Exploring Subfactors of Adult Cognitive Disengagement Syndrome and Impact on Neuropsychological Performance.

OBJECTIVE: This study investigated subfactors of cognitive disengagement syndrome (CDS; previously referred as sluggish cognitive tempo) among adults referred for neuropsychological evaluation of attentiondeficit/hyperactivity disorder (ADHD). METHOD: Retrospective analyses of data from 164 outpatient neuropsychological evaluations examined associations between CDS subfactors and self-reported psychological symptoms and cognitive performance. RESULTS: Factor analysis produced two distinct but positively correlated constructs: "Cognitive Complaints'' and "Lethargy." Both correlated positively with symptom reports (rs = 0.26-0.57). Cognitive Complaints correlated negatively with working memory, processing speed, and executive functioning performance (rs = -0.21 to -0.37), whereas Lethargy correlated negatively only with processing speed and executive functioning performance (rs = -0.26 to -0.42). Both predicted depression symptoms, but only Cognitive Complaints predicted inattention symptoms. Both subfactors demonstrated modest to nonsignificant associations with cognitive performance after accounting for estimated premorbid intelligence and inattention. CONCLUSION: Findings indicate a bidimensional conceptualization of CDS, with differential associations between its constituent subfactors, reported symptoms, and cognitive performance.

Management of Choroid Plexus Tumors and the Benefit of Preoperative Embolization in Pediatric Patients: Report of 46 Cases from a Single Institution.

OBJECTIVE: Optimal choroid plexus tumor (CPT) treatment involves gross total resection; however, intraoperative hemorrhage risk remains significant given tumor vascularity. This study describes pediatric CPT management and identifies patients most likely to benefit from preoperative embolization. METHODS: CPTs resected from 1997 to 2021 were included. The characteristics of embolized patients were compared to nonembolized patients; nonembolized patients were further stratified based on open vascular control-pedicle feeder ligation versus no pedicle ligation prior to tumor debulking. Statistical analyses identified factors associated with estimated blood loss (EBL), transfusion, length of stay, and complications. RESULTS: Among the 46 CPT cases identified, 98% achieved gross total resection, and 15% received embolization. Embolized patients were younger, smaller, and had larger tumors compared to nonembolized patients (median: 0.8 vs. 2.1 years; 9.3 vs. 14.4 kg; 91.08 vs. 5.5 cm3). Transfused patients were similarly younger and smaller (P < 0.05) than nontransfused patients. Among nonembolized patients, open vascular control was achieved in smaller tumors (<13 cm3) with significantly lower EBL (P = 0.002). Higher EBL was observed in patients with larger tumors, hydrocephalus, transependymal edema, vomiting, lethargy, and developmental regression (all P < 0.05). Patients with lethargy had longer hospital stays and a higher likelihood of postoperative complications (P < 0.05). There were no significant differences in complication rates between the embolization and nonembolization groups. CONCLUSIONS: Despite higher surgical risk profiles, embolized patients had similar complication rates and postoperative hydrocephalus management as nonembolized patients. Embolization was particularly beneficial in patients at high risk for surgical morbidity, such as those <2 years, weighing <10 kg, and with a tumor volume >15 cm3.

Clinical Reasoning: An Older Woman With Headaches and Lethargy After a Fall.

In this case, a 77-year-old woman presented with generalized weakness, difficulty ambulating, lethargy, loss of appetite, and headaches after a mechanical fall. This case discusses the management of acute neurologic emergencies such as subdural hematoma, status epilepticus, and bacterial meningitis. Potential etiologies for stroke and CNS infection are highlighted. Readers are led through the diagnostic approach to a patient presenting with a complex array of neurologic symptoms causing rapid clinical decompensation.

Brainstem ADCYAP1+ neurons control multiple aspects of sickness behaviour.

Infections induce a set of pleiotropic responses in animals, including anorexia, adipsia, lethargy and changes in temperature, collectively termed sickness behaviours1. Although these responses have been shown to be adaptive, the underlying neural mechanisms have not been elucidated2-4. Here we use of a set of unbiased methodologies to show that a specific subpopulation of neurons in the brainstem can control the diverse responses to a bacterial endotoxin (lipopolysaccharide (LPS)) that potently induces sickness behaviour. Whole-brain activity mapping revealed that subsets of neurons in the nucleus of the solitary tract (NTS) and the area postrema (AP) acutely express FOS after LPS treatment, and we found that subsequent reactivation of these specific neurons in FOS2A-iCreERT2 (also known as TRAP2) mice replicates the behavioural and thermal component of sickness. In addition, inhibition of LPS-activated neurons diminished all of the behavioural responses to LPS. Single-nucleus RNA sequencing of the NTS-AP was used to identify LPS-activated neural populations, and we found that activation of ADCYAP1+ neurons in the NTS-AP fully recapitulates the responses elicited by LPS. Furthermore, inhibition of these neurons significantly diminished the anorexia, adipsia and locomotor cessation seen after LPS injection. Together these studies map the pleiotropic effects of LPS to a neural population that is both necessary and sufficient for canonical elements of the sickness response, thus establishing a critical link between the brain and the response to infection.

Distal renal tubular acidosis and lethargy associated with zonisamide treatment in a dog with idiopathic epilepsy.

A 3-year-old neutered male golden retriever administered zonisamide for the treatment of seizures showed lethargy and had normal anion gap metabolic acidosis with hypokalaemia, hyperchloremia, and alkaline urine. The serum zonisamide concentration was close to the upper limit, which raised a suspicion of adverse effects of zonisamide. This is the first report showing that the fractional excretion of bicarbonate after compensation for the plasma bicarbonate concentration by a sodium bicarbonate infusion was approximately 5%, indicating distal renal tubular acidosis (RTA). The serum zonisamide concentration decreased, and adverse effects were abated by reducing the zonisamide dosage. Diagnostic therapy with bicarbonate served as a means of compensating for bicarbonate deficiency and contributed to the clinical diagnosis of the condition in zonisamide-associated RTA in dogs.

CT can identify characteristic features of hypaxial muscle abscesses in dogs due to presumed migrating vegetal foreign material as well as additional changes along the migratory tract in other anatomic regions.

Hypaxial muscle abscess is an important differential in dogs presenting for abdominal or back pain, lameness, and nonspecific signs like fever, lethargy, and hyporexia. It can occur concurrently with intrathoracic disease such as pyothorax secondary to migrating vegetal foreign material. Twelve dogs that underwent CT of the lumbar spine or abdomen and had a diagnosed hypaxial abscess on surgical and/or microbiological examination were included in this retrospective, descriptive case series. Computed tomography findings and findings from other imaging modalities employed were described. Eleven dogs were hunting breeds. Clinical signs included lethargy, fever, increased respiratory effort, and abdominal or back pain. Radiography and/or ultrasonography were employed during preliminary work up at clinician discretion and respectively revealed changes consistent with osteomyelitis in the cranial lumbar vertebrae and heterogenous, hypoechoic areas in the hypaxial musculature consistent with abscesses. Computed tomography findings included enlargement of hypaxial muscles with well-defined fluid attenuating noncontrast enhancing areas with a contrast-enhancing rim consistent with abscesses, periosteal reaction and lysis of vertebrae, and retroperitoneal effusion. Four of the 12 cases in this series had material identified and removed at surgery. The other eight cases were presumed to be the same disease process based on compatible signalment, imaging findings, and microbiological results. Migrating vegetal foreign bodies are a common problem at the authors' institution. Computed tomography provided expedient, thorough visualization of the relevant hypaxial lesions for diagnostic and surgical planning purposes and also characterized intrathoracic components of this disease.

Bradycardia in a newborn with accidental severe hypothermia: treat or don't touch? A case report.

BACKGROUND: Hypothermia significantly affects mortality and morbidity of newborns. Literature about severe accidental hypothermia in neonates is limited. We report a case of a neonate suffering from severe accidental hypothermia. An understanding of the physiology of neonatal thermoregulation and hypothermia is important to decide on treatment. CASE PRESENTATION: A low-birth-weight newborn was found with severe accidental hypothermia (rectal temperature 25.7 °C) due to prolonged exposure to low ambient temperature. The newborn presented bradycardic, bradypnoeic, lethargic, pale and cold. Bradycardia, bradypnea and impaired consciousness were interpreted in the context of the measured body temperature. Therefore, no reanimation or intubation was initiated. The newborn was closely monitored and successfully treated only with active and passive rewarming. CONCLUSION: Clinical parameters such as heart frequency, blood pressure, respiration and consciousness must be interpreted in light of the measured body temperature. Medical treatment should be adapted to the clinical presentation. External rewarming can be a safe and effective measure in neonatal patients.

Symptom Dimension of Interest-Activity Indicates Need for Aripiprazole Augmentation of Escitalopram in Major Depressive Disorder: A CAN-BIND-1 Report.

OBJECTIVE: Differential predictors of response to alternative treatment options are needed to improve the outcomes in major depressive disorder. The symptom dimension comprising loss of interest and reduced activity has been reported as a predictor of poor outcome of treatment with antidepressants. We hypothesized that augmentation with partial dopamine agonist aripiprazole will be effective for individuals with pronounced interest-activity symptoms. METHODS: We tested the hypothesis in the 2-phase Canadian Biomarker Integration Network in Depression trial 1 (CAN-BIND-1). All participants had a primary diagnosis of major depressive disorder confirmed with the Mini-International Neuropsychiatric Interview. In phase 1, 188 individuals received escitalopram monotherapy 10-20 mg daily for 8 weeks. In phase 2, nonresponders received augmentation with aripiprazole 2-10 mg daily while responders continued escitalopram monotherapy for another 8 weeks. Outcomes were measured with the Montgomery-Åsberg Depression Rating Scale (MADRS) every 2 weeks. Effects of baseline interest-activity symptoms on outcomes were tested in repeated-measures mixed-effects models. RESULTS: Higher baseline interest-activity score (indicative of more severe loss of interest and reduction in activity) predicted worse outcome of escitalopram monotherapy in phase 1 (b = 1.75; 95% CI, 0.45 to 3.05; P = .009), but the association disappeared with the augmentation option in phase 2 (b = -0.19; 95% CI, -1.30 to 0.92; P = .739). A significant interaction between the baseline interest-activity score and aripiprazole reflected the opposite direction of the relationship between baseline interest-activity score and degree of improvement with escitalopram monotherapy versus aripiprazole augmentation (b = -1.60; 95% CI, -2.35 to -0.84; P < .001). CONCLUSIONS: Individuals with prominent loss of interest and reduction in activity benefit less from escitalopram monotherapy and more from aripiprazole augmentation. Future trials may test the benefits of early prodopaminergic augmentation guided by interest-activity symptoms. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01655706.

Criteria for designation of clinical substage in canine lymphoma: a survey of veterinary oncologists.

Clinical substage is frequently reported to be prognostic in dogs with lymphoma, yet formal criteria for defining this parameter are lacking. The World Health Organization TNM Classification of Tumors of Domestic Animals simply defines substage as the absence or presence of systemic signs (substages a and b, respectively). We designed a survey to query veterinary oncologists on the criteria they use to determine clinical substage in practice. Gastrointestinal, constitutional and respiratory signs were the most commonly identified clinical factors, with greater than 90% respondents indicating that inappetence, vomiting, diarrhoea, changes in attitude, weakness and dyspnea were integral in assigning clinical substage. Nevertheless, more than three-quarters of respondents also considered metabolic, neurologic and nutritional parameters when making this determination. For most factors, respondents reported mild-to-moderate severity of clinical signs was sufficient for substage b designation.

A young boy with recurrent headache, lethargy, and hyponatremia.

BACKGROUND: To investigate and differentiate the causes of hyponatremia in an 8-y old boy. METHODS: An 8-y boy presented with headache, vomiting, and diplopia. Magnetic resonance imaging of the brain confirmed a mass in the pineal region. Pathology report demonstrated a mixed germ cell tumor with a yolk sac component. A multi-agent chemotherapy and radiation regimen was initiated. He developed hyponatremia, with sodium concentrations varying from 116 to 133 mEq/l. RESULTS: Serum levels of sodium, chloride, phosphorous, uric acid, and osmolality were low. Serum α-fetoprotein, ß-HCG, and lactate dehydrogenase were highly elevated. Urine sodium and osmolality were increased. CONCLUSIONS: These presentations suggest that the patient has cerebral salt-wasting syndrome caused by intracranial germ cell tumor. Recognition and differentiation of cerebral salt-wasting syndrome from other disorders are essential.

A Man in His 40s With Headache, Lethargy, and Altered Mental Status.

A man in his 40s presented with 1 month of worsening confusion, fatigue, and headache. Results from laboratory analyses were notable for a complete white blood cell count of 17 000/µL (31% blast cells), a platelet count of 76 000/µL, and a hemoglobin level of 16.6 g/dL. Imaging studies revealed a large mixed-attenuation subdural collection in the right frontal region with prominent mass effect. The patient underwent an emergency neurosurgical procedure. The differential diagnosis, pathologic findings, and diagnosis are discussed.

Early lethality and neuronal proteinopathy in mice expressing cytoplasm-targeted FUS that lacks the RNA recognition motif.

Mutations to the RNA binding protein, fused in sarcoma (FUS) occur in ∼5% of familial ALS and FUS-positive cytoplasmic inclusions are commonly observed in these patients. Altered RNA metabolism is increasingly implicated in ALS, yet it is not understood how the specificity with which FUS interacts with RNA in the cytoplasm can affect its aggregation in vivo. To further understand this, we expressed, in mice, a form of FUS (FUS ΔRRMcyt) that lacked the RNA recognition motif (RRM), thought to impart specificity to FUS-RNA interactions, and carried an ALS-associated point mutation, R522G, retaining the protein in the cytoplasm. Here we report the phenotype and results of histological assessment of the brain of transgenic mice expressing this isoform of FUS. Results demonstrated that neuronal expression of FUS ΔRRMcyt caused early lethality often preceded by severe tremor. Large FUS-positive cytoplasmic inclusions were found in many brain neurons; however, neither neuronal loss nor neuroinflammatory response was observed. In conclusion, the extensive FUS proteinopathy and severe phenotype of these mice suggests that affecting the interactions of FUS with RNA in vivo may augment its aggregation in the neuronal cytoplasm and the severity of disease processes.

A case of childhood stiff-person syndrome with striatal lesions: a possible entity distinct from the classical adult form.

Parainfectious or autoimmune striatal lesions have been repeatedly described in children. We report a 7-year-old girl with painful muscle spasms, leading to the diagnosis of childhood stiff-person syndrome (SPS). Striatal lesions were demonstrated by diffusion-weighted magnetic resonance imaging (MRI) and single-photon emission computed tomography but not by conventional MRI. Autoantibodies against glutamic acid decarboxylase (GAD) were absent. Steroid pulse therapy and high-dose intravenous immunoglobulin resolved all the symptoms with slight sequelae. Childhood SPS may be characterized by absent anti-GAD antibodies and a transient benign clinical course, and it may have a pathomechanism distinct from that in adult SPS.

Identification of cancer-related symptom clusters: an empirical comparison of exploratory factor analysis methods.

CONTEXT: Symptom clusters, important for symptom management strategies, have been determined empirically by various analytical methods. Guidance to select methods from the options available in standard statistical packages is limited. OBJECTIVES: To compare alternative common factor analysis (FA) extraction methods appropriate to the data, to assess whether or not they determine similar symptom clusters, and to propose analytical approaches that are useful in this clinical context. METHODS: Within one month of commencing chemotherapy, outpatients from oncology and hematology clinics (n = 202) reported their symptom experience on a modified Rotterdam Symptom Checklist. Symptom distress levels in the past week were rated on a scale of one (not at all) to four (very much). In a secondary data analysis of 42 symptoms, the associations between symptoms and factors were determined using alternative common FA methods: principal axis factoring, unweighted least squares, image factor analysis, and alpha factor analysis (AFA). Symptom inclusion in a cluster was based on the interpretation of pattern and structure coefficients, and importantly, clinical relevance of the grouping. RESULTS: Five symptom clusters were commonly identified across methods: musculoskeletal discomforts/lethargy, oral discomforts, upper gastrointestinal discomforts, vasomotor symptoms, and gastrointestinal toxicities. In AFA, three additional clusters were lethargy, somatic symptoms, and treatment-related symptom clusters. CONCLUSION: The most parsimonious solution resulted from principal axis factoring, but for large numbers of symptoms, AFA may be superior by identifying symptom clusters more useful for symptom management. Interpreting complex symptom relationships may lead to the investigation of pathophysiological mechanisms and intervention opportunities. Future studies should include psychological and cognitive symptoms.

Substantia nigra depigmentation and exposure to encephalitis lethargica.

OBJECTIVE: Parkinsonism has occasionally been reported as a consequence of infectious diseases. The present study examines the clinical and pathological correlates of parkinsonism across birth cohorts in relation to critical exposure to the encephalitis lethargica epidemic in the early 1900s. METHODS: The study population consisted of 678 participants in the Nun Study, of whom 432 died and came to autopsy. Qualitative indices of substantia nigra (SN) depigmentation were verified in a subset of 40 randomly selected subjects using quantitative stereological techniques. SN depigmentation, detected neuropathologically, was correlated with clinical parameters of Parkinson disease, age, and birth cohort. RESULTS: SN depigmentation was detected in 57 (13.2%) of the cohort. Although qualitative SN depigmentation correlated modestly with age (p = 0.02), it correlated best with birth cohort (p = 0.009) for women born in the years 1895-1899. Quantitative measures of SN depigmentation were increased in this birth cohort compared to age matched subjects from flanking birth cohorts 1890-1894 and 1900-1904 (p < 0.001). SN depigmentation correlated with speed of 6- and 50-foot walk (p < 0.0001), up and go test (p < 0.0001), and hand coordination (p < 0.0001). INTERPRETATION: Subjects in the birth cohort 1895-1899 would have been in their late teens and 20s at the onset and during the peak of the encephalitis lethargica epidemic. These were precisely the age ranges of persons who were most often affected by the illness. These data suggest the possibility that the coexistence of parkinsonism and SN depigmentation in this birth cohort may have resulted from the yet undetermined infectious agent responsible for encephalitis lethargica.