Efficacy and safety of ketamine and esketamine for unipolar and bipolar depression: an overview of systematic reviews with meta-analysis.

Background: Unipolar and bipolar depression present treatment challenges, with patients sometimes showing limited or no response to standard medications. Ketamine and its enantiomer, esketamine, offer promising alternative treatments that can quickly relieve suicidal thoughts. This Overview of Reviews (OoR) analyzed and synthesized systematic reviews (SRs) with meta-analysis on randomized clinical trials (RCTs) involving ketamine in various formulations (intravenous, intramuscular, intranasal, subcutaneous) for patients with unipolar or bipolar depression. We evaluated the efficacy and safety of ketamine and esketamine in treating major depressive episodes across various forms, including unipolar, bipolar, treatment-resistant, and non-resistant depression, in patient populations with and without suicidal ideation, aiming to comprehensively assess their therapeutic potential and safety profile. Methods: Following PRIOR guidelines, this OoR's protocol was registered on Implasy (ID:202150049). Searches in PubMed, Scopus, Cochrane Library, and Epistemonikos focused on English-language meta-analyses of RCTs of ketamine or esketamine, as monotherapy or add-on, evaluating outcomes like suicide risk, depressive symptoms, relapse, response rates, and side effects. We included studies involving both suicidal and non-suicidal patients; all routes and formulations of administration (intravenous, intramuscular, intranasal) were considered, as well as all available comparisons with control interventions. We excluded meta-analysis in which the intervention was used as anesthesia for electroconvulsive therapy or with a randomized ascending dose design. The selection, data extraction, and quality assessment of studies were carried out by pairs of reviewers in a blinded manner. Data on efficacy, acceptability, and tolerability were extracted. Results: Our analysis included 26 SRs and 44 RCTs, with 3,316 subjects. The intervention is effective and well-tolerated, although the quality of the included SRs and original studies is poor, resulting in low certainty of evidence. Limitations: This study is limited by poor-quality SRs and original studies, resulting in low certainty of the evidence. Additionally, insufficient available data prevents differentiation between the effects of ketamine and esketamine in unipolar and bipolar depression. Conclusion: While ketamine and esketamine show promising therapeutic potential, the current evidence suffers from low study quality. Enhanced methodological rigor in future research will allow for a more informed application of these interventions within the treatment guidelines for unipolar and bipolar depression. Systematic review registration: [https://inplasy.com/inplasy-2021-5-0049/], identifier (INPLASY202150049).

Neurological manifestations in patients and disease carriers in an Italian family with osteosclerosis.

BACKGROUND: Hereditary cranial hyperostosis is a rare disease never described in Italy, so the neurological manifestations in patients and carriers of the disease have been little studied. METHODS: We describe the neurological and neuroimaging features of patients and carriers of the gene from a large Italian family with sclerosteosis. RESULTS: In this family, genetic testing detected the homozygous p.Gln24X (c.70C > T) mutation of the SOST gene in the proband and a heterozygous mutation in 9 siblings. In homozygous adults, severe craniofacial hyperostosis was manifested by cranial neuropathy in childhood, chronic headache secondary to intracranial hypertension, and an obstructive sleep apnea syndrome in adults. In one of the adult patients, there was a compressible subcutaneous swelling in the occipital region caused by transosseous intracranial-extracranial occipital venous drainage, a compensation mechanism of obstructed venous drainage secondary to cranial hyperostosis. Mild cranial hyperostosis causing frequent headache and snoring was evident in the nine heterozygous subjects. CONCLUSIONS: Multiple cranial neuropathies and headache in children, while severe chronic headache and sleep disturbances in adults, are the neurological manifestations of the first Italian family with osteosclerosis. It is reasonable to extend neurological and neuroimaging evaluation to gene carriers as well.

Facemask headache: a new nosographic entity among healthcare providers in COVID-19 era.

BACKGROUND: SARS-CoV-2 is a novel infectious agent causing coronavirus disease 2019, which has been declared as pandemic in March 2020. Personal protective equipment has been mandatory for healthcare workers in order to contain the outbreak of pandemic disease. Mild neurological disturbances such as headache have been related to the extensive utilization of facemask. This study aims to examine headache variations related to the intensive utilization of facemask among a cohort of healthcare professionals in a setting of low-medium risk of exposure to SARS-CoV-2. METHODS: This is a cross-sectional study among healthcare providers from different hospital and clinics in Italy. Each participant completed a specifically designed self-administered questionnaire. Headache features and outcome measures' change from baseline were evaluated over a 4-month period, in which wearing facemask has become mandatory for Italian healthcare workers. RESULTS: A total of 400 healthcare providers completed the questionnaire, 383 of them met the inclusion criteria. The majority were doctors, with a mean age of 33.4 ± 9.2 years old. Among 166/383 subjects, who were headache free at baseline, 44 (26.5%) developed de novo headache. Furthermore, 217/383 reported a previous diagnosis of primary headache disorder: 137 were affected by migraine and 80 had tension-type headache. A proportion (31.3%) of these primary headache sufferers experienced worsening of their pre-existing headache disorder, mainly for migraine frequency and attack mean duration. CONCLUSIONS: Our data showed the appearance of de novo associated facemask headache in previous headache-free subjects and an exacerbation of pre-existing primary headache disorders, mostly experienced by people with migraine disease.

Botulinum toxin for the management of spasticity in multiple sclerosis: the Italian botulinum toxin network study.

BACKGROUND: Botulinum toxin (BT) is an effective and safe treatment for spasticity, with limited evidence in multiple sclerosis (MS). We aim to describe the use of BT for the management of MS spasticity in the clinical practice, its combination with other anti-spastic treatments in MS and possible MS clinical correlates. METHODS: This is a multicentre cross-sectional observational study including 386 MS patients, receiving BT for spasticity in 19 Italian centres (age 53.6 ± 10.9 years; female 228 (59.1%); disease duration 18.7 ± 9.2 years; baseline Expanded Disability Status Scale (EDSS) 6.5 (2.0-9.0)). RESULTS: BT was used for improving mobility (n = 170), functioning in activities of daily living (n = 56), pain (n = 56), posturing-hygiene (n = 63) and daily assistance (n = 41). BT formulations were AbobotulinumtoxinA (n = 138), OnabotulinumtoxinA (n = 133) and IncobotulinumtoxinA (n = 115). After conversion to unified dose units, higher BT dose was associated with higher EDSS (Coeff = 0.591; p < 0.001), higher modified Ashworth scale (Coeff = 0.796; p < 0.001) and non-ambulatory patients (Coeff = 209.382; p = 0.006). Lower BT dose was used in younger patients (Coeff = - 1.746; p = 0.009), with relapsing-remitting MS (Coeff = - 60.371; p = 0.012). BT dose was higher in patients with previous BT injections (Coeff = 5.167; p = 0.001), and with concomitant treatments (Coeff = 43.576; p = 0.022). Three patients (0.7%) reported on post-injection temporary asthenia/weakness (n = 2) and hypophonia (n = 1). CONCLUSION: BT was used for spasticity and its consequences from the early stages of MS, without significant adverse effects. MS-specific goals and injection characteristics can be used to refer MS patients to BT treatment, to decide for the strategy of BT injections and to guide the design of future clinical trials and observational studies.

Retinal Nerve Fiber Layer Thickness and Higher Relapse Frequency May Predict Poor Recovery after Optic Neuritis in MS Patients.

Optic neuritis (ON) is a common manifestation of multiple sclerosis (MS). Aiming to evaluate the retinal nerve fiber layer (RNFL) with optical coherence tomography (OCT), patients with relapsing-remitting (RR) MS experiencing ON were consecutively enrolled. RNFL, ganglion cell layer (GCL), foveal thickness, and macular volume were evaluated in both the ON and unaffected (nON) eye within six days from the relapse onset (T0) and after six months (T1). Ninety patients were enrolled. At T0, ON eyes showed a significantly increased RNFL when compared to the nON eyes (129.1 ± 19.5 vs. 100.5 ± 10.1, p < 0.001). At T1 versus T0, the ON eyes showed a thinner RNFL (129.1 ± 19.5 vs. 91.6 ± 20.2, p < 0.001) and a significantly decreased GCL (80.4 ± 8.8 vs. 73.8 ± 11.6; p < 0.005). No differences were found in the nON group in retinal parameters between T0 and T1. A multivariate logistic regression analysis showed that a higher number of relapses (not ON) and a greater swelling of RNFL at T0 were associated with poor recovery. The assessment of RNFL through OCT during and after ON could be used to predict persistent visual disability.

Periventricular white matter changes in idiopathic intracranial hypertension.

Objective: To evaluate whether increased cerebrospinal fluid (CSF) pressure causes alteration of periventricular white matter (WM) microstructure in patients with idiopathic intracranial hypertension (IIH). Methods: In a prospective study, patients with refractory chronic headache with and without IIH performed a neuroimaging study including 3T MRI, 3D Phase Contrast MR venography, and diffusion tensor imaging (DTI) of the brain. Whole-brain voxel-wise comparisons of DTI abnormalities of WM were performed using tract-based spatial statistics. A correlation analysis between DTI indices and CSF opening pressure, highest peak, and mean pressure was also performed in patients with IIH. Results: We enrolled 62 consecutive patients with refractory chronic headaches. Thirty-five patients with IIH, and 27 patients without increased intracranial pressure. DTI analysis revealed no fractional anisotropy changes, but decreased mean, axial, and radial diffusivity in body (IIHMD = 0.80 ± 0.04, non-IIHMD = 0.84 ± 0.4, IIHAD = 1.67 ± 0.07, non-IIHAD = 1.74 ± 0.05, IIHRD = 0.38 ± 0.04, non-IIHRD = 0.42 ± 0.05 [mm2/sec × 10-3]) of corpus callosum, and in right superior corona radiata (IIHMD = 0.75 ± 0.04, non-IIHMD = 0.79 ± 0.05, IIHAD = 1.19 ± 0.07, non-IIHAD = 1.28 ± 0.09, IIHRD = 0.59 ± 0.03, non-IIHRD = 0.53 ± 0.03 [mm2/sec × 10-3]) of 35 patients with IIH compared with 27 patients without increased intracranial pressure. DTI indices were negatively correlated with high CSF pressures (P < 0.05). After medical treatment, eight patients showed incremented MD in anterior corona radiata left and right and superior corona radiata right. Conclusions: There is significant DTI alteration in periventricular WM microstructure of patients with IIH suggesting tissue compaction correlated with high CSF pressure. This periventricular WM change may be partially reversible after medical treatment.

Validation of a self-reported instrument to assess work-related difficulties in patients with migraine: the HEADWORK questionnaire.

BACKGROUND: The degree to which work-related difficulties are recognized in headache research is poor and often carried out with inadequate information such as "reduced ability to work as usual", which do not capture at all the variety of difficulties and the factors that impact over them. The aim of this paper is to present the validation of the HEADWORK questionnaire, which addresses the amount and severity of difficulties in work-related tasks and the factors that impact over them. METHODS: We developed a set of items based on a previous literature review and patients' focus groups and tested it on a wide set of patients with episodic and chronic migraine attending eight different Italian headache centers. HEADWORK factor structure was assessed with exploratory and confirmatory factor analysis; internal consistency and construct validity were addressed as well. RESULTS: The validation sample (N = 373) was mostly composed of patients with episodic migraine without aura (64.3%) and of females (81%). Factor analysis retrieved two different scales: "Work-related difficulties", composed of eleven items which explain 67.1% of the total variance, and "Factors contributing to work difficulties", composed of six items which explain 52.1% of the total variance. Both HEADWORK subscales have good measurement properties, with higher scores being associated to higher disability, lower quality of life, lower productivity, higher headache frequency and pain intensity. CONCLUSIONS: HEADWORK is a 17-item, two-scale questionnaire addressing the impact of migraine on work-related difficulties in terms of difficulties in general or specific skills, and the factors contributing to these difficulties, defined as negative impact on work tasks. It can be used to address disability weights for the purpose of calculating the burden of migraine, and to assess the balance between therapeutic and side effects of medication on productivity.

Cerebrospinal Fluid Pressure-Related Features in Chronic Headache: A Prospective Study and Potential Diagnostic Implications.

Objective: To identify the pressure-related features of isolated cerebrospinal fluid hypertension (ICH) in order to differentiate headache sufferers with ICH from those with primary headache disorder. Methods: In this prospective study, patients with refractory chronic headaches and suspected of having cerebrospinal fluid-pressure elevation without papilledema or sixth nerve palsy, together with controls, underwent 1-h lumbar cerebrospinal fluid pressure monitoring via a spinal puncture needle. Results: We recruited 148 consecutive headache patients and 16 controls. Lumbar cerebrospinal fluid pressure monitoring showed high pressure and abnormal pressure pulsations in 93 (63 %) patients with headache: 37 of these patients with the most abnormal pressure parameters (opening pressure above 250 mm H2O, mean pressure 301 mm H2O, mean peak pressure 398 mm H2O, and severe abnormal pressure pulsations) had the most severe headaches and associated symptoms (nocturnal headache, postural headache, transient visual obscuration); 56 patients with the less abnormal pressure parameters (opening pressure between 200 and 250 mm H2O, mean pressure 228 mm H2O, mean peak pressure 316 mm H2O, and abnormal pressure pulsations) had less severe headaches and associated symptoms. Conclusions: Nocturnal and postural headache, and abnormal pressure pulsations are the more common pressure-related features of ICH in patients with chronic headache. Abnormal pressure pulsations may be considered a marker of ICH in chronic headache.