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.

The ability to generate human-induced pluripotent stem cell (hiPSC)-derived neural cells displaying region-specific phenotypes is of particular interest for modeling central nervous system biology in vitro. We describe a unique method by which spinal cord hiPSC-derived astrocytes (hiPSC-A) are cultured with spinal cord hiPSC-derived motor neurons (hiPSC-MN) in a multielectrode array (MEA) system to record electrophysiological activity over time. We show that hiPSC-A enhance hiPSC-MN electrophysiological maturation in a time-dependent fashion. The sequence of plating, density, and age in which hiPSC-A are cocultured with MN, but not their respective hiPSC line origin, are factors that influence neuronal electrophysiology. When compared to coculture with mouse primary spinal cord astrocytes, we observe an earlier and more robust electrophysiological maturation in the fully human cultures, suggesting that the human origin is relevant to the recapitulation of astrocyte/motor neuron crosstalk. Finally, we test pharmacological compounds on our MEA platform and observe changes in electrophysiological activity, which confirm hiPSC-MN maturation. These findings are supported by immunocytochemistry and real-time PCR studies in parallel cultures demonstrating human astrocyte mediated changes in the structural maturation and protein expression profiles of the neurons. Interestingly, this relationship is reciprocal and coculture with neurons influences astrocyte maturation as well. Taken together, these data indicate that in a human in vitro spinal cord culture system, astrocytes support hiPSC-MN maturation in a time-dependent and species-specific manner and suggest a closer approximation of in vivo conditions. STEM CELLS TRANSLATIONAL MEDICINE 2019;8:1272-1285 SIGNIFICANCE STATEMENTThis study develops a method by which human-induced pluripotent stem cell-derived astrocytes (hiPSC-A) with distinct spinal cord identity are cocultured with spinal cord motor neurons (hiPSC-MN) for multielectrode array (MEA) recordings. It also demonstrates that hiPSC-A influence the morphological, molecular, and electrophysiological maturation of hiPSC-MN. Similarly, this study shows that hiPSC-A maturation is enhanced by the coculture with hiPSC-MN. This fully human, spinal cord-specific, coculture platform with MEA analyses provides a new tool for investigating astrocyte/MN interactions and has the potential to more accurately model human diseases with spinal cord pathology, including spinal muscular atrophy and amyotrophic lateral sclerosis.

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.

BackgroundIn 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.MethodsThe 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).ResultsThe 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.ConclusionsBased on these epidemiological findings, it would be important to investigate the possible role, causative or protective, played by hormonal factors in CH pathogenesis.

The mean global prevalence of tension-type headache (TTH) in adult is 42 %. To date, there have been no Italian studies on TTH prevalence in the adult general population. Therefore, we conducted a cross-sectional study, called PACE (PArma CEfalea, or ''Headache in Parma''), aimed at detecting the prevalence and clinical features of primary headaches in the city of Parma's adult general population. Crude past-year prevalence for definite TTH was 19.4 % (95 % CI 16.8-21.9), namely 9.0 % (95 % CI 7.1-10.8) for infrequent TTH, 9.8 % (95 % CI 7.9-11.8) for frequent TTH, and 0.6 % (95 % CI 0.1-1) for chronic TTH. Crude prevalence for probable TTH was 2.3 % (95 % CI 1.3-3.3). Our study results indicate a TTH prevalence rate (19.4 %) at the lower limit of data ranges currently available for Western countries, and prevalence rates for infrequent forms (9 %) do not appear much different from those of frequent forms (9.8 %).

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.

Significance Our results demonstrate that connexin 43 hemichannels are the conduits for amyotrophic lateral sclerosis (ALS) astrocyte-mediated motor neuron toxicity and disease spread, acting as a common mechanism that can target both familial ALS and sporadic ALS populations. Furthermore, our present work provides proof of principle that tonabersat, as a drug already studied in clinical trials for other indications, could serve as a potential ALS therapeutic.

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.