The Manchester Triage System's performance in clinical risk prioritisation of patients presenting with headache in emergency department: A retrospective observational study.

OBJECTIVE: Non-traumatic headache is a frequent reason for visits to the emergency department (ED). We evaluated the performance of the Manchester Triage System (MTS) in prioritising patients presenting to the ED with non-traumatic headache. METHODS: In this single-centre observational retrospective study, we compared the association of MTS priority classification codes with a final diagnosis of a severe neurological condition requiring timely management (ischaemic or haemorrhagic stroke, subarachnoid haemorrhage, cerebral sinus venous thrombosis, central nervous system infection or brain tumour). The study was conducted and reported according to the STROBE statement. The overall prioritisation accuracy of MTS was estimated by the area under the receiver operating characteristic (ROC) curve. The correctness of triage prediction was estimated based on the "very urgent" MTS grouping. An undertriage was defined as a patient with an urgent and severe neurological who received a low priority/urgency MTS code (green/yellow). RESULTS: Over 30 months, 3002 triage evaluations of non-traumatic headache occurred (1.7% of ED visits). Of these, 2.3% (68/3002) were eventually diagnosed with an urgent and severe neurological condition. The MTS had an acceptable prioritisation accuracy, with an area under the ROC curve of 0.734 (95% CI 0.668-0.799). The sensitivity of the MTS for urgent codes (yellow, orange and red) was 79.4% (95% CI 74.5-84.3), with a specificity of 54.1% (95% CI 52.9-55.3). The triage prediction was incorrect in only 6.3% (190/3002) of patients with headache. CONCLUSION: The MTS is a safe and accurate tool for prioritising patients with non-traumatic headache in the ED. However, MTS may need further specific tools for evaluating the more complicated symptoms and for correctly identifying patients with urgent and severe underlying pathologies. RELEVANCE TO CLINICAL PRACTICE: The triage nurse using MTS may need additional tools to improve the assessment of patients with headache, although MTS provides a good safety profile.

Classification Accuracy of Transcranial Magnetic Stimulation for the Diagnosis of Neurodegenerative Dementias.

OBJECTIVE: Transcranial magnetic stimulation (TMS) has been suggested as a reliable, noninvasive, and inexpensive tool for the diagnosis of neurodegenerative dementias. In this study, we assessed the classification performance of TMS parameters in the differential diagnosis of common neurodegenerative disorders, including Alzheimer disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). METHODS: We performed a multicenter study enrolling patients referred to 4 dementia centers in Italy, in accordance with the Standards for Reporting of Diagnostic Accuracy. All patients underwent TMS assessment at recruitment (index test), with application of reference clinical criteria, to predict different neurodegenerative disorders. The investigators who performed the index test were masked to the results of the reference test and all other investigations. We trained and tested a random forest classifier using 5-fold cross-validation. The primary outcome measures were the classification accuracy, precision, recall, and F1 score of TMS in differentiating each neurodegenerative disorder. RESULTS: A total of 694 participants were included, namely 273 patients diagnosed as AD, 67 as DLB, and 207 as FTD, and 147 healthy controls (HC). A series of 3 binary classifiers was employed, and the prediction model exhibited high classification accuracy (ranging from 0.89 to 0.92), high precision (0.86-0.92), high recall (0.93-0.98), and high F1 scores (0.89-0.95) in differentiating each neurodegenerative disorder. INTERPRETATION: TMS is a noninvasive procedure that reliably and selectively distinguishes AD, DLB, FTD, and HC, representing a useful additional screening tool to be used in clinical practice. Ann Neurol 2020;87:394-404.

Effects of Intermittent Theta Burst Stimulation on the Clock Drawing Test Performances in Patients with Alzheimer's Disease.

The clock drawing test (CDT) is widely used in clinical neuropsychological practice. However, its neuroanatomical correlates have not been well established. This study investigated the effects of theta burst stimulation (TBS) applied over different brain regions on CDT scores in patients with Alzheimer's disease (AD). The 10-20 positions F3, F4, T3, T4, TP3, TP4, P3, P4, as determined by a 10-20 positioning cap, were targeted. Excitatory intermittent TBS (iTBS) was given over the above-mentioned eight regions to ten AD patients and ten control subjects on separate days. CDT was administered at baseline (T0), during the 5 min following the TBS (T1) and 60 min after TBS (T2), with an inter-session interval of at least 4 days. iTBS over TP4 and P4 transiently increased Rouleau CDT score in AD patients. When targeting TP4 and P4, mainly the area of the supramarginal/angular gyrus and the inferior parietal lobe, corresponding respectively to the Brodmann areas 40/39 and 7/40, are reached. iTBS thus seems able to modulate activity of the right posterior parietal cortex in AD patients performing the CDT. Our results provide physiological evidence that those parietal regions are functionally important for the execution of the Rouleau CDT. This finding suggests that CDT has reliable neuroanatomical correlates, and support the notion that this test can be used as a good marker of right parietal brain dysfunction. The present study also highlights the therapeutic potential of the induction of neuromodulatory effects using non-invasive brain stimulation techniques.

The Babinski sign in the first Italian reports.

The Babinski sign, named after Joseph François Félix Babinski (1857-1932), is one of the most important in clinical neurology. It refers to the upward movement of the great toe following stimulation of the foot sole and is associated with a dysfunction of the pyramidal tract. The BS was recognized and adopted by neurologists all over the world immediately after its first description. In 1899, this sign was first introduced to the Italian scientific community at two different medical meetings. Some opinions on its clinical value and underlying pathophysiology were discordant, possibly reflecting suboptimal diagnostic accuracy of the first observations. Giovanni Mingazzini (1859-1929) first suggested that the BS reflects a complex mechanism emerging in patients with pyramidal tract dysfunction, whereas Giovanni Boeri (1867-1946) emphasized that the BS can be elicited if the neuromuscular structures underlying it are intact. Although some of their opinions eventually proved wrong, early Italian neurologists further contributed to the advancement in the understanding of this phenomenon.

Stroke management during the coronavirus disease 2019 (COVID-19) pandemic: experience from three regions of the north east of Italy (Veneto, Friuli-Venezia-Giulia, Trentino-Alto-Adige).

BACKGROUND: Efficiency of care chain response and hospital reactivity were and are challenged for stroke acute care management during the pandemic period of coronavirus disease 2019 (COVID-19) in North-Eastern Italy (Veneto, Friuli-Venezia-Giulia, Trentino-Alto-Adige), counting 7,193,880 inhabitants (ISTAT), with consequences in acute treatment for patients with ischemic stroke. METHODS: We conducted a retrospective data collection of patients admitted to stroke units eventually treated with thrombolysis and thrombectomy, ranging from January to May 2020 from the beginning to the end of the main first pandemic period of COVID-19 in Italy. The primary endpoint was the number of patients arriving to these stroke units, and secondary endpoints were the number of thrombolysis and/or thrombectomy. Chi-square analysis was used on all patients; furthermore, patients were divided into two cohorts (pre-lockdown and lockdown periods) and the Kruskal-Wallis test was used to test differences on admission and reperfusive therapies. RESULTS: In total, 2536 patients were included in 22 centers. There was a significant decrease of admissions in April compared to January. Furthermore, we observed a significant decrease of thrombectomy during the lockdown period, while thrombolysis rate was unaffected in the same interval across all centers. CONCLUSIONS: Our study confirmed a decrease in admission rate of stroke patients in a large area of northern Italy during the lockdown period, especially during the first dramatic phase. Overall, there was no decrease in thrombolysis rate, confirming an effect of emergency care system for stroke patients. Instead, the significant decrease in thrombectomy rate during lockdown addresses some considerations of local and regional stroke networks during COVID-19 pandemic evolution.

Connectivity Analysis during Rubber Hand Illusion-A Pilot TMS-EEG Study in a Patient with SCI.

Background: Bodily self-perception is an important concept for several neurological disorders, including spinal cord injury (SCI). Changing one's bodily self-perception, e.g., via rubber hand illusion (RHI), induces alterations of bottom-up and top-down pathways and with this the connectivity between involved brain areas. We aim to examine whether (1) this process can be manipulated by changing cortical excitability, (2) connectivity between relevant brain areas differ when the RHI cannot be evoked, and (3) how this projection differs in a patient with SCI. Method: We applied RHI and facilitatory theta burst stimulation (TBS) on the right primary somatosensory cortex (S1) of 18 healthy participants and one patient with incomplete, cervical SCI. During RHI, we recorded high-density electroencephalography (HD-EEG) and extracted directed and nondirected connectivity measures. Results: There is no difference in connectivity between sham and real TBS or in the effectivity of RHI. We observed a higher laterality in the patient, i.e., higher connectivity of the right and lower of the left hemisphere. Besides this, connectivity patterns do not differ between healthy participants and the patient. Conclusion: This connectivity pattern might represent a neuroplastic response in the attempt to overcome the functional impairment of the patient resulting in a similar overall connectivity pattern to the healthy participants, yet with a higher sensitivity towards RHI and a higher laterality. The cortico-cortical communication was not altered depending on whether the illusion was provoked or not; hence, the perceptory illusion could not be observed in the EEG analysis.

Cannabidiol efficacy and clobazam status: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the potential impact of concomitant clobazam (CLB) use on the efficacy of cannabidiol (CBD) treatment in patients with Dravet syndrome and Lennox-Gastaut syndrome using meta-analytical techniques. METHODS: We searched for randomized, placebo-controlled, single- or double-blinded trials. The proportion of patients who achieved ≥50% reduction from baseline in seizure frequency during the treatment period was assessed according to CLB status. Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated. RESULTS: Four trials were included and enrolled 714 participants, 429 for the add-on CBD group and 285 for the add-on placebo group. Among CBD-treated patients, 240 (55.9%) were taking concomitant CLB (CLB-On) and 189 (44.1%) were not taking concomitant CLB (CLB-Off); in placebo-treated patients, 158 (55.4%) were CLB-On and 127 (44.6%) CLB-Off. The percentages of patients who had at least 50% reduction in seizure frequency during the treatment period were 29.1% in the CBD arm and 15.7% in the placebo group among CLB-Off patients (RR = 1.80, 95% CI = 1.12-2.90, P = .015). Among CBL-On patients, the ≥50% reduction in seizure frequency was found in 52.9% and 27.8% in the CBD and placebo groups, respectively (RR = 1.85, 95% CI = 1.40-2.44, P < .001). SIGNIFICANCE: CBD was associated with a higher rate of seizure response in comparison to placebo when added to the existing antiepileptic regimen both in patients taking and in those not taking concomitant CLB. The lack of randomization for CLB status and the limited sample size need to be considered in the interpretation of the findings.

Effects of intrathecal baclofen therapy in subjects with disorders of consciousness: a reappraisal.

Baclofen is a structural analogue of gamma-amino-butyric acid (GABA), which reduces spastic hypertonia of striated muscle due to a mechanism of GABAB-ergic inhibition of mono- and polysynaptic reflexes at the spinal level. There are reports of patients with severe disorders of consciousness that presented a substantial improvement following intrathecal baclofen (ITB) administration for severe spasticity. The neural mechanisms underlying the clinical recovery after ITB have not yet been clarified. Baclofen could modulate sleep-wake cycles that may be dysregulated and thus interfere with alertness and awareness. The diminished proprioceptive and nociceptive sensory inputs may relieve thalamo-cortical neural networks involved in maintaining the consciousness of the self and the world. ITB treatment might also promote the recovery of an impaired GABAergic cortical tone, restoring the balance between excitatory and inhibitory cortical activity. Furthermore, glutamatergic synapses are directly or indirectly modulated by GABAB-ergic receptors. Neurophysiological techniques (such as transcranial magnetic stimulation, electroencephalography, or the combination of both) can be helpful to explore the effects of intrathecal or oral baclofen on the modulation of neural cortical circuits in humans with disorders of consciousness.

Statins in primary prevention of poststroke seizures and epilepsy: A systematic review.

INTRODUCTION: Cerebrovascular disease is the most common cause of seizures in adults and the elderly. So far, no drug is recommended as primary prevention of acute symptomatic poststroke seizures (ASPSS) or poststroke epilepsy (PSE). This systematic review aimed to evaluate the association between the use of statins after stroke and the risk of developing ASPSS or PSE following cerebral infarct or hemorrhage (primary prevention). METHODS: We included studies evaluating the poststroke use of statins as primary prevention of ASPSS or PSE, irrespective of stroke type. We excluded uncontrolled studies and studies with prestroke statin use. The main outcome included the occurrence of ASPSS or PSE and the effect of statins by type and dose. The odds ratios (ORs) or hazard ratios (HR) with 95% confidence intervals (CIs) were used as the measures of association between treatment and outcome. RESULTS: Four studies were included. One study showed a reduced risk of ASPSS after ischemic stroke (OR: 0.25; 95% CI: 0.10-0.59; p = 0.0016). Three studies consistently reported a reduced risk of PSE after ischemic stroke, and one study a reduced risk of PSE after hemorrhagic stroke (HR: 0.62; 95% CI: 0.42-0.90; p = 0.01). CONCLUSIONS: Data from the literature suggest an association between statin use and a reduced risk of ASPSS after ischemic stroke and a reduced risk of PSE after ischemic and hemorrhagic stroke. Although the certainty of the evidence is low, these findings appear promising and worthy of further investigation.

Increased risk of stroke and myocardial infarction in patients with epilepsy: A systematic review of population-based cohort studies.

OBJECTIVE: The objective of the study was to review the current epidemiological evidence about the relationship between epilepsy and increased risk of cardio- and cerebrovascular events. METHODS: We systematically searched MEDLINE (from inception to 19th October 2018) to identify population-based cohort studies evaluating the risk of subsequent stroke or myocardial infarction (MI) in patients with epilepsy without history of prior cerebrovascular disease in comparison with subjects without epilepsy. RESULTS: A total of 16,641 records were screened, and 6 studies were included. Data on the risk of subsequent stroke and MI were provided by five and two studies, respectively. The adjusted hazard ratios (adjHRs) of subsequent ischemic stroke for patients with epilepsy ranged from 1.09 (95% confidence interval (CI): 1.00-1.19) to 2.85 (95% CI: 2.49-3.26). Two studies assessing the incidence of hemorrhagic stroke showed an increased risk in patients with epilepsy (adjHR: 3.30; 95% CI: 2.46-4.43 and adjHR: 2.27; 95% CI: 1.80-2.85). The adjHRs of subsequent MI ranged between 1.09 (95% CI: 1.00 to 1.19) and 1.48 (95% CI: 1.31-1.67). Age, hypertension, MI, diabetes, hyperlipidemia, and arteriosclerosis were significantly associated with the increase in stroke risk. A gradient between the antiepileptic drug (AED) dose and risk of subsequent stroke was found. In comparison with carbamazepine (CBZ), oxcarbazepine (OXC) was associated with an increased risk of stroke and valproate (VPA) with a reduction in risk of stroke and MI, whereas no significant associations with vascular disease were found for phenobarbital (PB), lamotrigine (LMT), phenytoin (PHT), clonazepam (CLZ), and clobazam (CLB). CONCLUSIONS: Patients with epilepsy are at higher risk of subsequent stroke and MI in comparison with subjects without epilepsy. Although individual AEDs may carry different risks of cardio- and cerebrovascular disease, the clinical relevance of the metabolic effects of the enzyme-inducing AEDs is still uncertain. This article is part of the Special Issue "Seizures & Stroke".

Intravenous thrombolysis with tPA and cortical involvement increase the risk of early poststroke seizures: Results of a case-control study.

The aim of this study was to identify the risk factors for early poststroke seizures (PSS) in patients with acute ischemic stroke. We undertook a case-control study at a single stroke center. Patients with seizure occurring during the first 7 days following ischemic stroke admitted between 2010 and 2016 were retrospectively identified and matched with controls (patients with stroke without early PSS) for age and sex. We included 79 cases and 158 controls. Blood sugar levels on admission, stroke localization, National Institutes of Health Stroke Scale (NIHSS) and Rankin score, and intravenous (i.v.) thrombolysis with recombinant tissue plasminogen activator (rtPA) were statistically associated with early PSS in univariate analysis. Multiple logistic regression after forward and backward variable selection identified cortical stroke localization (odds ratio (OR): 2.49; 95% confidence intervals (CI): 1.35 to 4.59; p = 0.003) and i.v. thrombolysis (OR: 2.26; 95% CI: 1.16 to 4.43; p = 0.008) as variables independently associated with early PSS. Cortical involvement and i.v. thrombolysis are independent risk factors associated with the occurrence of early PSS. This association is not explained by age or sex, concomitant drugs, diabetes or alcoholism, sodium and cholesterol levels, blood pressure on admission, stroke etiology or severity, and hemorrhage following i.v. thrombolysis. Further studies are required to fully elucidate the association between different reperfusion therapies and early PSS. This article is part of the Special Issue "Seizures & Stroke".

Giovanni Mingazzini (1859-1929) and his opposition to Pierre Marie's conception of motor aphasia.

This article describes the contribution of Giovanni Mingazzini (1859-1929), the "Father of Italian Neurology," in the description of the subcortical structures involved in motor aphasia and his opposition to Pierre Marie's (1853-1940) conception of aphasia. In one of the most famous controversies in the history of neurology, the French neurologists Joseph Jules Dejerine (1849-1917), Augusta Dejerine-Klumpke (1859-1927), and Pierre Marie (1853-1940) faced each other during the three symposiums of the French Society of Neurology in 1908. The debate, which was later called "the aphasia quarrel", focused on the subject of aphasia. In an article published in January of the same year, the Italian neurologist Giovanni Mingazzini had already explicitly challenged Pierre Marie's conception of aphasia. Mingazzini's contribution to the "aphasia debate" deserves to be remembered for the emphasis on the role of Broca's area, and for his detailed description of a subcortical region representing "the crossroad of the language pathways" which, if lesioned, could cause motor aphasia.

"Spreading the word of the master": the contribution of Italian physicians in the early dissemination of Jean-Martin Charcot's theories.

Jean-Martin Charcot (1825-1893) laid the foundations of modern neurology. The lectures he gave at La Salpêtrière Hospital in Paris attracted a large number of visitors from all over the world. Some of them transcribed these clinical lessons, translating and publishing them when returning home. This article discusses the contribution of some Italian physicians (Gaetano Rummo, 1853-1917; Domenico Miliotti; Giulio Melotti, 1857-19?; and Augusto Tebaldi, 1833-1895), who were pioneers in disseminating the ideas and discoveries of Charcot. The early Italian translations were based on personal handwritten notes and memories, not relying on official French versions personally revised or edited by Charcot himself. As such, their veracity cannot always be verified, particularly in the lack of other independent works reporting details on the same lectures. However, the Italian transcriptions providing information which cannot be found elsewhere in Charcot's corpus of works represent an invaluable and a unique source for fully understanding some theories by the French neurologist. Furthermore, they are the first documents providing original materials related to Charcot's teaching translated in a foreign language. The first Italian publications that included photographs of patients were deeply influenced by and clearly modeled on the famous volumes of the Iconographie photographique de la Salpêtrière and further contributed to the early dissemination of Charcot's theories.

Diagonal earlobe crease (Frank's sign) and increased risk of cerebrovascular diseases: review of the literature and implications for clinical practice.

Diagonal earlobe crease (DELC) or Frank's sign is a diagonal crease in the earlobe that extends diagonally from the tragus to the edge of the auricle with an angle of approximately 45°. Although its presence increases with advancing age, several studies have shown an independent association between DELC and cardiovascular diseases as well as peripheral vascular diseases. DELC has also been demonstrated to increase the risk of cerebrovascular events (mostly ischaemic stroke), probably through atherosclerotic mechanisms. A systematic literature search was conducted using PubMed and Embase to identify studies investigating the relationship between DELC and the occurrence of cerebrovascular diseases. We identified 5 articles (1469 subjects included). Since the presence of DELC can be easily evaluated, patients with the Frank's sign should undergo a diagnostic workup to detect vascular risk factors and implement preventative therapies.

Effects of Rubber Hand Illusion and Excitatory Theta Burst Stimulation on Tactile Sensation: A Pilot Study.

Synchronous visuotactile stimulation on the own hidden hand and a visible fake limb can alter bodily self-perception and influence spontaneous neuroplasticity. The rubber hand illusion (RHI) paradigm experimentally produces an illusion of rubber hand ownership and arm shift by simultaneously stroking a rubber hand in view and a participant's visually occluded hand. The aim of this cross-over, placebo-controlled, single-blind study was to assess whether RHI, in combination with high-frequency repetitive transcranial magnetic stimulation (rTMS) given as intermittent (excitatory) theta burst stimulation (iTBS) applied over the hand area of the primary sensory region (S1) can enhance tactile sensation in a group of 21 healthy subjects and one patient with cervical spinal cord injury. Four sessions covered all combinations of real and sham stimulations of the RHI and the TBS: real TBS and real RHI, real TBS and sham RHI, sham TBS and real RHI, and both conditions sham. The condition sham TBS and real RHI shows the greatest effect on the proprioceptive drift (median 2.3 cm, IQR 2) and on the score of RHI questionnaires (median 3, IQR 2) in the control group as well as in the real-real condition (median 2, IQR 2). The sham TBS and real RHI condition also shows the best results in the electrical perception test of the patient (median 1.9 mA). Conversely, the upregulation of the cortical excitability of S1 via TBS seems to impair the effect of the RHI. This might be due to a strengthening of the top-down connection between the central nervous system and the periphery, diminishing the RHI. This finding helps in understanding the mechanisms of top-down and bottom-up mechanisms in healthy subjects and patients with spinal cord injury. The RHI paradigm could represent an interesting therapeutic approach in improving tactile sensation and rTMS techniques could modulate these effects. Yet, further studies are needed, to examine the direction of the interaction effect of TMS and RH.

Cerebrovascular manifestations of herpes simplex virus infection of the central nervous system: a systematic review.

BACKGROUND: Intracerebral hemorrhage and ischemic stroke are increasingly recognized complications of central nervous system (CNS) infection by herpes simplex virus (HSV). AIM OF THE STUDY: To analyze clinical, imaging, and laboratory findings and outcomes of cerebrovascular manifestations of HSV infection. METHODS: Systematic literature review from January 2000 to July 2018. RESULTS: We identified 38 patients (median age 45 years, range 1-73) comprising 27 cases of intracerebral hemorrhage, 10 of ischemic stroke, and 1 with cerebral venous sinus thrombosis. Intracerebral hemorrhage was predominantly (89%) a complication of HSV encephalitis located in the temporal lobe. Hematoma was present on the first brain imaging in 32%, and hematoma evacuation was performed in 30% of these cases. Infarction was frequently multifocal, and at times preceded by hemorrhage (20%). Both a stroke-like presentation and presence of HSV encephalitis in a typical location were rare (25% and 10%, respectively). There was evidence of cerebral vasculitis in 63%, which was exclusively located in large-sized vessels. Overall mortality was 21% for hemorrhage and 0% for infarction. HSV-1 was a major cause of hemorrhagic complications, whereas HSV-2 was the most prevalent agent in the ischemic manifestations. CONCLUSION: We found a distinct pathogenesis, cause, and outcome for HSV-related cerebral hemorrhage and infarction. Vessel disruption within a temporal lobe lesion caused by HSV-1 is the presumed mechanism for hemorrhage, which may potentially have a fatal outcome. Brain ischemia is mostly related to multifocal cerebral large vessel vasculitis associated with HSV-2, where the outcome is more favorable.

Hypertrophic chronic pachymeningitis associated with Epstein-Barr virus reactivation: a case report.

Hypertrophic pachymeningitis is a rare inflammatory condition characterized by the thickening of the dura mater. We describe a patient who presented with intractable headache and complex cranial nerve palsy. Hypertrophy of the frontal dura was accompanied by pleocytosis and detection of Epstein-Barr virus (EBV) by PCR in cerebrospinal fluid. Clinical symptoms gradually improved after acyclovir and corticosteroid treatment, whereas dural pathology remained unchanged on neuroimaging. This case points at an expansion of the spectrum of neurological manifestations for EBV.

Antiepileptic drug monotherapy for epilepsy in the elderly: A systematic review and network meta-analysis.

OBJECTIVE: To estimate the comparative efficacy and safety of antiepileptic drugs (AEDs) in the elderly with new-onset epilepsy. METHODS: We searched electronic databases for randomized controlled trials (RCTs) of monotherapy AEDs to treat epilepsy in elderly. The following outcomes were analyzed: seizure freedom and withdrawal from the study for any cause at 6 and 12 months; withdrawal from the study for any adverse event (AE) at 12 months; and occurrence of any AE at 12 months. Effect sizes were estimated by network meta-analyses within a frequentist framework. The hierarchy of competing interventions was established using the surface under the cumulative ranking curve (SUCRA) and mean ranks. RESULTS: Five RCTs (1425 patients) were included. Included AEDs were carbamazepine immediate- and controlled-release (CBZ-IR, CBZ-CR), gabapentin (GBP), lacosamide (LCM), lamotrigine (LTG), levetiracetam (LEV), phenytoin (PHT), and valproic acid (VPA). At the pairwise and network meta-analyses, there were no differences in any of the comparison according to 6- and 12-month seizure freedom. The treatment with CBZ-IR and CBZ-CR was associated with a higher risk of withdrawal than LTG, LEV, or VPA, and CBZ-IR had the overall highest probability of discontinuation across all AEDs. According to SUCRA, the following had the greatest likelihood ranking best for seizure freedom at 6 and 12 months: LCM, LTG, and LEV. CBZ-CR and CBZ-IR had the highest probabilities of being worst for the 12-month retention. CBZ-IR, CBZ-CR, and GBP had the highest probabilities of withdrawal from the study for AEs, , and VPA had the highest probability of being the best-tolerated option. SIGNIFICANCE: Although no significant difference in efficacy was found across treatments, LCM, LTG, and LEV had the highest probability of ranking best for achieving seizure freedom. CBZ-IR and CBZ-CR showed a poor tolerability profile, leading to higher withdrawal rates compared to LEV and VPA.

Cholinergic transmission is impaired in patients with idiopathic normal-pressure hydrocephalus: a TMS study.

The pathophysiological mechanisms of cognitive and gait disturbances in subjects with normal-pressure hydrocephalus (NPH) are still unclear. Cholinergic and other neurotransmitter abnormalities have been reported in animal models of NPH. The objective of this study was to evaluate the short latency afferent inhibition (SAI), a transcranial magnetic stimulation protocol which gives the possibility to test an inhibitory cholinergic circuit in the human brain, in subjects with idiopathic NPH (iNPH). We applied SAI technique in twenty iNPH patients before ventricular shunt surgery. Besides SAI, also the resting motor threshold and the short intracortical inhibition to paired stimulation were assessed. A significant reduction of the SAI (p = 0.016), associated with a less pronounced decrease of the resting motor threshold and the short latency intracortical inhibition to paired stimulation, were observed in patients with iNPH at baseline evaluation. We also found significant (p < 0.001) correlations between SAI values and the gait function tests, as well as between SAI and the neuropsychological tests. These findings suggest that the impairment of cholinergic neurons markedly contributes to cognitive decline and gait impairment in subjects with iNPH.

Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network meta-analysis.

Second and third generation AEDs have been directly compared to controlled-release carbamazepine (CBZ-CR) as initial monotherapy for new-onset focal epilepsy. Conversely, no head-to-head trials have been performed. The aim of this study was to estimate the comparative efficacy and tolerability of the antiepileptic monotherapies in adults with newly diagnosed focal epilepsy through a network meta-analysis (NMA). Randomized, double-blinded, parallel group, monotherapy studies comparing any AED to CBZ-CR in adults with newly diagnosed untreated epilepsy with focal-onset seizures was identified. The outcome measures were the seizure freedom for 6 and 12 months, the occurrence of treatment-emergent adverse events (TEAEs), and the treatment withdrawal due to TEAEs. Mixed treatment comparisons were conducted by a Bayesian NMA using the Markov chain Monte Carlo methods. Effect sizes were calculated as odds ratios (ORs) with 95% credible intervals (CrIs). Four trials were included involving 2856 participants, 1445 for CBZ-CR and 1411 for the comparative AEDs. Monotherapy AEDs compared to CBR-CR were levetiracetam (LEV), zonisamide (ZNS), lacosamide (LCM), and eslicarbazepine acetate (ESL). There were no statistical differences in the 6- and 12-month seizure freedom and TEAEs occurrence between LEV, ZNS, LCM, ESL, and CBZ-CR In the analysis of drug withdrawal due to TEAEs, LCM treatment was associated with a significantly lower discontinuation rate than CBZ-CR (OR 0.659, 95% CrI 0.428-0.950). LEV, ZNS, LCM, and ESL are effective initial monotherapy treatments in adult patients with newly diagnosed focal epilepsy and represent suitable alternatives to CBZ-CR.