Toward a Unified Classification System for Brain-Mind Disorders: Putting Calls for Integrated Clinical Neuroscience Into Action.

Dividing the brain-mind into the specialized fields of neurology and psychiatry has produced many granular advantages, but these silos have imposed barriers to comprehensively understanding and contextualizing the fundamentals governing mental life and its maladies. Scientific inquiry into these fundamentals cannot reach its full potential without interdigitating the boundaries of two specialties of the same organ for both scholarship and clinical practice. We propose that to truly integrate disorders of the brain and the mind for research and clinical care, we must carefully reexamine the classification of its disorders (nosology) as an instrument to develop a coherent pathological and psychological framework. We call on professional organizations from neurology, psychiatry, behavioral neurology, neuropsychiatry, neuropsychology, and other relevant subspecialties (eg, geriatric psychiatry) to convene a multidisciplinary task force to define the current classification principles of their subspecialties and work toward developing an integrated nosology. The effect of a shared classification system, which we acknowledge is a difficult proposition philosophically and politically, would have transformative potential across educational, clinical, scientific, programmatic, and sociocultural realms. If accomplished, this initiative would provide a definitive step toward reducing stigma (and promoting reimbursement parity) for the full spectrum of complex brain disorders (regardless of traditional neurologic vs psychiatric conceptualizations).

Temporal changes in left ventricular strain with the development of rejection in paediatric heart transplant recipients.

INTRODUCTION: Myocardial strain measurements are increasingly used to detect complications following heart transplantation. However, the temporal association of these changes with allograft rejection is not well defined. The aim of this study was to describe the evolution of strain measurements prior to the diagnosis of rejection in paediatric heart transplant recipients. METHODS: All paediatric heart transplant recipients (2004-2015) with at least one episode of acute rejection were identified. Longitudinal and circumferential strain measurements were assessed at the time of rejection and retrospectively on all echocardiograms until the most recent negative biopsy. Smoothing technique (LOESS) was used to visualise the changes of each variable over time and estimate the time preceding rejection at which alterations are first detectable. RESULTS: A total of 58 rejection episodes were included from 37 unique patients. In the presence of rejection, there were decrements from baseline in global longitudinal strain (-18.2 versus -14.1), global circumferential strain (-24.1 versus -19.6), longitudinal strain rate (-1 versus -0.8), circumferential strain rate (-1.3 versus -1.1), peak longitudinal early diastolic strain rate (1.3 versus 1), and peak circumferential early diastolic strain rate (1.5 versus 1.3) (p<0.01 for all). The earliest detectable changes occurred 45 days prior to rejection with simultaneous alterations in myocardial strain and ejection fraction. CONCLUSIONS: Changes in graft function can be detected non-invasively prior to the diagnosis of rejection. However, changes in strain occur concurrently with a decline in ejection fraction. Strain measurements aid in the non-invasive detection of rejection, but may not facilitate earlier diagnosis compared to more traditional measures of ventricular function.

Changes in left ventricular strain parameters following pediatric heart transplantation.

STE is increasingly utilized to assess strain in a variety of pathologies. Strain measurements have demonstrated utility following HTx and may aid in the detection of rejection and CAV. Strain parameters have not been well defined in the pediatric HTx population. This study aimed to describe strain in pediatric HTx recipients compared to controls and assess changes over time. All pediatric HTx recipients with available echocardiograms (2004-2015) without rejection or CAV were identified. Longitudinal and circumferential strain was measured at <1 month, 1 year, 3 years, and 5 years post-transplant and compared to controls. A total of 218 echocardiograms were analyzed in 79 HTx recipients. At <1 month post-transplant, there was a significant decrement in longitudinal strain (GLS -14.6 vs -19.2, P < .001) with concurrent augmentation of circumferential strain (GCS -27.3 vs -24.3, P = .005). By 1 year post-HTx, all strain parameters normalized and were not significantly different from the control population. In the absence of graft complications, strain parameters did not change up to 5 years post-transplant. Abnormal longitudinal strain parameters are present in the early post-HTx period with a compensatory increase in circumferential strain. These changes normalize by 1 year post-transplant and do not change over time in the absence of graft complications.

Transcript expression levels of full-length alpha-synuclein and its three alternatively spliced variants in Parkinson's disease brain regions and in a transgenic mouse model of alpha-synuclein overexpression.

Alternative splicing is a complex post-transcriptional process that can be regulated by cis-acting elements located within genomic non-coding regions. Recent studies have identified that polymorphic variations in non-coding regions of the α-synuclein gene (SNCA) locus are associated with an increased risk for developing Parkinson's disease (PD). The underlying mechanism(s) for this susceptibility may involve changes in α-synuclein mRNA expression and alternative splicing. As a first step towards understanding the biology of α-synuclein splice variants in PD, we characterized the levels of the full-length SNCA-140 mRNA transcript and SNCA-126, -112, and -98 alternatively spliced variants in different neuronal regions from PD patients or transgenic mice overexpressing human α-synuclein (ASO). In human post-mortem tissue, α-synuclein spliced transcripts were expressed in a region-specific manner in the cortex, substantia nigra, and cerebellum. We observed increased nigral SNCA-140 and SNCA-126 transcript levels in PD patients when compared to neurologically unaffected cases. Human α-synuclein splicing changes were also found to occur in a region-specific manner in ASO mice. Here, SNCA-126, -112, and -98 transcript levels did not increase proportionally with SNCA-140 levels, or parallel the region-specific mouse transcript ratios seen in wild-type (WT) littermates. While most transcripts were elevated in ASO mice when compared to WT mice, the most prominent increase was found in the ventral midbrain of 15-month-old ASO mice. These results demonstrate region-specific human α-synuclein transcript level abnormalities in PD patients and in a transgenic mouse model of α-synucleinopathy. This study is relevant to understanding the normal, adaptive, or pathological role(s) of α-synuclein splice variants.

The Neurologic Exam.

For most of human history, diseases preying upon the nervous system could only be identified indirectly through neurological signs-making the neurology clinician's examination the principal diagnostic tool. While advanced imaging and electrophysiology of today's practice provides greater diagnostic precision, the wide array of tools available and their applications emphasizes the accuracy that the neurological examination provides to localization, which in turn enables our technology's precision to effectively and efficiently aid one's diagnosis.

A limited immunocytochemical panel for the distinction of subepithelial gastrointestinal mesenchymal neoplasms sampled by endoscopic ultrasound-guided fine-needle aspiration.

We studied the use of immunocytochemical analysis with material procured by endoscopic ultrasound-guided fine-needle aspiration (EUS-guided FNA) for the diagnosis of subepithelial intramural gastrointestinal (GI) mesenchymal neoplasms (SIGIMNs). We identified all EUS-guided FNA specimens of SIGIMNs that had undergone immunocytochemical analysis. Results were compared with follow-up histologic diagnoses. There were 95 aspirates that were diagnosed as GI mesenchymal tumors (GI stromal tumors [GISTs], n = 46), leiomyomas (n = 38), peripheral nerve sheath tumors (n = 5), and other neoplasms by cytologic examination. Immunoreactivity with antibodies to CD117 always predicted GIST at follow-up; 15 of 16 cases immunoreactive with antibodies to CD34 were found to be GISTs at follow-up. Strong immunoreactivity with antibodies to smooth muscle actin or desmin usually predicted a leiomyoma at follow-up aside from a single glomus tumor and a case with apparent nonneoplastic smooth muscle contaminant. When sufficient material is present, immunocytochemical analysis used with material obtained by EUS-guided FNA is highly predictive of final pathologic diagnosis.

After a punch: recurrence of compartment syndrome following minor trauma.

Acute compartment syndrome (ACS) is a diagnosis that requires high-clinical suspicion especially in cases when the initial causal event could be considered insignificant. We present a novel case presentation of ACS associated with minor trauma in a patient with a previous history of compartment syndrome in the same extremity from a motor vehicle accident 10 years prior to presentation. To the best of our knowledge, this is the first reported case of recurrent ACS. Due to the possibility of significant morbidity, including loss of limb, it is imperative to recognize the presentation quickly so proper surgical intervention can occur. This case shows compartment syndrome can occur after a low impact mechanism of injury and previous compartment syndrome may be a risk factor, lowering the threshold for a re-occurrence. Serial exams and compartment pressure measurements should be used to aid recognition in ambiguous clinical presentations.

Single Institutional Experience of Stereotactic Radiosurgery Alone for First Brain Metastatic Event and Salvage of Second Brain Metastatic Event in a Community Setting with Review of the Literature.

PURPOSE: To document survival for patients treated with stereotactic radiosurgery (SRS) alone for brain metastases either at initial presentation or for salvage in conjunction with other known prognostic factors in a single institutional community setting with comparison to current literature. METHODS: All patients treated for brain metastases with SRS between October 2006 and October 2013 were reviewed. We identified 91 patients treated with SRS alone for first brain metastatic event (FBME) and 87 patients treated with SRS for second brain metastatic event (SBME). We excluded the 14 patients treated with SRS for both FBME and SBME to satisfy the independence assumption for comparison of groups. Patient demographics, including age, gender, primary cancer type, presence of extracranial metastases, number of brain metastases, initial site of metastases (brain vs. other), recursive partitioning analysis (RPA), and Karnofsky Performance status (KPS) were documented. RESULTS: There were no significant differences in overall survival for patients treated with SRS for FBME compared with SBME (log-rank p = 0.9347). Univariate and multivariable Cox regression modeling revealed KPS (p = 0.0003) and RPA (p = 0.0143) were the only independent prognostic factors for survival. Specifically, patients with RPA 1 had a 61% decreased risk of death compared to those with RPA 3. Patients with RPA 2 had a 33% decreased risk of death compared to those with RPA 3. The 1-year survival rate was 36.5% for patients with RPA1, 33.3% for those with RPA 2, and 17.1% for those with RPA 3. Patients with KPS 90-100 had a 62% decreased risk of death compared to those with KPS < 70. The 1-year survival rate for patients KPS 90-100, 70-80, and <70 were 60.7, 24.6, and 16.7%, respectively. CONCLUSION: No difference in survival was noted for FBME and SBME with performance status, the single most important prognostic factor following SRS. Aggressive treatment should be considered for patients with good performance status regardless if presenting with FBME or SBME. Our results are consistent with single, multi-institutional, and randomized trials after literature review.

Interobserver variability with the interpretation of thyroid FNA specimens showing predominantly Hürthle cells.

Fine-needle aspiration (FNA) is used for the diagnosis and triaging of thyroid lesions. Recently, it has been shown that the pathologic interpretation of selected thyroid specimens can show a high degree of interobserver variability (IV). Because Hürthle cells may be seen in neoplastic and nonneoplastic disease, we investigated whether pathologists consistently interpret FNA specimens from these lesions. In the present study, 22 FNA specimens that showed Hürthle cells as the predominant cell type were reviewed by 7 pathologists. Cytologic features were assessed semiquantitatively. IV was calculated, and individual case diagnoses were compared with cytologic features. IV was high before diagnoses were collapsed into like diagnoses and triage recommendations (k = 0.17, 0.44, and 0.51, respectively). Overall cellularity, number of Hürthle cells, and number of lymphocytes all correlated with collapsed diagnostic agreement, and the number of air-dried rapid Romanowsky-stained slides, overall cellularity, number of Hürthle cells, and number of lymphocytes all correlated with collapsed triage recommendations.

Rapid assessment of fine needle aspiration and the final diagnosis--how often and why the diagnoses are changed.

BACKGROUND: On-site rapid interpretation (RI) of fine needle aspiration (FNA) has been shown to increase the diagnostic yield of FNA and decrease the need for repeat diagnostic procedures. Because the pathologist interprets only a fraction of the sample and has limited resources available at such times, an occasional RI diagnosis will be changed at the time of the final diagnosis. We investigated how often these changes in diagnoses occur and the possible reasons for the changes. METHODS: All cytology reports from 1/1/02 to 12/31/03 from a single institution were reviewed. Cases with RI with discrepant final diagnoses were noted. The discrepant diagnoses were categorized depending on how they were changed. Possible sources for changed diagnoses were noted. RESULTS: Between 1/1/02 and 12/31/03 there were 1368 RIs of FNAs. Of these 80 (5.8%) had discrepancies between the RIs and final diagnoses. Seventy-eight cases had additional slides and/or cell block at time of final diagnosis. 16 cases had ancillary studies available at final diagnosis. Consultant pathologists were used in 7 cases. Different pathologists interpreted the RI and final diagnosis in 31 cases. CONCLUSION: Although uncommon, discrepancies between RIs and final diagnoses occur 5.8% of the time at our institution. Most commonly, this involves a change of diagnosis from either "non-diagnostic" or "benign" to "malignancy". Although much of this is likely due to the presence of additional material and information at the time of final diagnosis, the number of cases that had different pathologists involved in the RI and final diagnosis suggests that inter-observer variability may also play some role.

Review of endoscopic ultrasound-guided fine-needle aspiration cytology.

This review, based on the Hennepin County Medical Center experience and review of the literature, vastly covers the up-to-date role of endoscopic ultrasonography (EUS) and EUS-guided fine-needle aspiration (FNA) in evaluating tumorous lesions of the gastrointestinal tract and adjacent organs. Emphasis is given to the tumoral and nodal staging of esophageal, pulmonary, and pancreatic cancer. This review also discusses technical, pathological, and gastroenterologic aspects and the role of the pathologist and endosonographer in the evaluation of these lesions, as well as the corresponding FNA cytology and differential diagnosis.

Cytology of pancreatic acinar cell carcinoma.

Acinar cell carcinoma (ACC) of the pancreas is extremely uncommon and its cytologic features have rarely been described. We describe the cytologic features of cases we have seen, review the literature regarding its cytologic features and discuss the pitfalls that may be encountered and the use of immunohistochemistry for its diagnosis. We searched our databases for all cases of histologically confirmed pancreatic ACC which had undergone prior fine needle aspiration (FNA) of the primary pancreatic lesion. The clinical histories, radiographic and sonographic findings, cytologic features, original cytologic diagnoses, and final histologic diagnoses were reviewed. Four cases of pancreatic ACC were found that had undergone FNA prior to histologic confirmation of the diagnoses. They were from 2 men and 2 women aged 50-75 yr. All masses were in the head of the pancreas, 2 had apparent peri-pancreatic adenopathy and 1 had an apparent liver metastasis. On review, all 4 had had diagnostic material on cytology samples. Original cytologic diagnoses included "acinar cell carcinoma," "pancreatic endocrine tumor," "favor neuroendocrine tumor, low-grade" and "non-diagnostic specimen." The cytologic features included small to moderate-sized loose groups with numerous single cells, prominent acinar formation, little anisonucleosis and prominent nucleoli. The cytologic features showed significant overlap with those of pancreatic endocrine tumors.

Evaluation of Echocardiographic Measures of Left Ventricular Function in Patients with Duchenne Muscular Dystrophy: Assessment of Reproducibility and Comparison to Cardiac Magnetic Resonance Imaging.

BACKGROUND: Patients with Duchenne muscular dystrophy (DMD) require frequent imaging to assess left ventricular (LV) function. Poor imaging windows can limit the diagnostic utility of echocardiography. Cardiac magnetic resonance imaging (CMR) is the gold standard for the assessment of LV function but has not been universally adopted in patients with DMD. The study objectives were (1) to evaluate the reproducibility of echocardiographic measures of LV function, (2) to evaluate which echocardiographic methods correlate best with CMR LV ejection fraction (LVEF), and (3) to evaluate whether CMR provides additional value compared with echocardiography. METHODS: Twenty-eight participants with DMD prospectively underwent echocardiography and CMR. Two blinded readers measured fractional shortening from M-mode and two-dimensional images and LVEF using four-chamber, biplane Simpson, 5/6 area-length, and three-dimensional methods. Speckle-tracking echocardiography was used to analyze circumferential strain. Readers subjectively rated function and segmental wall motion. Agreement was assessed using intraclass correlation coefficients, Bland-Altman plots, Spearman correlation, and weighted κ. RESULTS: Two-dimensional fractional shortening and 5/6 area-length LVEF had the best combination of reproducibility and correlation with CMR LVEF, though both misclassified approximately 20% as either normal or abnormal function. Other measures of LV function were less reproducible, with worse correlations with CMR LVEF. Thirty-seven percent of segments not visible on echocardiography were believed to have wall motion abnormalities by CMR. CONCLUSIONS: Two-dimensional fractional shortening and 5/6 area-length LVEF represent the most accurate and reproducible echocardiographic measures of LV function in patients with DMD. CMR should be considered when neither of these techniques is measurable or when it is necessary to detect more subtle cardiovascular changes.

Interobserver variability in thyroid fine-needle aspiration interpretation of lesions showing predominantly colloid and follicular groups.

We studied interobserver variability (IV) in the assessment of thyroid fine-needle aspiration (FNA). We limited our cases to those showing predominantly colloid and follicular cell groups. Twenty cases of thyroid FNA diagnosed by 1 experienced cytopathologist were reviewed by 4 other cytopathologists who made their own diagnoses while unaware of the original diagnoses. Two cytopathologists then assessed the cytologic features of the 20 cases. IV was calculated for noncollapsed and collapsed diagnoses. Diagnoses and observer agreement were compared with cytologic features. There was little correlation among observers regarding the diagnosis of follicular "lesion" vs "neoplasm." IV was somewhat poor before data were collapsed to treatment recommendations (kappa = 0.35) but was relatively good when data were collapsed (kappa = 0.65). Cellularity, cyst change, and amount of colloid correlated with treatment recommendations; no specific features correlated with poor performance. Thyroid FNA shows good interobserver agreement in the diagnoses of lesions showing predominantly colloid or follicular cells (when collapsed). We speculate that IV is poor in some cases owing to difficulty assessing thin colloid, some lack of agreement regarding criteria for adequacy, and a possible "gray zone" that might exist with lesions showing colloid and abundant follicular cells.

Esophageal carcinoma with a rhabdoid phenotype: a case report of diagnosis by endoscopic ultrasound-guided fine-needle aspiration.

Malignant extra renal tumors with rhabdoid phenotype are aggressive neoplasms associated with a poor prognosis. These tumors have been reported in soft tissue and various organs including the gastrointestinal tract. We report one of such tumors arising in the esophagus and discuss the cytopathologic, immunohistochemical, and ultrastructural features. Endoscopic ultrasound-guided fine-needle aspiration (FNA) cytology revealed a highly cellular tumor, consisting of polygonal poorly cohesive cells with prominent eosinophilic paranuclear cytoplasmic inclusions. Immunohistochemical staining showed strong cytoplasmic positivity for vimentin and cytokeratin. Electron microscopy revealed presence of numerous intermediate filaments. To the best of our knowledge, this is the first example of carcinoma with rhabdoid phenotype of the esophagus diagnosed by FNA cytology.

Sampling of the adrenal glands by endoscopic ultrasound-guided fine-needle aspiration.

Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) has proven to be a valuable modality for the primary diagnosis and staging of gastrointestinal, and perigastrointestinal malignancy. Aside from assessing thoracic and abdominal lymph nodes and the liver for metastases, EUS can assess and sample the adrenal glands, which are frequently involved by metastatic disease, but can also harbor benign primary neoplasms. The cytology files at our institution were reviewed for all cases of EUS-guided FNA of the adrenal glands. Clinical histories, sonographic findings, and cytologic findings of all cases were reviewed. Results were compared with overall EUS-guided FNA performance and the performance of non-EUS-guided FNA of the adrenal. The utility of cell block immunohistochemistry (IHC) in these cases was reviewed. Between 1/1/00 and 5/15/04 there were 24 cases of EUS-guided FNA of the adrenal gland from 22 different patients (13 men; 9 women) at our institution. This represented 1.4% of overall EUS-guided FNA and 77% of adrenal gland FNA. Patient ages ranged from 37 to 86 yr (mean 69 +/- 11 yr). Most patients had other cancers or mass lesions and were being staged at the time of the procedure (19 of 22). Almost all FNAs were of the left adrenal gland (23 of 24). Lesion size ranged from 0.9 to 7.9 cm (mean 2.5 +/- 1.6 cm). Diagnostic material was present in all cases when compared with an overall EUS-guided FNA diagnostic rate of 88%. Material for cell block was present in 21 cases, and IHC was used in 3 cases. Final diagnoses were as follows: cortical tissue consistent with cortical adenoma (19), metastatic adenocarcinoma (3), pheochromocytoma (1), and adrenal cortical carcinoma (1). EUS-guided FNA of the adrenal gland is primarily used in the staging of other malignancies when lesions of the left adrenal are recognized sonographically. Diagnostic tissue is easily obtained, including material for cell block IHC, which allows definitive diagnosis in cases that present difficult differential diagnoses.