Heart rate variability is reduced during the menstrual phase in women with catamenial C1-type temporal lobe epilepsy.

INTRODUCTION: Temporal lobe epilepsy (TLE) is the most frequent focal epilepsy in adulthood. Catamenial C1-type TLE, is characterized by a cyclic seizure exacerbation during the menstrual phase. The heart rate variability (HRV) analysis assesses cardiac autonomic control and may represent a biomarker for Sudden Unexpected Death in Epilepsy (SUDEP). It is plausible that female sex hormones can influence HRV. These changes might be more pronounced in patients suffering from catamenial C1-type TLE where hormonal changes also increase seizure susceptibility. To that aim, we evaluated HRV changes during the menstrual phase of women suffering from catamenial C1-type TLE. METHODS: We enrolled 12 adults with a diagnosis of catamenial C1-type TLE (Catamenial Group) and 12 age-, and seizure-frequency-matched controls with TLE (Non-Catamenial Group). Each patient underwent a 20-minute EEG + EKG recording in resting state during the menstrual phase. HRV parameters were calculated with a short-lasting analysis of EKG records. Time domain-related, frequency domain-related, as well as non-linear analysis parameters, were compared between the two groups. RESULT: Compared to the Non-Catamenial Group, the Catamenial Group showed significant reductions in SDNN (p-value = 0.01), RMSSD (p-value = 0.04), pNN50 (p-value = 0.001), LnLF ms2 (p-value = 0.05), LnHF ms2 (p-value = 0.007), SD1 (p-value = 0.02), and SD2 (p-value = 0.01). These results were independent from age, disease duration, numbers of ASM, and seizure etiology. CONCLUSION: Our data provide experimental evidence that vagal output is reduced during the menstrual phase in patients with catamenial C1-type TLE. These results indicate that, during the menstrual phase, patients with catamenial C1-type TLE may be at a higher risk of developing cardiac dysfunctions and SUDEP.

Cerebral venous thrombosis without thrombocytopenia after a single dose of COVID-19 (Ad26.COV2.S) vaccine injection: a case report.

BACKGROUND: The coronavirus pandemic became the hard challenge for the modern global health system. To date, vaccination is the best strategy against Sars-Cov-2-related illness. About 3 billions of people received at least one of the approved vaccines. The related adverse events were reported during the various experimental phases, but newer and less common side effects are emerging post-marketing. Vaccine-induced thrombocytopenia with thrombosis (VITT) is one of these insidious adverse reactions and it is considered responsible of venous thrombosis, in both the splanchnic and the cerebral circulation. Although its mechanism has been presumably established, resembling that observed in heparin-induced thrombocytopenia, some venous thromboses seem not to recognize this etiology and their pathogenesis remains unknown. Here we described a case of cerebral venous thrombosis after administration of the Ad26.COV2.S, presenting without thrombocytopenia, paving the way for possible novel causes of this vaccine-induced pathological condition. CASE PRESENTATION: A 45-year-old woman came to our observation for bilateral periorbital headache associated with retro-orbital pain started 8 days after administration of COVID vaccine Jannsen. Ophthalmologic exam showing a bilateral papilledema raised the suspicion of intracranial hypertension. Cerebral magnetic resonance imaging revealed signal alteration with T1-positive contrast enhancement in the right temporal and insular lobes suggestive of cerebral venous thrombosis. The absence of thrombocytopenia and platelet factor 4 (PF-4) antibodies led the clinicians to rule out VITT. The patient was treated successfully with warfarin. CONCLUSION: Venous thrombosis occurring after COVID-19 vaccination represents an adverse event of special interest. Patients with thrombosis and thrombocytopenia appear to be affected by a general thrombophilic state, sustained by an autoimmune mechanism, and show a higher mortality. Thrombosis without thrombocytopenia's pathogenesis has not yet been clarified, but laboratory data and good response to vitamin K antagonists help clinicians in the differential diagnosis with VITT. Future research will allow us to discover other possible mechanisms and maybe identify a subgroup of patients with a higher risk of developing this medical complication.

Status epilepticus and COVID-19: A systematic review.

PURPOSE: In March 2020, the World Health Organization declared the SARS-CoV-2 infection-related coronavirus Disease (COVID-19) a pandemic. During the first and second waves of the pandemic spread, there have been several reports of COVID-19-associated neurological manifestations, including acute seizures and status epilepticus (SE). In this systematic review, we summarized the available data on clinical features, diagnosis, and therapy of COVID-19-related SE. METHODS: We performed a systematic search of the literature to identify data on demographics, clinical, neurophysiological, and neuroradiological data of patients with COVID-19-related SE. We used regression models (linear or logistic) with a stepwise forward method to identify features associated with mortality or severity of SE. RESULTS: Thirty-nine articles were included with a total of 47 cases of SE associated with COVID-19. Age, time between the acute respiratory phase of SARS-CoV-2 infection and SE onset, and hospitalization correlated with a higher SE severity as assessed by quantitative validated scales. CONCLUSIONS: SE can be a neurological manifestation of SARS-CoV-2 infection. Although a possible association between SE and COVID-19 has been reported, the exact mechanisms are still not fully understood. Systemic inflammatory syndrome due to cytokine release could play a role in COVID-19-related SE.

New daily persistent headache after SARS-CoV-2 infection: a report of two cases.

BACKGROUND: The 2019 Coronavirus (SARS-CoV-2) is a novel respiratory virus which causes Coronavirus Disease19 (COVID-19). Although the predominant clinical picture of COVID-19 is represented by respiratory symptoms, neurological manifestations are being increasingly recognized. Headache, in particular migraine-like and tension types, has been largely reported in patients suffering from COVID-19 both in the acute and the healing phase of the infection. New daily persistent headache (NDPH) is a primary headache characterized by persistent and daily painful symptoms, with pain becoming continuous and non-remitting within 24 h, and lasting more than 3 months. Even though an increasing number of reports describe patients who develop a persistent headache, diagnosis of NPDH has been rarely explored in the context of COVID-19. METHODS: Two patients with persistent headache and Sars-CoV-2 infection were identified. Both underwent a full clinical and neuroradiological evaluation. Blood sample with inflammatory biomarkers search was also performed. RESULTS: According to International Classifications of Headache Disorders diagnosis of probable new daily persistent headache was made. The treatment with high doses of steroids was associated with relief of symptoms. CONCLUSIONS: Our report described two cases of probable NDPH due to SARS-CoV-2 infection. Clinical evaluation of COVID-19 patients presenting with persistent headache should take into consideration NDPH. Given the supposed major role for neuroinflammation in the genesis of Sars-CoV-2-driven NDPH, immunomodulatory therapy should be promptly started. In line with this hypothesis, we obtained a good therapeutic response to short-term high dose of corticosteroids.

Autophagic-Related Proteins in Brain Gliomas: Role, Mechanisms, and Targeting Agents.

The present review focuses on the phenomenon of autophagy, a catabolic cellular process, which allows for the recycling of damaged organelles, macromolecules, and misfolded proteins. The different steps able to activate autophagy start with the formation of the autophagosome, mainly controlled by the action of several autophagy-related proteins. It is remarkable that autophagy may exert a double role as a tumour promoter and a tumour suppressor. Herein, we analyse the molecular mechanisms as well as the regulatory pathways of autophagy, mainly addressing their involvement in human astrocytic neoplasms. Moreover, the relationships between autophagy, the tumour immune microenvironment, and glioma stem cells are discussed. Finally, an excursus concerning autophagy-targeting agents is included in the present review in order to obtain additional information for the better treatment and management of therapy-resistant patients.

Immunotherapy in Early-Stage Non-Small Cell Lung Cancer (NSCLC): Current Evidence and Perspectives.

Lung cancer is the leading cause of cancer deaths in the world. Surgery is the most potentially curative therapeutic option for patients with early-stage non-small cell lung cancer (NSCLC). The five-year survival for these patients remains poor and variable, depending on the stage of disease at diagnosis, and the risk of recurrence following tumor resection is high. During the last 20 years, there has been a modest improvement in the therapeutic strategies for resectable NSCLC. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, have become the cornerstone for the treatment of metastatic NSCLC patients. Recently, their clinical development has been shifted in the neoadjuvant and adjuvant settings where they have demonstrated remarkable efficacy, leading to improved clinical outcomes. Based on the positive results from phase III trials, ICIs have become a therapeutic option in neoadjuvant and adjuvant settings. On October 2021 the Food and Drug Administration (FDA) approved atezolizumab as an adjuvant treatment following surgery and platinum-based chemotherapy for patients with NSCLC whose tumors express PD-L1 ≥ 1%. In March 2022, nivolumab in combination with platinum-doublet chemotherapy was approved for adult patients with resectable NSCLC in the neoadjuvant setting. The current review provides an updated overview of the clinical trials exploring the role of immunotherapy in patients with early-stage NSCLC, focusing on the biological rationale for their use in the perioperative setting. We will also discuss the role of potential predictive biomarkers to personalize therapy and optimize the incorporation of immunotherapy into the multimodality management of stage I-III NSCLC.

Therapeutic strategies for HER2-positive breast cancer with central nervous system involvement: a literature review and future perspectives.

Background and Objective: Brain metastases (BMs) are present in approximately 55% of patients with HER2-positive breast cancer (HER2+ BC). The introduction of anti-HER2 agents has radically changed the prognosis of these patients by prolonging overall survival. Methods: In this review, we describe the biology of central nervous system (CNS) spreading in patients with HER2+ BC. We also provide a literature review of current treatment strategies of brain metastatic BC, focusing on HER2+ disease, and future perspectives. Key Content and Findings: Treatment of symptomatic BMs includes traditionally neurosurgery and/or radiotherapy, depending on the number of metastases, performance status and systemic disease control. Local treatments, such as surgical excision of BM and stereotactic radiosurgery (SRS), when feasible, are preferred over whole-brain radiotherapy, because of related cognitive impairment. These treatments can lead to a local control of the disease, however, systemic relapses can affect the prognosis of these patients. Recently, new anti-HER2 agents have demonstrated to be effective on BMs, thereby leading to improved survival outcomes with an acceptable quality of life. Despite the clinical benefit of these approaches, BMs still represent a cause of death and effective therapeutic strategies are needed. Conclusions: Different targeted agents have demonstrated significant efficacy with tolerable safety profiles in HER2+ BC patients with BM, and have already been approved for clinical use in this setting. A better understanding of the molecular mechanisms underlying the onset of BMs could suggest novel targeted approaches in order to prevent CNS localization or delay progression to CNS in HER-2 metastatic patients.

Autoimmune encephalitis during pregnancy: A diagnostic and therapeutic challenge-A systematic review with individual patients' analysis and clinical recommendations.

Several reports have described the autoimmune encephalitis' (AE) possible onset during pregnancy. In this systematic review, we summarize the available data on the diagnostic and therapeutic approach to AE during pregnancy, highlighting the associated maternal and fetal clinical outcomes. A systematic search of the literature was performed. The following databases were used: PubMed, Google Scholar, EMBASE, and CrossRef. The revision was registered on the PROSPERO platform (CRD42022336357). Forty-nine patients were included. AE onset was mainly observed during the first and the second trimester of pregnancy with psychiatric manifestations and seizures as main onset symptoms. CSF analysis showed AE-specific autoantibody positivity in 33 patients (anti-NMDA receptor as the most frequent). EEG generally showed normal findings. MRI revealed pathological findings in less than half of patients. Tumor screening was positive in 14 cases. First-line immunotherapy (single or combined) was generally employed while second line was administered in a minority of patients. Levetiracetam was the most used antiseizure medication. Cesarean section was performed in 18 women. Most of the women had an excellent early outcome after delivery but 22 showed persistent neurological deficits in long-term follow-up. Fetal outcome was positive in 33 cases, whereas 12 cases of fetal death were reported. A logistic regression showed that no variable significantly influenced the odds of good/bad maternal and fetal clinical outcome. Diagnosis and treatment of AE during pregnancy is challenging. The rate of miscarriage in women with AE seems to be higher than the general population. In addition, mothers may show long-term neurological deficits.

Anti N-methyl-D-aspartate receptor (NMDAr) encephalitis during pregnancy: A case report.

Anti-N-methyl-D-aspartate receptor (NMDAr) antibody encephalitis is an autoimmune disorder characterized by reduced synaptic activity of the NMDAr due to circulating antibodies that target the NR1 subunit. Few cases of anti-NMDAR encephalitis during pregnancy have been described. The permeation of anti-NR1 antibodies through the placenta can be instrumental in the development of complications in newborns. We describe a case of a young woman suffering from anti-NMDAR encephalitis during the first trimester of pregnancy and focus on diagnostic and therapeutic management.

Perampanel enhances the cardiovagal tone and heart rate variability (HRV) in patients with drug-resistant temporal lobe epilepsy.

OBJECTIVE: The temporal lobe plays a central role in the regulation of the "Central Autonomic Network" and cardiovascular functions. The blockade of glutamatergic pathways in the temporal lobe affects cardio-autonomic control. Perampanel (PER) is a non-competitive agonist of the AMPA receptor. This study evaluated PER effects on cardiac autonomic control in patients affected by drug-resistant TLE (DRTLE). METHODS: We enrolled 40 adults with DRTLE treated with PER as add-on therapy (PER group) and 32 DRTLE age, sex, and seizure-frequency matched controls treated with different additional anti-seizure medication (ASM) as add-on therapy (No-PER group). HRV analysis was performed on 5-minute EKG recording in resting state before and 6-months after the introduction of add-on ASM. Linear Mixed Models (LMM) were used to analyzed HRV variables according to time (baseline and 6-months follow-up) and groups. RESULTS: At baseline no differences were detected between PER group and No-PER group according to time-domain and frequency-domain HRV parameters. At the follow-up, in PER group a multiplicative effect for the interaction between treatment and time was observed for MeanRR (ms) (p=0.03), LnRMSSD (ms) (p=0.04), LnHF (ms2) (p<0.001), HF n.u. (p=0.001), HF% (p=0.002) with increased values, and for LnLF (ms2) (p=0.001), LF n.u. (p=0.001), LF% (p=0.01), and LF/HF (p<0.001) with reduced values. The change in seizure frequency after add-on therapy was comparable between the two groups (p=0.81) CONCLUSIONS: Our data support the notion that PER increases the vagal tone in DRTLE. This activity may exert a cardioprotective effect by reducing the risk of developing cardiac arrhythmias. Furthermore, given the correlations between HRV modifications and the occurrence of SUDEP, future studies will need to test the protective effects of PER on SUDEP.

Muscarinic Receptors Expression in the Peripheral Blood Cells Differentiate Dementia with Lewy Bodies from Alzheimer's Disease.

BACKGROUND: Central nervous system disruption of cholinergic (ACh) signaling, which plays a major role in cognitive processes, is well documented in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). The expression of muscarinic ACh receptors type 1 and 4 (CHRM1 and CHRM4) has been reported to be altered in the brain of DLB patients. OBJECTIVE: We aim to assess the peripheral gene expression of CHRM1 and 4 in DLB as a possible marker as compared to AD and healthy control (HC) subjects. METHODS: Peripheral blood mononuclear cells were collected from 21 DLB, 13 AD, and 8 HC matched subjects. RT-PCR was performed to estimate gene expression of CHRM1 and CHRM4. RESULTS: Peripheral CHRM1 expression was higher and CHRM4 was lower in DLB and AD compared to HC, whereas both CHRM1 and CHRM4 levels were higher in AD compared to DLB patients. Receiver operating characteristics curves, with logistic regression analysis, showed that combining peripheral CHRM1 and CHRM4 levels, DLB and AD subjects were classified with an accuracy of 76.0%. CONCLUSION: Alterations of peripheral CHRM1 and CHRM4 was found in both AD and DLB patients as compared to HC. CHRM1 and CHRM4 gene expression resulted to be lower in DLB patients compared to AD. In the future, peripheral CHRM expression could be studied as a possible marker of neurodegenerative conditions associated with cholinergic deficit and a possible marker of response to acetylcholinesterase inhibitors.

A Critical Review of Alien Limb-Related Phenomena and Implications for Functional Magnetic Resonance Imaging Studies.

Consensus criteria on corticobasal degeneration (CBD) include alien limb (AL) phenomena. However, the gist of the behavioral features of AL is still "a matter of debate." CBD-related AL has so far included the description of involuntary movements, frontal release phenomena (frontal AL), or asomatognosia (posterior or "real" AL). In this context, the most frequent symptoms are language and praxis deficits and cortical sensory misperception. However, asomatognosia requires, by definition, intact perception and cognition. Thus, to make a proper diagnosis of AL in the context of CBD, cognitive and language dysfunctions must be carefully verified and objectively assessed. We reviewed the current literature on AL in CBD and now propose that the generic use of the term AL should be avoided. This catchall AL term should instead be deconstructed. We propose that the term AL is appropriate to describe clinical features associated with specific brain lesions. More discrete sets of regionally bound clinical signs that depend on dysfunctions of specific brain areas need to be assessed and presented when posing the diagnosis. Thus, in our opinion, the AL term should be employed in association with precise descriptions of the accompanying involuntary movements, sensory misperceptions, agnosia-asomatognosia contents, and the presence of utilization behavior. The review also offers an overview of functional magnetic resonance imaging-based studies evaluating AL-related phenomena. In addition, we provide a complementary set of video clips depicting CBD-related involuntary movements that should not mistakenly be interpreted as signs of AL.

Agitation and Dementia: Prevention and Treatment Strategies in Acute and Chronic Conditions.

Agitation is a behavioral syndrome characterized by increased, often undirected, motor activity, restlessness, aggressiveness, and emotional distress. According to several observations, agitation prevalence ranges from 30 to 50% in Alzheimer's disease, 30% in dementia with Lewy bodies, 40% in frontotemporal dementia, and 40% in vascular dementia (VaD). With an overall prevalence of about 30%, agitation is the third most common neuropsychiatric symptoms (NPS) in dementia, after apathy and depression, and it is even more frequent (80%) in residents of nursing homes. The pathophysiological mechanism underlying agitation is represented by a frontal lobe dysfunction, mostly involving the anterior cingulate cortex (ACC) and the orbitofrontal cortex (OFC), respectively, meaningful in selecting the salient stimuli and subsequent decision-making and behavioral reactions. Furthermore, increased sensitivity to noradrenergic signaling has been observed, possibly due to a frontal lobe up-regulation of adrenergic receptors, as a reaction to the depletion of noradrenergic neurons within the locus coeruleus (LC). Indeed, LC neurons mainly project toward the OFC and ACC. These observations may explain the abnormal reactivity to weak stimuli and the global arousal found in many patients who have dementia. Furthermore, agitation can be precipitated by several factors, e.g., the sunset or low lighted environments as in the sundown syndrome, hospitalization, the admission to nursing residencies, or changes in pharmacological regimens. In recent days, the global pandemic has increased agitation incidence among dementia patients and generated higher distress levels in patients and caregivers. Hence, given the increasing presence of this condition and its related burden on society and the health system, the present point of view aims at providing an extensive guide to facilitate the identification, prevention, and management of acute and chronic agitation in dementia patients.

Psychogenic Non-epileptic Seizures and Pseudo-Refractory Epilepsy, a Management Challenge.

Psychogenic nonepileptic seizures (PNES) are neurobehavioral conditions positioned in a gray zone, not infrequently a no-man land, that lies in the intersection between Neurology and Psychiatry. According to the DSM 5, PNES are a subgroup of conversion disorders (CD), while the ICD 10 classifies PNES as dissociative disorders. The incidence of PNES is estimated to be in the range of 1.4-4.9/100,000/year, and the prevalence range is between 2 and 33 per 100,000. The International League Against Epilepsy (ILAE) has identified PNES as one of the 10 most critical neuropsychiatric conditions associated with epilepsy. Comorbidity between epilepsy and PNES, a condition leading to "dual diagnosis," is a serious diagnostic and therapeutic challenge for clinicians. The lack of prompt identification of PNES in epileptic patients can lead to potentially harmful increases in the dosage of anti-seizure drugs (ASD) as well as erroneous diagnoses of refractory epilepsy. Hence, pseudo-refractory epilepsy is the other critical side of the PNES coin as one out of four to five patients admitted to video-EEG monitoring units with a diagnosis of pharmaco-resistant epilepsy is later found to suffer from non-epileptic events. The majority of these events are of psychogenic origin. Thus, the diagnostic differentiation between pseudo and true refractory epilepsy is essential to prevent actions that lead to unnecessary treatments and ASD-related side effects as well as produce a negative impact on the patient's quality of life. In this article, we review and discuss recent evidence related to the neurobiology of PNES. We also provide an overview of the classifications and diagnostic steps that are employed in PNES management and dwell on the concept of pseudo-resistant epilepsy.

Comparison of Procalcitonin Assays on KRYPTOR and LIAISON® XL Analyzers.

Our laboratory performs procalcitonin (PCT) assays on a Brahms KRYPTOR analyzer with the Brahms PCT sensitive Kryptor kit. In this study, we wanted to compare the assays obtained in this way with the ones performed on the LIAISON® XL. From January to May 2017, 171 samples were analyzed, of which 65 from female patients (age: 22-98 years) and 106 from male patients (age: 16-97 years). The PCT determination was performed using the LIAISON® XL and KRYPTOR analyzers, by chemiluminescence (Chemiluminescence immunoassay-CLIA) (LIAISON® BRAHMS PCT® II GEN) and immunofluorescence (Brahms PCT sensitive Kryptor) assay, respectively. For the LIAISON® BRAHMS PCT® II GEN, 52% of the results were placed between 0.0 and 0.5 ng/mL, 18% between 0.5 and 2.0 ng/mL, and 30% between 2.0 and 100 ng/mL; the mean was 4.09 ng/mL, the median 0.456 ng/mL, the maximum value 97.2 ng/mL, and the minimum value 0.02 ng/mL. For the Brahms PCT sensitive Kryptor, 55% of the results were positioned between 0.0 and 0.5 ng/mL, 21% between 0.5 and 2.0 ng/mL, and 24% between 2.0 and 100 ng/mL; the mean was 3.72 ng/mL, the median 0.39 ng/mL, the maximum value 103 ng/mL, and the minimum value 0.01 ng/mL. The mean of the results obtained with the two methods showed no significant differences (3.717 for Kryptor and 4.094 for LIAISON®). PCT assay with Brahms reagents, both on the Kryptor and LIAISON®XL platforms, offers excellent performance in terms of sensitivity and specificity.

Assessment of Access hsTnI 99th percentiles upper reference limits following IFCC recommendations.

BACKGROUND: The detection of an increase and/or decrease of cardiac troponin (cTnI) values, with at least one value above the 99th percentile of the upper reference limit (URL) have a central role in acute myocardial infarction (AMI) diagnosis. The employment of sex specific 99th percentile URLs and High-sensitivity (Hs) assays are recommended. We assessed sex specific 99th percentile URL for Access Hs-cTnI and AccuTnI3+ (Beckman Coulter) using European donor reference population following recent International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) recommendations. METHODS: 300 males and 300 females plasma samples were collected. Both chemiluminescent immunoenzymatic assays were performed on UniCel DxI 800 platform (Beckman Coulter). RESULTS: For Access hsTnI, the observed sex-specific 99th percentile URLs were 5.5 (90% CI: 4.4-7.6) for females and 13.9 ng/L (90% CI: 7.4-17.4) for males. For AccuTnI+3 we could not establish them because the assay couldn't report detectable values of troponin for most of the analyzed samples. CONCLUSION: The sex-specific 99th percentile URLs established for Access hsTnI assay were significantly lower than those declared by the manufacturer caused by the different choice of population selection, age groups and sample types: for those reasons, we maintain the 99th URLs provided by manufacturer.

Improved efficiency and cost reduction in the emergency department by replacing contemporary sensitive with high-sensitivity cardiac troponin immunoassay.

BACKGROUND: Although unquestionable evidence has been provided that high-sensitive (HS) cardiac troponin (cTn) immunoassay outperform the former contemporary-sensitive techniques, some clinicians are still hesitant to implement HS methods in routine clinical practice. This study was hence planned to evaluate the impact of replacing a contemporary-sensitive with HS cTnI immunoassay on hospital and laboratory workload. METHODS: Information on the total number of cTnI tests ordered, total number of blood samples collected, total number of CK-MB tests ordered, number of patients with the first HS-cTnI value below the limit of detection (LoD) and cumulative HS-cTnI values was extracted from the local hospital information system for the semesters before and after the HS method was introduced. RESULTS: Although the total emergency department (ED) visits modestly increased after introducing HS-cTnI, the number of total cTnI tests declined by over 10%. A substantial reduction of single-sample test requests was noted, accompanied by a considerable decline of 3- and 4-sample collections (i.e., -61% and -73%, respectively). A high percentage of patients (27.5%) displayed HS-cTnI values

The Pharmacology of Visual Hallucinations in Synucleinopathies.

Visual hallucinations (VH) are commonly found in the course of synucleinopathies like Parkinson's disease and dementia with Lewy bodies. The incidence of VH in these conditions is so high that the absence of VH in the course of the disease should raise questions about the diagnosis. VH may take the form of early and simple phenomena or appear with late and complex presentations that include hallucinatory production and delusions. VH are an unmet treatment need. The review analyzes the past and recent hypotheses that are related to the underlying mechanisms of VH and then discusses their pharmacological modulation. Recent models for VH have been centered on the role played by the decoupling of the default mode network (DMN) when is released from the control of the fronto-parietal and salience networks. According to the proposed model, the process results in the perception of priors that are stored in the unconscious memory and the uncontrolled emergence of intrinsic narrative produced by the DMN. This DMN activity is triggered by the altered functioning of the thalamus and involves the dysregulated activity of the brain neurotransmitters. Historically, dopamine has been indicated as a major driver for the production of VH in synucleinopathies. In that context, nigrostriatal dysfunctions have been associated with the VH onset. The efficacy of antipsychotic compounds in VH treatment has further supported the notion of major involvement of dopamine in the production of the hallucinatory phenomena. However, more recent studies and growing evidence are also pointing toward an important role played by serotonergic and cholinergic dysfunctions. In that respect, in vivo and post-mortem studies have now proved that serotonergic impairment is often an early event in synucleinopathies. The prominent cholinergic impairment in DLB is also well established. Finally, glutamatergic and gamma aminobutyric acid (GABA)ergic modulations and changes in the overall balance between excitatory and inhibitory signaling are also contributing factors. The review provides an extensive overview of the pharmacology of VH and offers an up to date analysis of treatment options.