A case-control study of the pathology of oesophageal disease in systemic sclerosis (scleroderma).

BACKGROUND: Atrophy of the smooth muscle layers of the muscularis propria characterises oesophageal involvement in systemic sclerosis (scleroderma). The aetiology of this atrophy and of the resultant oesophageal dysfunction is unknown. OBJECTIVES: To examine oesophageal tissue for evidence of fibrosis, vascular disease, inflammatory reactions and neural abnormalities to determine the possible causes of this disease process. METHODS: A case-control survey was conducted using oesophageal tissue from 74 scleroderma cases and 74 age, race and sex-matched controls from our autopsy files. Histological evidence of oesophageal muscle atrophy was correlated with the degree of vascular changes, inflammatory infiltration, fibrosis, abnormalities of the myenteric plexus and reduction of interstitial cells of Cajal (ICC) using a predesigned semiquantitative descriptive method. RESULTS: Smooth-muscle atrophy was found in 94% of scleroderma cases, and in 5% of controls (p<0.001). Atrophy was evident in the circular smooth muscle in 93% of cases, and in the longitudinal smooth muscle in 66% of cases. Intimal proliferation of arterioles was found in 38% of cases and in 5% of controls (p<0.001), but was not associated with smooth-muscle atrophy (p = 0.29). Despite these vascular changes, there was no evidence of compromised perfusion, such as findings suggestive of acute ischaemic necroses. Minimal cellular infiltrates were seen in the myenteric plexus in 82% of cases and in 92% of controls (p = 0.091). ICC were found in fewer numbers in areas of atrophic smooth muscle compared with adjacent normal smooth muscle in selected scleroderma cases. CONCLUSION: The pathological findings of oesophageal lesions in scleroderma seem inconsistent with either an ischaemic or an inflammatory process. The loss of circular and longitudinal smooth muscle in the distal scleroderma oesophagus may represent loss of normal neural function followed by secondary tissue atrophy, or may be a primary smooth muscle lesion.

Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome.

OBJECTIVE: To define the clinical, radiologic, and genetic features of periventricular heterotopia (PH) with Ehlers-Danlos syndrome (EDS). METHODS: Exonic sequencing and single stranded conformational polymorphism (SSCP) analysis was performed on affected individuals. Linkage analysis using microsatellite markers on the X-chromosome was performed on a single pedigree. Western blotting evaluated for loss of filamin A (FLNA) protein and Southern blotting assessed for any potential chromosome rearrangement in this region. RESULTS: The authors report two familial cases and nine additional sporadic cases of the EDS-variant form of PH, which is characterized by nodular brain heterotopia, joint hypermobility, and development of aortic dilatation in early adulthood. MRI typically demonstrated bilateral nodular PH, indistinguishable from PH due to FLNA mutations. Exonic sequencing or SSCP analyses of FLNA revealed a 2762 delG single base pair deletion in one affected female. Another affected female harbored a C116 single point mutation, resulting in an A39G change. A third affected female had a 4147 delG single base pair deletion. One pedigree with no detectable exonic mutation demonstrated positive linkage to the FLNA locus Xq28, an affected individual in this family also had no detectable FLNA protein, but no chromosomal rearrangement was detected. CONCLUSION: These results suggest that the Ehlers-Danlos variant of periventricular heterotopia (PH), in part, represents an overlapping syndrome with X-linked dominant PH due to filamin A mutations.

Controversies in female urethral anatomy and their significance for understanding urinary continence: observations and literature review.

To re-examine the anatomy of the female urethra and related structures, three female pelves serially sectioned in sagittal, coronal or transverse planes, and four sets of transverse histological slides of female urethras, were studied. The observations were assembled, rendered as illustrations, and correlated with published works to present an overall explanation of the gross and histological anatomy of the female pelvis and perineum as related to continence. The figures accompanying the text present the anatomy in a series of views in the three anatomical planes. The anatomical relationships of the paraurethral and paravaginal tissues are examined in relation to the conflicting nomenclature applied to these structures. The figures show the spatial relationships within the pelves and perineum that explain their effective function in urinary continence.

Pathogenesis of acardiac twinning: clues from an almost acardiac twin.

OBJECTIVE: To search for clues to the pathogenesis of acardiac twinning. METHODS: We examined a case of monoamniotic twins in which twin A's only sonographic abnormality was a dilated, tortuous ductus venosus. Twin B also had this abnormality as well as multiple other anomalies that included enormous hydrops and a severely hypoplastic heart. Following termination of pregnancy, autopsy was performed. RESULTS: Postmortem examination of the placenta confirmed monochorionic, monoamniotic placentation with two adjacent trivascular cords. Autopsy confirmed the sonographic findings of enormous hydrops in twin B with a severely malformed, almost nonexistent heart. In addition, the liver was small and was represented by a cyst-like structure with thin rims of congested parenchyma surrounding large vascular spaces. CONCLUSION: We believe the sequence of events in this case was early twin-to-twin transfusion resulting in a dysfunctional heart in twin B. This enabled a twin reversal arterial perfusion sequence with further deterioration of twin B's heart and extreme congestion of deoxygenated blood exiting the heart into the inferior vena cava and ductus venosus. This case supports the concept that circulatory reversal in the face of an initially functioning heart may lead to congestion, tissue hypoxia and secondary organ atrophy.

Aortic and mitral fenfluramine-phentermine valvulopathy in 64 patients treated with anorectic agents.

CONTEXT: Few published studies of the pathology of fenfluramine-phentermine (fen-phen) valvulopathy, described by Connolly and colleagues in 1997, have appeared. OBJECTIVES: To define temporal changes in the morphology of the stuck-on plaques and to determine whether the plaques progress or regress after cessation of fen-phen. METHODS: The available clinical information and pathology material from 35 aortic valves (AVs) and 43 mitral valves (MVs) from 64 patients were reviewed. RESULTS: The valves fell into 3 groups: 17 AVs and 28 MVs had fen-phen lesions only, 2 AVs and 7 MVs had fen-phen changes associated with other valve diseases, and 16 AVs and 8 MVs had no fen-phen changes. Fenfluramine-phentermine-attributable dysfunction was regurgitation in all instances. Typical plaques showed proliferation of myofibroblastic cells with myxoid stroma. Small vascular channels and slight lymphocytic accumulations were often present. Deeper parts of some plaques had dense fibroelastic tissue underlying typical plaque. CONCLUSIONS: Considerable individual variation in the time course of anorectic agent use and the severity of fen-phen valvulopathy was observed. Possible plaque regression could not be assessed from this study. The observations suggest that in some patients fen-phen-induced plaques may continue to have surface proliferation despite drug withdrawal.

Lack of evidence for an association between neurofibromatosis type I and intracranial aneurysms: autopsy study and review of the literature.

BACKGROUND AND PURPOSE: Neurofibromatosis type I (NF1) is an autosomal dominant, hereditary, neurocutaneous syndrome purported to be associated with intracranial aneurysms. To study the relationship between NF1 and intracranial aneurysms, we have analyzed all intracranial autopsies of NF1 patients performed at our institution from 1889 to 1999 and analyzed all intracranial aneurysm cases at our institution from 1990 to 1999 in an attempt to identify patients with NF1. In addition, we have reviewed published clinical series of NF1 patients. METHODS: The autopsy database at our institution, which contains 50 000 cases from 1889 to 1999, was searched to identify NF1 patients, and the results of these autopsies were reviewed. The prevalence of intracranial aneurysms in these NF1 patients was compared with the prevalence of intracranial aneurysms in our hospital's autopsy population and with the published prevalence of intracranial aneurysms in the general population. To identify patients with intracranial aneurysms and NF1, our institution's intracranial aneurysm database was searched for patients with clinical manifestations of NF1. Published clinical series of NF1 patients were identified through searches of the literature. RESULTS: None of the 25 autopsy patients with NF1 had an intracranial aneurysm. None of the 925 patients treated for intracranial aneurysms were affected by NF1. A review of the literature identified 8 comprehensive clinical studies, all of which failed to document any relationship between NF1 and intracranial aneurysms. CONCLUSIONS: The autopsy prevalence of no NF1 patients with intracranial aneurysms out of 25 is not different from the prevalence of intracranial aneurysms in the general autopsy population. In addition, no patients treated for intracranial aneurysms at this institution had NF1. These findings are supported by the observation that an association between NF1 and intracranial aneurysms has never been identified in 8 large clinical studies of NF1 patients. We conclude that there is a lack of evidence for any association between NF1 and intracranial aneurysms.

Association between nonbacterial thrombotic endocarditis and hypoxigenic pulmonary diseases.

Observation of patients with nonbacterial thrombotic endocarditis (NBTE) in the setting of hypoxia from various lung diseases raised the question of a possible pathogenetic relationship between hypoxia and the development of NBTE. We reviewed 50 autopsied patients with NBTE and compared them with 50 age/race/gender-matched control patients without NBTE. We noted the lung weight and graded the histopathological severity of lung involvement by disease, clinical respiratory compromise, and the extent of any cancer present. Patients with NBTE had heavier lungs (P < 0.01) and histologically and clinically more severe pulmonary disease (both P < 0.005). There was no statistically significant difference in the extent of metastatic cancer between the NBTE patients and the controls (P > 0.5). When patients with cancer were excluded from the group of NBTE cases, there was still a statistically significant preponderance in the mean lung injury and clinical compromise scores of the NBTE patients (both P < 0.05), but the difference in lung weight was no longer statistically significant (P > 0.05). The study suggests that, in some patients, hypoxia may lead to NBTE, possibly through altered coagulation states.

Meningeal-cutaneous relationships in anencephaly: evidence for a primary mesenchymal abnormality.

The pathogenesis of cranial and spinal dysraphia has been controversial. Studies of spinal dysraphia have shown that the relationships of the pia and dura to the cutaneous layers were best understood as the result of a primary abnormality of mesenchymal structures, with the nervous system lesions occurring as a result of exposure of the bare spinal cord on the body surface. This study was undertaken to determine if the relationship of the cutaneous layers in anencephaly were similar to those found in spinal dysraphia. We reviewed serial histologic sections of the cranial structures of 10 anencephalic fetuses autopsied at The Johns Hopkins Hospital. We found the dura to be continuous with the deep dermis and the pia continuous with the superficial dermis and epidermis, the same arrangement observed in myelomeningocele. The development of eyes and cranial nerves, the absence of a bony calvarium, and the meningeal-cutaneous relationships found in this study support the idea that anencephaly can originate as an abnormality of mesenchymal structures and that the brain is secondarily lost to injury in utero because of its exposed position.

Problems with proper completion and accuracy of the cause-of-death statement.

BACKGROUND: Mortality statistics are largely based on death certificates, so it is important that the data on the death certificate is accurate. At our institution, clinicians complete cause-of-death statements (CODs) prior to autopsy. Since May 1995, separate CODs have been included in autopsy face sheets. METHODS: Clinical and autopsy-based CODs filled out separately on 494 cases between June 1995 and February 1997 were compared for proper reporting and accuracy using the published guidelines and definitions of immediate, intermediate, and underlying causes of death put forth by the College of American Pathologists and the National Center for Health Statistics. RESULTS: Of the 494 death certificates, 204 (41%) contained improperly completed CODs. Of these, 49 (24%) contained major discrepancies between clinicians' and pathologists' CODs. Of the 494 death certificates, 290 (59%) had properly completed CODs. Of the 290 properly completed CODs, 141 (49%) contained disagreements: 73 (52%) on underlying CODs; 44 (31%) on immediate CODs; and 47 (33%) on other significant conditions (part II). CONCLUSIONS: The reliability and accuracy of CODs remain a significant problem. Despite its limitations, the autopsy remains the best standard against which to judge premortem diagnoses. The CODs of the death certificate may be improved if death certificates are completed in conjunction with the postmortem examination and amended when the autopsy findings show a discrepancy.

Fatal infection after a bee sting.

Life-threatening or even fatal bee infections can rarely develop after bee stings.

Von Willebrand factor-cleaving protease activity and proteolysis of von Willebrand factor in bone marrow transplant-associated thrombotic microangiopathy.

INTRODUCTION: Thrombotic microangiopathy (TM) of the fulminant type occurring in patients following bone marrow transplant (BMT) has clinical manifestations that are similar to thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome, but the outcome is generally fatal despite conventional therapy. Idiopathic acquired TTP has been associated with IgG inhibitors to the cleaving protease of von Willebrand factor (vWF) in plasma. In this study, we investigated the role of the vWF protease and vWF proteolysis in the pathogenesis of BMT-associated TM of the fulminant type. METHODS: vWF antigen level, vWF multimeric pattern, and vWF metalloprotease activity were investigated in the plasma samples of six consecutive patients with acute BMT-associated TM. Histologic and immunohistochemical studies were also performed on autopsy kidney specimens from four of the patients. All six patients had the fulminant type of the disorder with a fatal outcome and none of the patients responded to plasma infusion. RESULTS: The vWF-cleaving protease activity in plasma was normal in all patients. However, analysis of the vWF multimeric pattern showed a decrease of high molecular weight multimers. The decrease of large multimers may be caused by vWF-platelet binding as well as shear enhanced proteolysis of vWF. In the four patients who had an autopsy, a pattern of arteriolar thrombosis, distinct from that of TTP, was detected in the kidneys. CONCLUSION: These findings suggest that BMT-associated TM of the fulminant type is a heterogeneous process and distinct from TTP in pathogenesis. Analysis of vWF protease and vWF multimeric distribution are valuable tools in making the distinction between BMT-associated TM and TTP.

Patterns of congenital lower urinary tract obstructive uropathy: relation to abnormal prostate and bladder development and the prune belly syndrome.

The pathogenesis of lower urinary tract obstruction is disputed, particularly its relation to both abnormal prostatic development and the prune belly syndrome (PBS). In an attempt to clarify this issue we examined 11 males (17-38 weeks gestation) with PBS who were autopsied at our institution. The lower urinary tract was embedded intact and prepared as serial histologic sections. Of the 11 cases, 8 demonstrated mechanical obstruction of the lower urinary tract. In five of these eight cases, a "flap-valve" structure was formed by an abnormal angulation between the prostatic and penile portions of the urethra. These had dilated, thin-walled bladders and prostates and moderate to severe renal dysplasia. One of the eight cases had a valve-like obstruction at the level of the mid-prostatic urethra associated with a complex cloacal malformation and a thin-walled bladder, another case had an epithelial plug at the penile meatus, and the last of the eight cases had a posterior urethral valve. The three remaining cases showed no mechanical obstruction. However, each had megacystis with marked thickening, interstitial fibrosis, and disarray of smooth muscle bundles in the bladder wall. In 10 cases, the prostate had no or only sparse, flattened glands. These results suggest that the abnormal development of the prostate in PBS may be explained as a pressure-induced dysplasia rather than a primary maldevelopment. The findings further suggest that abnormal prostatic development and the prune belly syndrome may arise from either anatomic obstruction of various types or functional obstruction from megacystis.

Echocardiographic findings in fulminant and acute myocarditis.

OBJECTIVES: We sought to use echocardiography to assess the presentation and potential for recovery of left ventricular (LV) function of patients with fulminant myocarditis compared with those with acute myocarditis. BACKGROUND: The clinical course of patients with myocarditis remains poorly defined. We have previously proposed a classification that provides prognostic information in myocarditis patients. Fulminant myocarditis causes a distinct onset of illness and severe hemodynamic compromise, whereas acute myocarditis has an indistinct presentation, less severe hemodynamic compromise and a greater likelihood of progression to dilated cardiomyopathy. METHODS: Echocardiography was performed at presentation and at six months to test the hypothesis that fulminant (n = 11) or acute (n = 43) myocarditis could be distinguished morphologically. RESULTS: Patients with both fulminant (fractional shortening 19 +/- 4%) and acute myocarditis (17 +/- 7%) had LV systolic dysfunction. Patients with fulminant myocarditis had near normal LV diastolic dimensions (5.3 +/- 0.9 cm) but increased septal thickness (1.2 +/- 0.2 cm) at presentation, while those with acute myocarditis had increased diastolic dimensions (6.1 +/- 0.8 cm, p < 0.01 vs. fulminant) but normal septal thickness (1.0 +/- 0.1 cm, p = 0.01 vs. fulminant). At six months, patients with fulminant myocarditis had dramatic improvement in fractional shortening (30 +/- 8%) compared with no improvement in patients with acute myocarditis (19 +/- 7%, p < 0.01 for interaction between time and type of myocarditis). CONCLUSIONS: Fulminant myocarditis is distinguishable from acute myocarditis by echocardiography. Patients with fulminant myocarditis exhibit a substantial improvement in ventricular function at six months compared with those with acute myocarditis. Echocardiography has value in classifying patients with myocarditis and may provide prognostic information.

Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis.

BACKGROUND: Lymphocytic myocarditis causes left ventricular dysfunction that may be persistent or reversible. There are no clinical criteria that predict which patients will recover ventricular function and which cases will progress to dilated cardiomyopathy. We hypothesized that patients with fulminant myocarditis may have a better long-term prognosis than those with acute (nonfulminant) myocarditis. METHODS: We identified 147 patients considered to have myocarditis according to the findings on endomyocardial biopsy and the Dallas histopathological criteria. Fulminant myocarditis was diagnosed on the basis of clinical features at presentation, including the presence of severe hemodynamic compromise, rapid onset of symptoms, and fever. Patients with acute myocarditis did not have these features. The incidence of the end point of this study, death or heart transplantation, was ascertained by contact with the patient or the patient's family or by a search of the National Death Index. The average period of follow-up was 5.6 years. RESULTS: A total of 15 patients met the criteria for fulminant myocarditis, and 132 met the criteria for acute myocarditis. Among the patients with fulminant myocarditis, 93 percent were alive without having received a heart transplant 11 years after biopsy (95 percent confidence interval, 59 to 99 percent), as compared with only 45 percent of those with acute myocarditis (95 percent confidence interval, 30 to 58 percent; P=0.05 by the log-rank test). Fulminant myocarditis was an independent predictor of survival after adjustments were made for age, histopathological findings, and hemodynamic variables. The rate of transplantation-free survival did not differ significantly between the patients considered to have borderline myocarditis and those considered to have active myocarditis according to the Dallas histopathological criteria. CONCLUSIONS: Fulminant myocarditis is a distinct clinical entity with an excellent long-term prognosis. Aggressive hemodynamic support is warranted for patients with this condition.

Prospective comparison of lesions created using a multipolar microcatheter ablation system with those created using a pullback approach with standard radiofrequency ablation in the canine atrium.

The aim of this study was to compare the lesions created using a multipolar microcatheter (MICRO) ablation system in the right canine atrium to a pullback approach with a standard radiofrequency (STND RF) ablation and to determine the value of electrogram amplitude and pacing threshold in predicting transmurality of lesions. Ten dogs underwent right atrial ablation using a MICRO (6 dogs) or STND RF (4 dogs) ablation system in each animal. Attempts were made to create linear RF lesions at four predetermined atrial sites. RF energy was delivered for 60 seconds using closed-loop, temperature control to achieve a target temperature of 60 degrees C for STND RF and 50 degrees C for MICRO. Unipolar atrial electrogram amplitude and atrial pacing threshold were obtained before and after ablation. Pathological analysis was determined at 4 weeks after ablation. Lesions created with MICRO were narrower, more likely to be continuous, and more likely to be anchored to an anatomic structure than those lesions which were created using a STND RF. No difference was observed in overall lesion length or in the proportion of lesions that were transmural over at least 50% of their length. Of lesions created using MICRO, a significant relation was observed between transmurality of lesion and unipolar electrogram amplitude as well as pacing threshold. Further studies are needed to determine if this type of ablation technique and parameters during ablation may facilitate a successful catheter-based MAZE procedure.

Practice guidelines for autopsy pathology: autopsy reporting. Autopsy Committee of the College of American Pathologists.

The Autopsy Committee of the College of American Pathologists has prepared this revised guideline to reflect changes that have occurred in the reporting of autopsies since the original guideline was published in February 1995. It is intended to be an instrument to assist pathologists in the reporting of autopsies. The guideline is to be regarded as being primarily an educational tool. Application of these recommendations on autopsy reporting is to be made on the basis of the judgment of the pathologist engaged in a specific case.