Search

This article discusses a case study of a 30-year-old man with slowly progressive gait disturbances and imbalance since childhood. The patient also developed slurred speech and had high levels of blood cholesterol. Clinical examination revealed a wide-based gait, areflexia, and decreased vibration sense in the lower limbs, but no oculomotor apraxia. Brain MRI showed cerebellar atrophy and dentate nuclei abnormalities. Genetic testing identified a compound heterozygous mutation in the APTX gene, which is associated with ataxia with oculomotor apraxia type 1 (AOA1). The patient's phenotype was milder than typical AOA1 cases, possibly due to the specific genotype. The study highlights the importance of considering AOA1 as a diagnosis even without oculomotor apraxia, especially when suggestive brain MRI findings are present. [Extracted from the article]

Objective: Biallelic mutations in PRDX3 have been linked to autosomal recessive spinocerebellar ataxia type 32. In this study, which aims to contribute to the growing body of knowledge on this rare disease, we identified two unrelated patients with mutations in PRDX3. We explored the impact of PRDX3 mutation in patient skin fibroblasts and the role of the gene in neurodevelopment. Methods: We performed trio exome sequencing that identified mutations in PRDX3 in two unrelated patients. We also performed functional studies in patient skin fibroblasts and generated a "crispant" zebrafish (Danio rerio) model to investigate the role of the gene during nervous system development. Results: Our study reports two additional patients. Patient 1 is a 19‐year‐old male who showed a novel homozygous c.525_535delGTTAGAAGGTT (p. Leu176TrpfsTer11) mutation as the genetic cause of cerebellar ataxia. Patient 2 is a 20‐year‐old male who was found to present the known c.425C>G/p. Ala142Gly variant in compound heterozygosity with the p. Leu176TrpfsTer11 one. While the fibroblast model failed to recapitulate the pathological features associated with PRDX3 loss of function, our functional characterization of the prdx3 zebrafish model revealed motor defects, increased susceptibility to reactive oxygen species‐triggered apoptosis, and an impaired oxygen consumption rate. Conclusions: We identified a new variant, thereby expanding the genetic spectrum of PRDX3‐related disease. We developed a novel zebrafish model to investigate the consequences of prdx3 depletion on neurodevelopment and thus offered a potential new tool for identifying new treatment opportunities. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive complaints (SCCs) in Parkinson's disease (PD) are reported frequently, but their prevalence and association with changes on objective testing are not fully known. Objective: We aimed to determine the prevalence, clinical correlates, and predictive value of SCCs in PD. Methods: We conducted a systematic review and meta‐analysis. From 204 abstracts, we selected 31 studies (n = 3441 patients), and from these, identified the prevalence, clinical features, associations with neuropsychiatric symptoms, and predictive values of SCCs in PD. Results: The meta‐analysis showed an SCC prevalence of 36%. This prevalence, however, was significantly moderated by study heterogeneity regarding female sex, disease severity, levodopa equivalent daily dosage, exclusion from the overall sample of patients with objective cognitive impairment, and measurement instrument. SCC prevalence did not differ between de novo and treated PD patients. SCCs were weakly and negligibly associated with cognitive changes on objective testing in cross‐sectional studies. However, in cognitively healthy patients, SCCs had a risk ratio of 2.71 for later cognitive decline over a mean follow‐up of 3.16 years. Moreover, SCCs were moderately related to co‐occurring symptoms of depression, anxiety, or apathy and were more strongly related to these neuropsychiatric symptoms than objective cognitive functioning. Conclusion: Our analyses suggest that SCCs in patients with and without objective cognitive impairment are frequent, occurring in more than one third of PD patients. Establishing uniform measurement instruments for identifying PD‐related SCCs is critical to understand their implications. Even in cases lacking evidence of objective cognitive impairment and where SCCs might reflect underlying neuropsychiatric symptoms, the possibility of later cognitive deterioration should not be excluded. Therefore, SCCs in PD patients warrant close monitoring for opportunities for targeted and effective interventions. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Memory deficits in mild cognitive impairment related to Parkinson's disease (PD‐MCI) are quite heterogeneous, and there is no general agreement on their genesis. Objectives: To define memory phenotypes in de novo PD‐MCI and their associations with motor and non‐motor features and patients' quality of life. Methods: From a sample of 183 early de novo patients with PD, cluster analysis was applied to neuropsychological measures of memory function of 82 patients with PD‐MCI (44.8%). The remaining patients free of cognitive impairment were considered as a comparison group (n = 101). Cognitive measures and structural magnetic resonance imaging‐based neural correlates of memory function were used to substantiate the results. Results: A three‐cluster model produced the best solution. Cluster A (65.85%) included memory unimpaired patients; Cluster B (23.17%) included patients with mild episodic memory disorder related to a "prefrontal executive‐dependent phenotype"; Cluster C (10.97%) included patients with severe episodic memory disorder related to a "hybrid phenotype," where hippocampal‐dependent deficits co‐occurred with prefrontal executive‐dependent memory dysfunctions. Cognitive and brain structural imaging correlates substantiated the findings. The three phenotypes did not differ in terms of motor and non‐motor features, but the attention/executive deficits progressively increased from Cluster A, through Cluster B, to Cluster C. This last cluster had worse quality of life compared to others. Conclusions: Our results demonstrated the memory heterogeneity of de novo PD‐MCI, suggesting existence of three distinct memory‐related phenotypes. Identification of such phenotypes can be fruitful in understanding the pathophysiological mechanisms underlying PD‐MCI and its subtypes and in guiding appropriate treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The clinical connectome fingerprint (CCF) was recently introduced as a way to assess brain dynamics. It is an approach able to recognize individuals, based on the brain network. It showed its applicability providing network features used to predict the cognitive decline in preclinical Alzheimer's disease. In this article, we explore the performance of CCF in 47 Parkinson's disease (PD) patients and 47 healthy controls, under the hypothesis that patients would show reduced identifiability as compared to controls, and that such reduction could be used to predict motor impairment. We used source‐reconstructed magnetoencephalography signals to build two functional connectomes for 47 patients with PD and 47 healthy controls. Then, exploiting the two connectomes per individual, we investigated the identifiability characteristics of each subject in each group. We observed reduced identifiability in patients compared to healthy individuals in the beta band. Furthermore, we found that the reduction in identifiability was proportional to the motor impairment, assessed through the Unified Parkinson's Disease Rating Scale, and, interestingly, able to predict it (at the subject level), through a cross‐validated regression model. Along with previous evidence, this article shows that CCF captures disrupted dynamics in neurodegenerative diseases and is particularly effective in predicting motor clinical impairment in PD. [ABSTRACT FROM AUTHOR]

Background: Cluster headache is commonly reported to follow an annual pattern with a peak in the spring and a second peak in autumn. Patients with headache frequently use search engines, such as Google, to look for terms related to their disease, creating trend data that can be analyzed with Google Trends. Indeed, Google Trends has been used for surveillance studies and can provide indirect estimates of the burden of diseases and symptoms. The present cross‐sectional study investigated the seasonality of searches for "cluster headache" in the northern and southern hemispheres using 10 years of Google Trends data. Methods: The term "cluster headache" or its translation in the 10 most spoken languages in the world was searched on Google Trends to obtain relative search volumes (from 0 to 100), in order to compare variations in searches across periods. Twenty‐eight countries were selected according to the following criteria: (1) a relative search volume of >40 for the term for cluster headache; and (2) a population of at least 5 million inhabitants. For statistical purposes, countries were grouped in relation to hemisphere (northern or southern). Relative search volumes were extracted from January 2012 to January 2022 and analyzed according to two subgroups based on meteorological seasons (summer and winter vs. spring and autumn). Results: A seasonal trend for in searches for cluster headache was found worldwide exhibiting higher relative search volumes in spring and autumn compared with summer and winter (17 [0, 39] vs. 13 [0, 37]; p = 0.016). Conclusion: Higher search volumes for the term during the meteorological seasons of spring and autumn clearly reflect a circannual pattern of cluster headache occurrence, representing new evidence for its seasonality. [ABSTRACT FROM AUTHOR]

The European Journal of Neurology has published a special issue titled "Lessons From the Past to Understand the Future" to commemorate its 30th anniversary. The issue explores the evolution of neurology in Europe, including patient care, teaching, and research. It highlights the merger of two societies in 2014 to form the European Academy of Neurology, which represents both national neurological societies and individual European neurologists. The issue also discusses the connections between European neurology and other neuroscience societies, patient organizations, and global health organizations. Additionally, it examines the management of neurological diseases and draws lessons from the Spanish flu pandemic in relation to the recent SARS-CoV-2 pandemic. The objective of this special issue is to provide European neurologists with a better understanding of the past to prepare for the future. [Extracted from the article]

Background and purpose: Although disabling fatigue is common in Parkinson disease (PD), available consensus‐based diagnostic criteria have not yet been empirically validated. The aim of this study was to evaluate the clinimetric properties of the criteria. Methods: A sample of outpatients with PD was evaluated for demographic, clinical, behavioral, and cognitive features. Fatigue was diagnosed according to the new diagnostic criteria and was rated by means of the Parkinson Fatigue Scale (PFS) and Fatigue Severity Scale (FSS). Acceptability, concurrent and discriminant validity, and interrater reliability were evaluated with binary logistic regression analyses and Cohen kappa (κ). Results: Of 241 included patients, 17 (7.1%) met the diagnostic criteria for PD‐related fatigue. Eight of nine symptoms described in Section A of the diagnostic criteria occurred in >50% of patients with fatigue. Acceptability (missing data = 0.8%) of the criteria was good, as was their concurrent validity with the PFS (odds ratio = 3.65) and FSS (odds ratio = 3.63). The discriminant validity of fatigue criteria with other PD‐related behavioral and cognitive features was good (odds ratio < 1.68). The interrater reliability was excellent (κ = 0.92). Conclusions: This is the first study to test the clinimetric properties of case definition diagnostic criteria for PD‐related fatigue. Our results suggest that current diagnostic criteria may be useful in both clinical practice and research. Future longitudinal studies should examine their long‐term stability. [ABSTRACT FROM AUTHOR]

Background: Differentiating progressive supranuclear palsy‐parkinsonism (PSP‐P) from Parkinson's disease (PD) is clinically challenging. Objective: This study aimed to develop an automated Magnetic Resonance Parkinsonism Index 2.0 (MRPI 2.0) algorithm to distinguish PSP‐P from PD and to validate its diagnostic performance in two large independent cohorts. Methods: We enrolled 676 participants: a training cohort (n = 346; 43 PSP‐P, 194 PD, and 109 control subjects) from our center and an independent testing cohort (n = 330; 62 PSP‐P, 171 PD, and 97 control subjects) from an international research group. We developed a new in‐house algorithm for MRPI 2.0 calculation and assessed its performance in distinguishing PSP‐P from PD and control subjects in both cohorts using receiver operating characteristic curves. Results: The automated MRPI 2.0 showed excellent performance in differentiating patients with PSP‐P from patients with PD and control subjects both in the training cohort (area under the receiver operating characteristic curve [AUC] = 0.93 [95% confidence interval, 0.89–0.98] and AUC = 0.97 [0.93–1.00], respectively) and in the international testing cohort (PSP‐P versus PD, AUC = 0.92 [0.87–0.97]; PSP‐P versus controls, AUC = 0.94 [0.90–0.98]), suggesting the generalizability of the results. The automated MRPI 2.0 also accurately distinguished between PSP‐P and PD in the early stage of the diseases (AUC = 0.91 [0.84–0.97]). A strong correlation (r = 0.91, P < 0.001) was found between automated and manual MRPI 2.0 values. Conclusions: Our study provides an automated, validated, and generalizable magnetic resonance biomarker to distinguish PSP‐P from PD. The use of the automated MRPI 2.0 algorithm rather than manual measurements could be important to standardize measures in patients with PSP‐P across centers, with a positive impact on multicenter studies and clinical trials involving patients from different geographic regions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Although remarkable progress has been achieved in understanding cluster headache (CH) pathophysiology, there are still several gaps about the mechanisms through which independent subcortical and cortical brain structures interact with each other. These gaps could be partially elucidated by structural and functional advanced neuroimaging investigations. Objective: Although we are aware that substantial achievements have come from preclinical, neurophysiological, and biochemical experiments, the present narrative review aims to summarize the most significant findings from structural, microstructural, and functional neuroimaging investigations, as well as the consequent progresses in understanding CH pathophysiological mechanisms, to achieve a comprehensive and unifying model. Results: Advanced neuroimaging techniques have contributed to overcoming the peripheral hypothesis that CH is of cavernous sinus pathology, in transitioning from the pure vascular hypothesis to a more comprehensive trigeminovascular model, and, above all, in clarifying the role of the hypothalamus and its connections in the genesis of CH. Conclusion: Altogether, neuroimaging findings strongly suggest that, beyond the theoretical model of the "pain matrix," the model of the "neurolimbic pain network" that is accepted in migraine research could also be extended to CH. Indeed, although the hypothalamus' role is undeniable, the genesis of CH attacks is complex and seems to not be just the result of a single "generator." Cortical‐hypothalamic‐brainstem functional interconnections that can switch between out‐of‐bout and in‐bout periods, igniting the trigeminovascular system (probably by means of top‐down mechanisms) and the consensual trigeminal autonomic reflexes, may represent the "neuronal background" of CH. [ABSTRACT FROM AUTHOR]

To address the impact of COVID‐19 olfactory loss on the brain, we analyzed the neural connectivity of the central olfactory system in recently SARS‐CoV‐2 infected subjects with persisting olfactory impairment (hyposmia). Twenty‐seven previously SARS‐CoV‐2 infected subjects (10 males, mean age ± SD 40.0 ± 7.6 years) with clinically confirmed COVID‐19 related hyposmia, and eighteen healthy, never SARS‐CoV‐2 infected, normosmic subjects (6 males, mean age ± SD 36.0 ± 7.1 years), were recruited in a 3 Tesla MRI study including high angular resolution diffusion and resting‐state functional MRI acquisitions. Specialized metrics of structural and functional connectivity were derived from a standard parcellation of olfactory brain areas and a previously validated graph‐theoretic model of the human olfactory functional network. These metrics were compared between groups and correlated to a clinical index of olfactory impairment. On the scanning day, all subjects were virus‐free and cognitively unimpaired. Compared to control, both structural and functional connectivity metrics were found significantly increased in previously SARS‐CoV‐2 infected subjects. Greater residual olfactory impairment was associated with more segregated processing within regions more functionally connected to the anterior piriform cortex. An increased neural connectivity within the olfactory cortex was associated with a recent SARS‐CoV‐2 infection when the olfactory loss was a residual COVID‐19 symptom. The functional connectivity of the anterior piriform cortex, the largest cortical recipient of afferent fibers from the olfactory bulb, accounted for the inter‐individual variability in the sensory impairment. Albeit preliminary, these findings could feature a characteristic brain connectivity response in the presence of COVID‐19 related residual hyposmia. [ABSTRACT FROM AUTHOR]

Background and purpose: Although the majority of migraine with aura (MwA) patients experience simple visual aura, a discrete percentage also report somatosensory, dysphasic or motor symptoms (the so‐called complex auras). The wide aura clinical spectrum led to an investigation of whether the heterogeneity of the aura phenomenon could be produced by different neural correlates, suggesting an increased visual cortical excitability in complex MwA. The aim was to explore whether complex MwA patients are characterized by more pronounced connectivity changes of the visual network and whether functional abnormalities may extend beyond the visual network encompassing also the sensorimotor network in complex MwA patients compared to simple visual MwA patients. Methods: By using a resting‐state functional magnetic resonance imaging approach, the resting‐state functional connectivity (RS‐Fc) of both visual and sensorimotor networks in 20 complex MwA patients was compared with 20 simple visual MwA patients and 20 migraine without aura patients. Results: Complex MwA patients showed a significantly higher RS‐Fc of the left lingual gyrus, within the visual network, and of the right anterior insula, within the sensorimotor network, compared to both simple visual MwA and migraine without aura patients (p < 0.001). The abnormal right anterior insula RS‐Fc was able to discriminate complex MwA patients from simple aura MwA patients as demonstrated by logistic regression analysis (area under the curve 0.83). Conclusion: Our findings suggest that higher extrastriate RS‐Fc might promote cortical spreading depression onset representing the neural correlate of simple visual aura that can propagate to sensorimotor regions if an increased insula RS‐Fc coexists, leading to complex aura phenotypes. [ABSTRACT FROM AUTHOR]

Background: People with cluster headache (CH) are frequently burdened by misdiagnosis or diagnostic delay. The peculiar somatic and behavioral changes characterizing patients with CH are not useful to improve diagnostic accuracy. In our clinical experience, we noticed a typical voice quality with low and croaking tone in patients with CH. In this cross‐sectional study, we evaluated, by digital voice analysis, whether it is possible to identify typical voice quality characterizing patients with CH compared with healthy controls (HCs). Furthermore, to investigate whether putative differences in voice characteristics could be underpinned by constitutional aspects or pathological processes of vocal cords, subjects underwent a videolaryngostroboscopy. Smoking habits and alcohol consumption were specifically investigated. Methods: After conducting digital recording of the voices from both patients with CH and HCs in a soundproof insulated cabin in the laboratory of the Audiology Department, a set of voice parameters was analyzed. We included the measures of fundamental frequency, calculations of jitter and shimmer, and noise‐to‐harmonics ratios as well as quantities related to the spectral tilt (i.e., H1–H2, H1–A1, H1–A2, and H1–A3) in 20 patients with CH and in 13 HCs. A videolaryngostroboscopy was performed in all subjects. Results: Patients with CH, explored during the cluster bout period, showed significantly lower second harmonic (H1–H2) values compared with HCs (−6.9 ± 7.6 vs. 2.1 ± 6.7, p = 0.002), usually characterizing the so‐called creaky voice. By using a laryngoscopy investigation, a significantly higher prevalence of mild to moderate vocal cord edema and laryngopharyngeal reflux signs were found in patients with CH (100% of patients with CH vs. 15% of HC, p < 0.001). Conclusion: Creaky phonation is a "physiological mode of laryngeal operation" usually underpinned by shortened and thickened vocal folds. Creaky voice phonation can be due to a vocal fold's reduced capability to become slack or flaccid secondary to vocal cord edema underpinned by laryngopharyngeal reflux affecting the phonatory mechanisms in patients with CH. The laryngopharyngeal reflux may represent a dysautonomic sign related to the increased parasympathetic tone during in‐bout period, reinforcing the hypothesis of an extracranial autonomic dysfunction as part of CH clinical picture. [ABSTRACT FROM AUTHOR]

Background: Functional brain connectivity alterations may be detectable even before the occurrence of brain atrophy, indicating their potential as early markers of pathological processes. Objective: We aimed to determine the whole‐brain network topologic organization of the functional connectome in a large cohort of drug‐naïve Parkinson's disease (PD) patients using resting‐state functional magnetic resonance imaging and to explore whether baseline connectivity changes may predict clinical progression. Methods: One hundred and forty‐seven drug‐naïve, cognitively unimpaired PD patients were enrolled in the study at baseline and compared to 38 age‐ and gender‐matched controls. Non‐hierarchical cluster analysis using motor and non‐motor data was applied to stratify PD patients into two subtypes: 77 early/mild and 70 early/severe. Graph theory analysis and connectomics were used to assess global and local topological network properties and regional functional connectivity at baseline. Stepwise multivariate regression analysis investigated whether baseline functional imaging data were predictors of clinical progression over 2 years. Results: At baseline, widespread functional connectivity abnormalities were detected in the basal ganglia, sensorimotor, frontal, and occipital networks in PD patients compared to controls. Decreased regional functional connectivity involving mostly striato‐frontal, temporal, occipital, and limbic connections differentiated early/mild from early/severe PD patients. Connectivity changes were found to be independent predictors of cognitive progression at 2‐year follow‐up. Conclusions: Our findings revealed that functional reorganization of the brain connectome occurs early in PD and underlies crucial involvement of striatal projections. Connectomic measures may be helpful to identify a specific PD patient subtype, characterized by severe motor and non‐motor clinical burden as well as widespread functional connectivity abnormalities. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Anxiety symptoms are common in Parkinson's disease (PD). A link between anxiety and cognitive impairment in PD has been demonstrated. Objectives: Using resting‐state functional magnetic resonance imaging, we investigated intrinsic brain network connectivity correlates of anxiety symptoms in a cohort of drug‐naive, cognitively unimpaired patients with PD. Methods: The intrinsic functional brain connectivity of 25 drug‐naive, cognitively unimpaired PD patients with anxiety, 25 without anxiety, and 20 matched healthy controls was compared. All patients underwent a detailed behavioral and neuropsychological evaluation. Anxiety presence and severity were assessed using the Parkinson's Disease Anxiety Scale. Single‐subject and group‐level independent component analyses were used to investigate functional connectivity differences within and between the major resting‐state networks. Results: Decreased connectivity within the default‐mode and sensorimotor networks (SMN), increased connectivity within the executive‐control network (ECN), and divergent connectivity measures within salience and frontoparietal networks (SN and FPN) were detected in PD patients with anxiety compared with those without anxiety. Moreover, patients with anxiety showed a disrupted inter‐network connectivity between SN and SMN, ECN, and FPN. Anxiety severity was correlated with functional abnormalities within these networks. Conclusions: Our findings demonstrated that an abnormal intrinsic connectivity within and between the most reported large‐scale networks may represent a potential neural correlate of anxiety symptoms in drug‐naive PD patients even in the absence of clinically relevant cognitive impairment. We hypothesize that these specific cognitive and limbic network architecture changes may represent a potential biomarker of treatment response in clinical trials. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Following the severe consequences of the COVID‐19 outbreak, on March 9, 2020, the Italian government implemented extraordinary measures to limit viral transmission, including restrictive quarantine measures. This resulted in a rapid and profound change of people's daily lives. Objective: We assessed the psychological impact of the 40‐day quarantine in a large cohort of patients with Parkinson's disease (PD) and caregivers. Moreover, we analyzed whether prelockdown clinical features may be associated with subjective response of patients with PD to this traumatic event. Methods: A total of 94 patients with PD were enrolled in the study. The Impact of Event Scale‐Revised, the Kessler Psychological Distress Scale, and the 12‐item Zarit Burden Inventory were obtained from patients and caregivers by email. A multivariate regression analysis was performed to determine whether prelockdown clinical motor and nonmotor features were associated with the psychological impact of lockdown. Results: Regression analyses showed that prelockdown levels of anxiety, treatment‐related motor complications, patients' quality of life, and lockdown hours per day were significantly associated with psychological impact measures of the 40‐day quarantine. In addition, we showed that caregiver burden was correlated with overall patient autonomy and attention/memory impairment. Conclusions: We identified specific PD motor and nonmotor features potentially predisposing to higher psychological impact of stressful situations, such as quarantine. This may help guide postpandemic interventions and preventive strategies to avoid further impairment of psychological well‐being in patients with PD. [ABSTRACT FROM AUTHOR]

The article presents a case study related to 67-year-old woman with a 30-year history of migraine with aura (MwA), presented with an acute episode of visual symptoms such as scotomas and flashing lights which subsequently spread within 15 minutes into the right visual hemifield. Topics include tingling type paresthesia has occurred starting from the right hand and spreading, and the usual therapy of a naproxen tablet and obtained a slight improvement in headache intensity.

Background: The differential diagnosis between multiple system atrophy parkinsonism type (MSA-P) and Parkinson's disease with orthostatic hypotension (PD+OH) is difficult because the 2 diseases have a similar clinical picture. The aim of this study is to distinguish MSA-P from PD+OH by immunostaining for abnormal phosphorylated α-synuclein at serine 129 (p-syn) in cutaneous nerves.Method: We recruited 50 patients with parkinsonism and chronic orthostatic hypotension: 25 patients fulfilled the diagnostic criteria for MSA-P and 25 patients for PD+OH. The patients underwent a skin biopsy from the cervical area, thigh, and leg to analyze somatic and autonomic skin innervation and p-syn in skin nerves.Results: Intraneural p-syn positivity was found in 72% of patients with MSA-P, mainly in distal skin sites. More important, p-syn deposits in MSA-P differed from PD+OH because they were mainly found in somatic fibers of subepidermal plexi, whereas scant autonomic fiber involvement was found in only 3 patients. All patients with PD+OH displayed widely distributed p-syn deposits in the autonomic skin fibers of proximal and distal skin sites, whereas somatic fibers were affected only slightly in 4 patients with PD+OH. Skin innervation mirrored p-syn deposits because somatic innervation was mainly reduced in MSA-P. Sympathetic innervation was damaged in PD+OH but fairly preserved in MSA-P.Conclusions: The p-syn in cutaneous nerves allows the differentiation of MSA-P from PD+OH; MSA-P mainly shows somatic fiber involvement with relatively preserved autonomic innervation; and by contrast, PD+OH displays prevalent abnormal p-syn deposits and denervation in autonomic postganglionic nerves. © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Two‐thirds of patients with migraine without aura (MwoA) complain ictal cutaneous allodynia (CA), clinical sign of central nociceptive pathway sensitization, and independent predictor for migraine chronification. Aim: We aimed to investigate whether functional abnormalities, structural, or microstructural changes of the main cognitive networks (default mode network [DMN], salience network [SN], and central executive network [CEN]) could predict the development of CA in patients with MwoA. Methods: Baseline 3‐Tesla MRI images of 50 patients with MwoA were analyzed between 2009 and 2015. Over a three‐year period, patients were then stratified into 2 groups based on CA development and compared with matched healthy controls (HC). Group‐level independent components analysis was used to investigate intrinsic functional connectivity (FC) differences within the cognitive resting‐state networks. Voxel‐based morphometry (VBM) was used to assess whether group differences in cognitive network FC were related to structural differences. Tract‐based spatial statistical analyses (TBSS) were conducted to assess the microstructural properties of white matter tracts. We also compared internetwork connectivity between patients. Finally, a logistic regression analysis was used to investigate baseline imaging predictors of CA development. Results and Discussion: We observed a significantly reduced FC of both DMN and CEN in patients with MwoA developing CA (MwoA dCA) when compared with both patients with MwoA not developing CA (MwoA ndCA) and HC. Within the DMN, the PCC/precuneus is a key hub aimed to anti‐nociception and multisensory integration. The reduced intrinsic PCC/precuneus FC observed in patients with MwoA dCA could subtend abnormal inputs integration, from different sensory modalities, allowing the development of CA. On the other hand, within the CEN, a central role in pain modulation as well as in executive functions is played by ACC and MFG. Our finding of reduced ACC and MFG FC in MwoA dCA may represent the neuronal substrate of both subclinical impairment of complex executive functions and dysfunctional anti‐nociceptive pathway, making these patients more prone to migraine chronification. TBSS analyses showed a statistically significant reduced corpus callosum (CC) FA in patients with MwoA dCA as previously demonstrated in migraine patients with other chronification factors such as medication overuse or affective disorders. No VBM differences in both global and local volumes were revealed between groups. No significant correlations have been found between the observed functional and microstructural changes and clinical parameters of disease severity. Logistic regression analysis indicated that the full model containing all predictors was statistically significant while the decreased ACC‐FC was significantly associated with CA development. Conclusion: We suggest that DMN and CEN FC abnormalities as well as CC microstructural changes could represent a prognostic imaging biomarker able to identify migraine patients more prone to experiencing CA and therefore, more inclined to chronic migraine. In the new pharmacological scenario, it would be useful to address therapeutic resources to specific migraine populations with a high risk of more severe clinical phenotype. [ABSTRACT FROM AUTHOR]

Background: Although migraine is recognized as one of the most common and disabling diseases in the world, it is nonetheless still underestimated, underdiagnosed, and undertreated. The fact that migraine patients often tend to access the Web to search for headache‐related information hinders patient‐doctor relationships and one should also bear in mind that, unfortunately, text readability and medical literacy in the overall population may be the reason why patients' understanding of health information is compromised. Aim: We aimed to assess the readability of the home page of the top 10 patient – oriented migraine‐related websites and the educational level required to be in a position to broach them. Methods: On April 15, 2018, we conducted a descriptive study on the international version of Google by entering the words "headache" and "migraine." We then analyzed the overall level of readability of texts of the home pages of the top 10 patient‐oriented websites, by means of the Simple Measure of Gobbledygook Readability Calculator. Results: Entering "headache" on the home pages of the top 10 patient‐oriented websites on Google we found that to understand these particular websites with ease, an average grade level of 12.4 (±1.5 standard deviation, SD) and an average 13.3 years of formal education (±1.7 SD) were required. Similarly, typing "migraine" on Google we found an average grade level of 10.8 (±1.2 SD) and an average of 12.5 years of formal education (±1.9 SD) were required. The most frequently viewed websites all failed to meet the USA National Institutes of Health guidelines, which recommend a range between 6th and 7th grade level readability. Discussion: The present study shows the low readability level resulting from the top 10 patient‐oriented headache/migraine websites and the consequent barrier this creates in the dissemination of headache/migraine‐related medical information. Although the actual physicians, both primary care physicians and headache specialists are the principal source of understandable headache‐related information, only a minority of people consult these professionals. Given the foregoing, the majority of migraine patients is, therefore, unable to obtain adequate comprehensible health information on the Web. Furthermore, the existing gap between migraine‐related website content readability and the unmet need for migraine patients to obtain pertinent and correct information might well contribute to the worldwide neglect of migraine as a major public health problem. Conclusion: Physician experts in headache and migraine should actively cooperate in planning informative material to establish what information patients need to know, how they should use it, and how readable that material actually is. Readability ought to be established before the final website publication. Plain language ought to be used and written messages should be supplemented with visual content such as simple drawings. We recommend the setting up of a new dynamic, modern, plain‐talking, and efficient approach in communication aimed at catching the public's attention with its readability and thus satisfying a migraine and headache web scenario. [ABSTRACT FROM AUTHOR]

Background: Monoclonal antibodies (mABs) against calcitonin gene‐related peptide (CGRP) or its receptor have emerged as effective and well‐tolerated preventive medications for migraine. The key role played by CGRP has been recently demonstrated also in the pathophysiology of cluster headache (CH), paving the way for studies aimed to investigate the effectiveness of mABs targeting CGRP also in CH. However, no trials have been conducted so far to test the efficacy and tolerability of erenumab as CH preventive treatment. Case Series: We describe the cases of 5 patients with both migraines and CH with previous failures of preventive treatments. All patients were treated with monthly erenumab (70 or 140 mg) showing good results not only on migraine but also on CH attacks frequency and intensity. Improvements of both intensity and frequency of CH attacks occurred only after at least 3 months of treatment, with monthly erenumab 140 mg, suggesting that longer treatment and higher doses are needed in CH in comparison to migraine. Discussion and Conclusion: Our findings support the efficacy and tolerability of monthly erenumab 140 mg as a preventive treatment in patients suffering from both migraines without aura and CH. We speculate that erenumab could represent a low‐risk alternative for CH patients (with or without comorbid migraine) who did not tolerate common CH preventatives therapies or for whom the therapies were not successful. Certainly, randomized trials are needed to confirm these observations and we hope that our data, showing a delayed therapeutic effect only with the highest dose of erenumab (140 mg/month), can be taken into account in designing future trials. [ABSTRACT FROM AUTHOR]

Background: Sex difference is related to specific clinical features in PD patients over the disease course.Objectives: To investigate the potential sex-difference effect on the spontaneous neuronal activity within the most reported resting-state networks in early untreated PD patients and its correlation with baseline and longitudinal clinical features.Methods: Fifty-six drug-naïve PD patients (30/26 male/female) and 30 (15/15 male/female) matched controls were enrolled in the study. Topological and spectral resting-state functional MRI features of the sensorimotor, dorsal and ventral attention, frontoparietal, and default-mode networks were analyzed for possible sex-difference effects in both PD patients and controls groups. Additionally, a region-of-interest analysis was performed to test for a sex effect on basal ganglia connectivity. Multivariate ordinal regression was used to investigate whether connectivity findings at baseline were predictors of motor impairment over a 2-year follow-up period.Results: Compared to female PD patients and controls, male PD patients showed an abnormal spectral composition of the sensorimotor and dorsal attention networks in the slow-5 band. The region-of-interest analysis showed an increased connectivity within the basal ganglia in female PD patients compared to males. Functional sensorimotor connectivity changes at baseline showed to be an independent predictor of disease severity at 2-year follow-up.Conclusions: Our findings revealed the presence of a disease-related, sex-specific cortical and subcortical connectivity pattern within the sensorimotor network, in the early stage of PD. We hypothesize that these findings may be related to the presence of different sex-specific nigrostriatal dopaminergic pathways and might predict PD progression. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Introduction: Migraine is a complex neurological disorder characterized by severe headaches associated with a plethora of sensory hypersensitivity and neurovegetative symptoms. In about one‐third of the cases, a set of fully reversible focal neurological symptoms, the aura, accompanies the headache. In the last decades, advanced neuroimaging investigations allowed identification of structural, microstructural, and functional abnormalities characterizing the brain of patients with migraine with aura (MwA). However, mechanisms underlying the aura phenomena are still a matter of debate. Aims: This article reviews the most significant findings from advanced neuroimaging studies in patients with MwA both to provide a unifying physiopathological model of the aura phenomena and to clarify the potential impact of advanced neuroimaging investigation in the clinical field. Methods: A comprehensive review of PubMed citations was conducted by entering the key words "magnetic resonance imaging" combined with "migraine" AND "aura." Other key words included "grey matter" OR "white matter," "structural" OR "functional." The only restriction was to English‐language publications. The abstracts of all articles published between 1997 and 2018 meeting these criteria were reviewed, and the full texts were examined for relevance to the topic. Conclusion: Although several advanced neuroimaging studies have been conducted to investigate the neural correlates of aura phenomena, they have failed in identifying underlying pathophysiological mechanisms in their entirety. Nevertheless, functional and structural neuroimaging findings concerning the extrastriate visual cortex are characterized by a high level of reproducibility, so much so that they could be applied, in a not so far future, as diagnostic, prognostic, or therapeutic biomarkers for MwA. [ABSTRACT FROM AUTHOR]

We conducted a systematic review and meta-analysis aimed at establishing robust prevalence estimates and identifying clinical correlates of fatigue in PD. From 2,459 titles and abstracts, we selected 44 relevant studies (n = 7427 patients). Overall, the meta-analysis showed a prevalence of fatigue of 50% in PD. This prevalence estimate, however, was significantly moderated by study heterogeneity in measurement scales and cut-off thresholds. In contrast, demographic features, disease severity, cognitive impairment, and depression did not moderate prevalence estimates. Moreover, fatigue prevalence did not differ between de novo and treated PD patients. Compared to nonfatigued patients, fatigued patients had sligthly higher age (1.44 years), disease duration (0.93 years), l-dopa equivalent daily dose (50.89 units), UPDRS-III (4.99 points), and H & Y (0.33 points), as well as risk of comorbid depression (risk ratio = 1.89) and had a little lower MMSE score (-0.66 points). Fatigue was moderately associated with apathy (Hedges' g = 0.55), anxiety (Hedges' g = 0.67), daytime somnolence (Hedges' g = 0.43), sleep disturbances (Hedges' g = 0.66), and poorer quality of life (Hedges' g = 1.23). Our analyses suggest that fatigue is a frequent, independent nonmotor symptom in PD appearing early and persisting throughout the disease course, and that establishing uniform diagnostic criteria for PD-related fatigue is critical. In addition, several nonmotor symptoms appear to be associated with fatigue and negatively impact quality of life. Pharmacological and nonpharmacological interventions targeting fatigue and associated symptoms may improve quality of life in patients with PD. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is the second‐most common neurodegenerative disorder after Alzheimer's disease; however, to date, there is no approved treatment that stops or slows down disease progression. Over the past decades, neuroimaging studies, including molecular imaging and MRI are trying to provide insights into the mechanisms underlying PD. Methods: This work utilized a literature review. Results: It is now becoming clear that these imaging modalities can provide biomarkers that can objectively detect brain changes related to PD and monitor these changes as the disease progresses, and these biomarkers are required to establish a breakthrough in neuroprotective or disease‐modifying therapeutics. Conclusions: Here, we provide a review of recent observations deriving from PET, single‐positron emission tomography, and MRI studies exploring PD and other parkinsonian disorders. [ABSTRACT FROM AUTHOR]

Abstract: Background: Despite its clinical relevance, the pathophysiology of pain in Parkinson's disease (PD) is still largely unknown, and both central and peripheral mechanisms have been invoked. Objectives: To investigate whether central pain processing is altered in “drug‐naive” pain‐free PD (dnPD) patients. Methods: Using event‐related functional MRI (fMRI), functional response to forearm heat stimulation (FHS) at two different intensities (41°C and 53°C) was investigated in 20 pain‐free dnPD patients, compared with 18 healthy controls (HCs). Secondary analyses were performed to evaluate associations between BOLD signal changes and PD clinical features and behavioral responses. Results: During low‐innocuous FHS (41°C), no activation differences were found between dnPD patients and HCs. During high‐noxious FHS (53°C) a significantly increased activation in the left somatosensory cortex, left cerebellum, and right low pons was observed in dnPD patients compared to HCs. In the latter experimental condition, fMRI BOLD signal changes in the right low pons (p < .0001; R = −0.8) and in the cerebellum (p = .004; R = −0.7) were negatively correlated with pain intensity ratings only in dnPD patients. No statistically significant difference in experimental pain perception was detected between dnPD patients and HCs. Conclusions: Our findings suggest that a functional remodulation of pain processing pathways occurs even in the absence of clinically overt pain symptoms in dnPD patients. These mechanisms may eventually become dysfunctional over time, contributing to the emergence of pain symptoms in more advanced PD stages. The comprehension of pain‐related mechanisms may improve the clinical approach and therapeutic management of this disabling nonmotor symptom. [ABSTRACT FROM AUTHOR]

Abstract: Background: Impulse control disorders can be triggered by dopamine replacement therapies in patients with PD. Using resting‐state functional MRI, we investigated the intrinsic brain network connectivity at baseline in a cohort of drug‐naive PD patients who successively developed impulse control disorders over a 36‐month follow‐up period compared with patients who did not. Methods: Baseline 3‐Tesla MRI images of 30 drug‐naive PD patients and 20 matched healthy controls were analyzed. The impulse control disorders' presence and severity at follow‐up were assessed by the Questionnaire for Impulsive‐Compulsive Disorders in Parkinson's Disease Rating Scale. Single‐subject and group‐level independent component analysis was used to investigate functional connectivity differences within the major resting‐state networks. We also compared internetwork connectivity between patients. Finally, a multivariate Cox regression model was used to investigate baseline predictors of impulse control disorder development. Results: At baseline, decreased connectivity in the default‐mode and right central executive networks and increased connectivity in the salience network were detected in PD patients with impulse control disorders at follow‐up compared with those without. Increased default‐mode/central executive internetwork connectivity was significantly associated with impulse control disorders development (P < 0.05). Conclusions: Our findings demonstrated that abnormal brain connectivity in the three large‐scale networks characterizes drug‐naive PD patients who will eventually develop impulse control disorders while on dopaminergic treatment. We hypothesize that these divergent cognitive and limbic network connectivity changes could represent a potential biomarker and an additional risk factor for the emergence of impulse control disorders. © 2017 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Historically, magnetic resonance imaging (MRI) has contributed little to the study of Parkinson's disease (PD), but modern MRI approaches have unveiled several complementary markers that are useful for research and clinical applications. Iron- and neuromelanin-sensitive MRI detect qualitative changes in the substantia nigra. Quantitative MRI markers can be derived from diffusion weighted and iron-sensitive imaging or volumetry. Functional brain alterations at rest or during task performance have been captured with functional and arterial spin labeling perfusion MRI. These markers are useful for the diagnosis of PD and atypical parkinsonism, to track disease progression from the premotor stages of these diseases and to better understand the neurobiological basis of clinical deficits. A current research goal using MRI is to generate time-dependent models of the evolution of PD biomarkers that can help understand neurodegeneration and provide reliable markers for therapeutic trials. This article reviews recent advances in MRI biomarker research at high-field (3T) and ultra high field-imaging (7T) in PD and atypical parkinsonism. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Introduction: Fatigue is a common problem in PD either in the early or later stage of the disease. Using resting-state functional MRI, we investigated the functional correlates of fatigue in a cohort of "drug-naïve" patients with PD.Methods: MRI at 3Tesla was collected in 40 patients with PD, 20 with and 20 without fatigue, and 20 matched healthy controls. Presence and the severity of fatigue were defined based on the 16-item Parkinson fatigue scale. Single-subject and group-level independent component analysis was used to investigate functional connectivity differences within the major resting state networks between patients subgroups and healthy controls. In addition, we used voxel-based morphometry to test whether between-group functional changes were related to structural differences.Results: Distressing fatigue was associated with a decreased connectivity in the supplementary motor area within the sensorimotor network and an increased connectivity in the prefrontal and posterior cingulate cortices within the default mode network (P < 0.05 corrected). Fatigue severity was correlated with both sensorimotor and default mode networks connectivity changes. Voxel-based morphometry analysis did not reveal any significant volume differences between all patients with PD and healthy controls and between patients with PD with and without fatigue (P < 0.05; family-wise error).Conclusions: Our findings revealed that primary PD-related fatigue is associated with an altered default mode network and sensorimotor network connectivity in drug-naïve patients. We hypothesize that these divergent motor and cognitive networks connectivity changes and their adaptive or maladaptive functional outcome may play a prominent role in the pathophysiology of fatigue in PD. © 2016 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Objective To evaluate the executive control network connectivity integrity in patients with migraine with aura, in the interictal period, in comparison to patients with migraine without aura and healthy controls. Methods Using resting-state functional magnetic resonance imaging, we compared executive control network functional connectivity in 20 patients with migraine with aura vs 20 sex and age-matched patients with migraine without aura and 20 healthy controls, and assessed the correlation between executive control network functional connectivity and clinical features of patients with migraine. We used voxel-based morphometry and diffusion tensor imaging to investigate potential structural or microstructural changes. Results Neuropsychological data revealed no significant executive dysfunction in patients with migraine. Resting-state functional magnetic resonance imaging showed significant group differences in right middle frontal gyrus ( Talairach coordinates x, y, z: +26, +2, +48) and dorsal anterior cingulate cortex ( Talairach coordinates x, y, z: +6, +13, +49), indicating that these areas had a decreased component activity in both patients with migraine with and without aura when compared with healthy controls. Conversely, there were no significant differences in the executive control network functional connectivity between patients with migraine with and without aura ( P < .05, cluster-level corrected). These functional abnormalities are independent of structural and microstructural changes and did not significantly correlate with clinical parameters. Conclusions Our data demonstrate a disrupted executive control network functional connectivity in patients with migraine with and without aura, in the interictal period. Although this functional phenomenon is present in the absence of clinically relevant executive deficits, it may reflect a vulnerability to executive high-demanding conditions of daily living activities in patients with migraine. [ABSTRACT FROM AUTHOR]

The article presents a case study of 38-year-old patient with sporadic severe, unilateral, throbbing headaches associated with nausea and vomiting and history of severe migraine attacks. Topiramate therapy was started for migraine which resulted in improved condition associated with mood changes and needing little sleep, and after sometimes with sudden onset of persistent of depressive symptoms. After topiramate discontinuation therapy program with lamotrigine was undertaken.

Insulin-like growth factors (IGF-I and IGF-II) have been shown to have several neurotrophic actions and IGF system may be impaired in neurodegenerative disorders. The aim of this study was to investigate the IGF system in patients with MSA and to evaluate correlations between this endocrine system and clinical features of the disease. Serum levels of IGF-I, IGF-II, insulin, IGF-binding protein 1 (BP1), and IGF-binding protein 3 (BP3) were measured in 25 patients with probable MSA and 25 age, sex and BMI-matched healthy controls. Clinical status of each patient was evaluated with the Unified Multiple System Atrophy Rating Scale (UMSARS) Part II and the Hoehn and Yahr rating scale. IGF-I levels were significantly higher in MSA (164.1 + 66.2 μg/L) than in healthy controls (111.7 + 60.3 μg/L; p = 0.001). Insulin levels were significantly higher in MSA patients (21.9 ± 14.4 μU/mL) than in healthy controls (13.3 ± 5.1 μU/mL, p = 0.048). No significant difference was found in serum IGF-II, IGF-BP1, and IGF- BP3 levels between patients with MSA and healthy controls. There was a trend toward significantly higher IGF-II levels in MSA patients with UMSARS score <26 (1026.3 ± 442.6 μg/L) than MSA patients with UMSARS score >26 (796.1 ± 234 μg/L, p = 0.055). The results of this study demonstrated that IGF system is altered in MSA. The degenerative process in MSA could lead to a compensatory increase in IGF-I and insulin in an attempt to provide additional support to degenerating neurons. © 2010 Movement Disorder Society. [ABSTRACT FROM AUTHOR]

OnabotulinumtoxinA (BoNT-A) has been reported as an effective prophylactic treatment for chronic migraine to reduce disease severity improving health-related quality of life. However, BoNT-A, due to its activity on either the injected or adjacent muscles of the upper face, may induce well-known side-effects, such as the eyebrow or eyelid ptosis. However, unusual muscular side effects, related to the neurotoxic mechanism, may also arise. We describe the clinical case of a 55-year-old male patient who has been treated for chronic migraine by the injection of BoNT-A, according to the PREEMPT protocol. Two weeks later, the patient developed two symmetrical bumps on the upper part of the forehead similar to the horns of a ram. We report, for the first time, this peculiar BoNT-A side effect and suggest that the injection of additional BoNT-A doses in the upper medial frontal fibers, for each side, can normalize the forehead shape over two weeks. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 32-year-old man experiencing episodes of strictly unilateral, unbearable, stabbing pain involving the left orbitotemporal region, associated with mild ipsilateral cranial autonomic features such as conjunctival injection, tearing, and nasal congestion. The patient attacks could be triggered by facial skin stimulation, chewing, or mandibular overstretching, and the patient was symptom-free during the interictal phase.

The Tolosa-Hunt syndrome consists of a painful ophthalmoplegia related to a granulomatous inflammatory process in the cavernous sinus, which may be documented by cerebral magnetic resonance imaging with gadolinium enhancement. Two cases of Tolosa-Hunt syndrome preceded by facial palsy observed in 1998 at the Department of Neurosurgery of the Second University of Naples are presented here. Both patients developed Tolosa-Hunt syndrome following an ipsilateral facial palsy that resolved in about 15 days with medical treatment. Cerebral magnetic resonance imaging with gadolinium enhancement showed, in both cases, inflammatory tissue in the cavernous sinus. The patients underwent corticosteroid therapy (prednisolone, 80 mg per day, intravenously) with pain regression. In the first case, the patient experienced recurrence of the syndrome that was definitively resolved with further corticosteroid treatment. The rare reports of facial palsy in patients with Tolosa-Hunt syndrome suggest the inclusion of this disease in the so-called multiple cranial nerve palsy syndrome. It is probable that Tolosa-Hunt syndrome has an inflammatory pathogenesis. [ABSTRACT FROM AUTHOR]

Objective: Refractory migraine (Ref-M) represents a conundrum that headache experts have to face with. We aim to investigate whether a peculiar profile may characterize patients with Ref-M according to 2020 European Headache Federation criteria. Furthermore, to substantiate a dysfunctional dopaminergic pathway involvement in these patients, we explored the effectiveness of olanzapine., Materials & Methods: Eighty-four patients (fitting previous Ref-M criteria of the 2014) were treated with erenumab for six months. Differences between clinical and demographic features of responder (Ref-M according to 2014 criteria) and not-responder (Ref-M according to 2020 criteria) patients to CGRP-mAbs were investigated and their predictive values assessed. In fifteen patients with Ref-M not responders to CGRP-mAbs, olanzapine was administered (5 mg/die) for 3 months and frequency and pain intensity of migraine attacks were estimated., Results: Patients with Ref-M not responsive to CGRP-mAbs (29/84) when compared with Ref-M responsive to CGRP-mAbs showed higher baseline frequency of migraine attacks, medication overuse and pain catastrophizing scale (PCS) scores. Logistic regression analyses showed that frequency of attacks, medication overuse and PCS score represent independent negative predictors of CGRP-mAbs response. A ≥50% reduction of headache days/month was observed after olanzapine treatment in 67% of patients with Ref-M not responsive to CGRP-mAbs., Conclusions: We outline that higher frequency of migraine attacks, medication overuse and pain catastrophizing characterize patients with Ref-M not responsive to CGRP-mAbs. In this frame, olanzapine effectiveness on frequency and pain intensity of migraine attacks supports the hypothesis that migraine refractoriness may be subtended by a prominent involvement of the dopaminergic pathway., (© 2021 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)