To the Editor: From February 28 through March 21, 2020, in three hospitals in northern Italy, we examined five patients who had Guillain-Barré syndrome after the onset of coronavirus disease 2019 , the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). During that period, an estimated 1000 to 1200 patients with Covid-19 were admitted to these hospitals. Four of the patients in this series had a positive nasopharyngeal swab for SARS-CoV-2 at the onset of the neurologic syndrome, and one had a negative nasopharyngeal swab and negative bronchoalveolar lavage but subsequently had a positive serologic test for the virus. Detailed case reports are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org.The first symptoms of Guillain-Barré syndrome were lower-limb weakness and paresthesia in four patients and facial diplegia followed by ataxia and paresthesia in one patient (Table 1). Generalized, flaccid tetraparesis or tetraplegia evolved over a period of 36 hours to 4 days in four patients; three received mechanical ventilation. The interval between the onset of symptoms of Covid-19 and the first symptoms of Guillain-Barré syndrome ranged from 5 to 10 days (Table 1 and Fig. S1 in the Supplementary Appendix). None of the patients had dysautonomic features.On analysis of the cerebrospinal fluid (CSF), two patients had a normal protein level and all the patients had a white-cell count of less than 5 per cubic millimeter. Antiganglioside antibodies were absent in the three patients who were tested. In all the patients, a real-time polymerase-chain-reaction assay of the CSF was negative for SARS-CoV-2. Results of electrophysiological studies are shown in Table S1. Compound muscle action potential amplitudes were low but could be obtained; two patients had prolonged motor distal latencies. On electromyography, fibrillation potentials were pres-* Covid-19 denotes coronavirus disease 2019, CSF cerebrospinal fluid, ICU intensive care unit, IVIG intravenous immune globulin, MRI magnetic resonance imaging, PCR polymerase chain reaction, and SARS-CoV-2 severe acute respiratory syndrome coronavirus 2. † On CSF analysis, all the patients had a normal glucose level and IgG index and a polyclonal pattern on electrophoresis. The normal range for the protein level is 15 to 45 mg per deciliter. ‡ An enzyme-linked immunosorbent assay was used to test for antibodies to GM1, GQ1b, and GD1b.

Anamnestic data and clinical features were accurately investigated in 180 patients with cluster headache; 161 were episodic sufferers and 19 were chronic. A significantly high familial incidence of coronary heart disease was found. The patients' medical history revealed a significantly high incidence of peptic ulcer disease and head injury with brain concussion. It is stressed that the side on which head injury took place is very frequently the same side on which cluster headache is located, although the latency between the two events appears to be a long one. The study of timing of cluster periods suggests, for some patients, a constant, typical temporal pattern not necessarily related to seasons or the months of of the year. Cluster attacks frequently occur during certain periods of the day (onset being most frequent between 1 and 3 p.m.). Cluster headache cannot be considered as a nocturnal headache.

Admission to a stroke-unit ward with dedicated beds and staff within 48 h of onset should be recommended for all patients with acute stroke.

Chronic Cluster Headache (CCH) treatment is troublesome; since there are no pain-free periods, it must be continuous. The most effective CCH prophylactic drug today is lithium carbonate but long-term use of this drug is limited by the possibility of side effects. Recently, calcium antagonists have been successfully employed to prevent migraine, and preliminary studies also indicate that verapamil in particular is an efficacious treatment for CCH. We have conducted a multicenter trial employing a double-dummy, double blind, cross-over protocol, comparing verapamil with the established efficacy of lithium carbonate, in preventing CCH attacks. Both lithium carbonate and verapamil were effective in preventing CCH but verapamil caused fewer side effects and had a shorter latency period. We did not observe any correlation between plasma levels of the two drugs and their clinical efficacy. Both the drugs tested here may exert their effect by restoring a normal inhibitory tone to the pain modulating pathways from the trigemino-vascular system, a circuit putatively implicated in CCH.

The innate immune system plays a dualistic role in the evolution of ischemic brain damage and has also been implicated in ischemic tolerance produced by different conditioning stimuli. Early after ischemia, perivascular astrocytes release cytokines and activate metalloproteases (MMPs) that contribute to blood–brain barrier (BBB) disruption and vasogenic oedema; whereas at later stages, they provide extracellular glutamate uptake, BBB regeneration and neurotrophic factors release. Similarly, early activation of microglia contributes to ischemic brain injury via the production of inflammatory cytokines, including tumor necrosis factor (TNF) and interleukin (IL)-1, reactive oxygen and nitrogen species and proteases. Nevertheless, microglia also contributes to the resolution of inflammation, by releasing IL-10 and tumor growth factor (TGF)-β, and to the late reparative processes by phagocytic activity and growth factors production. Indeed, after ischemia, microglia/macrophages differentiate toward several phenotypes: the M1 pro-inflammatory phenotype is classically activated via toll-like receptors or interferon-γ, whereas M2 phenotypes are alternatively activated by regulatory mediators, such as ILs 4, 10, 13, or TGF-β. Thus, immune cells exert a dualistic role on the evolution of ischemic brain damage, since the classic phenotypes promote injury, whereas alternatively activated M2 macrophages or N2 neutrophils prompt tissue remodeling and repair. Moreover, a subdued activation of the immune system has been involved in ischemic tolerance, since different preconditioning stimuli act via modulation of inflammatory mediators, including toll-like receptors and cytokine signaling pathways. This further underscores that the immuno-modulatory approach for the treatment of ischemic stroke should be aimed at blocking the detrimental effects, while promoting the beneficial responses of the immune reaction.

Background and Purpose-Although several studies have demonstrated the effectiveness of specialist Stroke Unit (SU) care of stroke patients, there is still disagreement over how these units are best organized. We sought to clarify the role of continuous monitoring of physiological parameters in acute ischemic stroke. Methods-We conducted a prospective study of 268 first-ever ischemic stroke patients admitted to our Cerebrovascular Department and allocated, according to the availability of beds, to the SU or Cerebrovascular Unit (CU). Statistical analysis compared mortality and outcome at discharge, medical and neurological complications, and length of hospitalization in the 2 care settings. Results-Two hundred sixty-eight patients were enrolled. A good outcome at discharge, observed in 114 SU patients (85%) and 78 CU patients (58%) (odds ratio, 2.63; 95% CI, 1.4 to 4.8; PϽ0.02), was found, on multivariate analysis, to be significantly related to type of care (SU versus CU). A significantly greater proportion of SU patients showed adverse changes in monitored parameters, which required acute medical treatment (SU: 64%; CU: 19%; PϽ0.0001).The mean duration of these complications was significantly shorter in the SU patients (SU: 1.0 day; CU: 2.4 days; PϽ0.02), and the outcome in patients experiencing complications covered by the monitoring protocol was significantly better in the SU (66%) than in the CU (35%) group (PϽ0.0001). Conclusions-Admission

One-hundred-and-eighty-nine cluster headache patients, referred to Parma and Pavia Headache Centres between 1976 and 1986 with a disease duration of over 10 years, were interviewed about the course of cluster headache. They were classified as episodic (n = 140) or chronic (n = 49) cluster headache patients on the basis of course during the year of onset. Episodic patients showed the following outcome: maintenance of an episodic form (primary episodic form) in 80.7% of cases, shift towards a chronic form (secondary chronic form) in 12.9% and shift towards an intermediate pattern ("combined" form) in 6.4%. In chronic patients, cluster headache was still chronic (primary chronic form) at the moment of observation in 52.4% of cases, while it turned into an episodic form ("secondary" episodic form) in 32.6% and into a "combined" form in 14.3%. Nineteen patients (10%) had had no attacks for at least three years at the moment of examination. We can conclude from our data that: cluster headache is a disease of long duration, perhaps lifelong; episodic cluster headache tends to worsen; chronic cluster headache may easily turn into a better prognostic episodic form; prophylactic drugs are unable to induce recovery. The following factors seem related to a poor outcome: a later onset, the male gender and a disease duration of over 20 years for the episodic forms.

Background and Purpose: We aimed to investigate the rate of hospital admissions for cerebrovascular events and of revascularization treatments for acute ischemic stroke in Italy during the coronavirus disease 2019 (COVID-19) outbreak. Methods: The Italian Stroke Organization performed a multicenter study involving 93 Italian Stroke Units. We collected information on hospital admissions for cerebrovascular events from March 1 to March 31, 2020 (study period), and from March 1 to March 31, 2019 (control period). Results: Ischemic strokes decreased from 2399 in 2019 to 1810 in 2020, with a corresponding hospitalization rate ratio (RR) of 0.75 ([95% CI, 0.71–0.80] P <0.001); intracerebral hemorrhages decreased from 400 to 322 (hospitalization RR, 0.81 [95% CI, 0.69–0.93]; P =0.004), and transient ischemic attacks decreased from 322 to 196 (hospitalization RR, 0.61 [95% CI, 0.51–0.73]; P <0.001). Hospitalizations decreased in Northern, Central, and Southern Italy. Intravenous thrombolyses decreased from 531 (22.1%) in 2019 to 345 in 2020 (19.1%; RR, 0.86 [95% CI, 0.75–0.99]; P =0.032), while primary endovascular procedures increased in Northern Italy (RR, 1.61 [95% CI, 1.13–2.32]; P =0.008). We found no correlation ( P =0.517) between the hospitalization RRs for all strokes or transient ischemic attack and COVID-19 incidence in the different areas. Conclusions: Hospitalizations for stroke or transient ischemic attacks across Italy were reduced during the worst period of the COVID-19 outbreak. Intravenous thrombolytic treatments also decreased, while endovascular treatments remained unchanged and even increased in the area of maximum expression of the outbreak. Limited hospitalization of the less severe patients and delays in hospital admission, due to overcharge of the emergency system by COVID-19 patients, may explain these data.