Effects of OnabotulinumtoxinA on Allodynia and Interictal Burden of Patients with Chronic Migraine.

BACKGROUND: We primarily aimed to ascertain whether treatment with OnabotulinumtoxinA (BoNTA) might influence the extent of the interictal burden and cutaneous allodynia in patients with chronic migraine (CM). METHODS: Seventy CM patients, who received three consecutive cycles of BoNTA, were studied. The interictal burden was assessed with the Migraine Interictal Burden Scale (MIBS-4), while cutaneous allodynia was examined with the Allodynia Symptom Checklist (ASC-12) together with PI-NRS VAS to obtain hair brushing scores, and then these were compared from baseline (T0) to the last efficacy evaluation follow-up (T1). Efficacy outcomes, mostly mean headache days (MHD) and "Headache Impact Test" scores, were also assessed between T0 and T1. RESULTS: BONTA improved the interictal burden, with a decrease in MIBS-4 scoring by an average of -7 at T1, compared to baseline (p < 0.001). The percentage of patients with a moderate/severe interictal burden was substantially decreased. Likewise, BoNTA reduced the extent of cutaneous allodynia, with a significant reduction in both the ASC-12 (1 vs. 6; p < 0.001) and PI-NRS VAS (1 vs. 5; p < 0.001) to hair brushing median scores at T1, compared to baseline. Reduced MHD rates were significantly associated with a smaller interictal burden at T1. The efficacy of BoNTA, with a significant reduction in MHD and HIT-6 scores at T1 compared to T0, was re-confirmed. CONCLUSIONS: BoNTA resulted in a statistically significant reduction in the interictal burden and also improved cutaneous allodynia. The reduction in ictal burden was associated with the down-scaling of the interictal burden. Hence, BoNTA improved the full spectrum of migraine impairment by diminishing the clinical expression of central sensitization.

Incidence and risk factors for developing chemotherapy-induced neuropathic pain in 500 cancer patients: A file-based observational study.

OBJECTIVE: To define the incidence and risk factors for developing chemotherapy-induced neuropathic pain (CINP). METHODS: Retrospective, file-based analysis on cancer patients who received any type of conventional chemotherapy and for whom neurological evaluation was asked to reveal the extent of chemotherapy-induced peripheral neurotoxicity (CIPN) with or without CINP. CINP was assessed by means of the PI-NRS and Douleur Neuropathique-4 questionnaire. The total neuropathy score-clinical version graded the severity of CIPN. RESULTS: The medical files of 500 chemotherapy-treated cancer patients were reviewed. Any grade chronic CIPN was disclosed in 343 (68.6%) patients and CINP in 127 (37%) of them, corresponding to an overall percentage of 25.4% among all 500 included patients. The logistic regression analysis identified as independent predictors for CINP development the presence of uncomplicated diabetes (OR: 2.17; p = .039) and grade 2-3 chronic CIPN (OR: 1.61; p < .001) as also the administration of combined paclitaxel plus cisplatin (reference variable), compared to oxaliplatin (OR: 0.18; p = .001) and taxanes (OR: 0.16; p < .001). The increased severity of acute OXAIPN was associated with CINP (OR: 4.51; p < .001). OXA-treated patients with persistent CINP presented a worst likelihood to improve after chemotherapy discontinuation, than patients receiving combined paclitaxel plus cisplatin (OR: 50; p < .001). CONCLUSION: The incidence of CINP in our cohort was comparable to previous reports, with severities fluctuating upwards during chemotherapy and declined post-chemotherapy. Uncomplicated diabetes, the combined paclitaxel plus cisplatin treatment and the increased severity of acute oxaliplatin neurotoxicity mostly increase the risk for developing CINP. OXA-treated patients present less possibilities to recover from CINP after chemotherapy discontinuation, than other chemotherapies.

Nine-Month Continuous Fremanezumab Prophylaxis on the Response to Triptans and Also on the Incidence of Triggers, Hypersensitivity and Prodromal Symptoms of Patients with High-Frequency Episodic Migraine.

Objective: To investigate whether the incidence of triggers, prodromal symptoms, hypersensitivity symptoms accompanying headache and responses to triptans were modified during a continuous 9-month fremanezumab therapy for migraine prophylaxis. Patients and methods: We studied 63 patients with high-frequency episodic migraine (HFEM). Enrolled patients received fremanezumab for nine consecutive months before defining the response rates and being stratified into treatment responders (≥50-74% reduction in monthly headache days (MHDs)), super responders (≥75%), partial non-responders (<50%) and super non-responders (<30%). Through headache diaries, patients provided data in order to document the impact of fremanezumab on the incidence of triggers, associated symptoms followed by headache and response to triptans (the use of the migraine treatment optimization questionnaire-4 (mTOQ-4)) during the 9-month treatment period. Results: Fremanezumab had early (after 3 monthly cycles) beneficial effects on the response to triptans in the majority of responders with relevant increases in mTOQ-4 scoring, but also in half of partial non-responders. A significant reduction in median days with migraine-associated symptoms was seen in responders after 6 months of therapy with fremanezumab, mostly for osmophobia, photophobia, phonophobia and nausea/vomiting, but partial non-responders also benefited. Likewise, the incidence of self-reported prodromal symptoms was significantly reduced in responders and was modestly diminished in partial non-responders. Triggers remained unaffected in both responders and non-responders. Conclusions: Fremanezumab given for at least 6-9 months may exert neuromodulatory effects in the migraine brain. These effects could result both in the inhibition of migraine chronification, but also in the diminishing of the magnitude of migraine-associated symptoms, mostly in responders and in partial non-responders.

Effects of Fremanezumab on Psychiatric Comorbidities in Difficult-to-Treat Patients with Chronic Migraine: Post Hoc Analysis of a Prospective, Multicenter, Real-World Greek Registry.

OBJECTIVE: this post hoc analysis aimed to evaluate the efficacy of fremanezumab in difficult-to-treat chronic migraine (CM) patients with and without psychiatric comorbidities (PCs), mainly anxiety and/or depression. METHODS: We assessed data from CM patients with and without PCs who failed at least 3 preventives and eventually received at least 3 consecutive monthly doses of fremanezumab 225 mg. Outcomes included the crude response (≥50% reduction in monthly headache days (MHDs)) rates to fremanezumab from the baseline to the last clinical follow-up. The changes in MHDs; MHDs of moderate/greater severity; monthly days with intake of abortive medication; and the proportion of patients' changing status from with PCs to decreased/without PCs were also compared. Disability and quality of life (QOL) outcomes were also assessed. RESULTS: Of 107 patients enrolled, 65 (60.7%) had baseline PCs. The percentage of patients with (n = 38/65; 58.5%) and without (n = 28/42; 66.6%) PCs that achieved a ≥50% reduction in MHDs with fremanezumab was comparable (p = 0.41), whereas MHDs were significantly reduced (difference vs. baseline) in both patients with PCs (mean -8.9 (standard error: 6.8); p < 0.001) and without PCs (-9.8 (7.5); p < 0.001). Both groups experienced significant improvements in all other efficacy, disability, and QOL outcomes at comparable rates, including in MHD reduction. A significant proportion of fremanezumab-treated patients with baseline PCs de-escalated in corresponding severities or even reverted to no PCs (28/65; 43.1%) post-fremanezumab. CONCLUSIONS: fremanezumab appears to be effective as a preventive treatment in difficult-to-treat CM patients with and without PCs while also being beneficial in reducing the severity of comorbid anxiety and/or depression.

Predictors of Response to Fremanezumab in Migraine Patients with at Least Three Previous Preventive Failures: Post Hoc Analysis of a Prospective, Multicenter, Real-World Greek Registry.

OBJECTIVE: To define, in a real-world population of patients with high-frequency episodic (HFEM) or chronic migraine (CM), the predictive role of socio-demographic or phenotypic profiling of responders to fremanezumab. PATIENTS AND METHODS: Two-hundred and four adult fremanezumab-treated patients with either HFEM or CM, who failed to at least three preventive treatments, provided data at baseline on several individual socio-demographic and phenotypic variables. These variables were analyzed for their ability to independently predict the response (50-74% response rates) or super-response (≥ 75% response rates) to fremanezumab. Patients were followed from 3-18 months of fremanezumab exposure. RESULTS: The main finding to emerge from univariate analyses was that three baseline socio-demographic/clinical variables, i.e., age group 41-70 years (p = 0.02); female gender (p = 0.03); patients with HFEM (p = 0.001), and three clinical phenotypic variables, i.e., strict unilateral pain (p = 0.05); pain in the ophthalmic trigeminal branch (p = 0.04); and the "imploding" quality of pain (p = 0.05), were significantly related to fremanezumab response. However, in multivariate analysis, only HFEM (p = 0.02), the presence of strict unilateral (p = 0.03), and pain location in the ophthalmic trigeminal branch (p = 0.036) were independently associated with good fremanezumab response. Allodynia (p = 0.04) was the only clinical predictive variable of super-responsiveness to fremanezumab. CONCLUSIONS: A precise phenotypic profiling with identification of pain characteristics consistent with peripheral and/or central sensitization might reliably predict the responsiveness to fremanezumab in migraine prophylaxis.

Efficacy and safety of fremanezumab for migraine prophylaxis in patients with at least three previous preventive failures: Prospective, multicenter, real-world data from a Greek registry.

OBJECTIVE: To prospectively assess the efficacy and safety of fremanezumab for migraine prophylaxis in patients with failure of at least three previous preventive treatments. Changes in disability as quality-of-life outcomes after fremanezumab treatment were also examined. METHODS: Two hundred and four patients with either high-frequency EM (HFEM) or chronic migraine (CM), who attained at least three consecutive monthly sessions with fremanezumab 225 mg and otherwise met the inclusion criteria, were included in the study. The crude response (at least 50% reduction in monthly headache days [MHD]) rates to fremanezumab were assessed. Scores in the following efficacy outcomes were then compared from baseline to the last efficacy evaluation follow-up: (i) MHD, (ii) monthly days with moderate/severe peak headache intensity, and (iii) monthly days with intake of abortive medication. The disability was evaluated with the Migraine Disability Assessment; the quality of life (QOL) status was assessed with the Headache Impact-6 Test, and the EQ-5D questionnaire. RESULTS: In the majority of HFEM cases (n = 81/97; 83.5%) and CM patients (n = 67/107; 62.6%), fremanezumab proved effective in reducing the MHDs by at least 50% and was associated with clinically meaningful improvement in all other efficacy variables. The migraine-related disability experienced by our patients decreased and their QOL increased. We recorded just 36 cases reporting mild adverse events, including pain, rash or pruritus (n = 26), flu-like symptoms (n = 8), and hair loss (n = 2). CONCLUSION: With our prospective results, we provide further real-world data to support the favorable benefit/risk profile of fremanezumab in the prophylaxis of both HFEM and CM.

An updated brief overview on post-traumatic headache and a systematic review of the non-pharmacological interventions for its management.

INTRODUCTION: Post-traumatic headache (PTH), a common type of headache secondary to traumatic brain injury (TBI) or whiplash, carries a relevant burden on patients. PTH is still an undertreated condition because of limited pharmacological treatment options. Therefore, multimodal non-pharmacologic approaches, which account for comorbidities and biopsychosocial factors, are often used in PTH patients. AREAS COVERED: After providing a brief overview of PTH, a systematic review was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations on recently published (2015-2020) papers on non-pharmacological interventions for PTH. We also collected data on ongoing trials on this topic. Studies and results are reviewed and discussed. EXPERT OPINION: PTH is one of the most common complications of TBI and accounts for almost 4% of symptomatic headache disorders. The most common clinical presentations of PTH are migraine-like or tension type (TTH)-like headache, neck pain, cognitive complaints, and psychological/psychiatric symptoms. Growing evidence suggests that combined pharmacological and non-pharmacological interventions, encompassing noninvasive neuromodulation, physical therapy, cognitive-behavioral treatment, and education, may be the best approaches for PTH and related comorbidities. Acute/preemptive pharmacological treatments for PTH include drugs used for migraine and TTH. When PTH management is multidisciplinary, the patient benefits most.

Recently available and emerging therapeutic strategies for the acute and prophylactic management of cluster headache: a systematic review and expert opinion.

Introduction: Although it causes a huge burden to sufferers, cluster headache (CH), remains an undertreated condition, partly due to the absence of established acute and prophylactic treatment options. New therapeutic approaches providing fast and safe relief from CH are needed. Areas covered: A systematic review was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendation on recently published (last 5 years) papers on CH treatment. The authors also collected preliminary results from ongoing trials on emerging therapeutic/preventive pharmacological and interventional approaches for CH. Studies and results are reviewed and discussed. Expert opinion: The complexity of CH pathophysiology prevents the definition of reliable acute and preventive treatments. In the real-world clinical setting, several treatments are combined to provide relief to patients and increase their quality of life. Drugs targeting neuropeptides or their receptors within the trigeminovascular network are of particular interest to prevent CH attacks. Calcitonin gene-related peptide (CGRP) blockade seems attractive and promising, but studies on anti-CGRP monoclonal antibodies indicated rather modest or even absence of a prophylactic effect. A deeper insight into CH pathophysiology, and combined approaches may lead the path to new, more effective, and personalized CH therapies.

Oxaliplatin rechallenge in metastatic colorectal cancer patients with clinically significant oxaliplatin-induced peripheral neurotoxicity.

We investigated whether rechallenge with oxaliplatin (OXA) can worsen the pre-existing oxaliplatin-induced peripheral neurotoxicity (OXAIPN) in metastatic colorectal cancer (mCRC) patients. Patients previously treated with OXA, having clinically significant grade 1 or 2 OXAIPN were assessed, after receiving rechallenge with OXA, using the clinical version of the Total Neuropathy Score (TNSc). Peripheral neuropathy was assessed at the end of first OXA exposure and at completion of OXA rechallenge. The first line OXA-based chemotherapy was completed at least 9 months earlier (OXA-free interval). We studied 25 mCRC patients, 14 males and 11 females, with a median age of 63 (35-77) years. After their first exposure to OXA-based chemotherapy, 9 (36%) patients developed grade 1 OXAIPN and 16 patients grade 2 (64%) neurotoxicity. OXA reintroduction with a median of 10 (8-14) cycles led to grade 1 OXAIPN in two patients (8%), grade 2 in 19 patients (76%), and grade 3 neuropathy in 4 (16%) patients Worsening of pre-existing OXAIPN was documented in seven (28%) patients and was significantly associated with higher OXA delivered cumulative dose (P < .001). Median TNSc scores following treatment (10; range 4-18) were significantly increased (P < .001), when compared to the scores recorded at the end of first line treatment (8; range 2-12). Rechallenging OXA appears to relatively worsen the severity of existing OXAIPN. However, the majority of rechallenged patients developed a clinically significant (grade 2) OXAIPN, rather than treatment-emergent grade 3. As such, OXA rechallenge might be a feasible option in patients previously having OXAIPN.

Open Label Prospective Experience of Supplementation with a Fixed Combination of Magnesium, Vitamin B2, Feverfew, Andrographis Paniculata and Coenzyme Q10 for Episodic Migraine Prophylaxis.

BACKGROUND: To investigate the efficacy and safety of supplementation with a fixed combination of magnesium, vitamin B2, feverfew, andrographis paniculata and coenzyme Q10 in episodic migraine (EM) prevention. METHODS: A pilot, single-arm, open-label study was conducted. After a one-month baseline period, the above-described supplementation was introduced in 113 EM Greek patients, who were prospectively followed-up for three months. The primary endpoint was the change in monthly migraine days between baseline period (BSL) and the third month of supplementation (T3). Secondary endpoints included changes in mean intensity of migraine and in days with use of acute migraine medications. Changes in scores of Migraine Disability Assessment questionnaire (MIDAS), Headache Impact Test-6 (HIT-6), Migraine Therapy Assessment questionnaire (MTAQ), Migraine-Specific Quality-of-life questionnaire (MSQ-QOL), Hospital Anxiety and Depression Scale (HADS) were also evaluated. Those with ≥50% reduction in monthly migraine days at T3, compared to BSL were considered supplementation-responders. RESULTS: The mean number of migraine days was significantly decreased between BSL and T3 (9.4 ± 3.7 vs. 6.1 ± 3.5; p < 0.001). Likewise, days with peak headache intensity of >4/10 (5.7 ± 3.4 vs. 4.9 ± 3.1; p < 0.001) as well as days using acute headache medications per month (8.9 ± 3.6 vs. 5.7 ± 3.4; p < 0.001) were significantly reduced. At T3, 64 patients (56.6%) were classified as responders. The beneficial effect of supplementation was also associated with significant changes in HIT-6, MIDAS, MTAQ and MSQ-QOL scores. There were no safety concerns. CONCLUSIONS: The supplementation we have tested appears to be an effective and well-tolerated preventive approach against EM. A randomized, placebo-controlled study is needed to confirm our results.

Pneumococcal Otogenic Meningitis Complicated With Pneumocephalus and Coma State.

We herein describe the unusual case of a male patient with pneumococcal otogenic meningitis, which was complicated with non-traumatic pneumocephalus and coma, in the absence of head trauma or a neurosurgical procedure. The initiation of an aggressive, empirical scheme with wide-spectrum antibiotics was achieved to stop the progression of meningitis, pneumocephalus, and their underlying causes in this patient. We propose pathogenetic mechanisms to explain this life-threatening condition.

Real world, open label experience with lacosamide against acute painful oxaliplatin-induced peripheral neurotoxicity.

We report the outcome of a pilot, open-label study that tested the potential of lacosamide (200 mg/bi.d) as an effective and safe symptomatic treatment against acute painful oxaliplatin-induced peripheral neurotoxicity (OXAIPN). Lacosamide was introduced in 18 colorectal cancer patients with evidence of clinically significant acute, painful OXAIPN after infusion of the third course (T1) of oxaliplatin-based chemotherapy (FOLFOX4) and was maintained until completion of all 12 courses (T4). The OXA-Neuropathy Questionnaire (OXA-NQ) was used to record the severity of acute OXAIPN; the PI-NRS estimated the severity of neuropathic pain, while the chronic OXAIPN was graded with TNSc. The EuroQOL (EQ-5D) instrument was also applied. The Patient Global Impression of Change (PGIC) scale measured the lacosamide-attributed perception of change. LCM-responders were considered those with ≥50% reduction in PI-NRS and OXA-NQ scores at T4, compared to T1. Patients experienced on T1 a median number of acute OXAIPN symptoms of 4 and had a median neuropathic pain severity score of 6, which was strongly related to lower quality of life, according to EQ-VAS (P < .001). At T4, 12 patients (66.7%) were classified as responders. A significant clinical improvement was documented in the severity of acute OXAIPN and neuropathic pain in relation to lacosamide (P < .001) at T4 compared to T1, which was associated with improved EQ-VAS scores (P < .001). Twelve patients scored PGIC ≥5 (lacosamide-attributed) at T4. There were no incidences of early drop-outs for safety reasons. Lacosamide appears to be an effective and well-tolerated symptomatic treatment against acute, painful OXAIPN.

Assessing risk factors of falls in cancer patients with chemotherapy-induced peripheral neurotoxicity.

AIM: To identify the risk factors of falls in a well-characterized cohort of cancer patients with chemotherapy-induced peripheral neurotoxicity (CIPN). PATIENTS AND METHODS: We studied 122 cancer patients experiencing any grade of CIPN, following completion of different chemotherapeutic regimens for various non-hematological malignancies. The results of the clinical examination were summarized by means of the Total Neuropathy Score-clinical version (TNSc®). A neurophysiological examination was also carried out. RESULTS: Among 122 patients, 21 (17.2%) of them reported falls. These were 7 males and 14 females with a mean age of 57.3 ± 8.1 years. All of them (21; 100%) had grade 3 CIPN, according to TNSc® with a median value of 15. Univariate analysis showed that the following variables were strongly associated with falls: TNSc® score of > 14 corresponding to grade 3 CIPN, evidence of motor impairment, evidence of sensory ataxia with positive Romberg sign, and decrease of sural a-SAP > 50% from the baseline value. Multivariate regression analysis failed to define independent predictors of falls. However, ROC analysis demonstrated that a discriminative TNSc® cutoff value of > 14 predicted falls with a sensitivity of 100% and specificity of 87%, whereas sensory ataxia predicted falls with a sensitivity of 95% and specificity of 83%. CONCLUSION: Grade 3 CIPN, as assessed with TNSc®, and evidence of sensory ataxia with a positive Romberg sign were strongly associated with an increased risk of falls. Although our results need further validation, the TNSc® scale appears to be a practical and easy tool for identifying patients at higher risk of falling.

Irreversible diffuse hypoxic-ischemic encephalopathy, secondary to type I Kounis syndrome.

We herein describe the unusual case of irreversible diffuse hypoxic-ischemic encephalopathy secondary to type I Kounis syndrome. The patient survived and remained in a vegetative state after being mechanically ventilated in the intensive care unit for long. A brief review of the literature on mechanisms for KS-associated brain injury is also presented.

Fatal, paraparetic acute motor axonal neuropathy, early complicating chemotherapy with nab-paclitaxel.

So far, very few cases describing an interrelation between chemotherapy and Guillain-Barré syndrome have been published. We describe the first case of a paraparetic, pure acute motor axonal neuropathy variant of Guillain-Barré syndrome, early complicating protein-bound paclitaxel (nab-paclitaxel/abraxane) chemotherapy (first and sole session at a 350 mg dose) in a female patient with metastatic breast cancer. Although our patient was treated with the standard regimen of intravenous immunoglobulin for 5 days, she showed no evidence of motor improvement and died 1 month after the onset of the neurological deficit.