Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study.

BACKGROUND: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. METHODS: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. RESULTS: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. CONCLUSIONS: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions.

Circulatory shock associated with left insular stroke and chronic steroid treatment.

BACKGROUND: Damage to the insula has been associated with various types of cardiovascular dysfunction, including arrhythmias and blood pressure imbalances. Acute neuroendocrine disturbances following insular damage have also been described. CASE PRESENTATION: A 50-year-old right-handed man with a left insular ischemic lesion exhibited aphasia and right central VII nerve palsy. Five days after the stroke, the patient exhibited severe bradycardia and hypotension. He had been treated for ocular trauma with prednisone for the preceding 3 weeks. Cortisol and adrenocorticotropic hormone levels indicated secondary adrenal insufficiency. Despite adequate fluid intake, the patient's blood pressure dropped, requiring norepinephrine administration. Midodrine was also initiated, leading to clinical improvement. The therapy was gradually discontinued as vital signs normalized. By Day 24, electrocardiogram monitoring was unremarkable, hormonal levels normalized, and the neurological examination revealed only mild residual speech fluency impairment. Computed tomography scans confirmed a recovering ischemic lesion of the left insula. CONCLUSIONS: This case reveals the inhibitory effect exerted by a left-sided insular stroke on the autonomic system. It also highlights the still largely unexplored neuroendocrine complications of damage to this brain region.

The central role of the Thalamus in psychosis, lessons from neurodegenerative diseases and psychedelics.

The PD-DLB psychosis complex found in Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) includes hallucinations, Somatic Symptom/Functional Disorders, and delusions. These disorders exhibit similar presentation patterns and progression. Mechanisms at the root of these symptoms also share similarities with processes promoting altered states of consciousness found in Rapid Eye Movement sleep, psychiatric disorders, or the intake of psychedelic compounds. We propose that these mechanisms find a crucial driver and trigger in the dysregulated activity of high-order thalamic nuclei set in motion by ThalamoCortical Dysrhythmia (TCD). TCD generates the loss of finely tuned cortico-cortical modulations promoted by the thalamus and unleashes the aberrant activity of the Default Mode Network (DMN). TCD moves in parallel with altered thalamic filtering of external and internal information. The process produces an input overload to the cortex, thereby exacerbating DMN decoupling from task-positive networks. These phenomena alter the brain metastability, creating dreamlike, dissociative, or altered states of consciousness. In support of this hypothesis, mind-altering psychedelic drugs also modulate thalamic-cortical pathways. Understanding the pathophysiological background of these conditions provides a conceptual bridge between neurology and psychiatry, thereby helping to generate a promising and converging area of investigation and therapeutic efforts.

Role of neurorehabilitation in the recovery of bilateral thalamic stroke related to the artery of Percheron anatomical variant.

Bilateral thalamic stroke is a rare condition, mostly related to the presence of the artery of Percheron (AoP) variant. The clinical presentation of AoP-related strokes is remarkably heterogeneous and often includes cognitive and behavioural alterations. Our report describes the clinical course of an AoP-related bilateral thalamic stroke and highlights the pivotal role of a tailored rehabilitation programme plays in enhancing recovery. A man in his 40s was admitted to the neurology ward due to the abrupt onset of mental status alterations and weakness in his left limbs. The first brain CT scan and subsequent MRI exam revealed a bilateral thalamic stroke and the presence of an AoP anatomical variant. After the first critical phase, the patient's condition became stable, but he still suffered from severe attention, memory and speech deficits. The patient was then transferred to the rehabilitation unit and was subjected to a tailored neurorehabilitation programme that allowed a complete recovery of the symptoms. Neurorehabilitation plays a pivotal role in the patient's recovery and should always be pursued to minimise the residual deficits and, most importantly, to prevent permanent cognitive deficits.

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.

Diagnosis and treatment of late-onset myoclonic epilepsy in Down syndrome (LOMEDS): A systematic review with individual patients' data analysis.

INTRODUCTION: The late onset myoclonic epilepsy in Down Syndrome (LOMEDS) is a peculiar epilepsy type characterized by cortical myoclonus and generalized tonic-clonic seizures (GTCS), in people suffering from cognitive decline in Down syndrome (DS). In this review, we analyzed available data on the diagnostic and therapeutic management of individuals with LOMEDS. METHODS: We performed a systematic search of the literature to identify the diagnostic and therapeutic management of patients with LOMEDS. The following databases were used: PubMed, Google Scholar, EMBASE, CrossRef. The protocol was registered on PROSPERO (registration code: CRD42023390748). RESULTS: Data from 46 patients were included. DS was diagnosed according to the patient's clinical and genetic characteristics. Diagnosis of Alzheimer's dementia (AD) preceded the onset of epilepsy in all cases. Both myoclonic seizures (MS) and generalized tonic-clonic seizures (GTCS) were reported, the latter preceding the onset of MS in 28 cases. EEG was performed in 45 patients, showing diffuse theta/delta slowing with superimposed generalized spike-and-wave or polyspike-and-wave. A diffuse cortical atrophy was detected in 34 patients on neuroimaging. Twenty-seven patients were treated with antiseizure medication (ASM) monotherapy, with reduced seizure frequency in 17 patients. Levetiracetam and valproic acid were the most used ASMs. Up to 41% of patients were unresponsive to first-line treatment and needed adjunctive therapy for seizure control. CONCLUSIONS: AD-related pathological changes in the brain may play a role in LOMEDS onset, although the mechanism underlying this phenomenon is still unknown. EEG remains the most relevant investigation to be performed. A significant percentage of patients developed a first-line ASM refractory epilepsy. ASMs which modulate the glutamatergic system may represent a good therapeutic option.

Atypical progression of motor symptoms in facio-scapulo-humeral dystrophy: clinical worsening or overlap?

Facio-scapulo-humeral dystrophy (FSHD) is a common muscular dystrophy featuring progressive weakness, mostly involving facial muscles and the scapular cingulum. FSHD is an autosomal-dominant inherited disease driven by the contraction of the D4Z4 region of chromosome 4. Patients with FSHD have a high life expectancy, about 20% of FSHD subjects need wheelchairs in their 50s, and extramuscular involvement is rare, however, no epidemiological studies have been carried out on this data.Our case describes a man affected by FSHD who, in his 60s, developed atypical Parkinsonism diagnosed as progressive supranuclear palsy (PSP).FSHD symptoms can hide other neuromuscular diseases developed on ageing. This case highlights the importance of considering possible overlaps with other neurodegenerative diseases.

Functional Neurologic Disorders, disorders to be managed by neurologists, or are neurologists wandering in a dangerous field with inadequate resources?

In recent years, some neurologists reconsidered their approach to Medically Unexplained Symptoms and proposed Functional Neurologic Disorders (FND) as a new entity, claiming that neurology could offer alternative treatment options to the psychotherapies provided in psychiatry settings. FNDs, for this purpose, should include only the disorders listed as Conversion from the Somatic Symptom and Related Disorders (SSRD) group. The present review analyzes the rationale of this position and challenges the arguments provided for its support. The review also discusses the systematization of these disorders as provided by public health systems. It outlines risks stemming from economic support and public funding uncertainty, given their negligible epidemiological dimensions resulting from the parcellation of SSRD. The review underlines the unresolved issue of Factitious Disorders, which are in the same SSRD category of the international classification but are, nonetheless, overlooked by the theoretical proponents of the FND entity. Comorbidity with other psychiatric disorders is also analyzed. We propose a model that supports the continuum between different SSRD conditions, including Factitious Disorders. The model is based on the emergence of feigned death reflex and deception from frontal lobe dysfunction. Finally, the paper summarizes the wealth of historical psychiatric and psychodynamic approaches and critical reviews. The study also puts in context the categorization and interpretation efforts provided by the most eminent researchers of the past century.

Heart rate variability modification as a predictive factor of sudden unexpected death in epilepsy: How far are we? A systematic review and meta-analysis.

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is a sudden, unexpected death in people with epilepsy, with or without evidence of an epileptic seizure. The pathophysiological mechanism underlying SUDEP appears to be partly associated with an autonomic nervous system (ANS) dysfunction. Heart rate variability (HRV) analysis is a reliable, non-invasive method for detecting fluctuations in the ANS. In this systematic review we analyzed the data available in the literature on changes in HRV parameters in patients with SUDEP. METHODS: We carried out a systematic search of the literature to identify the quantitative variations of HRV in epileptic patients with SUDEP. The following databases were used: Pubmed, Google Scholar, EMBASE, and CrossRef. A pooled analysis was carried out, and the results obtained were compared using mean difference (MD). The review was registered on the PROSPERO platform (CRD42021291586). RESULTS: Seven articles were included, with a total of 72 SUDEP cases associated with altered HRV parameters. Generally, a reduction of SDNN (standard deviation of the RR intervals) and RMSSD (root mean square differences of successive RR intervals) was reported in most SUDEP patients. According to MD, the SUDEP patients showed no differences in time and frequency domain parameters compared to controls. However, a trend toward increased low frequency and high frequency ratio (LF/HF) was observed in the SUDEP patients. CONCLUSIONS: HRV analysis is a valuable method for assessing cardiovascular risk and cardioautonomic impairment. Although a possible association between HRV variation and SUDEP has been reported, further studies are needed to assess the potential role of HRV modifications as a SUDEP biomarker.

Heart rate variability modifications in adult patients with early versus late-onset temporal lobe epilepsy: A comparative observational study.

OBJECTIVES: Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsy. TLE is associated with cardio-autonomic dysfunction and increased cardiovascular (CV) risk in patients over the fifth decade of age. In these subjects, TLE can be classified as early-onset (EOTLE; i.e., patients who had developed epilepsy in their youth) and late-onset (LOTLE; i.e., patients who developed epilepsy in adulthood). Heart rate variability (HRV) analysis is useful for assessing cardio-autonomic function and identifying patients with increased CV risk. This study compared changes in HRV occurring in patients over the age of 50, with EOTLE or LOTLE. METHODS: We enrolled twenty-seven adults with LOTLE and 23 with EOTLE. Each patient underwent a EEG and EKG recording during 20-minutes of resting state and a 5-minutes hyperventilation (HV). Short-term HRV analysis was performed both in time and frequency domains. Linear Mixed Models (LMM) were used to analyze HRV parameters according to the condition (baseline and HV) and group (LOTLE and EOTLE groups). RESULTS: Compared to the LOTLE group, the EOTLE group showed significantly decreased LnRMSSD (natural logarithm of the root mean square of the difference between contiguous RR intervals) (p-value=0.05), LnHF ms2 (natural logarithm of high frequency absolute power) (p-value=0.05), HF n.u. (high frequency power expressed in normalized units) (p-value=0.008) and HF% (high frequency power expressed in percentage) (p-value=0.01). In addition, EOTLE patients exhibited increased LF n.u. (low frequency power expressed in normalized units) (p-value=0.008) and LF/HF (low frequency/high frequency) ratio (p-value=0.007). During HV, the LOTLE group exhibited a multiplicative effect for the interaction between group and condition with increased LF n.u. (p = 0.003) and LF% (low frequency expressed in percentage) (p = 0.05) values. CONCLUSIONS: EOTLE is associated with reduced vagal tone compared to LOTLE. Patients with EOTLE may have a higher risk of developing cardiac dysfunction or cardiac arrhythmia than LOTLE patients.

Biomarkers of diagnosis, prognosis, pathogenesis, response to therapy: Convergence or divergence? Lessons from Alzheimer's disease and synucleinopathies.

Alzheimer's disease (AD) is the most common disorder associated with cognitive impairment. Recent observations emphasize the pathogenic role of multiple factors inside and outside the central nervous system, supporting the notion that AD is a syndrome of many etiologies rather than a "heterogeneous" but ultimately unifying disease entity. Moreover, the defining pathology of amyloid and tau coexists with many others, such as α-synuclein, TDP-43, and others, as a rule, not an exception. Thus, an effort to shift our AD paradigm as an amyloidopathy must be reconsidered. Along with amyloid accumulation in its insoluble state, ß-amyloid is becoming depleted in its soluble, normal states, as a result of biological, toxic, and infectious triggers, requiring a shift from convergence to divergence in our approach to neurodegeneration. These aspects are reflected-in vivo-by biomarkers, which have become increasingly strategic in dementia. Similarly, synucleinopathies are primarily characterized by abnormal deposition of misfolded α-synuclein in neurons and glial cells and, in the process, depleting the levels of the normal, soluble α-synuclein that the brain needs for many physiological functions. The soluble to insoluble conversion also affects other normal brain proteins, such as TDP-43 and tau, accumulating in their insoluble states in both AD and dementia with Lewy bodies (DLB). The two diseases have been distinguished by the differential burden and distribution of insoluble proteins, with neocortical phosphorylated tau deposition more typical of AD and neocortical α-synuclein deposition peculiar to DLB. We propose a reappraisal of the diagnostic approach to cognitive impairment from convergence (based on clinicopathologic criteria) to divergence (based on what differs across individuals affected) as a necessary step for the launch of precision medicine.

Comparison of Machine Learning-based Approaches to Predict the Conversion to Alzheimer's Disease from Mild Cognitive Impairment.

In Mild Cognitive Impairment (MCI), identifying a high risk of conversion to Alzheimer's Disease Dementia (AD) is a primary goal for patient management. Machine Learning (ML) algorithms are widely employed to pursue data-driven diagnostic and prognostic goals. An agreement on the stability of these algorithms -when applied to different biomarkers and other conditions- is far from being reached. In this study, we compared the different prognostic performances of three supervised ML algorithms fed with multimodal biomarkers of MCI subjects obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Random Forest, Gradient Boosting, and eXtreme Gradient Boosting algorithms predict MCI conversion to AD. They can also be simultaneously employed -with the voting procedure- to improve predictivity. AD prediction accuracy is influenced by the nature of the data (i.e., neuropsychological test scores, cerebrospinal fluid AD-related proteins and APOE ε4, cerebral structural MRI (sMRI) data). In our study, independent of the applied ML algorithms, sMRI data showed the lowest accuracy (0.79) compared to other classes. Multimodal data were helpful in the algorithms' performances by combining clinical and biological measures. Accordingly, using the three ML algorithms, the highest accuracy (0.90) was reached by employing neuropsychological and AD-related biomarkers. Finally, the feature selection procedure indicated that the most critical variables in the respective classes were the ADAS-Cog-13 scale, the medial temporal lobe and hippocampus atrophy, and the ratio between phosphorylated Tau and Aß42 proteins. In conclusion, our data support the notion that using multiple ML algorithms and multimodal biomarkers helps make more accurate and solid predictions.

Migraine Pharmacological Treatment and Cognitive Impairment: Risks and Benefits.

Migraine is a common neurological disorder impairing the quality of life of patients. The condition requires, as an acute or prophylactic line of intervention, the frequent use of drugs acting on the central nervous system (CNS). The long-term impact of these medications on cognition and neurodegeneration has never been consistently assessed. The paper reviews pharmacological migraine treatments and discusses their biological and clinical effects on the CNS. The different anti-migraine drugs show distinct profiles concerning neurodegeneration and the risk of cognitive deficits. These features should be carefully evaluated when prescribing a pharmacological treatment as many migraineurs are of scholar or working age and their performances may be affected by drug misuse. Thus, a reconsideration of therapy guidelines is warranted. Furthermore, since conflicting results have emerged in the relationship between migraine and dementia, future studies must consider present and past pharmacological regimens as potential confounding factors.

Psychogenic non-epileptic seizures (PNES) in the COVID-19 pandemic era: A systematic review with individual patients' analysis.

OBJECTIVE: Psychogenic non-epileptic seizures (PNES) resemble epileptic seizures but are not due to underlying epileptic activity and in some cases coexist alongside epilepsy. We described the clinical characteristics of patients with PNES as reported in the literature from the outbreak of the COVID-19 pandemic. We evaluated differences between patients with a diagnosis made immediately before the pandemic (pPNES) and those newly diagnosed during it (nPNES). METHODS: A systematic search with individual patient analysis of PNES cases published since the COVID-19 pandemic outbreak was performed. Differences between pPNES and nPNES were analyzed using Chi-square or Fisher exact test. RESULTS: Eleven articles were included, with 133 patients (106 pPNES and 27 nPNES). In the pPNES group, PNES frequency increased during the pandemic in 20/106 patients, whereas in 78/106, the frequency remained stable or decreased. nPNES was associated with higher risks of SARS-CoV-2 infection and epilepsy diagnosis, whereas psychiatric comorbidities were less frequent. CONCLUSIONS: During the pandemic, most patients with pPNES remained stable or improved, whereas nPNES was associated with a lower burden of psychiatric comorbidities. These intriguing findings suggest that, at least in some patients, the COVID-19 pandemic may not necessarily lead to worsening in the frequency of PNES and quality of life.

Altered Medial Prefrontal Connectivity in Parkinson's Disease Patients with Somatic Symptoms.

BACKGROUND: The high co-occurrence of somatic symptom disorder (SSD) in Parkinson's disease (PD) patients suggests overlapping pathophysiology. However, little is known about the neural correlates of SSD and their possible interactions with PD. Existing studies have shown that SSD is associated with reduced task-evoked activity in the medial prefrontal cortex (mPFC), a central node of the default-mode network (DMN). SSD is also associated with abnormal γ-aminobutyric acid (GABA) content, a marker of local inhibitory tone and regional hypoactivity, in the same area when SSD co-occurs with PD. OBJECTIVES: To disentangle the individual and shared effects of SSD and PD on mPFC neurotransmission and connectivity patterns and help disclose the neural mechanisms of comorbidity in the PD population. METHODS: The study cohort included 18 PD patients with SSD (PD + SSD), 18 PD patients, 13 SSD patients who did not exhibit neurologic disorders, and 17 healthy subjects (HC). Proton magnetic resonance (MR) spectroscopy evaluated GABA levels within a volume of interest centered on the mPFC. Resting-state functional MR imaging investigated the region's functional connectivity patterns. RESULTS: Compared to HC or PD groups, the mPFC of SSD subjects exhibited higher GABA levels and connectivity. Higher mPFC connectivity involved DMN regions in SSD patients without PD and regions of the executive and attentional networks (EAN) in patients with PD comorbidity. CONCLUSIONS: Aberrant reconfigurations of connectivity patterns between the mPFC and the EAN are distinct features of the PD + SSD comorbidity. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Young Man with Cognitive Impairment and a Heart Condition.

A 43-year-old came to our observation for progressive cognitive impairment, confirmed by the neuropsychological evaluation. A diagnosis of multidomain amnestic mild cognitive impairment, due to unknown reasons, was posited at the first assessment. The patient's neurological exam was otherwise completely normal. The patient's mother was clinically diagnosed with frontotemporal dementia in her forties. The patient underwent neuroimaging investigations and cerebrospinal fluid analysis. Our diagnostic work-up pointed toward a neurodegenerative etiology, but the presence of concurrent cardiomyopathy emerged in the meantime. Due to the patient's family history, a thorough genetic screening was performed. The results revealed a unique genetic asset, with heterozygotic variants of three amyloid-related genes (PSEN1, APP, and MYBPC3). PSEN1 and MYBPC3 mutations showed distinct pathogenic features and accounted for the patient's brain and cardiac amyloidosis, whereas the APP variant was of uncertain pathological implications.

EEG Abnormalities During Delirium as a Prodromal Feature of Dementia with Lewy Bodies: A Case Report.

Background: A 79-year-old woman was admitted to the Neurology Clinic of the University of Chieti-Pescara for a syncope. At admission, the occurrence of an acute stroke was ruled out. Her cognitive status was unimpaired. After three days from the hospitalization, the patient experienced an episode of mixed delirium. Objective: The present case report shows a case of delirium-onset dementia with Lewy bodies (DLB) with a specific electroencephalographic (EEG) pattern from its prodromal stage. Methods: Delirium was assessed by 4AT test. During the hospitalization, the patient underwent a quantitative EEG (QEEG) with spectral analysis. At six months from the episode of delirium, she was tested by neuropsychological evaluation, QEEG, and 18F-fluorodeoxyglucose PET/CT to assess the onset of a possible cognitive decline. Results: At baseline, the QEEG exam showed a dominant frequency (DF) in the pre-alpha band (7.5 Hz) with a dominant frequency variability (DFV) of 2 Hz. This pattern is typical of DLB at early stage. After six months, she reported attention deficits in association with cognitive fluctuation and REM sleep behavior disorder. The neurological examination revealed signs of parkinsonism. Cognitive status resulted to be impaired (MoCA = 15/30). QEEG recording confirmed the presence of a DLB-typical pattern (DF = 7.5 Hz, DFV = 2.5 Hz). The 18F-FDG-PET/CT showed a moderate bilateral posterior hypometabolism (occipital and temporal cortex), with relative sparing of the posterior cingulate cortex compared to cuneus/precuneus (Cingulate Island sign), and mild bilateral hypometabolism in frontal regions (suggestive of a DLB diagnosis). Conclusion: EEGs may represent supportive and validated biomarkers for delirium-onset prodromal DLB.

COVID-19 and first manic episodes: a systematic review.

Sars-CoV-2 is a respiratory virus that can access the central nervous system, as indicated by the presence of the virus in patients' cerebrospinal fluid and the occurrence of several neurological syndromes during and after COVID-19. Growing evidence indicates that Sars-CoV-2 can also trigger the acute onset of mood disorders or psychotic symptoms. COVID-19-related first episodes of mania, in subjects with no known history of bipolar disorder, have never been systematically analyzed. Thus, the present study assesses a potential link between the two conditions. This systematic review analyzes cases of first appearance of manic episodes associated with COVID-19. Clinical features, pharmacological therapies, and relationships with pre-existing medical conditions are also appraised. Medical records of twenty-three patients fulfilling the current DSM-5 criteria for manic episode were included. Manic episodes started, on average, after 12.71±6.65 days from the infection onset. Psychotic symptoms were frequently reported. 82.61% of patients exhibited delusions, whereas 39.13% of patients presented hallucinations. A large discrepancy in the diagnostic workups was observed. Mania represents an underestimated clinical presentation of COVID-19. Further studies should focus on the pathophysiological substrates of COVID-19-related mania and pursue appropriate and specific diagnostic and therapeutic workups.