Neuronal dysplasia: a controversial pathological correlate of intestinal pseudo-obstruction

The infant or child with intestinal pseudo-obstruction poses many challenges for geneticists and other specialists. Although a well-defined anatomic diagnosis (e.g., Hirschsprung disease) can be established for a subset of patients, the pathological correlates for many patients are non-existent or controversial. Intestinal neuronal dysplasia (IND) is frequently considered in the differential diagnosis, despite the fact that existence and significance of the abnormal histopathological features that characterize IND are hotly debated. This review highlights some of the concerns regarding this diagnosis including problems with the diagnostic criteria, the manner in which these criteria are applied in contemporary pathology practices, and the likelihood that many of the pathological findings are secondary consequences of impaired motility with no other clear clinical significance. Possible genetic and developmental bases for IND are also discussed.     

Bacterial endocarditis and lymphadenopathy mimicking Kawasaki disease

Two children whose illness initially fulfilled the clinical criteria for the diagnosis of Kawasaki disease were both subsequently found to have acute bacterial endocarditis and one child had a disseminated non-Hodgkins lymphoma. We describe their clinical course and emphasize the importance of the exclusion of other diagnosis as well as strict adherence to the accepted diagnostic criteria of Kawasaki disease.     

Diagnostic certainty of a voluntary bipolar disorder case registry.

BACKGROUND: Strategies for identifying and recruiting persons with bipolar disorder are of importance as interest in studying this relatively uncommon, but highly disabling illness increases. The development and implementation of a bipolar disorder case registry and the assessment of diagnostic certainty of the resulting sample are described. METHODS: Eight hundred and four individuals who self-reported a history of bipolar disorder were recruited. Telephone interviewers gathered demographic information and clinical, medical and treatment history information. One hundred randomly-selected registrants completed an in-person structured diagnostic interview. Self-report of diagnosis was compared to the results of the diagnostic interview. RESULTS: Ninety three percent of registrants interviewed met criteria for a lifetime bipolar spectrum diagnosis; of those, 76.3% were diagnosed with bipolar I disorder. Agreement between self-reported and SCID diagnoses was 93%, indicating that self-report of a bipolar diagnosis is highly reliable. Two-thirds had experienced at least one other lifetime Axis I diagnosis, with substance abuse/dependence (55.9%) and panic disorder (19.4%) the most common comorbidities. LIMITATIONS: Since nearly all of the sample have previously been diagnosed as having bipolar disorder by a professional, the sample's representativeness of the population as a whole may be somewhat limited. CONCLUSIONS: Persons with bipolar disorder can accurately identify themselves as having the disorder via a telephone interview, indicating that a case registry method is a useful strategy for recruiting very large samples of persons with this disorder. Such large samples will allow for further study of treatment variations among patient subgroups, of pathways to treatment, and of the effectiveness of new treatments.     

The surgical pathology of gastrointestinal Hodgkin's disease

The files of the National Cancer Institute were searched for all surgical specimens from the gastrointestinal (GI) tract with the diagnosis of Hodgkin's disease (HD) that were accessioned during the years 1953-1990; six patients with a histologically reconfirmed diagnosis were identified. Of these patients, four presented with GI HD and two had recurrent HD. Primary HD appeared in the stomach (three patients) and the duodenum (one patient); recurrent HD after diagnosis in a conventional nodal site appeared in the stomach (one patient) and the colon (one patient). One of the cases of primary gastric disease was a composite lymphoma consisting of HD and diffuse large cell lymphoma. In view of the rarity of GI tract involvement by HD, a diagnosis of primary GI HD should be viewed with skepticism; support for such a diagnosis may be provided by both classic histopathologic features of HD and immunostaining, but no single feature can be regarded as pathognomonic.     

Kongenitale Innervationsstörungen des Kolon

Hirschsprung's disease (HD, aganglionosis) is the most important form of congenital disturbance of intestinal innervation, requiring surgical intervention. Furthermore, hypoganglionosis of the transitional zone forms the most significant factor in morbidity. Pre-operative definition of the length of neuronally disturbed segment is still a diagnostic challenge for both clinical physician and pathologist. Enzyme histochemical studies form the method of choice, but certain limitations in their use must be observed.Other dysganglionoses, particularly the so-called "Intestinal Neuronal Dysplasia" (IND) cannot-because of an excessive overlapping with age-correlated normal values-unequivocally be defined as an entity on its own. The only exception to this, is the ganglionic neuromatosis, which arises as part of a genetic illness.     

Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)

Hereditary Hemorrhagic Telangiectasia (HHT) is easily recognized in individuals displaying the classical triad of epistaxis, telangiectasia, and a suitable family history, but the disease is more difficult to diagnosis in many patients. Serious consequences may result if visceral arteriovenous malformations, particularly in the pulmonary circulation, are unrecognized and left untreated. In spite of the identification of two of the disease-causing genes (endoglin and ALK-1), only a clinical diagnosis of HHT can be provided for the majority of individuals. On behalf of the Scientific Advisory Board of the HHT Foundation International, Inc., we present consensus clinical diagnostic criteria. The four criteria (epistaxes, telangiectasia, visceral lesions and an appropriate family history) are carefully delineated. The HHT diagnosis is definite if three criteria are present. A diagnosis of HHT cannot be established in patients with only two criteria, but should be recorded as possible or suspected to maintain a high index of clinical suspicion. If fewer than two criteria are present, HHT is unlikely, although children of affected individuals should be considered at risk in view of age-related penetration in this disorder. These criteria may be refined as molecular diagnostic tests become available in the next few years.     

Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu‐Osler‐Weber syndrome)

Hereditary Hemorrhagic Telangiectasia (HHT) is easily recognized in individuals displaying the classical triad of epistaxis, telangiectasia, and a suitable family history, but the disease is more difficult to diagnosis in many patients. Serious consequences may result if visceral arteriovenous malformations, particularly in the pulmonary circulation, are unrecognized and left untreated. In spite of the identification of two of the disease‐causing genes (endoglin and ALK‐1), only a clinical diagnosis of HHT can be provided for the majority of individuals. On behalf of the Scientific Advisory Board of the HHT Foundation International, Inc., we present consensus clinical diagnostic criteria. The four criteria (epistaxes, telangiectasia, visceral lesions and an appropriate family history) are carefully delineated. The HHT diagnosis is definite if three criteria are present. A diagnosis of HHT cannot be established in patients with only two criteria, but should be recorded as possible or suspected to maintain a high index of clinical suspicion. If fewer than two criteria are present, HHT is unlikely, although children of affected individuals should be considered at risk in view of age‐related penetration in this disorder. These criteria may be refined as molecular diagnostic tests become available in the next few years. Am. J. Med. Genet. 91:66–67, 2000. © 2000 Wiley‐Liss, Inc.     

Chronic intestinal pseudo-obstruction: systematic histopathological approach can clinch vital clues

The histopathological approach of chronic intestinal pseudo-obstruction (CIP) is critical, and the findings are often missed by the histopathologists for lack of awareness and nonavailability of standard criteria. We aimed to describe a detailed histopathological approach for working-up cases of CIP by citing our experience. Eight suspected cases of CIP were included in the study to determine and describe an approach for reaching the histopathological diagnosis collected over a period of the last 1.5 years. The Hirschsprung’s disease was put apart from the scope of this study. A detailed light microscopic analysis was performed along with special and immunohistochemical stains. Transmission electron microscopy was carried out on tissue retrieved from paraffin embedded tissue blocks. Among the eight cases, three were neonates, one in the pediatric age group, two adolescent, and two adults. After following the described critical approach, we achieved the histological diagnoses in all the cases. The causes of CIP noted were primary intestinal neuronal dysplasia (IND) type B (in 4), mesenchymopathy (in 2), lymphocytic myenteric ganglionitis (in 1), and duplication of myenteric plexus with leiomyopathy (in 1). Desmosis was noted in all of them along with other primary pathologies. One of the IND patients also had visceral myopathy, type IV. Histopathologists need to follow a systematic approach comprising of diligent histological examination and use of immunohistochemistry, immunocytochemistry, and electron microscopy in CIP workup. Therapy and prognosis vary depending on lesions identified by pathologists. These lesions can be seen in isolation or in combinations.     

The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies

BACKGROUND: This study examined the persistence of attention deficit hyperactivity disorder (ADHD) into adulthood. METHOD: We analyzed data from published follow-up studies of ADHD. To be included in the analysis, these additional studies had to meet the following criteria: the study included a control group and it was clear from the methods if the diagnosis of ADHD included subjects who did not meet full criteria but showed residual and impairing signs of the disorder. We used a meta-analysis regression model to separately assess the syndromatic and symptomatic persistence of ADHD. RESULTS: When we define only those meeting full criteria for ADHD as having 'persistent ADHD', the rate of persistence is low, approximately 15% at age 25 years. But when we include cases consistent with DSM-IV's definition of ADHD in partial remission, the rate of persistence is much higher, approximately 65%. CONCLUSIONS: Our results show that estimates of ADHD's persistence rely heavily on how one defines persistence. Yet, regardless of definition, our analyses show that evidence for ADHD lessens with age. More work is needed to determine if this reflects true remission of ADHD symptoms or is due to the developmental insensitivity of diagnostic criteria for the disorder.     

New tools for preimplantation genetic diagnosis of Huntington's disease and their clinical applications

Huntington's disease (HD) is a late-onset neurodegenerative disorder transmitted as an autosomal dominant trait. The causative mutation was characterised in 1993. For HD carriers willing to create a family, prenatal diagnosis (PND) or preimplantation genetic diagnosis (PGD) based on the mutation identification can be offered. For at-risk persons who do not want to undergo presymptomatic testing (PT), an exclusion test can be proposed. With such a test, only foetuses or embryos that inherit an allele from the unaffected grandparent are considered as unaffected. In cases of PND, if the foetus has one allele of the affected grandparent, termination of pregnancy is proposed. In cases of PGD, only not at-risk embryos are transferred. Since the beginning of our PGD activity, we have had 43 PGD referrals for HD, of which 24 were from patients who know their genetic status and 19 from patients who do not wish to perform PT. We have developed 12 multiplex fluorescent PCR protocols applied at the single-cell level for PGD, some of which target the CAG repeat while others use two different polymorphic microsatellites. We present here these different protocols and their clinical applications, as well as the characterisation and use of a new highly polymorphic intragenic marker. Between May 2001 and December 2003, 39 PGD cycles have been performed for 17 couples, 11 of whom had a known genetic status and six who did not wish to perform PT, resulting in four pregnancies.     

HOX11L1: a promoter study to evaluate possible expression defects in intestinal motility disorders

Intestinal Neuronal Dysplasia (IND) is a congenital disorder characterized by intestinal motility defects associated with hyperplasia of enteric ganglia. A phenotype resembling human IND has been observed in mice knocked-out for a member of the Hox11 homeobox gene family, Hox11l1, suggesting that the human homologue of this gene could be responsible for congenital disorders of intestinal innervation. However, previous mutation analysis of the coding sequence of the HOX11L1 gene in patients affected with IND detected neither mutations nor other nucleotide variants. In the present work, a detailed study of the non coding promoter region of this gene was undertaken in patients affected with IND, with Hirschsprung associated IND and with neurogenic chronic intestinal pseudo-obstruction. No alterations potentially impairing expression of HOX11L1, such as nucleotide variants, small deletions or cytogenetic alterations, could be identified thus further excluding the direct involvement of this gene in the pathogenesis of human intestinal motility disorders.     

Hodgkin's disease occurring in monocytoid B-cell clusters

The authors report three cases of Hodgkin's disease (HD) occurring in monocytoid B-cell (MBC) clusters within lymph nodes, a finding heretofore not published. MBC clusters were found mainly in a perisinusoidal and perifollicular distribution in all three cases. Within some of the MBC clusters of each case, small foci of overt necrosis were evident. Sternberg-Reed cells or their variants were found adjacent to all of these foci, as well as within some MBC clusters that were free of necrosis. These findings suggest that the presence of necrosis within MBC clusters has diagnostic utility. In two cases, evidence of HD was detected only within MBC clusters and nowhere else. In the third case, HD was found primarily within MBC clusters. These observations imply that HD arose within MBC clusters. Minimal involvement of lymph node by HD can occur within MBC clusters and should be recognized as such on the basis of morphologic features. The earlier a diagnosis of HD can be made, the better is the patient's outlook for survival.     

Polydiagnostic approaches to measuring and classifying psychopathology.

Modern explicit diagnostic criteria have greatly improved the reliability of diagnosis in genetic and other types of psychiatric research. However, there are several sets of different diagnostic criteria that can be used, particularly in the case of studies focusing on the major psychoses. These different criteria do not always agree well with each other and there is a further difficulty that reliability does not necessarily ensure validity. A polydiagnostic approach is advocated whereby research data are collected in such a way as to allow the application of competing definitions of disorder. This is accomplished in the OPCRIT system by "decomposing" diagnostic criteria into their component items. These can then be reassembled using algorithms based on the original criteria or used to generate novel categories or dimensions. This is necessary if psychiatric diagnoses are ultimately going to be refined and validated against biological criteria.     

Value and limitations of fine-needle aspiration cytology in diagnosis and classification of lymphomas: A review.

The fine needle aspiration (FNA) cytologic diagnosis of non-Hodgkin's lymphoma (NHL) depends upon finding a relatively monotonous population of lymphoid cells in smears. Lymphomas have successfully been classified by FNA cytology following the prevalent histologic classifications. The success rate of FNA cytology ranges from 80%-90% in diagnosis of NHL and from 67.5%-86% in its subtyping. The cytodiagnosis of Hodgkin's disease (HD) depends upon demonstration of Reed-Sternberg cells or Hodgkin's cells amongst appropriate reactive cell components. The diagnostic accuracy of FNA cytology for HD has also been invariably high (>85%). Yet, the role of cytology in primary diagnosis, subclassification and management of patients with lymphoma remains controversial. The differential diagnostic problems for NHL include a group of small round cell tumors, nonlymphoid acute leukemias and HD. Reservations have been expressed regarding the efficacy of cytology in separating florid reactive hyperplasia from low-grade malignant lymphoma. The reported cytodiagnostic accuracy for follicular lymphomas and nodular sclerosis type of HD is less compared to other subtypes of NHL and HD respectively since nodular pattern and sclerosis are strict histologic criteria which can not be appreciated in cytologic preparations. Entities like atypical lymphoproliferative disorders, peripheral T-cell lymphomas and Ki-1 positive anaplastic large cell lymphomas pose diagnostic challenges to cytologists. Despite these limitations, FNA cytology remains the first line of investigations (screening test) used in cases of lymphadenopathy. Besides initial diagnosis of lymphoma, it helps in detection of residual disease, recurrences and progression of low-grade to high-grade lymphoma, and helps in staging the disease. Availability of prior FNA cytology report facilitates the histologic diagnosis and classification of NHL. Various special ancillary techniques are now being performed on lymph node aspirates to diagnose lymphoma versus other malignancies, and to decide the functional character of lymphomas and their clonal nature. Diagn. Cytopathol. 1999;21:240-249.     

The misdiagnosis of bipolar disorder as a psychotic disorder: some of its causes and their influence on therapy

ObjectivesLooking at chart records bipolar disorder is often misdiagnosed as a psychotic disorder but no study has ever systematically looked into the reasons. One reason for misdiagnoses could be that clinicians use heuristics like the prototype approach in routine practice instead of strictly adhering to the diagnostic criteria. Using an experimental approach we investigated if the use of heuristics can explain when a diagnosis of psychotic disorder is given instead of bipolar disorder. We systematically varied information about the presence or absence of specific symptoms, i.e. hallucinations and decreased need for sleep during a manic episode.MethodsExperimentally varied case vignettes were randomly sent to psychiatrists in Southern Germany. The four versions of the case vignette all described the same person in a manic state and differed only in two aspects: the presence or absence of auditory hallucinations and of decreased need for sleep. The psychiatrists were asked to make a diagnosis, to rate their confidence in their diagnosis, and to recommend treatments.ResultsAlmost half of the 142 psychiatrists (45%) did not diagnose bipolar disorder. Mentioning hallucinations decreased the likelihood of diagnosing bipolar disorder. The information about decreased need for sleep only affected the diagnosis significantly, if schizoaffective disorder was considered a bipolar disorder.ConclusionsOur results suggest that clinicians indeed use heuristics when making diagnostic decisions instead of strictly adhering to diagnostic criteria. More research is needed to better understand diagnostic decision making, especially under real life settings, and this might also be of interest when revising diagnostic manuals such as DSM.     

Malignant histiocytosis in childhood: Morphologic Considerations

Eight cases diagnosed over a ten-year period as malignant histiocytosis (MH; histiocytic medullary reticulosis) were reviewed to clarify diagnostic criteria for the childhood disease and to identify sources of diagnostic confusion. Five of the eight cases met the authors' criteria for diagnosis; i.e., they were characterized by loose mixed infiltrates composed of three cell types--well-differentiated histiocytes, prohistiocytes, and malignant histiocytes--and they had no leukemic phase. Three cases did not share these features and were reclassified. The liver was found to be the organ most useful in premortem diagnosis, and immunoperoxidase staining for immunoglobulins and lysozyme was also helpful. The clinical and morphologic features of the five cases confirm the authors' view that diagnoses of MH should be limited to cases in which there is a loose pleomorphic population of all three types of histiocytes and that cases with monomorphous populations of aggregated malignant cells should be classified as lymphomas.     

Epidural involvement in Hodgkin's disease

Epidural involvement is analyzed retrospectively in 512 patients with primary treatment and follow up for Hodgkin's disease (HD) between 1970 and 1999. In one case (0.2%) epidural manifestation was the first symptom and in six cases (1.2%) it occurred later, at a disseminated, advanced stage. All seven patients were male: three had mixed cellularity and four nodular sclerosis histological subtype. The thoracic segment was involved in four cases, the lumbar in two and the cervical segment in one case. The most frequent symptoms were back pain, limb weakness, paresis/plegia, incontinence. Computer tomography, magnetic resonance imaging and myelography were used as diagnostic procedures and in planning the treatment. Functional recovery was achieved by laminectomy, loco-regional irradiation and adjuvant polychemotherapy with remission of HD for 6-100 months. Later, however, six patients died due mainly to relapse/progression of HD. We emphasize the importance of an interdisciplinary approach in the treatment of HD with this relatively rare appearance, which requires close co-operation among oncohematologists, neurologists, radiologists, neurosurgeons, radiotherapists and physiotherapists.     

Diagnostic accuracy of imprint cytology in the assessment of Hodgkin's disease in Japan

Our objective was to evaluate the usefulness of cytomorphologic assessment in the accuracy of diagnosis of Hodgkin's disease (HD), using imprint cytological preparations over a 18-yr period. Imprint materials from 34 HD cases were reviewed using cytomorphological and immunocytochemical studies. Twenty-six cases (76.5%) were diagnosed to be HD and 6 cases (17.6%) were suspected to be HD, but 2 cases (5.9%) were cytologically diagnosed as reactive lesions, because of an insufficient number of Reed-Sternberg (RS) cells. The 6 suspected cases were definitively diagnosed as HD, using immunocytochemistry. Immunophenotyping of RS cells in 32 cases (excluding the two cases of reactive lesions) showed CD30+ in 31 (96.9%) cases, CD15+ in 22 (68.8%) cases and CD20+ in 12 (37.5%) cases. RS cells were immunophenotypically classified into five groups: A, (CD 30+, 15+, 20-) 15 (46.9%); B, (CD30+, 15-, 20-) 5 (15.6%); C, (CD 30+, 15+, 20+) 6 (18.8%); D, (CD30+, 15-, 20+) 5 (15.6%); and E, (CD30-, 15+, 20+) 1 (3.1%). Cytomorphologic differences in RS cells were identified between group D and other groups (CD15+ and/ or CD20-). The former had a low polymorphic shape (like popcorn), and the latter had a more classical polymorphic shape. Epstein-Barr virus (EBV)-latent membrane protein-1(LMP-1) was identified in 16 (50%) cases. LMP-1 expression was found not only in classic RS cells, but also in smaller variants. These variants did not match the morphologic criteria of RS cells, but expressed the common phenotype (CD30+, CD15+/-) of RS cells, suggesting the same cellular origin as RS cells. This study demonstrated that imprint cytology from lymph node biopsies can be a useful tool for the diagnosis and the evaluation of the cellular biology of HD.     

Carcinoma of the nasopharynx. Histopathological examination with supplementary immunohistochemistry

One hundred and one nasopharyngeal malignancies, clinically accepted and treated as carcinomas, were histologically reviewed. Originally, all of them had been given the histopathological diagnosis of carcinoma or possible carcinoma. A wide variety of diagnostic formulations had been used, some of them inconclusive. The review was based on strict morphological WHO criteria, and a definite diagnosis was attained in most cases. Three of the neoplasms, however, did not fulfil the criteria of carcinoma, and were given the diagnosis of malignant tumour, probable lymphoma. Immunohistochemistry with routinely processed tissue was performed on 69 of the poorly differentiated non-keratinizing neoplasms, including the three possible non-Hodgkin's malignant lymphomas. The neoplasms were positive for cytokeratin PKKl with four exceptions: the three possible lymphomas and a large cell tumour with epithelial growth and prominent nucleoli which was found to be positive only for neurone-specific enolase. Two of three possible lymphomas were verified as such by being positive for leucocyte common antigen. This study showed that the WHO classification is quite useful when strictly applied. The histopathological diagnosis of this category of neoplasms can easily be confirmed by immunohistochemistry on routinely processed material and this adjunct can usually resolve questionable cases.     

Some children with growing pains may actually have restless legs syndrome

STUDY OBJECTIVES: Growing pains may be an important clue to the diagnosis of childhood restless legs syndrome (RLS). However, there are no previous studies to determine whether a subpopulation of children with growing pains meet the diagnostic criteria for RLS. The purpose of this study is to determine if some children with growing pains meet diagnostic criteria for RLS and to compare the polysomnographic characteristics of these children to controls. DESIGN/PARTICIPANTS/MEASUREMENTS: Eleven children from a pediatric neurology clinic with an emphasis on attention-deficit/hyperactivity disorder (ADHD) and with a diagnosis of growing pains were referred. They were interviewed with the parent to determine if their symptoms of growing pains met criteria for definite RLS. Those who met clinical criteria for RLS underwent polysomnography, and the results of their polysomnographic studies were compared to those of a control group (10 children, mean age 9.7 years). SETTING: Academic medical center. RESULTS: Ten (mean age 10.4 years) of the 11 children with growing pains met clinical criteria for RLS. In 4 of 8 families of these 10 children, 1 parent had RLS. Six of the 10 children had ADHD. There were no differences in the polysomnographic findings between the growing-pain and control groups, and none of the children with RLS had what is considered to be a clinically significant number of periodic limb movements of sleep. There were no differences in the polysomnographic findings between the "growing-pain ADHD" and "growing-pain non-ADHD" subgroups. The growing pains were severe enough for the patients and family to ask for treatment in 4 cases, and carbidopa/levodopa was utilized. CONCLUSIONS: Some children diagnosed with growing pains meet diagnostic criteria for RLS, and a family history of RLS is common in these children. In some cases symptoms are severe enough to warrant treatment.