Extrapyramidal Research Articles

Resection of the quadrangular lobule of the cerebellum to increase exposure of the cerebellomesencephalic fissure: an anatomical study with clinical correlation.

The lateral aspect of the cerebellomesencephalic fissure frequently harbors vascular pathology and is a common surgical corridor used to access the pons tegmentum, as well as the cerebellum and its superior and middle peduncles. The quadrangular lobule of the cerebellum (QLC) represents an obstacle to reach these structures. The authors sought to analyze and compare exposure of the cerebellar interpeduncular region (CIPR) before and after QLC resection and provide a case series to evaluate its clinical applicability. Forty-two sides of human brainstems were prepared with Klingler's method and dissected. The exposure area before and after resection of the QLC was measured and statistically studied. A case series of 59 patients who underwent QLC resection for the treatment of CIPR lesions was presented and clinical outcomes were evaluated at 1-year follow-up. The anteroposterior surgical corridor of the CIPR increased by 10.3 mm after resection of the QLC. The mean exposure areas were 42 mm2 before resection of the QLC and 159.6 mm2 after resection. In this series, ataxia, extrapyramidal syndrome, and akinetic mutism were found after surgery. However, all these cases resolved within 1 year of follow-up. Modified Rankin Scale score improved by 1 grade, on average. QLC resection significantly increased the exposure area, mainly in the anteroposterior axis. This surgical strategy appears to be safe and may help the neurosurgeon when operating on the lateral aspect of the cerebellomesencephalic fissure.

Choking as Cause of Death Among the Mentally Ill: A Literature review

Introduction According to data, choking is one of the principal causes of death in mental health units. Specifically, research reveals that psychiatric patients -compared to the general population- are 43 times more likely to die due to choking. Nevertheless, only a limited number of studies has been focused on the risk factors of choking among this category of patients. Interestingly, dysphagia and choking on food are underdiagnosed and underreported in the UK psychiatry departments while there is an important insufficiency of provided information in national guidance archives as well as in regional clinical settings for adults with mental health diseases.ObjectivesTo explore the risk factors of choking among psychiatric patients and to highlight interventions of preventing choking-related incidents.MethodsA review of 36 articles -from 2010 to 2023- on PubMed and Google Scholar regarding choking-related incidents among inpatients of mental health units.Articles exploring choking suicide-related incidents or choking as cause of neurological illness, were excluded from the research. Keywords: choking, psychiatric patients, death.ResultsNumerous risk factors of choking have been identified, such as:Antipsychotics,Anxiolytics,Bradykinetic dysphagia (extra-pyramidal syndrome),Intellectual disabilities,Dementia,Anxiety,Coughing while eating,Fast paced eating and cramming food,Mealtime-related stressors such as willingness of avoiding peers.ConclusionsThere is an absolute need for a specialized training of nurses, caregivers, mental health clinicians to prevent incidents and injuries of inpatients due to choking. Close supervision, routine screening during the mealtime, and detailed information from relatives about the patient’s eating habits are essential for the safety and the ameliorated quality of hospitalization for the mentally ill.Disclosure of InterestNone Declared

The Impact of Psychotropics on Sexuality: A Literature Review

IntroductionSexual dysfunctions related to psychotropic drugs are among the most distressing adverse effects and can lead to non-adherence to treatment.ObjectivesTo elucidate the mechanisms of psychotropic-induced sexual dysfunctions and to suggest strategies for their management.Methods Literature review based on the keywords “psychotropics,” “sexuality,” and “sexual dysfunction”.ResultsPsychotropic medications can impact sexuality either directly or indirectly. The direct effect is primarily due to a decrease in the mesocortical dopaminergic atmosphere, either by blocking D2 receptors or by stimulating 5HT2A receptors. D2 receptor blockade in the tubero-infundibular pathway triggers an increase in prolactin secretion, which can subsequently lead to erection problems, decreased libido, and difficulties achieving orgasm. Action in the nigrostriatal pathway may result in an extrapyramidal syndrome, which can, in turn, hinder intimate physical relations. The indirect effect can also be caused by metabolic complications, which are significant risk factors for sexual dysfunction, as they can lead to male hypogonadism and a negative self-image.Therapeutic strategies suggest either reducing doses (if the patient’s condition allows), changing the drug, or adding an adjunctive medication. Aripiprazole, being a partial agonist of D2 and 5-HT1A receptors and an antagonist of D3 and 5-HT2A receptors, appears to cause fewer sexual dysfunctions and can reduce hyperprolactinemia when added to other antipsychotics.ConclusionsHealthcare professionals must proactively gather information on sexuality given its impact on quality of life and treatment adherence. Prioritizing this dimension of well-being demonstrates a respectful approach toward the patient and establishes the foundation for a strong therapeutic alliance.Disclosure of InterestNone Declared

Prescription practices for antipsychotic medication in an acute inpatient ward: Risks / benefits discussions with patients and performance of baseline investigations as per NICE guidelines

IntroductionAntipsychotic medications are essential for managing psychiatric disorders, offering symptom relief and improved functioning. However, their use carries potential risks. Vigilant monitoring and patient engagement are crucial when initiating antipsychotics.ObjectivesTo explore whether comprehensive discussions with patients concerning the benefits and risks of antipsychotics are taking place, and whether baseline investigations are performed before initiation of antipsychotics as per NICE guidelines.MethodsThis retrospective study focused on admissions to a male acute ward between March 1 and May 31, 2023. Data from electronic patient records included demographics, Mental Health Act (MHA) status, psychiatric diagnoses, medical co-morbidities, documentation of medication benefits / side effects discussions with patients, medication information provision, as well as baseline investigations involving weight, height, waist/hip circumference, pulse, blood pressure, blood glucose, HbA1c, lipid profile, prolactin levels, movement disorder assessment, nutritional status, diet, physical activity, and ECG.ResultsAmong 23 admitted patients, 15 were newly initiated or reintroduced to antipsychotics, with 14(93.3%) admitted under the MHA. Primary diagnoses included Paranoid Schizophrenia (33.33%), Unspecified Non-Organic Psychosis (20%), Bipolar Affective Disorder (20%), and others. Medical comorbidities were observed in 10(66.7%), notably type 2 diabetes (40%). Among initiates, 6(40%) were new to treatment, while in 9(60%) it was re-initiated.Within the 15-patient group, discussions on treatment benefits engaged 11(73.3%), while 4(26.7%) lacked complete documentation. Only 6(40%) had discussions about side effects. Metabolic side effects were discussed with 3(20%), extrapyramidal effects with 2(13.33%), while 4(26.7%) had general side effect talks. Patient information leaflets were given to 5(33.3%) patients. Baseline measurements: 12(80%) had weight/height, 4(26.7%) waist/hip, and 14(93.3%) pulse/blood pressure assessed. Blood tests were declined by 4(26.7%). Baseline glucose, HbA1c, lipids, and prolactin were assessed in 8(53.3%), 10(66.7%), 9(60%), and 8(53.3%) patients respectively. Nutritional status was assessed in 13(86.7%), movement disorders in 1(6.7%), and physical activity in 1(6.7%). All 15(100%) patients were offered ECGs, although 5(33.3%) declined.ConclusionsAdherence to NICE guidelines for baseline investigations and risk/benefit discussions prior to antipsychotic initiation was low, apart from ECGs, weight/height, pulse/blood pressure, assessment of nutritional status, and discussions about antipsychotics’ benefits. Implementing effective monitoring and patient engagement to mitigate potential side effects, is crucial to facilitating the safe and efficient utilisation of antipsychotics.Disclosure of InterestNone Declared

Patterns of antipsychotic prescription in inpatient and outpatient psychiatric settings: a real world study

IntroductionAntipsychotic (AP) are increasingly prescribed off-label and used as, but not limited to, anti-aggressive, anti-impulsive, and anti-suicidal medication. The use of second-generation AP (SGAs) has progressively increased compared to first-generation AP (FGAs). FGAs cause more extrapyramidal motor side effects and tardive dyskinesia than SGAs, whereas SGAs generally cause more weight gain and cardiometabolic adverse effects.ObjectivesAim of this observational study was to describe the socio-demographic and clinical features of the patients receiving new AP treatment and the features of the pharmacological treatment itself in “real world” context. Furthermore, we aimed to compare socio-demographic and clinical characteristics of the subjects who were prescribed either FGAs or SGAs.MethodsData were collected on the latest new AP prescriptions issued across different settings (two psychiatric wards; five outpatients clinics; and one rehabilitation community) belonging to ASST Fatebenefratelli Sacco (located in Milan) in reverse chronological order from May 2023. Socio-demographic and clinical variables of the subjects who received new AP treatment were collected through medical records. We compared age, age at onset, age at first pharmacological treatment, duration of illness, duration of untreated illness, treatment duration, number of hospitalization and admissions to Day Hospital services, involuntary commitments and suicidal attempts in patients who received either FGAs or SGAs. Chi-square was used for qualitative variables and t-test for quantitative variables. Data were collected anonymously and analyzed using SPSS v.27.ResultsThe sample included 155 new AP prescriptions, out of which 29.2% were formulated in the psychiatric wards, 66.9% in the outpatient clinics e 3.9% in the rehabilitative community. Mean age of the subjects was 41.1 ± 16.9 years, 53.2% were male.The most represented diagnoses were psychotic disorders (32.2%), personality disorders (24.8%), bipolar disorder (16.1%) and depressive disorder (12.8%).90.7% of new AP prescriptions were SGAs. The most prescribed were aripiprazole (30.5%), quetiapine (21.2%) and olanzapine (15.2%); while the most prescribed FGAs were haloperidol (5.3%), zuclopenthixol (2%) and chlorpromazine (1.3%). 26.2% of the prescriptions were in monotherapy and 83.8% were for oral administration.The reasons for introduction were partial or absent response to previous treatments (52.3%), disease onset (23.5%), non-compliance (8.3%), adverse effects to previous treatments (6.8%) or other (9.1%). Patients treated with FGA had a longer duration of untreated illness (p<0,001) and a greater number of lifetime hospitalizations (p<0,001) and involuntary commitments (p=0,002).ConclusionsPatients treated with SGAs have a shorter duration of untreated illness and also lower chance of lifetime hospitalization and involuntary commitment.Disclosure of InterestNone Declared

Subjective discomfort and lack of volitional drive with neuroleptic pharmacotherapy - a phenomenological case study

IntroductionIn comparison to extrapyramidal and metabolic side effects, the subjective aspects of neuroleptic treatment have been less extensively researched. Nevertheless, they are equally significant given their potential to influence adherence and functional outcome. Historically, terms such as “neuroleptic dysphoria,” “neuroleptic-induced psychic indifference,” and “neuroleptic-induced deficit syndrome” were used to characterize a range of unpleasant mood states on the one hand and a documented and observable motivational deficit on the other. The latter aligns with the findings from preclinical neuroscientific studies and animal models highlighting the significant involvement of mesolimbic dopamine in motivational processes. Despite an abundance of anecdotal data these adverse effects are often undetectable in large-scale clinical studies that utilize standardized assessment measures.ObjectivesTo present adverse subjective changes in arousal, mood and volitional drive resulting from neuroleptic intake from a patient’s perspective.MethodsThe subject is a patient, with no reported negative symptoms or lasting functional impairment described, who underwent a gradual 6-month discontinuation of risperidone in an outpatient setting following a complete recovery after a single psychotic episode. A semi-structured interview modelled after The Clinical Assessment Interview for Negative Symptoms (CAINS) was conducted. We aimed to elicit descriptions of the subjective experience while ensuring our approach remained non-suggestive.ResultsIn addition to describing potential akathisia and lethargy at higher doses, the subject reported a significant lack of motivation and a notably reduced willingness to exert effort towards achieving specific goals or engaging in activities that he still found rewarding or pleasurable. Furthermore, he consistently noted gradual improvements across various psycho-social aspects following the discontinuation of the medication. These adverse and unpleasant experiences were presented as the primary reason for wanting to discontinue pharmacological treatment.ConclusionsCertain adverse effects of antipsychotic medications can only be elucidated by the clinician through the examination of the patient’s subjective experiences. Medication induced dysphoria and volitional deficits have the potential to profoundly impact treatment adherence, leading to unrecommended discontinuation of neuroleptics, and can cause important functional impairment.Disclosure of InterestNone Declared

Efficiency of Vortioxetine in Depressive Symptoms in Parkinson’s Disease

IntroductionParkinson’s disease (PD) is the most common serious movement disorder in the world, affecting about 1% of adults older than 60 years. The disease is attributed to selective loss of neurons in the substantia nigra, and its cause is enigmatic in most individuals. Patients with PD display both motor and non-motor symptoms. For some patients, the non-motor symptoms are more bothersome than the motor symptoms. One of the most common non-motor symptoms of PD is depression.ObjectivesTreatment of depression with antidepressant drugs is well established. In the last 20 years use of antidepressant has risen mainly due to the introduction of the selective serotonin reuptake inhibitors (SSRIs). Our primary aim was to demonstrate an improvement in depressive symptoms in patients who started treatment with vortioxetine. A secondary aim was to show those who was successfully treated with vortioxetine but was unresponsive to paroxetine and escitalopram without worsening the extrapyramidal symptoms of PD.MethodsIn collaboration with the Department of Neurology, we included patients who are being treated for Parkinson’s disease and who meet the criteria for depressive disorder after a psychiatric examination. We divided the patients into two groups: those who had not previously taken any antidepressant drugs and those who were already on therapy with paroxetine and escitalopram but without the expected therapeutic response. All patients were prescribed vortioxetine in their treatment, and the Hamilton Depression Rating Scale (HDRS) was determined during their first meeting with the psychiatrist, and then again after 6 weeks of taking the medication. Also, we used Mini mental state examination (MMSE) to measure cognitive impairment.Our primary outcome measure was the number of patients in each treatment group who responded to treatment. Response was defined as the proportion of patients who had a reduction of at least 50% from the baseline score on the Hamilton Depression Rating Scale (HDRS)ResultsOur primary outcome measure was the number of patients in each treatment group who responded to treatment. Response was defined as the proportion of patients who had a reduction of at least 50% from the baseline score on the Hamilton Depression Rating Scale (HDRS)ConclusionsIn our research, vortioxetine has proven to be effective in treating depressive symptoms without worsening Parkinson’s disease, unlike paroxetine and escitalopram, which resulted in partial effects.Disclosure of InterestNone Declared

Syndrome of Irreversible Lithium-Effectuated Neurotoxicity: Silent, but not innocent

IntroductionLithium is one of the main drugs used in Bipolar Affective Disorder. However, it has a narrow therapeutic window, which requires close monitoring and progressive dose adjustment, according to serum levels, clinical response and the appearance of side effects. The term ‘SILENT’ explains descriptively persistent neurological sequelae related to lithium salt intoxication when symptoms persist for more than 2 months after stopping treatment. SILENT Syndrome is more common in females, at ages ranging from 21 to 77 years and is characterized mainly by avermian-type cerebellar disorder, persistent extrapyramidal syndrome, brainstem dysfunction and dementia of varying severity. It can also result in apraxia of the body, changes in the coordination and balance, dysarthria, as well as intentional and kinetic cerebellar tremor, involuntary movements of orofacial dyskinesias or resting tremor.ObjectivesThe authors intend to review the relevant and current literature in order to extend the knowledge about this condition and find the best conducts for clinical practice.MethodsNon-systematic literature review.ResultsComplications from the use of lithium known in the medical literature include mainly nephrotoxicity, endocrine alterations and neurotoxicity. The neurotoxic effects of lithium usually occur at high serum concentrations. However, they can also occur with lithium in the therapeutic range, and memory, attention and ataxia impairment may be some of the permanent sequelae. The etiopathogenesis is unclear, but demyelination has been detected in multiple brain regions, mainly in the cerebellum. The mechanism of lithium-induced cerebellar injury is believed to be mediated by the entry of calcium into the cells of this organ. The main factors that predispose to greater side effects and risk of toxicity are patients with decreased renal function, advanced age, use of diuretics, dementia, pregnancy, low sodium intake and physical illness with vomiting and/or diarrhea.ConclusionsLithium is a drug used mostly in affective disorders and given the narrow therapeutic window, it requires close monitoring in order to avoid side effects that can be permanent. In this way, it is important to review the factors that increase the lithium toxicity and make recommendations about it.Disclosure of InterestNone Declared

Guanfacine in the Treatment of a Child Diagnosed with Tourette Syndrome: A Case Report

Introduction Tourette syndrome (TS) is a neurodevelopmental disorder characterized by the development of persistent and changing motor and phonic tics over time. The presence of at least two motor tics and one vocal tic that have persisted for at least a period of 1 year is required, and which developed before the age of 18. The most commonly used pharmacological treatment are antipsychotics, with a preference for atypical antipsychotics such as aripiprazole or risperidone. Clonidine and guanfacine have shown effectiveness in suppressing tics, and although generally less effective than antipsychotics, some authors are considering them as first-line treatments. The treatment is also influenced by any comorbidities the patient may present.ObjectivesTo enumerate in a clinical case the pharmacological alternatives for TS, which vary according to the patient’s comorbidities and the intensity of the tic symptoms.MethodsCase study. Anamnesis of the patient and their family.Results A 12-year-old boy presenting simple motor and vocal tics for over a year. At the same time that a valuation is requested by child psychiatry, the mother also requests follow-up by neuropediatrics. Other causes are ruled out, an EEG is performed, and a TS diagnosis is made. The initial treatment was low-dose aripiprazole with partial effectiveness. After 3 months, he presents an exacerbation of the tics, interfering with his social and academic life, making it impossible to attend classes. The mother takes him to emergency services, and he is admitted to pediatrics. During the stay in pediatrics, he is diagnosed with Attention Deficit Hyperactivity Disorder, in addition to confirming the TS diagnosis. Extended-release methylphenidate is initiated (neuropediatrics). After starting methylphenidate, the patient’s tics worsen, also presenting insomnia and hyporexia. Due to the diagnosis of ADHD, school failure, and affective symptoms (hypothymia), atomoxetine is initiated. The tics become constant and incapacitating. As the dose of aripiprazole is increased, the child presents extrapyramidal effects. As a therapeutic alternative, guanfacine is initiated, progressively discontinuing aripiprazole. Currently, the child is stable from motor and vocal tics, allowing him to lead a normalized life.ConclusionsAlthough guanfacine is not as effective in reducing tics as antipsychotics, since the latter produce more side effects, it is justifiable to use it. This drug is capable of enhancing the therapeutic effect and reducing the adverse effects that antipsychotics could produce. Guanfacine may be a good alternative as a first line in the treatment of Tourette Syndrome with or without attention deficit disorder and hyperactivity .Disclosure of InterestNone Declared

Transcranial Sonography Characteristics of Cerebellar Neurodegenerative Ataxias.

Cerebellar neurodegenerative ataxias are a group of disorders affecting the cerebellum and its pathways with different neurological structures. Transcranial sonography (TCS) has been used for the evaluation of brain parenchymal structures in various diseases because of its fast and safe utilization, especially in neuropsychiatric and neurodegenerative diseases. The aim of our study was to investigate TCS characteristics of patients with neurodegenerative cerebellar ataxias. In our study, we included 74 patients with cerebellar degenerative ataxia; 36.5% had autosomal dominant onset, while 33.8% had sporadic onset. Standardized ultrasonographic planes were used for the identification of brain structures of interest. The SARA, INAS, neuropsychological and psychiatric scales were used for the further clinical evaluation of our study participants. The brainstem raphe was discontinued in 33.8% of the patients. The substantia nigra (SN) hyperechogenicity was identified in 79.7%. The third and fourth ventricle enlargement had 79.7% and 45.9% of patients, respectively. A positive and statistically significant correlation was found between SN hyperechogenicity with dystonia (p < 0.01), rigidity and dyskinesia (p < 0.05). The higher SARA total score is statistically significantly correlated with the larger diameter of the III (r = 0.373; p = 0.001) and IV ventricles (r = 0.324; p = 0.005). In such patients, the echogenicity of substantia nigra has been linked to extrapyramidal signs, and raphe discontinuity to depression. Furthermore, ataxia and its clinical subtypes have positively correlated with the IV ventricle diameter, indicating brain atrophy and brain mass reduction.

Impact of aripiprazole discontinuation in remitted major depressive disorder: a randomized placebo-controlled trial

RationaleThe efficacy and safety of antidepressant augmentation therapy with aripiprazole (AATA) has been established; however, the ongoing effects of continuing aripiprazole after remission remain unclear because no studies have examined this issue.ObjectivesWe aimed to explore the effect of AATA discontinuation on the major depressive disorder (MDD) recurrence risk in patients with remitted MDD after AATA.MethodsThis 24-week, multicenter, placebo-controlled, double-blind, randomized trial evaluated recurrence risk in patients with MDD who achieved remission with AATA. Differences in MDD recurrence, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, between the two groups were compared using survival analysis. The differences in depressive symptom severity and social functioning between the two groups were compared using a mixed model with repeated measures. Extrapyramidal symptoms and akathisia were also assessed.ResultsTwenty-three participants were randomized and treated. Two patients in each group experienced recurrence during the study. Kaplan–Meier analysis with Log-rank comparison showed no difference in recurrence between groups (p = 0.642). No significant difference in interactions between group and period was observed in the 17-item Hamilton depression rating scale (p = 0.492) or the Social and Occupational Functioning Assessment Scale (p = 0.638). No patients developed extrapyramidal symptoms or akathisia.ConclusionsDefinitive conclusions could not be drawn owing to the small sample size. This study represents a starting point for investigating the safety of aripiprazole discontinuation on recurrence in patients with MDD who have achieved remission with AATA. Future studies with appropriate sample sizes calculated based on this study are needed.

Effects of CYP2D6 gene polymorphism on plasma concentration and therapeutic effect of olanzapine

This study aimed to evaluate the relationship between gene polymorphisms of metabolic enzymes, particularly the CYP2D6 gene, and the plasma concentration of olanzapine, as well as treatment response in patients with chronic schizophrenia. We recruited olanzapine-treated patients and examined their plasma olanzapine levels. Additionally, a common mutation site within each of the nine exons of the full-length CYP2D6 sequence was assayed. The Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, and Overall Clinical Impression were used to assess schizophrenic symptoms, whereas the Barnes Akathisia Scale and Extrapyramidal Symptom Rating Scale were used to evaluate adverse effects. The results showed no significant differences in plasma olanzapine concentrations, treatment response, or the occurrence of adverse effects among different CYP2D6 genotypes. However, an association between olanzapine concentrations and improvement in clinical symptoms and adverse reactions was observed. In conclusion, the CYP2D6 genotype did not significantly impact plasma olanzapine concentrations, treatment response, or the occurrence of adverse effects.

A Review of Advances in Bioanalytical Methods for the Detection and Quantification of Olanzapine and Its Metabolites in Complex Biological Matrices.

Schizophrenia is a serious mental disorder that significantly affects the social and professional life of patients, causing distortion of reality and loss of identity and cognitive abilities. Psychopharmacological treatment is an integral part of modern psychiatry, and the introduction of new "atypical" antipsychotic drugs has brought significant progress in the treatment of this disorder. One of these drugs is olanzapine, which has an effective effect on the productive symptoms of schizophrenia while having an almost minimal potential to cause extrapyramidal syndrome. However, its effectiveness is confronted with frequent side effects, referred to as "metabolic disorders". Therefore, to ensure the effectiveness of treatment and to minimize the side effects caused by olanzapine, it is recommended to monitor the drug level during therapy. This article reviews the bioanalytical methodologies that enable efficient extraction and sensitive analysis of olanzapine. We considered the advantages and disadvantages of different sample pretreatment methods, including traditional and novel strategies. The analytical conditions required for the separation and detection of olanzapine and its metabolites were analyzed using chromatographic methods combined with various detectors.

Quantitative methods in the analysis of clozapine in human matrices – A scoping review

Abstract Clozapine (CLZ) has retained its clinical utility in the management of schizophrenia despite the discovery of novel antipsychotics, as it possesses unique efficacy in the setting of treatment resistant schizophrenia while causing minimal extrapyramidal symptoms. However, these benefits are offset by the risk of agranulocytosis and other side effects, and therapeutic drug monitoring (TDM) is routinely recommended for patients undergoing treatment with CLZ. A multitude of approaches for the quantification of CLZ have been developed for different settings such as TDM, quality control of pharmaceutical dosage forms, and toxicology studies. Primarily, these approaches fall under one of three branches of analysis, namely, chromatography, electrochemical analysis, and spectrophotometry. This study provides a scoping review of the recent advances in the methods of quantification for CLZ and highlights the potential utility of novel methods in the field of drug quantification.

Successful skipping of abnormal pseudoexon by antisense oligonucleotides in vitro for a patient with beta-propeller protein-associated neurodegeneration

Pathogenic variants in WDR45 on chromosome Xp11 cause neurodegenerative disorder beta-propeller protein-associated neurodegeneration (BPAN). Currently, there is no effective therapy for BPAN. Here we report a 17-year-old female patient with BPAN and show that antisense oligonucleotide (ASO) was effective in vitro. The patient had developmental delay and later showed extrapyramidal signs since the age of 15 years. MRI findings showed iron deposition in the globus pallidus and substantia nigra on T2 MRI. Whole genome sequencing and RNA sequencing revealed generation of pseudoexon due to inclusion of intronic sequences triggered by an intronic variant that is remote from the exon–intron junction: WDR45 (OMIM #300526) chrX(GRCh37):g.48935143G > C, (NM_007075.4:c.235 + 159C > G). We recapitulated the exonization of intron sequences by a mini-gene assay and further sought antisense oligonucleotide that induce pseudoexon skipping using our recently developed, a dual fluorescent splicing reporter system that encodes two fluorescent proteins, mCherry, a transfection marker designed to facilitate evaluation of exon skipping and split eGFP, a splicing reaction marker. The results showed that the 24-base ASO was the strongest inducer of pseudoexon skipping. Our data presented here have provided supportive evidence for in vivo preclinical studies.

Evaluation of the structural integrity of different spinal cord tracts with magnetization transfer ratio in degenerative cervical myelopathy.

Degenerative cervical myelopathy (DCM) is a common cause of spinal cord dysfunction. In this study, we explored the potential of magnetization transfer ratio (MTR) for evaluating the structural integrity of spinal cord tracts in patients with clinically significant DCM. Fifty-three patients with DCM and 41 patients with cervical radiculopathy were evaluated using high-resolution cervical spinal cord magnetic resonance imaging (MRI), which included the magnetization transfer technique. MRI data were analyzed with the Spinal Cord Toolbox (v5.5); MTR values in each spinal tract were calculated and compared between groups after correction for patient age and sex. Correlations between MTR values and patients' clinical disability rate were also evaluated. A statistically significant reduction in the average MTR of the spinal cord white matter, as well as the MTR of the ventral columns and lateral funiculi, was revealed in the DCM group (adjusted p < 0.01 for all comparisons). Furthermore, reductions in MTR values in the fasciculus cuneatus, spinocerebellar, rubrospinal, and reticulospinal tracts were found in patients with DCM (adjusted p < 0.01 for all comparisons). Positive correlations between the JOA score and the MTR within the ventral columns of the spinal cord (R = 0.38, adjusted p < 0.05) and the ventral spinocerebellar tract (R = 0.41, adjusted p < 0.05) were revealed. The findings of our study indicate that demyelination in patients with DCM primarily affects the spinal tracts of the extrapyramidal system, and the extent of these changes is related to the severity of the condition.

Hand knob sign in osmotic demyelinating syndrome

BackgroundOsmotic demyelinating syndrome, commonly recognized as a consequence of the rapid correction of hyponatremia, has been known to cause motor, neuropsychiatric, or extrapyramidal symptoms. We reported a patient with an unusual presentation involving bilateral hand weakness, and pseudobulbar affect. The imaging was compatible with osmotic demyelinating syndrome with bilateral hand knob lesions, despite no history of overcorrection of hyponatremia.Case presentationA 44-year-old female presented with three weeks of emotional lability, spastic dysarthria, and bilateral hand weakness following ankle surgery and a mild head injury. Physical examination revealed weakness in the intrinsic hand muscles, leading to a claw-like deformity of the hands, although sensation remained unimpaired. Magnetic resonance imaging (MRI) of the brain revealed several hyperintensities on fluid-attenuated inversion recovery imaging involving various areas, including the hand knob area of the bilateral precentral gyri, caudate, lentiform nuclei, and pons, suggestive of osmotic demyelinating syndrome. Clinical improvement was observed following a trial of intravenous pulse methylprednisolone and plasmapheresis.ConclusionsBilateral hand weakness is an unusual manifestation of osmotic demyelinating syndrome. The precentral gyrus, specifically in the hand knob area, is the vulnerable region that can result from osmotic demyelinating syndrome.

Эссенциальный тремор: современный взгляд на проблему и новые возможности нейрохирургических методов лечения

The review is focused on essential tremor (ET), the most common extrapyramidal system disorder. Current understanding of the disease pathogenesis is provided; issues of classification and differential diagnosis are discussed. Modern ET treatment methods include therapeutic approaches and surgical interventions. The benefits of the new ET treatment method, the magnetic resonance-guided focused ultrasound treatment (MRgFUS), are described; the world’s experience of using the method, indications and contraindications are summarized.

Correlative factors of poor prognosis and abnormal cellular immune function in patients with Alzheimer's disease.

Alzheimer's disease (AD) is a serious disease causing human dementia and social problems. The quality of life and prognosis of AD patients have attracted much attention. The role of chronic immune inflammation in the pathogenesis of AD is becoming more and more important. To study the relationship among cognitive dysfunction, abnormal cellular immune function, neuroimaging results and poor prognostic factors in patients. A retrospective analysis of 62 hospitalized patients clinical diagnosed with AD who were admitted to our hospital from November 2015 to November 2020. Collect cognitive dysfunction performance characteristics, laboratory test data and neuroimaging data from medical records within 24 h of admission, including Mini Mental State Examination Scale score, drawing clock test, blood T lymphocyte subsets, and neutrophils and lymphocyte ratio (NLR), disturbance of consciousness, extrapyramidal symptoms, electroencephalogram (EEG) and head nucleus magnetic spectroscopy (MRS) and other data. Multivariate logistic regression analysis was used to determine independent prognostic factors. the modified Rankin scale (mRS) was used to determine whether the prognosis was good. The correlation between drug treatment and prognostic mRS score was tested by the rank sum test. Univariate analysis showed that abnormal cellular immune function, extrapyramidal symptoms, obvious disturbance of consciousness, abnormal EEG, increased NLR, abnormal MRS, and complicated pneumonia were related to the poor prognosis of AD patients. Multivariate logistic regression analysis showed that the decrease in the proportion of T lymphocytes in the blood after abnormal cellular immune function (odd ratio: 2.078, 95% confidence interval: 1.156-3.986, P < 0.05) was an independent risk factor for predicting the poor prognosis of AD. The number of days of donepezil treatment to improve cognitive function was negatively correlated with mRS score (r = 0.578, P < 0.05). The decrease in the proportion of T lymphocytes may have predictive value for the poor prognosis of AD. It is recommended that the proportion of T lymphocytes < 55% is used as the cut-off threshold for predicting the poor prognosis of AD. The early and continuous drug treatment is associated with a good prognosis.

Targeting GRP75 with a Chlorpromazine Derivative Inhibits Endometrial Cancer Progression Through GRP75-IP3R-Ca2+-AMPK Axis.

Tumors often overexpress glucose-regulated proteins, and agents that interfere with the production or activity of these proteins may represent novel cancer treatments. The chlorpromazine derivative JX57 exhibits promising effects against endometrial cancer with minimal extrapyramidal side effects; however, its mechanisms of action are currently unknown. Here, glucose-regulated protein 75kD (GRP75) is identified as a direct target of JX57 using activity-based protein profiling and loss-of-function experiments. The findings show that GRP75 is necessary for the biological activity of JX57, as JX57 exhibits moderate anticancer properties in GRP75-deficient cancer cells, both in vitro and in vivo. High GRP75 expression is correlated with poor differentiation and poor survival in patients with endometrial cancer, whereas the knockdown of GRP75 can significantly suppress tumor growth. Mechanistically, the direct binding of JX57 to GRP75 impairs the structure of the mitochondria-associated endoplasmic reticulum membrane and disrupts the endoplasmic reticulum-mitochondrial calcium homeostasis, resulting in a mitochondrial energy crisis and AMP-activated protein kinase activation. Taken together, these findings highlight GRP75 as a potential prognostic biomarker and direct therapeutic target in endometrial cancer and suggest that the chlorpromazine derivative JX57 can potentially be a new therapeutic option for endometrial cancer.