Complex Disease Course Research Articles

Predicting Survival in Mucinous Adenocarcinoma of the Appendix: Demographics, Disease Presentation, and Treatment Methodology

BackgroundMucinous adenocarcinoma of the appendix (MACA) follows a complex disease course with variable survival. Large-scale predictive modeling may determine subtle yet important prognostic factors otherwise unseen in smaller cohort analyses.MethodsPatients with MACA were identified from the Surveillance, Epidemiology, and End Results (SEER) Research Plus database (2005–2019). Primary, secondary, and tertiary outcomes were disease-specific survival (DSS), overall survival (OS), and average annual percent change (AAPC) in incidence.ResultsAmong 4,258 included patients, MACA was most frequently diagnosed at 50 to 69 years (52.0%), with female preponderance (55.9%). MACA incidence AAPC was 3.8 (95% confidence interval [CI] 1.9–5.9). For patients with exclusive, first-diagnosis MACA included in survival analysis (3,222 patients), median DSS and OS were 118 and 88 months, respectively. In DSS-based multivariable analysis, worse prognosis was associated with non-Hispanic Black background (HR 1.36, 95% CI 1.02–1.82; p = 0.036), high grade (grade 3 HR 3.10, 95% CI 2.44–3.92; p < 0.001), lymphatic spread (HR 2.73, 95% CI 2.26–3.30; p < 0.001), and distant metastasis (HR 5.84, 95% CI 3.86–8.83; p < 0.001). In subcohort analysis of patients with rationale for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC, 2,387 patients), CRS-HIPEC was associated with survival benefit compared with surgery alone but only for moderate-grade tumors (median DSS/OS 138/138 vs. 116/87 months; p < 0.001).ConclusionsMucinous adenocarcinoma of the appendix incidence is increasing in the United States. Survival rates are affected by both demographics and classical risk factors, and CRS-HIPEC-associated survival benefit predominantly occurs in moderate-grade tumors. Further exploration of biologic and clinicopathologic features may enhance risk stratification for this disease.

Predictors of Developing a Complex Course of Osteomyelitis in Patients with Sickle Cell Anaemia.

Despite the numerous advances in management strategies, treating osteomyelitis in individuals with sickle cell disease (SCD) remains a significant challenge, leading to severe long-term consequences. This study aimed to assess the key factors potentially linked to a complex progression of osteomyelitis in patients diagnosed with SCD. A cohort of 34 patients was identified and their progress was monitored over a span of 12 months during a 10-year period (2010-2020). The variables under investigation encompassed demographic and clinical traits, laboratory analyses and imaging data, as well as the treatment strategies employed. The risk prediction model pinpointed 5 factors (severity of SCD, involvement of lower limbs, presence of bacteraemia, magnetic resonance image [MRI] findings and utilisation of surgical debridement) that exhibited an area under the curve (AUC) exceeding 0.7. Causative organisms were identified in 9 out of the total 34 patients (26.47%). A total of 17 patients displayed a severe course of SCD (AUC = 7.88), with MRI being highlighted as a valuable contributing factor (AUC = 7.88). Furthermore, 13 patients (38.2%) underwent surgical debridement, a procedure that yielded a statistically significant P value of 0.012 and an AUC of 0.714. Osteomyelitis within the context of severe SCD, particularly when accompanied by lower extremity infection, bacteraemia, positive MRI findings and the need for surgical debridement, emerges as a cluster of risk factors predisposing individuals to osteomyelitis relapse and a more complex disease course.

Hypertrophic Cardiomyopathy Diagnosis and Treatment in High- and Low-Income Countries: A Narrative Review.

Hypertrophic cardiomyopathy (HCM) is a hereditary cardiac condition characterized by unexplained left ventricular hypertrophy without a hemodynamic cause. This condition is prevalent in the United States, resulting in various clinical manifestations, including diastolic dysfunction, left ventricular outflow obstruction, cardiac ischemia, and atrial fibrillation. HCM is associated with several genetic mutations, with sarcomeric mutations being the most common and contributing to a more complex disease course. Early diagnosis of HCM is essential for effective management, as late diagnosis often requires invasive treatments and creates a substantial financial burden.Disparities in HCM diagnosis and treatment exist between high-income and low-income countries. High-income countries have more resources to investigate and implement advanced diagnostic and treatment modalities. In contrast, low-income countries face challenges in accessing diagnostic equipment, trained personnel, and affordable medications, leading to a lower quality of life and life expectancy for affected individuals. Diagnostic tools for HCM include imaging studies such as 2D echocardiography, cardiovascular magnetic resonance (CMR), and electrocardiograms (ECGs). CMR is considered the gold standard but remains inaccessible to a significant portion of the world's population, especially in low-income countries. Genetics plays a crucial role in HCM, with numerous mutations identified in various genes. Genetic counseling is essential but often limited in low-income countries due to resource constraints. Disparities in healthcare access and adherence to treatment recommendations exist between high-income and low-income countries, leading to differences in patient outcomes. Addressing these disparities is essential to improve the overall management of HCM on a global scale. In conclusion, this review highlights the complex nature of HCM, emphasizing the importance of early diagnosis, genetic counseling, and access to appropriate diagnostic and therapeutic interventions. Addressing healthcare disparities is crucial to ensure that all individuals with HCM receive timely and effective care, regardless of their geographic location or socioeconomic status.

Growing beyond sickle cell disease: A metasynthesis of children, adolescents, and young adult experiences living with sickle cell disease.

Children, adolescents, and young adults living with sickle cell disease (SCD) often experience an unpredictable and complex disease course. Although there is a growing literature on the lived experience of patients with SCD, qualitative syntheses are lacking. Therefore, a qualitative metasynthesis was conducted to inform care and potential interventions. Noblit and Hare's phases of metaethnographic research were used to guide the synthesis of qualitative data. Data extracted from the identified studies were directly compared through reciprocal translation. The 12 studies that met inclusion criteria for the meta-synthesis included 177 participants ranging in age from 6 to 35 years old from six different countries. The authors identified three key metaphors: Ubiquitous Intrusion, Coping to Learn: Learning to Cope, and Part of the Whole. The metaphors were elucidated by three essential concepts that underlie the experience of children, adolescents, and young adults living with SCD: (1) recognition of SCD implications, (2) identifying ways to balance responsibilities, and (3) positioning oneself to thrive with SCD. The metaphors and essential concepts support the global theme of "Growing Beyond SCD." The metasynthesis revealed the shared complexity of living with SCD among children, adolescents, and young adults from diverse cultures in which the yearning for a normal life drove learning to adapt and manage SCD with their support network. The key metaphors may be used to guide development of nursing interventions designed to promote self-acceptance, coping, and adaptation skills among children, adolescents, and young adults that will help them to flourish while managing SCD as a chronic condition.

Use of Temporary Double-J Stent Placement for Children With Congenital Hydronephrosis: A Long-Term Single-Center Cohort Study

ObjectiveTo evaluate the utilization of double-J stents in children with congenital hydronephrosis in order to avoid or postpone more invasive surgical intervention. Numerous studies have demonstrated that congenital hydronephrosis caused by ureteropelvic junction obstruction (UPJO) or primary obstructive megaureter (POM) may require a surgical correction in up to 20% of cases. MethodsAll infants with severe hydronephrosis and/or an obstructive pattern on renal scintigraphy that received double-J stent placement between 2010 to 2015 in our center were analyzed. Children were followed regularly with ultrasound and received antibiotic metaphylaxis. Urinary tract infection (UTI) and double-J dislocation were defined as complications. Treatment success was defined as avoidance of surgery and reduction of hydronephrosis to grade 1 or 0 during the observation period. Results29 children were included, in these, 34 (23 UPJO, 7 POM, 4 UPJO and POM) treatment attempts were performed. Stent implantation failed in six cases, resulting in 28 double-J stent treatments, of which 19 (69%) were successful within the follow-up period of 20 to 104 months. The most common complications were febrile UTI in 6 of29 cases and double-J dislocation in 3 of 29 cases. ConclusionDuring the observation period, the success rate of temporary double-J in urodynamically relevant obstruction was relatively high. However, urinary tract infections and a complex disease course due to renal stent dislocation, as well as the need for repeated anesthesia and radiation exposure, should be taken into account. Hence, we do not recommend double-J stents placement in all children with congenital hydronephrosis; it may be useful in selected cases.

34504 Mixed methods validation of a patient-centered educational atopic dermatitis mobile health application

Atopic dermatitis (AD) has a complex disease course and treatment landscape; bidirectional exchange of disease and patient information is challenging within short a dermatology encounter. Patients often turn to digital resources to seek guidance for self-management, yet many current eczema apps insufficiently support evidence-based guidelines and lack patient engagement in their development. EczemaQ was co-developed with patients as an evidence-based mobile health educational tool to address this gap. In order to validate EczemaQ’s use with AD patient and clinician end-users, ethics approval was granted by the McGill University Center for Applied Ethics for an iterative, explanatory sequential mixed methods (QUAN-QUAL) study. First, quantitative (QUAN) data will be collected through Technology Acceptance Model 2 and Patient Activation Measure questionnaires to obtain preliminary app usability information, and analyzed via descriptive statistics. This data will then inform qualitative (QUAL) data collection via semi-structured focus groups to gain a deeper understanding of end-user priorities, analyzed via thematic analysis. Two QUAN-QUAL arms will occur simultaneously: one arm for patients (eligible patients diagnosed with AD), and one arm for clinicians (AD experts including dermatologists, nurses, pharmacists, and general physicians). A Beta version of the EczemaQ app will be created based on the first iteration of the two arms of the QUAN-QUAL model; EczemaQ Beta will then undergo a second iteration of the process to obtain a finalized EczemaQ app. We offer an example of an integrated knowledge translation tool, featuring genuine patient and clinician partnership, towards bettering AD patient care.

Pulmonary vascular volume is associated with DLCO and fibrotic score in idiopathic pulmonary fibrosis: an observational study

BackgroundIdiopathic pulmonary fibrosis (IPF) is a disease that primarily occurs in elderly individuals. However, it is difficult to diagnose and has a complex disease course. High-resolution computed tomography (HRCT) and lung function testing are crucial for its diagnosis and follow-up. However, the correlation of HRCT findings with lung function test results has not been extensively investigated.MethodsThis study retrospectively analysed the medical records and images of patients with IPF. Patients with evident emphysema and lung cancer were excluded. The diagnosis of all the included cases was confirmed following a discussion among specialists from multiple disciplines. The correlation of HRCT findings, including fibrotic score, HRCT lung volume, pulmonary artery trunk (PA) diameter and pulmonary vascular volume (PVV), with lung function test parameters, such as forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), was analysed.ResultsA total of 32 patients were included. Higher fibrotic and PVV scores were significantly correlated with lower DLCO (r = − 0.59, p = 0.01; r = − 0.43, p = 0.03, respectively) but not with FVC. Higher PVV score significantly correlated with higher fibrotic score (r = 0.59, p < 0.01) and PA diameter (r = 0.47, p = 0.006).ConclusionOur study demonstrated the structural and functional correlation of IPF. The extent of lung fibrosis (fibrotic score) and PVV score were associated with DLCO but not with FVC. The PA diameter, which reflects the pulmonary artery pressure, was found to be associated with the PVV score.

Dementia and Depresion: A Glance of Neuropsychiatry

Dementia has a complex disease course and one of them can affect the psychology of the sufferer. People with dementia tend to experience stress and anxiety symptoms due to the limitations they experience. This article will provide a theoretical overview of the relationship between the two in general and theoretically so that it can be understood that the two are a unity in the neuropsychiatric aspect.

Decreased ATM Function Causes Delayed DNA Repair and Apoptosis in Common Variable Immunodeficiency Disorders

PurposeCommon variable immunodeficiency disorders (CVID) is characterized by low/absent serum immunoglobulins and susceptibility to bacterial infection. Patients can develop an infections-only phenotype or a complex disease course with inflammatory, autoimmune, and/or malignant complications. We hypothesized that deficient DNA repair mechanisms may be responsible for the antibody deficiency and susceptibility to inflammation and cancer in some patients.MethodsGermline variants were identified following targeted sequencing of n = 252 genes related to DNA repair in n = 38 patients. NanoString nCounter PlexSet assay measured gene expression in n = 20 CVID patients and n = 7 controls. DNA damage and apoptosis were assessed by flow cytometry in n = 34 CVID patients and n = 11 controls.ResultsTargeted sequencing supported enrichment of rare genetic variants in genes related to DNA repair pathways with novel and rare likely pathogenic variants identified and an altered gene expression signature that distinguished patients from controls and complex patients from those with an infections-only phenotype. Consistent with this, flow cytometric analyses of lymphocytes following DNA damage revealed a subset of CVID patients whose immune cells have downregulated ATM, impairing the recruitment of other repair factors, delaying repair and promoting apoptosis.ConclusionThese data suggest that germline genetics and altered gene expression predispose a subset of CVID patients to increased sensitivity to DNA damage and reduced DNA repair capacity.

Towards a definition of Ancient Rare Diseases (ARD): Presenting a complex case of probable Legg-Calvé-Perthes Disease from the North Caucasian Bronze Age (2200-1650 cal BCE)

ObjectiveThis study discusses the challenges and possibilities of establishing a definition for Ancient Rare Diseases (ARD) in a probable case of Legg-Calvé-Perthes Disease (LCPD) from the Bronze Age cemetery Kudachurt 14, situated in the Northern Caucasus. MaterialsWe investigated the skeletal remains of a male aged 35–45 years at death. For comparison we examined other males buried at Kudachurt 14 (n = 24) and reviewed 22 LCPD cases from the paleopathological literature. MethodsWe use macroscopic as well as osteometric examination methods and imaging techniques. ResultsThe morphology of the left hip joint corresponds to skeletal characteristics for LCPD. Co-occurring osteochondrosis dissecans, femoral anteversion, and atrophy of the left femoral shaft suggest a complex disease course. ConclusionsModern criteria of rare diseases applied on ancient skeletal remains are either non-transferable or require completion. We conclude that rarity is dynamic, etiological uncertainty has to be accepted, and the respective socioeconomic context is crucial. Degree of disability and level of sociomedical investment are not defining criteria for ARD. SignificanceDating 2200-1650 cal BCE, this study currently presents the earliest case of probable LCPD. This is the first attempt to transform modern characteristics of rare diseases for establishing a paleopathological concept of ARD. LimitationsAs this study is limited to LCPD, our conclusions are not directly applicable to other ARD in question. Suggestions for further researchMore focused paleopathological research on skeletal populations from different cultures and time periods is needed, enabling an evolutionary perspective on the comparability of ancient, modern and future rare diseases.

The outcome for surgical fixation of distal radial fractures in patients with idiopathic Parkinson\u2019s disease: a cohort study

IntroductionIdiopathic Parkinson’s disease (PD) is a progressive neurologic disorder causing postural instability and unsteady gait. These patients are at increased risk for fractures and have inferior outcomes after treatment. Several studies have evaluated the incidence and outcome of PD patients after hip fractures. However, there are limited studies assessing the outcome of upper extremity fractures in these patients. In this study, we evaluated the outcome of PD patients that received surgical intervention for distal radial fractures (DRF). We hypothesize that these patients have an inferior outcome after surgery in comparison with non-PD patients.MethodsBetween May 2005 and May 2017, we retrospectively reviewed all of the patients with DRF and subsequently underwent open reduction and internal fixation (ORIF) at a level 1 trauma center. All of the surgeries were performed by fellowship-trained orthopedic surgeons. The inclusion criteria include patients with a definitive diagnosis of PD, non-pathological DRF, and a minimum follow-up of 1 year or up until the time of treatment failure was noted. Each PD patient was matched for age and gender to 3 non-PD patients. The primary objective was to determine the failure rate after surgical fixation for DRF. The secondary outcomes include time to treatment failure, reoperation rate, readmission rate, length of hospital stay, and postoperative complications.ResultsA total of 88 patients were included in this study (23 PD, 65 non-PD patients). All underwent ORIF and received standard postoperative follow-ups. The overall treatment failure rate in PD was 39.1% vs. 4.6% in the non-PD group (p < 0.05). The time to treatment failure were 9.11 ± 3.86 weeks and 14.67 ± 5.8 weeks for PD and non-PD, respectively (p < 0.05). PD patients had a significantly higher rate of failure when k-wires and ESF were used (p < 0.05%), while loss of reduction was the most common mode of failure in PD (44.4%). The length of hospital stay for PD was 5.3 ± 4.69 days compared with 3.78 ± 0.96 days for non-PD (p = 0.01). There were 3 PD patients readmitted within 30 days after surgery, and 1 patient had pneumonia after the surgery.ConclusionThis study revealed that patients with PD have a high treatment failure rate despite surgical intervention for DRF. PD patients had a longer hospital stay and had a shorter time to treatment failure. In treating PD patients complicated with DRF, the surgeon must take into consideration the complex disease course of PD and the associated comorbidities such as osteoporosis, frail status, and frequent falls. Rehabilitation and disposition plans should be discussed in advance and longer hospital stays should be expected.Level of evidenceLevel IV, retrospective cohort study

Advance care planning for patients with chronic respiratory diseases: a systematic review of preferences and practices

BackgroundAdvance care planning (ACP) supports patients in identifying and documenting their preferences and timely discussing them with their relatives and healthcare professionals (HCPs). Since the British Thoracic Society encourages ACP...

AGR-1Acute Myeloid Leukemia: Rare Condition, Complex Disease Course, and Neuropsychological Investigation

AGR-1Acute Myeloid Leukemia: Rare Condition, Complex Disease Course, and Neuropsychological Investigation

Partial lipodystrophy in patients who have undergone hematopoietic stem cell transplantation during childhood: an institutional cross-sectional survey.

.Partial lipodystrophy (PD), a condition similar to metabolic syndrome without obesity, is one of the late complications of hematopoietic stem cell transplantation (HSCT) performed during childhood. We aimed to investigate the prevalence and risk factors of PD. A cross-sectional survey was performed in a children’s hospital, targeting patients treated for a malignancy or hematological disorder, and who were disease-free for > 24 mo. PD was defined as gluteal lipoatrophy and lipohypertrophy of the cheeks or neck associated with diabetes and/or fatty liver disease. In total, 65 patients were enrolled. Six patients (9.2%) were judged to have PD, all of whom had received 10–14 Gy total body irradiation. Compared with the patients without PD, patients with PD were older at investigation (P < 0.01), had a longer elapsed time following HSCT (P < 0.01), had more frequent disease recurrence (P < 0.05), and were more likely to have undergone multiple HSCT (P < 0.05). In addition, they had higher blood pressure and showed higher levels of low-density lipoprotein-cholesterol and triglycerides, whereas their adiponectin levels were significantly lower. In conclusion, a large number of patients developed PD following HSCT, with unfavorable metabolic profiles at a later age, especially when they experienced a complex disease course.

Complications of Pediatric Otitis Media.

Otitis media (OM) is a common diagnosis in the pediatric population that is usually managed on an outpatient basis. A small proportion of children are admitted due to a complex disease course. The aim of this study was to investigate the demographics of those patients and the resources utilized during their admissions. Retrospective review based on the 2009 Kids' Inpatient Database. Nationwide administrative database. A review based on the 2009 Kids' Inpatient Database was conducted. Inclusion criteria were clinical modification codes for OM (ICD-9 code 382). Data recorded included patient demographics, concurrent discharge diagnosis codes, length of stay, total charges, and frequency of procedures performed. There were 61,783 (92,548 nationally weighted) admissions with OM, which were analyzed. The average age (SD) for the patients was 2.18 (3.49) years, and the average length of stay was 2.88 days. The majority (80.75%) of patients did not have to undergo a procedure during admission, whereas a small proportion (5.4%) underwent a major operating room procedure. There were 21 deaths recorded (0.03%). A diagnosis of mastoiditis, meningitis, venous sinus thrombosis, or intracranial abscess was associated with significantly increased length of stay, incidence of procedures, and total cost of admission. Complicated pediatric OM remains of concern requiring prompt and thorough management. Major complications include mastoiditis and meningitis, and unfortunately, fatalities still occur in patients with OM. An understanding of resource utilization and socioeconomic implications can identify and drive opportunities for targeted quality improvement.

Abstract 3417: The genomic landscape of canine melanoma reveals broad mutational heterogeneity and recurrent patterns of structural variation

Abstract Despite remarkable therapeutic advances in malignant melanoma, an incomplete understanding of melanoma's extraordinary genetic diversity, complex disease course and ability to resist treatment continues to impede rational, curative clinical intervention. This is particularly true for the understudied “dark matter” of the melanoma genome, i.e. cases that lack mutations in the three most commonly-mutated melanoma genes (BRAF, NRAS, NF1) and that display extensive mutational heterogeneity. Clearly a pressing need exists for transformative approaches to melanoma medicine. We have therefore broadened our traditional focus on melanoma in human patients to include canine melanoma as a model of human disease. Given canine melanoma's clinicopathological resemblance to human non-cutaneous triple-negative subtypes, study of this disease in each species may inform the other. Further, the accelerated clinical course of canine melanoma and flexibility in veterinary clinical trial design may allow for evaluation of novel treatment designs that would not be possible in human cancer trials. Thus, we have undertaken a first-in-dog genomic characterization study of canine melanomas from a cohort of 37 dogs to further explore the landscape of this comparative model. This analysis combines comprehensive genomics (whole genome, whole genome long-insert, RNA sequencing, and array comparative genomic hybridization) in 7 matched canine melanoma/normal tissues with targeted analysis in an additional 27 tumors and 3 cell lines. These canine tumors display striking patterns of mutation and subtype heterogeneity resembling that of their non-cutaneous human counterparts with the majority being BRAF, NRAS, and NF1 wild type and lacking recurrent single nucleotide variants. Despite heterogeneity at the single nucleotide level, shared patterns of structural variation and gene expression exist and these patterns suggest core pathways that may define therapeutic vulnerabilities in these disease subtypes. These data provide the genomic framework for further clinical pursuit of melanoma in the canine model as a paradigm for drug development. Citation Format: William P. Hendricks, Victoria Zismann, Berry Button, Christophe Legendre, Waibhav Tembe, Holly Yin, Michael Bittner, Donald Berry, Matthew Huentelman, Chand Khanna, Patricia LoRusso, Matthew Breen, Aleksandar Sekulic, Jeffrey Trent. The genomic landscape of canine melanoma reveals broad mutational heterogeneity and recurrent patterns of structural variation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3417. doi:10.1158/1538-7445.AM2014-3417

Long-term efficacy and safety of rituximab in refractory and relapsing systemic lupus erythematosus

Systemic lupus erythematosus is a relapsing autoimmune disease. Conventional therapy increases the risk of infection and malignancies; furthermore, a minority of patients suffer from refractory disease. B-cell depletion with the chimeric +AFw-anti-CD20 monoclonal antibody, rituximab, is an alternative therapy for relapsing and refractory systemic lupus erythematosus. We sought to assess the long-term efficacy and safety of rituximab in this patient subgroup. Thirty-one sequential patients with relapsing or refractory systemic lupus erythematosus, 11 of whom had active lupus nephritis, received rituximab [either 375mg/m(2)/week × 4 (n = 16) or 1000mg × 2 (n = 15)]. The median follow-up was 30months. Thirty of 31 (97%) patients had depleted peripheral B cells. Twenty-seven of 31 (87%) patients achieved remission (17 complete, 10 partial). Renal response occurred in 10/11 patients (4 complete, 6 partial) with active glomerulonephritis. Clinical improvement was reflected by reductions of disease activity, proteinuria and daily prednisolone dose. Eighteen of 27 (67%) patients relapsed after a median of 11months. Relapses occurred on or after the return of circulating B cells in 10 but in the absence of B-cell return in 8. Re-treatment with rituximab was effective. Infusion reactions were common (18/31; 58%), and infections occurred in 8/31 (26%) patients. Rituximab had a high rate of efficacy in relapsing or refractory systemic lupus erythematosus with or without renal involvement. Although relapse was common, it responded to re-treatment. The contribution of rituximab to infection risk was uncertain in view of the complex disease course and concomitant therapy of the patients studied.

The progression of pathology in longitudinally followed patients with Parkinson’s disease

The present study describes the pathological progression of longitudinally followed cases with levodopa-responsive Parkinson's disease who came to autopsy during the Sydney Multicenter Study of Parkinson's disease. Standardised clinical and neuropathological assessments over five epochs of time verified three different clinicopathological groups. A group of younger onset patients with a typical long duration clinical course of Parkinson's disease. This group of cases had Lewy body distributions consistent with the Braak staging of disease. In this group, brainstem Lewy bodies dominate in those surviving to 5 years; by 13 years, 50% of cases have a limbic distribution of Lewy bodies; and by 18 years, all will have at least this pathological phenotype. Approximately 25% of cases had an early malignant, dementia-dominant syndrome and severe neocortical disease consistent with dementia with Lewy bodies. The last group had an older onset, shorter survival, and a more complex disease course with higher Lewy body loads and a higher proportion with additional neuropathologies. These cases with higher loads of Lewy bodies and shorter survivals suggest that widespread Lewy body pathology either occurs at the onset of clinical disease or rapidly infiltrates the brain. In these cases with shorter survivals, there was more plaque pathology, supporting a more aggressive and linked phenotype. Our data suggest that the selection of similar study cohorts by pathology alone would not be able to differentiate the three different phenotypes identified. The data are also not consistent with a unitary concept of the pathogenesis of Lewy body disease.