Circadian rhythm of neutrophil counts and granulocyte macrophage-colony stimulating factor (GM-CSF) under clozapine treatment: A case report

Agranulocytosis is a severe side effect of clozapine which requires stopping this medication immediately in the case of progressive neutropenia. There are, however, cases of benign neutropenia under clozapine that do not progress. The ability to predict progression vs. non-progression in neutropenia cases under clozapine would be highly valuable for avoiding unnecessary treatment withdrawals. In this context, we closely monitored circadian neutrophil counts and granulocyte macrophage-colony stimulating factor (GM-CSF) levels in a patient who had low normal neutrophil counts at baseline and developed neutropenia under clozapine treatment. Methods. Venous blood samples were drawn in close intervals for 4 weeks. At several time points blood was sampled in the morning between 08:30 and 9:30 h and a second time in the afternoon between 14:00 and 15:00 h. Results. The circadian rhythm of neutrophil counts and GM-CSF levels was unchanged. There was no progression to agranulocytosis, and clozapine could be continued. Conclusions. In view of the available literature and the presented case it is suggested that further studying of circadian profiles of neutrophil counts, neutrophil regulatory factors, such as GM-CSF, and their intercorrelation may help to find a biomarker of benign vs. malign neutropenia under clozapine.     

Care Process of Recanalization Therapy for Acute Stroke during the COVID-19 Outbreak in South Korea

Background and PurposeWe aimed to determine whether the care process and outcomes in patients with acute stroke who received recanalization therapy changed during the outbreak of coronavirus disease 2019 (COVID-19) in South Korea.MethodsWe used data from a prospective multicenter reperfusion therapy registry to compare the care process—including the time from symptom onset to treatment, number of treated patients, and discharge disposition—and treatment outcomes between before and during the COVID-19 outbreak in South Korea.ResultsUpon the COVID-19 outbreak in South Korea, the number of patients receiving endovascular treatment to decrease temporarily but considerably. The use of emergency medical services by stroke patients increased from 91.5% before to 100.0% during the COVID-19 outbreak (p=0.025), as did the median time from symptom onset to hospital visit [median (interquartile range), 91.0 minutes (39.8–277.0) vs. 176.0 minutes (56.0–391.5), p=0.029]. Furthermore, more functionally dependent patients with disabilities were discharged home (59.5% vs. 26.1%, p=0.020) rather than staying in a regional or rehabilitation hospital. In contrast, there were no COVID-19-related changes in the times from the hospital visit to brain imaging and treatment or in the functional outcome, successful recanalization rate, or rate of symptomatic intracerebral hemorrhage.ConclusionsThese findings suggest that a prehospital delay occurred during the COVID-19 outbreak, and that patients with acute stroke might have been reluctant to visit and stay in hospitals. Our findings indicate that attention should be paid to prehospital care and the behavior of patients with acute stroke during the COVID-19 outbreak.     

Impact of the Coronavirus Disease Pandemic on Patients with Head Injuries in South Korea

ObjectiveThe coronavirus disease 2019 (COVID-19) pandemic is affecting the characteristics of patients with head injuries. This study aimed to evaluate the effect of the COVID-19 pandemic on patients with head injuries at a regional emergency medical center in South Korea. MethodsFrom April 2019 to November 2020, 350 patients with head injuries were admitted to our hospital. The study period was divided into the pre-COVID-19 (n=169) and COVID-19 (n=181) eras (10 months each). Patients with severe head injuries requiring surgery (n=74) were categorized into those who underwent surgery (n=41) and those who refused surgery (n=33). ResultsHead injuries in pediatric patients (<3 years) were more frequent in the COVID-19 era than in the pre-COVID-19 era (8.8% vs. 3.6%, p=0.048). More patients refused surgery in the COVID-19 era than in the pre-COVID-19 era (57.9% vs. 30.6%, p=0.021). Refusal of surgery was associated with old age (67.7±14.5 vs. 52.4±19.1, p<0.001), marital status (married, 84.8% vs. 61.0%, p=0.037), unemployment (42.4% vs. 68.3%, p=0.034), COVID-19 era (66.7% vs. 39.0%, p=0.021), and lower Glasgow coma scale scores (6.12±3.08 vs. 10.6±3.80, p<0.001). Multivariable logistic regression analysis revealed that refusal of surgery was independently associated with old age (adjusted odds ratio [OR], 1.084; 95% confidence interval [CI], 1.030–1.140; p=0.002), COVID-19 era (adjusted OR, 6.869; 95% CI, 1.624–29.054; p=0.009), and lower Glasgow coma scale scores (adjusted OR, 0.694; 95% CI, 0.568–0.848; p<0.001). ConclusionWe observed an increased prevalence of head injuries in pediatric patients (<3 years) during the COVID-19 pandemic. Additionally, among patients with severe head injuries requiring surgery, more patients refused to undergo surgery during the COVID-19 pandemic.     

Changes in Characteristics,Treatment and Outcome in Patients with Hemorrhagic Stroke During COVID-19

Background and PurposeThe coronavirus disease 2019 (COVID-19) pandemic has had a comprehensive impact on healthcare services worldwide. We sought to determine whether COVID-19 affected the treatment and prognosis of hemorrhagic stroke in a regional medical center in mainland China.MethodsPatients with hemorrhagic stroke admitted in the Neurosurgery Department of West China Hospital from January 24, 2020, to March 25, 2020 (COVID-19 period), and from January 24, 2019, to March 25, 2019 (pre-COVID-19 period), were identified. Clinical characteristics, hospital arrival to neurosurgery department arrival time (door-to-department time), reporting rate of pneumonia and 3-month mRS (outcome) were compared.ResultsA total of 224 patients in the pre-COVID-19 period were compared with 126 patients in the COVID-19 period. Milder stroke severity was observed in the COVID-19 period (NIHSS 6 [2–20] vs. 3 [2–15], p = 0.005). The median door-to-department time in the COVID-19 period was approximately 50 minutes longer than that in the pre-COVID-19 period (96.5 [70.3–193.3] vs. 144.5 [93.8–504.5], p = 0.000). A higher rate of pneumonia complications was reported in the COVID-19 period (40.6% vs. 60.7%, p = 0.000). In patients with moderate hemorrhagic stroke, the percentage of good outcomes (mRS < 3) in the pre-COVID-19 period was much higher than that in the COVID-19 period (53.1% vs. 26.3%, p = 0.047).ConclusionsCOVID-19 may have several impacts on the treatment of hemorrhagic stroke and may influence the clinical outcomes of specific patients. Improvements in the treatment process for patients with moderate stroke may help to improve the overall outcome of hemorrhagic stroke during COVID-19.     

Hematological adverse events in clozapine-treated children and adolescents

OBJECTIVE: To retrospectively examine rates of hematological adverse events (HAEs) in psychiatrically ill, hospitalized children treated with clozapine. METHOD: Clozapine treatment was administered in an open-label fashion using a flexible titration schedule, and data from weekly complete blood counts was obtained. The rate of neutropenia and agranulocytosis (HAEs) development was determined for 172 eligible patients (mean age at clozapine initiation, 15.03 +/- 2.13 years) with a median observation period of 8 months. RESULTS: Neutropenia (absolute neutrophil count <1,500/mm) developed in 23 (13%) patients and agranulocytosis (absolute neutrophil count <500/mm) in one (0.6%) patient. The cumulative probability of developing an initial HAE at 1 year of clozapine treatment was 16.1% (95% confidence interval 9.7%-22.5%). Eleven (48%) of 24 patients who developed an HAE were successfully rechallenged on clozapine. Eight (5%) of 172 patients from this sample eventually discontinued clozapine because of an HAE (one agranulocytosis, seven neutropenia). CONCLUSIONS: The occurrence of HAEs is a significant risk associated with the administration of clozapine. However, in this sample, few children actually discontinued therapy because of an HAE and the incidence of agranulocytosis does not appear higher than what has been reported in the adult literature.     

A case study; ethnicity and clozapine, a risky combination?

Agranulocytosis is a very serious side-effect of treatment with clozapine. For this reason, the Dutch guidelines state the specific values of leukocyte and neutrophil counts at which treatment with clozapine should be discontinued. We focus on a patient with a benign ethnic neutropenia who, despite a low neutrophil count, was allowed to continue taking clozapine. We discuss a number of important practical considerations that can affect the way in which leukocyte and neutrophil counts are interpreted in relation to the use of clozapine.     

Neutropenia in a patient receiving intravenous immune globulin

A child with Guillain-Barré syndrome treated with intravenous immune globulin (IVIG) developed neutropenia (absolute neutrophil count — 390), which resolved 3 days after completion of the therapy. Potential mechanisms for the development of neutropenia during the use of IVIG therapy are discussed. In this case, testing of the IVIG used revealed the presence of a high concentration of anti-neutrophil antibodies compared to other samples. It is recommended that white blood cell and neutrophil counts be monitored daily during the use of such therapy.     

Ethnic inequalities in clozapine use among people with treatment-resistant schizophrenia: a retrospective cohort study using data from electronic clinical records

Purpose

Clozapine is the most effective intervention for treatment-resistant schizophrenia (TRS). Several studies report ethnic disparities in clozapine treatment. However, few studies restrict analyses to TRS cohorts alone or address confounding by benign ethnic neutropenia. This study investigates ethnic equity in access to clozapine treatment for people with treatment-resistant schizophrenia spectrum disorder.

Methods

A retrospective cohort study, using information from 11 years of clinical records (2007–2017) from the South London and Maudsley NHS Trust. We identified a cohort of service-users with TRS using a validated algorithm. We investigated associations between ethnicity and clozapine treatment, adjusting for sociodemographic factors, psychiatric multi-morbidity, substance misuse, neutropenia, and service-use.

Results

Among 2239 cases of TRS, Black service-users were less likely to be receive clozapine compared with White British service-users after adjusting for confounders (Black African aOR = 0.49, 95% CI [0.33, 0.74], p = 0.001; Black Caribbean aOR = 0.64, 95% CI [0.43, 0.93], p = 0.019; Black British aOR = 0.61, 95% CI [0.41, 0.91], p = 0.016). It was additionally observed that neutropenia was not related to treatment with clozapine. Also, a detention under the Mental Health Act was negatively associated clozapine receipt, suggesting people with TRS who were detained are less likely to be treated with clozapine.

Conclusion

Black service-users with TRS were less likely to receive clozapine than White British service-users. Considering the protective effect of treatment with clozapine, these inequities may place Black service-users at higher risk for hospital admissions and mortality.

     

Elevated Serum Leukocytes are Predictive of Cardiac Injury Following Aneurysmal Subarachnoid Hemorrhage

ObjectivesAneurysmal subarachnoid hemorrhage (aSAH) accounts for 5% of strokes but results in significant morbidity and mortality. In addition to systemic inflammation, up to half of patients develop cardiac injury; however, the relationship between systemic inflammation and cardiac injury after aSAH is unknown. We investigated changes in leukocyte counts in relation to cardiac dysfunctionMaterials and methodsWe reviewed the records of consecutive patients with SAH at our large academic medical referral center. The inclusion criteria were aSAH and available cardiac troponin I (cTnI) levels within 48 h of admission. The primary outcome was cardiac injury, defined as cTnI ≥0.04 ng/mL (lab reference range 0.01–0.03 ng/mL). We compared baseline characteristics, including serum leukocyte counts and performed univariable and multivariable logistic regression analysis to determine whether changes in leukocyte subpopulations predict cardiac injury.ResultsOf 288 SAH patients, 250 met inclusion criteria. Of these, 116 (46.4%) had elevated cTnI. In univariable analysis, total leukocyte count (p < 0.001), absolute neutrophil count (ANC, p < 0.001), and absolute monocyte count (p = 0.013), were associated with elevated cTnI. in multivariable analysis, total leukocyte count (OR=1.079, p = 0.037) and ANC (OR=1.081, p = 0.044) remained predictors of elevated cTnI. Adjusted ANC distinguishes between aSAH patients with normal and elevated TnI (area under the curve=0.766, p < 0.001) with specificity of 89.2%.ConclusionsElevated total leukocytes and ANC are independently associated with cardiac injury in aSAH. Systemic inflammatory responses after aSAH may play a role in cardiac dysfunction, warranting additional studies to further characterize how cardiac inflammation after aSAH drives subsequent morbidity and mortality.     

Incidence and risk factors for stroke in patients with COVID-19 in the Philippines: An analysis of 10,881 cases

BackgroundWhile most large studies on the possible association of COVID-19 and stroke were done in high-income countries, only a few studies consisting of small sample populations have been done in low- to middle-income countries like the Philippines.ObjectivesTo determine the risk factors of stroke among hospitalized COVID19 patients in the Philippines; to determine the possible association between these risk factors and stroke among the same cohort; and to determine if there is an association between mortality and stroke in this same group.MethodologyWe obtained relevant clinical and neurological, including stroke data from the Philippine CORONA study, an observational study involving 10,881 patients with COVID-19 admitted in 37 referral hospitals from all over the Philippines.ResultsThe incidence of stroke among patients with COVID-19 was 3.4% (n = 367). There were more deaths among patients with stroke and COVID-19 than those without stroke and COVID-19 (42.2% vs 14.7%, p < 0.01). In addition, more patients with stroke were admitted in the ICU (43.3% vs 15.0%, p < 0.01) regardless of cause. Smoking (OR: 1.5, 95% CI: 1.3 to 1.7, p < 0.0001), hypertension (OR:1.75, 95% CI:1.53 to 1.97, p < 0.0001), presence of heart failure (OR: 1.4, 95% CI: 1.07 to 1.86, p = 0.01), presence of any neurologic co-morbidities (OR: 1.4, 95% CI:1.11 to 1.46, p = 0.004), and history of stroke (OR:2.3, 95% CI:1.82 to 2.97, p < 0.0001) had direct significant correlation with stroke; while being a health care worker (OR: 0.5, 95% CI: 0.33 to 0.70, p < 0.0004) had an inverse significant association with stroke.ConclusionCOVID-19 stroke patients in the Philippines have a higher mortality and ICU admission rates than patients with COVID-19 alone or COVID-19 stroke patients from developed countries. Our cohort has similar cardiovascular and metabolic risk factors to western patients with stroke, highlighting that COVID-19 may only have a small contribution to stroke incidence.     

Réintroduction de la clozapine après neutropénie dans la schizophrénie résistante : revue des données de la littérature

IntroductionClozapine is an atypical antipsychotic known for its efficacy in refractory schizophrenia. One of the adverse effects is neutropenia. This dysplasia is a rare but major side effect which leads to a discontinuation and constitutes further contraindication. Thereafter, therapeutic options decrease dramatically. Mechanisms involved are not well known at this time and can be combined. A toxic hypothesis may be more likely than an immune-allergic one.MethodsWe have reviewed publications on Medline describing procedures that allowed clozapine rechallenge after blood dyscrasia in refractory schizophrenia. Three different procedures were found: simple rechallenge, rechallenge with lithium and rechallenge with Granulocyte - colony stimulating factor (G-CSF). Rechallenge could be simple or multiple.ResultsThese past years, clozapine have been rechallenged successfully after neutropenia thanks to different procedures, the different options being simple rechallenge, rechallenge with lithium and/or rechallenge with G-CSF. Lithium as G-CSF are used to increase neutrophil blood rate and prevent neutropenia recurrence after clozapine rechallenge. G-CSF was first used within the context of chemotherapy and extends now to clozapine-induced neutropenia. Both for lithium and G-CSF, numerous procedures are reviewed and cannot be compared.DiscussionPublications are limited but increasing, and they point out that a careful rechallenge can be successful. However, interesting data can be extracted. First, clozapine is more likely to be incriminated in neutropenia when patients receive many drugs, but a careful study could prevent some discontinuation. Indeed, other drugs or a hematologic disease could be involved. Moreover, several contributing factors have been found such as HLA group and drug interaction. Ethnic origin also affects neutrophil rate. That is why, in Great Britain, a subgroup of patients “benign ethnic neutropenia” has been introduced to enlarge threshold and allow these patients to access clozapine despite lower blood counts. Then, rechallenge choice has to be done on a case-by-case basis and only after considering the benefits and risks of such a treatment. Most of the time, clinical advice of rechallenge arises from the inefficiency of other antipsychotics and even sismotherapy failure. Patients and sometimes families have to be informed and give their consent. Preventive measures have been found such as taking a hematologic recommendation and doing twice-a-week blood sample monitoring. With regards lithium and G-CSF, some efficient doses are assumed (lithium: 0,4–1,1 mEq/L and G-CSF > 0,3 mg/week). Lithium as G-CSF may have other adverse effects which need to be considered. There is no successful rechallenge reported after agranulocytosis. Some publications highlight that if neutropenia occurs on rechallenge, it will do so more quickly and more severe than at the time of initial trial of clozapine.ConclusionThere is emerging evidence of successful clozapine rechallenging. However, further investigations are required as randomized controlled trials to reassess guidelines and establish the safety and effectiveness of the different procedures. Because of the practical and ethical difficulties of designing such studies, referral hospitals could be elected, and common background writing proposed in order to ease data comparison.     

COVID-19 and Stroke Recurrence by Subtypes: A Propensity-Score Matched Analyses of Stroke Subtypes in 44,994 Patients

BackgroundCerebrovascular diseases (CVDs), including varying strokes, can recur in patients upon coronavirus disease 2019 (COVID-19) diagnosis, but risk factor stratification based on stroke subtypes and outcomes is not well studied in large studies using propensity-score matching. We identified risk factors and stroke recurrence based on varying subtypes in patients with a prior CVD and COVID-19.MethodsWe analyzed data from 45 health care organizations and created cohorts based on ICDs for varying stroke subtypes utilizing the TriNetX Analytics Network. We measured the odds ratios and risk differences of hospitalization, ICU/critical care services, intubation, mortality, and stroke recurrence in patients with COVID-19 compared to propensity-score matched cohorts without COVID-19 within 90-days.Results22,497 patients with a prior history of CVD within 10 years and COVID-19 diagnosis were identified. All cohorts with a previous CVD diagnosis had an increased risk of hospitalization, ICU, and mortality. Additionally, the data demonstrated that a history of ischemic stroke increased the risk for hemorrhagic stroke and transient ischemic attack (TIA) (OR:1.59, 1.75, p-value: 0.044*, 0.043*), but a history of hemorrhagic stroke was associated with a higher risk for hemorrhagic strokes only (ORs 3.2, 1.7, 1.7 and p-value: 0.001*, 0.028*, 0.001*). History of TIA was not associated with increased risk for subsequent strokes upon COVID-19 infection (all p-values: ≥ 0.05).ConclusionsCOVID-19 was associated with an increased risk for hemorrhagic strokes and TIA among all ischemic stroke patients, an increased risk for hemorrhagic stroke in hemorrhagic stroke patients, and no associated increased risk for any subsequent strokes in TIA patients.     

COVID-19 Prevalence and Mortality Among Schizophrenia Patients: A Large-Scale Retrospective Cohort Study

ObjectiveIndividuals with schizophrenia may be at an increased risk for COVID-19 morbidity due to the disease characteristics. In this study, we aimed to explore the odds of significant COVID-19 morbidity and mortality among schizophrenia patients while controlling for potential sociodemographic and medical confounders.MethodsSchizophrenia patients and age-and-sex matched controls (total n = 51 078) were assessed for frequency of COVID-19 positivity, hospitalizations, and mortality. The odds for COVID-19-associated hospitalization and mortality were calculated using logistic regression models, while controlling for age, sex, marital status, sector, socioeconomic status, diabetes, ischemic heart disease, hypertension, hyperlipidemia, obesity, smoking, and chronic obstructive pulmonary disease.ResultsIndividuals with schizophrenia were less likely to test positive for COVID-19; however, they were twice as likely to be hospitalized for COVID-19 (OR 2.15 95% CI 1.63–2.82, P < .0001), even after controlling for sociodemographic and clinical risk factors (OR 1.88 95% CI 1.39–2.55, P < .0001). Furthermore, they were 3 times more likely to experience COVID-19 mortality (OR 3.27 95% CI 1.39–7.68, P < .0001), compared to controls.ConclusionsWe found evidence of associations between schizophrenia and increased COVID-19 morbidity and mortality compared to controls regardless of sociodemographic and medical factors. As these patients present with a combination of potential risk factors for mortality, efforts should be made to minimize the effects of the pandemic on this vulnerable population.     

Code Stroke Patient Referral by Emergency Medical Services During the Public COVID-19 Pandemic Lockdown

BackgroundThe COVID-19 pandemic caused public lockdowns around the world. We analyzed if the public lockdown altered the referral pattern of Code Stroke patients by Emergency Medical Services (EMS) to our Comprehensive Stroke Center.MethodsRetrospective single-center study at a Bavarian Comprehensive Stroke Center. Patients who were directly referred to our stroke unit by EMS between the 1^st of January 2020 and the 19^th of April 2020 were identified and number of referrals, clinical characteristics and treatment strategies were analyzed during the public lockdown and before. The public lockdown started on 21^st of March and ended on 19^th April 2020.ResultsIn total 241 patients were referred to our center during the study period, i.e. 171 before and 70 during the lockdown. The absolute daily number of Code Stroke referrals and the portion of patients with stroke mimics remained stable. The portion of female stroke patients decreased (55% to 33%; p = 0.03), and stroke severity as measured by the National Institutes of Health Stroke Scale (median 3 (IQR 0-7) versus 6 (IQR 1-15.5) points; p = 0.04) increased during the lockdown. There was no difference of daily numbers of patients receiving thrombolysis and thrombectomy.ConclusionsReferral of Code Stroke patients by EMS could be maintained sufficiently despite the COVID-19 pandemic lockdown. However, patients’ health care utilization of the EMS may have changed within the public lockdown. EMS remains a useful tool for Code Stroke patient referral during lockdowns, but public education about stroke is required prior to further lockdowns.     

Clozapine Is Better Tolerated in Younger Patients: Risk Factors for Discontinuation from a Nationwide Database in Japan

Objective The effectiveness of clozapine is clearly superior to other antipsychotics in the treatment of refractory schizophrenia. Clozapine leads to various side effects, and therefore many patients are forced to discontinue. In this study, we analyzed the registry database of all cases in Japan to identify risk factors for discontinuation of clozapine. Methods The Clozaril patient monitoring service^® (CPMS) database from July 31, 2009 to January 26, 2020 was acquired. We defined the following exclusion criteria: patients who had ever taken clozapine by a non-CPMS method, such as an individual import or clinical trial, patients who did not receive clozapine after being enrolled in CPMS, and patients with initial doses other than 12.5 mg (outside the current protocol). Therefore, all patients in this study are new users. Multivariate Cox regression analysis was used to investigate independent risk factors associated with time to discontinuation of clozapine. Results We identified 8,263 patients as the study population. Clozapine discontinuation was significantly associated with age 40 and older [hazard ratio (HR)=1.66, p<0.001], intolerance to olanzapine (HR=1.31, p=0.018), previous treatment with clozapine (HR=1.30, p=0.001), and leukocyte counts <6,000/mm³ (HR=1.24, p<0.001). The Kaplan-Meier curves for clozapine discontinuation by age group revealed that older age at the time of clozapine introduction tended to have lower continuation rates. Conclusion Careful administration is important because patients with these factors have a high risk of discontinuation. In addition, the initiation of clozapine during the younger period was more effective and more tolerated.     

Clinical Characteristics of Stroke with COVID-19: A Systematic Review and Meta-Analysis

BackgroundThe coronavirus disease 2019 (COVID-19) potentially increases the risk of thromboembolism and stroke. Numerous case reports and retrospective cohort studies have been published with mixed characteristics of COVID-19 patients with stroke regarding age, comorbidities, treatment, and outcome. We aimed to depict the frequency and clinical characteristics of COVID-19 patients with stroke.MethodsPubMed and EMBASE were searched on June 10, 2020, to investigate COVID-19 and stroke through retrospective cross-sectional studies, case series/reports according to PRISMA guidelines. Study-specific estimates were combined using one-group meta-analysis in a random-effects model.Results10 retrospective cohort studies and 16 case series/reports were identified including 183 patients with COVID-19 and stroke. The frequency of detected stroke in hospitalized COVID-19 patients was 1.1% ([95% confidential interval (CI)]: [0.6-1.6], I² = 62.9%). Mean age was 66.6 ([58.4-74.9], I² = 95.1%), 65.6% was male (61/93 patients). Mean days from symptom onset of COVID-19 to stroke was 8.0 ([4.1-11.9], p< 0.001, I² = 93.1%). D-dimer was 3.3 μg/mL ([1.7-4.9], I² = 86.3%), and cryptogenic stroke was most common as etiology at 50.7% ([31.0-70.4] I² = 64.1%, 39/71patients). Case fatality rate was 44.2% ([27.9-60.5], I² = 66.7%, 40/100 patients).ConclusionsThis systematic review assessed the frequency and clinical characteristics of stroke in COVID-19 patients. The frequency of detected stroke in hospitalized COVID-19 patients was 1.1% and associated with older age and stroke risk factors. Frequent cryptogenic stroke and elevated d-dimer level support increased risk of thromboembolism in COVID-19 associated with high mortality. Further study is needed to elucidate the pathophysiology and prognosis of stroke in COVID-19 to achieve most effective care for this population.     

Chemotherapy during clozapine treatment. Increased risk of agranulocytosis?

In a 37-year-old female, a combined treatment consisting of chemotherapy and radiation was considered for cervical cancer. However, she was using clozapine for the treatment of schizophrenia. As both clozapine and chemotherapy can induce decrease of white blood cell counts, we had to decide if clozapine and chemotherapy could be safely co-prescribed. Hypotheses concerning the mechanisms underlying clozapine-induced decrease of white blood cell counts and case reports on combining chemotherapy and clozapine are discussed. After cessation of clozapine the psychosis recurred despite treatment with risperidone. The decision was made to administer radiotherapy only and to reinstate the treatment with clozapine. The radiotherapy treatment went according to plan and the psychosis receded.     

Effects of an Infection Control Protocol for Coronavirus Disease in Emergency Mechanical Thrombectomy

ObjectiveSince the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, neurointerventionists have been increasingly concerned regarding the prevention of infection and time delay in performing emergency thrombectomy procedures in patients with acute stroke. This study aimed to analyze the effects of changes in mechanical thrombectomy protocol before and after the COVID-19 pandemic on procedure time and patient outcomes and to identify factors that significantly impact procedure time. MethodsThe last-normal-to-door, first-abnormal-to-door, door-to-imaging, door-to-puncture, and puncture-to-recanalization times of 88 patients (45 treated with conventional pre-COVID-19 protocol and 43 with COVID-19 protection protocol) were retrospectively analyzed. The recanalization time, success rate of mechanical thrombectomy, and modified Rankin score of patients at discharge were assessed. A multivariate analysis was conducted to identify variables that significantly influenced the time delay in the door-to-puncture time and total procedure time. ResultsThe door-to-imaging time significantly increased under the COVID-19 protection protocol (p=0.0257) compared to that with the conventional pre-COVID-19 protocol. This increase was even more pronounced in patients who were suspected to be COVID-19-positive than in those who were negative. The door-to-puncture time showed no statistical difference between the conventional and COVID-19 protocol groups (p=0.5042). However, in the multivariate analysis, the last-normal-to-door time and door-to-imaging time were shown to affect the door-to-puncture time (p=0.0068 and 0.0097). The total procedure time was affected by the occlusion site, last-normal-to-door time, door-to-imaging time, and type of anesthesia (p=0.0001, 0.0231, 0.0103, and 0.0207, respectively). ConclusionThe COVID-19 protection protocol significantly impacted the door-to-imaging time. Shortening the door-to-imaging time and performing the procedure under local anesthesia, if possible, may be required to reduce the door-to-puncture and door-to-recanalization times. The effect of various aspects of the protection protocol on emergency thrombectomy should be further studied.     

Adjunctive Minocycline in Clozapine-Treated Patients with Schizophrenia: Analyzing the Effects of Minocycline on Clozapine Plasma Levels

Clozapine is the sole antipsychotic agent effective for the treatment of refractory schizophrenia. Sixty percent of clozapine-treated patients, however, fail to adequately respond. Minocycline, a tetracycline antibiotic, possesses antiinflammatory and neuroprotective properties that may play a role in schizophrenia. Clozapine is mainly metabolized by CYP1A2 enzymes, and minocycline may potentially inhibit CYP1A2 as hypothesized by case report data. To date, no pharmacokinetic interaction has been reported between minocycline and clozapine. This is a secondary analysis of a 10-week controlled study of adjunctive minocycline to clozapine in treatment refractory schizophrenia. Clozapine plasma levels were collected every two weeks during the study. 28 participants assigned to receive minocycline and 22 assigned to placebo were included. No differences existed in baseline demographics, clozapine dose or plasma levels. Average changes from baseline in clozapine plasma level (p = 0.033) were significantly higher in the minocycline group despite maintenance of stable doses. No statistically significant treatment differences were found in the norclozapine (p = 0.754) or total clozapine (p = 0.053) changes in plasma levels, although possible changes in total clozapine levels require further investigation. This analysis suggests that minocycline administration may lead to increased clozapine plasma levels. Further study is needed to examine possible explanations.     

Clozapine underutilization and discontinuation in African Americans due to leucopenia

Clozapine use has been notably lower in African American patients than in Caucasians. It has been suggested that lower normal ranges for white blood cell (WBC) counts in African Americans, known as benign ethnic neutropenia, may account partially for the disparity. We examined the rates of leucopenia and agranulocytosis as reasons for discontinuation of clozapine in a sample of 1875 patients with schizophrenia treated in the State of Maryland. Between 1989 and 1999, 5.3% (31/588) of African Americans and 2.4% (31/1287) of Caucasians discontinued clozapine treatment due to leucopenia (chi square = 10.35, df = 1, P = 0.001). No African American patients developed agranulocytosis while 8 Caucasian patients (0.62%) developed this blood dyscrasia. Discontinuations due to leucopenia occurred throughout treatment. Discontinuations due to agranulocytosis occurred primarily in the first 18 weeks (7/8; 87.5% patients with agranulocytosis). It is likely that African Americans had clozapine discontinued unnecessarily due to benign ethnic neutropenia. We concur with recent recommendations to acknowledge differences in WBC values in African Americans and to modify prescribing guidelines or formally acknowledge benign ethnic leucopenia like in other countries in order to facilitate greater use of clozapine in these patients.