge of treatment strategies and therapeutic options. When MS develops at a young age, it usually has a very inflammatory disease course, with many relapses and disease activity as seen in magnetic resonance imaging (MRI). Therefore, treatment with immunomodulatory drugs may be beneficial in these patients. However, limited data are available to date on the treatment of pediatric MS. Although observational, prospective, and retrospective studies provide some information on its treatment course, only one clinical trial in pediatric patients has been published, the PARADIGMS trial, which showed an 82% reduction in relapse rate with fingolimod (0.5 mg/day) versus interferon ß-1a (30 µg once weekly intramuscularly). Here, we present the case of a pediatric patient with MS (age of onset, 13 years), who was initially treated with interferon ß-1a for 2 years and subsequently switched to fingolimod, owing to clinical and radiological activity despite treatment with interferon ß-1a.

Diagnostic Accuracy of a Bedside Screening Tool for Dysphagia (BSTD) in Acute Stroke Patients.

BACKGROUND AND PURPOSE: an estimated 40-80% of acute ischemic stroke patients have dysphagia and about 14% develop stroke-associated pneumonia. However, it may be difficult to detect swallowing problems at admission. Moreover, there might not be an on-duty specialist skilled in the diagnosis of this condition. This study aimed at developing a user-friendly bedside examination to identify the risk of dysphagia in stroke patients at hospital admission. METHODS: a diagnostic accuracy study was carried out to assess the concurrent validity of a simple Bedside Screening Tool for Dysphagia (BSTD) in acute stroke. All the consecutive stroke patients admitted between January and April 2018 were enrolled. Sensitivity, specificity, positive (PPV), negative predictive values (NPV) and the Cohen K concordance index scores, reported by nurses and speech-pathologists, were assessed. RESULTS: a total of 67/120 patients (55.8%) were male; overall average age was 67.4 (range 45-91) and 80.8% of the whole population had a history of ischemic stroke. The nursing staff identified 33.3% of dysphagia cases at admission and the speech pathologists 30%. The Cohen K was 0.92 (optimal concordance when K was > 0.8), sensitivity was 100%, specificity 95.2%, PPV 90% and NPV 100%. CONCLUSIONS: our BSTD had a 100% negative predictive value, indicating that this screening test is very useful in ruling out/confirming dysphagia in acute stroke patients.

Screening for Fabry disease in unknown origin axonal polyneuropathy: to do or not to do, this is the question!

Fabry disease (FD) is a systemic X-linked lysosomal disorder. A 'peripheral nerve variant' of FD has been hypothesized in subjects with neuropathy, without the early manifestations of the classic phenotype. A cohort of undiagnosed neuropathy patients with chronic polyneuropathy of undetermined aetiology and demyelinating neuropathy, unresponsive to immunomodulating treatment, were screened for FD. A total of 103 patients (64% males), were enrolled. No typical pathogenetic mutations for FD were identified. We are aware that the study sample was very small, but only a large, unfeasible theoretical sample size could demonstrate a statistically significant increased prevalence of FD in neuropathy patients, as peripheral neuropathy of undetermined cause is uncommon and there is a low prevalence of FD in the general population. Therefore, we are of the opinion that including tailored FD screening in the neuropathy diagnostic work-up, particularly when there are additional clinical characteristics, should be considered.