Cx43 hemichannels contribute to astrocyte-mediated toxicity in sporadic and familial ALS.

Connexin 43 (Cx43) gap junctions and hemichannels mediate astrocyte intercellular communication in the central nervous system under normal conditions and contribute to astrocyte-mediated neurotoxicity in amyotrophic lateral sclerosis (ALS). Here, we show that astrocyte-specific knockout of Cx43 in a mouse model of ALS slows disease progression both spatially and temporally, provides motor neuron (MN) protection, and improves survival. In addition, Cx43 expression is up-regulated in human postmortem tissue and cerebrospinal fluid from ALS patients. Using human induced pluripotent stem cell­derived astrocytes (hiPSC-A) from both familial and sporadic ALS, we establish that Cx43 is up-regulated and that Cx43-hemichannels are enriched at the astrocyte membrane. We also demonstrate that the pharmacological blockade of Cx43-hemichannels in ALS astrocytes using GAP 19, a mimetic peptide blocker, and tonabersat, a clinically tested small molecule, provides neuroprotection of hiPSC-MN and reduces ALS astrocyte-mediated neuronal hyperexcitability. Extending the in vitro application of tonabersat with chronic administration to SOD1G93A mice results in MN protection with a reduction in reactive astrocytosis and microgliosis. Taking these data together, our studies identify Cx43 hemichannels as conduits of astrocyte-mediated disease progression and a pharmacological target for disease-modifying ALS therapies.

COVID-19 and the peripheral nervous system. A 2-year review from the pandemic to the vaccine era.

Increasing literature has linked COVID-19 to peripheral nervous system (PNS) diseases. In addition, as we move from the pandemic to the vaccination era, literature interest is shifting towards the potential association between COVID-19 vaccines and PNS manifestations. We reviewed published literature on COVID-19, COVID-19 vaccines and PNS manifestations between 1 January 2020 and 1 December 2021. For Guillain-Barré syndrome (GBS), isolated cranial neuropathy (ICN) and myositis associated with COVID-19, the demographic, clinical, laboratory, electrophysiological and imaging features were included in a narrative synthesis. We identified 169 studies on COVID-19-associated complications, including 63 papers (92 patients) on GBS, 29 papers (37 patients) on ICN and 11 papers (18 patients) on myositis. Additional clinical phenotypes included chronic inflammatory demyelinating polyneuropathy, vasculitic neuropathies, neuralgic amyotrophy, critical care-related complications, and myasthenia gravis. PNS complications secondary to COVID-19 vaccines have been reported during randomized clinical trials, in real-world case reports, and during large-scale surveillance programs. These mainly include cases of GBS, Bell's palsy, and cases of neuralgic amyotrophy. Based on our extensive review of the literature, any conclusion about a pathophysiological correlation between COVID-19 and PNS disorders remains premature, and solely supported by their temporal association, while epidemiological and pathological data are insufficient. The occurrence of PNS complications after COVID-19 vaccines seems limited to a possible higher risk of facial nerve palsy and GBS, to a degree that widespread access to the ongoing vaccination campaign should not be discouraged, while awaiting for more definitive data from large-scale surveillance studies.

Persistent Cyfip1 Expression Is Required to Maintain the Adult Subventricular Zone Neurogenic Niche.

Neural stem cells (NSCs) persist throughout life in the subventricular zone (SVZ) neurogenic niche of the lateral ventricles as Type B1 cells in adult mice. Maintaining this population of NSCs depends on the balance between quiescence and self-renewing or self-depleting cell divisions. Interactions between B1 cells and the surrounding niche are important in regulating this balance, but the mechanisms governing these processes have not been fully elucidated. The cytoplasmic FMRP-interacting protein (Cyfip1) regulates apical-basal polarity in the embryonic brain. Loss of Cyfip1 during embryonic development in mice disrupts the embryonic niche and affects cortical neurogenesis. However, a direct role for Cyfip1 in the regulation of adult NSCs has not been established. Here, we demonstrate that Cyfip1 expression is preferentially localized to B1 cells in the adult mouse SVZ. Loss of Cyfip1 in the embryonic mouse brain results in altered adult SVZ architecture and expansion of the adult B1 cell population at the ventricular surface. Furthermore, acute deletion of Cyfip1 in adult NSCs results in a rapid change in adherens junction proteins as well as increased proliferation and number of B1 cells at the ventricular surface. Together, these data indicate that Cyfip1 plays a critical role in the formation and maintenance of the adult SVZ niche; furthermore, deletion of Cyfip1 unleashes the capacity of adult B1 cells for symmetric renewal to increase the adult NSC pool.SIGNIFICANCE STATEMENT Neural stem cells (NSCs) persist in the subventricular zone of the lateral ventricles in adult mammals, and the size of this population is determined by the balance between quiescence and self-depleting or renewing cell division. The mechanisms regulating these processes are not fully understood. This study establishes that the cytoplasmic FMRP interacting protein 1 (Cyfip1) regulates NSC fate decisions in the adult subventricular zone and adult NSCs that are quiescent or typically undergo self-depleting divisions retain the ability to self-renew. These results contribute to our understanding of how adult NSCs are regulated throughout life and has potential implications for human brain disorders.

A novel HSPB1 mutation associated with a late onset CMT2 phenotype: Case presentation and systematic review of the literature.

Mutations in the HSPB1 gene are associated with Charcot-Marie-Tooth (CMT) disease type 2F (CMT2F) and distal hereditary motor neuropathy type 2 (dHMN2). More than 18 pathogenic mutations spanning across the whole HSPB1 gene have been reported. Three family members with a novel p.P57S (c.169C>T) HSPB1 mutation resulting in a late onset axonal neuropathy with heterogeneous clinical and electrophysiological features are detailed. We systematically reviewed published case reports and case series on HSPB1 mutations. While a genotype-phenotype correlation was not obvious, we identified a common phenotype, which included adult onset, male predominance, motor more frequently than sensory involvement, distal and symmetric distribution with preferential involvement of plantar flexors, and a motor and axonal electrophysiological picture.

Radial Nerve F-wave reference values with surface electrodes from the anconeus muscle.

INTRODUCTION: We sought to obtain normative values for radial nerve F-wave variables, recording with surface electrodes from the anconeus muscle. METHODS: We tested 30 healthy participants (17 women, 13 men) and measured the following variables: number of F waves/40 traces (F%); minimum, maximum, and mean F-wave latency (FMIN, FMAX, FMED, respectively); F-wave chronodispersion (FCHR); interside differences of F% and FMIN (DF% and DFMIN, respectively). RESULTS: The mean F% was 41.3%; the normative values of FMIN, FMED, FMAX, and FCHR were < 21.2, <22.1, <23.3, and < 4.0 ms, respectively; and normative values of DF% and DFMIN were < 16.6% and < 1.1 ms, respectively. Height was the sole independent predictor in a regression model of FMIN, FMED, and FMAX; this explained 37%-44% of the variability. DISCUSSION: We identified a feasible and useful technique to record radial nerve F waves from the anconeus muscle and obtained normative values of F-wave variables. Muscle Nerve 59:244-246, 2019.

Cluster headache in relation to different age groups.

Cluster headache (CH) has always been considered a type of primary headache affecting predominantly male subjects in early and medium adulthood. However, recent studies carried out in large case series of patients with CH show that not infrequently it may set in also after age 50; by contrast, onset before adolescence is very rare. Additionally, when onset occurs before age 14 or from the sixth decade of life onward, male predominance decreases to the point that in chronic forms CH predominantly affects the female sex. This particular pattern of the gender ratio in relation to onset in different age groups suggests that hormonal factors may actually play a role in the genesis of CH. In particular, future studies should be aimed at investigating the possible protective role of estrogen.

Ictal headache: Insights from two cases.

BACKGROUND: We report the first literature description of ictal epileptic headaches closely mimicking glossopharyngeal neuralgia and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. CASE 1: A 37-year-old man complained of short-lasting, electric-shock like headache, confined to the pharynx. During the episodes, he could not speak because he felt "words blocked at the throat". An EEG recorded epileptic discharges concomitant with headache; a brain MRI disclosed frontal polymicrogyria. CASE 2: A 66-year-old man complained of short-lasting, right periocular headache, associated with ipsilateral ptosis, conjunctival injection and lacrimation. Some episodes were followed by tonic contraction of the right facial and limb muscles; on one occasion, headache was followed by a generalized seizure. A brain MRI revealed hippocampal abnormalities. DISCUSSION: These cases highlight the complex relationship between headache and epilepsy, and suggest a possible contribution of cortical structures to the genesis of paroxysmal headaches such as glossopharyngeal neuralgia and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.

A case-report of migraine "sine headache".

Background and objectives We describe a case of a female patient whose otherwise "typical" migraine attacks turned into episodes with a full spectrum of associated symptoms but without headache. Case report We evaluated a 53-year-old woman with a long history of migraine without aura. In concomitance with premenopausal menstrual dysregulation, she reported episodes of nausea and vomiting, associated with photophobia, phonophobia and osmophobia, but without headache; these episodes were responsive to oral triptans. Alternative diagnoses were excluded through extensive examinations. Discussion To date, no reports have been published in the literature on otherwise typical migraine attacks that are not accompanied by headache, nor did our case seem comparable to cases of abdominal migraine and cyclic vomiting syndrome. Conclusion Pathophysiologically, we hypothesize that functional dysregulation of the hypothalamus-brainstem connectivity may generate migraine attacks with a full spectrum of associated symptoms but without pain.

Headache as a presenting symptom of glioma: A cross-sectional study.

Objective The objective of this study was to analyse the prevalence and the clinical features of headache as a presenting symptom of glioma. Methods We interviewed 527 consecutive adult patients with histologically confirmed glioma, admitted to the Regina Elena National Cancer Institute between 2010 and 2015. We defined four headache phenotypes: Tension-type-like headache (TTH), migraine-like headache, worsening of a pre-existing headache (WPH) and classic brain tumour headache (BTH). Logistic regression analysis was carried out to investigate potential risk factors for headache at presentation of glioma. Results 12.5% (n = 66) of patients with glioma indicated headache as a presenting symptom of their disease. Of these, 31 patients (47%) had TTH, while BTH and WPH were reported by 28 (42%) and seven (11%) patients, respectively. We did not find any case of migraine-like headache. Infratentorial ( p = 0.038) and right-sided tumours ( p = 0.013) were more frequently associated with the presence of headache at onset. Patients with TTH were older than patients with BTH and WPH ( p = 0.035). BTH was less frequently associated with other neurological signs ( p < 0.0001). The multivariate logistic regression analysis showed the localization of the brain tumour in the left hemisphere to be a protective factor for the development of headache. Conclusions Our study includes a very large series of patients with glioma, providing a description of headache phenotype at first presentation of disease and investigating possible factors that may influence the clinical features of headache.

Childhood-Onset Cluster Headache: Observations From a Personal Case-Series and Review of the Literature.

BACKGROUND/OBJECTIVES: Puberty seems to be a turning point in cluster headache (CH) onset. To verify its influence on CH phenotype, we focused on cases with onset ≤13 years. A review of the literature follows. METHOD: We considered CH cases with age-of-onset ≤13 years evaluated at our center between 1975 and 2015; these cases were matched by sex to two consecutive patients with age-of-onset as close as possible (±2 years) to the median age-of-onset of the overall CH population. RESULTS: Of the overall 808 cases (585 men and 223 women, M:F ratio = 2.6), 38 patients (20 men and 18 women, M:F ratio = 1.1) had pediatric onset (PO). The diagnostic delay was significantly higher among cases with PO (21.2 ± 12.4 years, P < .0001). In this group, females had more frequently a chronic course and a familiarity for CH. Men with PO had some significant distinctive features, including higher frequency and longer duration of headache attacks, and higher proportion of various cranial autonomic and migraine-like symptoms. CONCLUSIONS: We confirmed that CH with childhood onset does not show a male predominance, which was actually inverted for chronic cases. Furthermore, males with PO seem to have a specific clinical phenotype.

Cluster Headache With Accompanying Migraine-Like Features: A Possible Clinical Phenotype.

BACKGROUND: There are limited literature data on migraine-like accompanying features (MLF) in patients with cluster headache (CH). These symptoms are frequently reported by patients and may delay CH diagnosis. OBJECTIVE: The aim of the present study was to investigate the occurrence of migraine-like symptoms in an Italian case series of CH patients and to determine whether these features influence the clinical phenotype of CH. METHODS: A cross-sectional study was performed in all consecutive patients referred to the Parma Headache Centre between 1975 and 2013 affected by CH; the cases were subsequently reviewed applying the ICHD3-beta criteria. Our initial study sample consisted of 785 subjects, 569 men (72.5%) and 216 women (27.5%). We then identified those patients who reported at least one of the migraine accompanying symptoms (ie, nausea or vomiting or photophobia and phonophobia). RESULTS: We found 362 patients (46%) with MLF, 250 men (43.9% of the initial male sample) and 112 women (51.9% of the initial female sample), and 423 patients (54%) without MLF, 319 men (56.1% of the initial male sample) and 104 women (48.1% of the initial female sample). Multiple logistic regression analysis highlighted some demographic and clinical features that significantly characterized patients with MLF after adjusting for confounding: they were more frequently female (OR 1.78, CI 1.11-2.80), with a relatively younger age of onset (OR 1.82, CI 1.06-2.91) than expected, attacks were longer in duration (OR 1.85, CI 1.04-2.46) and accompanied by a more frequent ptosis (OR 1.67, CI 1.04-2.34), sweating (OR 1.63, CI 1.02-2.21), and miosis (OR 1.54, CI 1.12-1.93); osmophobia was also more frequently reported (OR 1.76, CI 1.28-2.46). CONCLUSION: Our study confirms the high proportion of CH patients with MLF, which is reported in literature. The presence of MLF seems to relate to some peculiar demographic and clinical characteristics of CH sufferers. Whether these features influence the response to therapy remains to be determined.

The PACE study: lifetime and past-year prevalence of headache in Parma's adult general population.

Headache is a widespread disorder and therefore it has a strong impact on quality of life. In the present work we focused on lifetime and past-year prevalence of headache in general and by gender, in a population-based sample in Parma. A total of 904 subjects representative of Parma's adult general population were interviewed face-to-face by a physician from the Parma Headache Centre, using a validated questionnaire. The lifetime prevalence of headache was 69.1%, i.e. 75.8% in women and 60.6% in men; the crude past-year prevalence of headache was 42.8%, i.e. 52.0% in women and 31.1% in men. Both lifetime and past-year prevalence rates were significantly higher in females than in males (odds ratio, respectively, 2.0 and 2.4). In our study, past-year prevalence decreased after age 50 in both genders. Most people suffer from one headache subtype. In over 80% of cases, headache starts before age 40 and therefore people were not very likely to develop headache after 50 years. The past-year and lifetime prevalence rate of headache in general that we found in our study falls within the lower range of values for headache prevalence in European countries. Further researches need to be set in the Italian epidemiological background.

Neurobiology of chronicization.

In the past few years, research on chronicization of headache has focussed primarily on migraine, even though there are other types of primary headache that over time can turn into chronic forms. Only a minority of migraine sufferers will develop a chronic condition, with attacks that are likely to vary in their clinical features. As a result, in chronic migraine the specific diagnostic criteria for this headache type do not always exhibit the typical features of migraine. Among the factors that play a major role in favouring chronicization are a high frequency of migraine attacks since the beginning, overuse of symptomatic medication and onset of depression or arterial hypertension. Several neurophysiology, biochemistry and functional neuroimaging studies suggest that chronic migraine may be associated with structural, functional and metabolic changes in the brain, especially involving the brainstem.

Pediatric migraine with aura in an Italian case series.

The aim of the present study was to describe the characteristics of migraine with aura (MwA) in a case series of patients with headache onset before 12 years of age. We considered all consecutive patients referred to the Parma Headache Centre between 1975 and 2015 affected by MwA, diagnosed by our team of trained neurologists; the cases were subsequently reviewed applying the ICHD3-beta criteria. We then identified those cases with headache age-of-onset <12 years (i.e., "pediatric" cases), which were compared to all remaining cases. We identified 283 cases with pediatric onset (87 males and 196 females). The male-to-female ratio was 1:2.3 in both "pediatric" and "non-pediatric" cases. The time lag between MwA onset and our first evaluation was significantly higher among the pediatric cases (18.7 ± 13.3 vs 10.4 ± 10.4 years). In both groups of patients, visual aura was the most common type of aura, followed by sensory and speech disturbances; however, these two latter aura symptoms were significantly more common among pediatric cases. In this group of patients, aura without headache was significantly less frequent (1.8 vs 5.3%); furthermore, headache had migraine characteristics in a higher proportion of cases (90.1 vs 82.6%). A family history of MwA was significantly more frequent among cases with pediatric onset (31.1 vs 16.9%). Males but not females with pediatric MwA had more frequently a comorbid migraine without aura (27.6 vs 16.8%). Among cases with pediatric onset, we did not find any significant differences between males and females. In conclusion, in our very large case series of MwA, patients with headache onset before 12 years of age seem to have a specific clinical phenotype, without significant gender differences.

The use of onabotulinum toxin A (Botox(®)) in the treatment of chronic migraine at the Parma Headache Centre: a prospective observational study.

Chronic migraine is a debilitating headache, whose treatment is often complicated by the concomitant overuse of symptomatic medication and by the poor efficacy of standard prophylactic treatments. The PREEMPT studies have demonstrated the efficacy and tolerability of onabotulinum toxin A (Botox(®)) in the treatment of this headache type. Data about its use in clinical practice are still scarce. Our study evaluated all subjects with chronic migraine who were treated with onabotulinum toxin A between February 2014 and November 2015 at the Parma Headache Centre. Botox was injected according to the PREEMPT paradigm every 3 months. The data about variations in the number of headache days and in symptomatic medication intake before and after the Botox injections were collected from the patients' headache diaries. The study also evaluated tolerability to treatment, disability, and depressive symptoms. Of the 52 treated subjects, 14 received Botox treatment for at least 9 months and showed a significant decrease in the median number of headache days (from 19 to 14.5, p = 0.011) and in the median number of days of symptomatic medications intake and symptomatic drugs. Overall, the treatment was well tolerated. The average MIDAS and BDI-II scores after 9 months were reduced, though not significantly. The treatment with Botox proved effective and well tolerated in our clinical practice. Further studies on larger patient samples will help shed light on the persistence of the drug's effect at long term and identify the predictive factors of response to treatment.

Age of onset of episodic and chronic cluster headache - a review of a large case series from a single headache centre.

BACKGROUND: In the largest case series of cluster headache (CH) published in the literature, age of onset varies between 29.6 and 31.6 years. Differences in onset age based on gender and subtype diagnosis are reported, while there are only few data on patients with childhood and elderly onset. We therefore deemed it useful to review our own large case series of CH patients. METHODS: The age of onset of cluster headache was investigated in a consecutive case series of 808 patients (585 men and 223 women), including 686 (503 men and 183 women) with episodic cluster headache (ECH), 103 (66 men and 37 women) with chronic cluster headache (CCH), and 19 with an indeterminate form of CH (16 men and three women). RESULTS: The mean age of onset was 30.2 ± 13.8 years (30.1 ± 13.0 in men and 30.4 ± 15.7 in women). The women with primary CCH had a mean onset age of 42.8 ± 21.7 years, while the women with secondary CCH did not differ much from those with ECH. Distribution of the study subjects by decades of onset age showed a peak in the third decade both in men and in women, but when only CCH patients were considered it displayed a more marked bimodal pattern in women (with peaks in the second and the sixth decade) than men (with peaks in the third and the fifth decade). The clear male predominance in cases with onset in the central age groups became attenuated in the extreme age groups. In patients with onset between ≤ 15 years and ≥ 50 years, the traditional male-to-female ratio was actually inverted in CCH. CONCLUSIONS: Based on these epidemiological findings, it would be important to investigate the possible role, causative or protective, played by hormonal factors in CH pathogenesis.