Clinicopathologic heterogeneity in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) due to microtubule-associated protein tau (MAPT) p.P301L mutation, including a patient with globular glial tauopathy.

AIM: The p.P301L mutation in microtubule-associated protein tau (MAPT) is a common cause of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We compare clinicopathologic features of five unrelated and three related (brother, sister and cousin) patients with FTDP-17 due to p.P301L mutation. METHODS: Genealogical, clinical, neuropathologic and genetic data were reviewed from eight individuals. RESULTS: The series consisted of five men and three women with an average age of death of 58 years (52-65 years) and average disease duration of 9 years (3-14 years). The first symptoms were those of behavioural variant frontotemporal dementia in seven patients and semantic variant of primary progressive aphasia in one. Three patients were homozygous for the MAPT H1 haplotype; five had H1/H2 genotype. The apolipoprotein E genotype was ϵ3/ϵ3 in seven and ϵ3/ϵ4 in one. The average brain weight was 1015 g (876-1188 g). All had frontotemporal lobar or more diffuse cortical atrophy. Except for one patient, the hippocampus and parahippocampal gyrus had minimal atrophy, whereas there was atrophy of middle and inferior temporal gyri. Dentate fascia neuronal dispersion was identified in three patients, two of whom had epilepsy. In one patient there was extensive white matter tau involvement with Gallyas-positive globular glial inclusions typical of globular glial tauopathy (GGT). CONCLUSIONS: This clinicopathologic study shows inter- and intra-familial clinicopathologic heterogeneity of FTDP-17 due to MAPT p.P301L mutation, including GGT in one patient.

Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder.

OBJECTIVE: To determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder. METHODS: The clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria. RESULTS: 172 cases were identified, of whom 143 (83%) were men. The mean±SD age of onset in years for the core features were as follows - RBD, 62±14 (range, 20-93), cognitive impairment (n=147); 69±10 (range, 22-90), parkinsonism (n=151); 68±9 (range, 20-92), and autonomic dysfunction (n=42); 62±12 (range, 23-81). Death age was 75±9 years (range, 24-96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10±12 (range, 1-61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n=97), Parkinson's disease with or without mild cognitive impairment or dementia (n=32), multiple system atrophy (MSA) (n=19), Alzheimer's disease (AD)(n=9) and other various disorders including secondary narcolepsy (n=2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n=1). The neuropathologic diagnoses were Lewy body disease (LBD)(n=77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n=59), MSA (n=19), AD (n=6), progressive supranulear palsy (PSP) (n=2), other mixed neurodegenerative pathologies (n=6), NBIA-1/LBD/tauopathy (n=1), and hypothalamic structural lesions (n=2). Among the neurodegenerative disorders associated with RBD (n=170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features. CONCLUSIONS: In this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.

Neuropathological analysis of brainstem cholinergic and catecholaminergic nuclei in relation to rapid eye movement (REM) sleep behaviour disorder.

AIMS: Rapid eye movement sleep behaviour disorder (RBD) is characterized by loss of muscle atonia during rapid eye movement sleep and is associated with dream enactment behaviour. RBD is often associated with α-synuclein pathology, and we examined if there is a relationship of RBD with cholinergic neuronal loss in the pedunculopontine/laterodorsal tegmental nucleus (PPN/LDT), compared to catecholaminergic neurones in a neighbouring nucleus, the locus coeruleus (LC). METHODS: This retrospective study utilized human brain banked tissues of 11 Lewy body disease (LBD) cases with RBD, 10 LBD without RBD, 19 Alzheimer's disease (AD) and 10 neurologically normal controls. Tissues were stained with choline acetyl transferase immunohistochemistry to label neurones of PPN/LDT and tyrosine hydroxylase for the LC. The burden of tau and α-synuclein pathology was measured in the same regions with immunohistochemistry. RESULTS: Both the LC and PPN/LDT were vulnerable to α-synuclein pathology in LBD and tau pathology in AD, but significant neuronal loss was only detected in these nuclei in LBD. Greater cholinergic depletion was found in both LBD groups, regardless of RBD status, when compared with normals and AD. There were no differences in either degree of neuronal loss or burden of α-synuclein pathology in LBD with and without RBD. CONCLUSIONS: Whether decreases in brainstem cholinergic neurones in LBD contribute to RBD is uncertain, but our findings indicate these neurones are highly vulnerable to α-synuclein pathology in LBD and tau pathology in AD. The mechanism of selective α-synuclein-mediated neuronal loss in these nuclei remains to be determined.

MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study.

BACKGROUND: Neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau proteins, are one of the pathologic hallmarks of Alzheimer disease (AD). We aimed to determine whether patterns of gray matter atrophy from antemortem MRI correlate with Braak staging of NFT pathology. METHODS: Eighty-three subjects with Braak stage III through VI, a pathologic diagnosis of low- to high-probability AD, and MRI within 4 years of death were identified. Voxel-based morphometry assessed gray matter atrophy in each Braak stage compared with 20 pathologic control subjects (Braak stages 0 through II). RESULTS: In pairwise comparisons with Braak stages 0 through II, a graded response was observed across Braak stages V and VI, with more severe and widespread loss identified at Braak stage VI. No regions of loss were identified in Braak stage III or IV compared with Braak stages 0 through II. The lack of findings in Braak stages III and IV could be because Braak stage is based on the presence of any NFT pathology regardless of severity. Actual NFT burden may vary by Braak stage. Therefore, tau burden was assessed in subjects with Braak stages 0 through IV. Those with high tau burden showed greater gray matter loss in medial and lateral temporal lobes than those with low tau burden. CONCLUSIONS: Patterns of gray matter loss are associated with neurofibrillary tangle (NFT) pathology, specifically with NFT burden at Braak stages III and IV and with Braak stage itself at higher stages. This validates three-dimensional patterns of atrophy on MRI as an approximate in vivo surrogate indicator of the full brain topographic representation of the neurodegenerative aspect of Alzheimer disease pathology.

Vascular dementia: clinical, neuroradiologic and neuropathologic aspects.

Vascular dementia (VaD) is the second most common form of dementia after Alzheimer's disease (AD), and some studies suggest that the frequency increases exponentially over the age of 65 years. This review brings attention to the current challenges in the clinical and pathologic diagnoses of vascular dementia, provides an overview of diagnostic schemes in the clinical setting, and discusses the post-mortem pathology associated with VaD. While memory impairment is essential for diagnosis of AD, the clinical syndrome in VaD is often characterized by executive dysfunction rather than memory impairment. Nevertheless, the cognitive symptoms of VaD are so pleomorphic that no single cognitive syndrome captures the range of symptomology. Additionally, there are no widely accepted neuropathologic criteria for VaD. Imaging studies provide information about the distribution and volume of lesions and provide supportive information that differentiates VaD from AD, but are complicated by the concept of ''silent infarcts''. The heterogeneity of cerebrovascular disease and the wide range of pathologic lesions suggest that classification of VaD should include specific subtypes. The main challenge in clinicopathologic correlative studies is the lack of a gold standard for pathologic diagnosis of VaD that includes thresholds for number, size and location of infarcts and ischemic injury to white matter and strategic sites such as the thalamus and hippocampus. VaD is an entity that provides many challenges to the clinician, neuroradiologist and neuropathologist in part because evidence-based studies often lack clear definitions of the disease.

Self-care actions to manage fatigue among myasthenia gravis patients.

Fatigue is the most frequently reported symptom by myasthenia gravis (MG)patients. Despite the prevalence of fatigue, treatment protocols are lacking, thus patients are left to self-manage. The purpose of this study was to describe self-care actions used to manage fatigue among patients with MG. A national sample (N = 250) of MG patients responded to two structured instruments. The Fatigue Survey (FS), modified with permission of authors Hubsky and Sears; and the Myasthenia Gravis Fatigue Scale (MGFS). Both instruments were based on the concept of fatigue. Participants identified three major categories of self-managed actions: mental interventions (76%), physical interventions (78%) and rest/sleep (80%). A subset of the respondents (N = 36) reported using aerobic exercise to attempt to relieve fatigue which is usually contradicted with MG. No significant difference in fatigue scores was found between those reporting aerobic exercise to be helpful and those not finding exercise helpful. However, those utilizing aerobic exercise reported the highest functional status categories. A question arises as to whether aerobic exercise is performed by the least ill MG patients, or aerobic exercise improves functional status. When demographic and functional status variables were associated with fatigue scores and selfcare actions, only gender and functional status were significantly correlated with fatigue score. Effective self-care actions include stress reduction techniques, pacing all activities and increased rest and sleep. Further investigation into the role of aerobic exercise is indicated as a self-care action for MG fatigue.

The clinical importance of axillary lymphadenopathy detected on screening mammography.

The aim of this study was to determine the incidence and cause of axillary lymphadenopathy detected by screening mammography and to devise a management protocol for this pathology. In a retrospective study of 95,806 consecutive screening mammograms, 37 cases of 'pathological' axillary nodes were identified using two or more of the following criteria: size > 2 cm, replacement of fatty hilum, rounded shape and generalized increased density. In 16 cases with an additional mammographic abnormality, 12 had a mass (10 malignant and two benign) and four had suspicious calcification (all malignant). In 12 of these cases, the lymph nodes showed malignancy (75%). In 21 patients with lymphadenopathy alone on screening, six patients had a known underlying diagnosis and were not recalled from screening. The remaining 15 patients were recalled for further assessment including fine needle aspiration cytology (FNAC). The ultimate diagnosis was benign in 10 cases (48%)--six reactive changes, one healed granulomatous disease, one rheumatoid arthritis, one amyloid and one acute infection--and malignant in 11 cases (52%)--six non-Hodgkin's lymphoma, four metastatic carcinoma and one leukaemia. In conclusion, there is a high incidence of malignant nodal involvement in cases of screen detected lymphadenopathy (62% of cases in our series). We would advise that patients with lymphadenopathy as the sole finding on screening mammography and in whom there is no known underlying cause should undergo FNAC followed by excision biopsy. Fifty per cent of such patients in this study had underlying malignancy.

Comparisons of outcomes of maternity care by obstetricians and certified nurse-midwives.

OBJECTIVE: To determine whether pregnancy outcomes differ by provider group when alternative explanations are taken into account. METHODS: Pregnancy outcomes were compared for 710 women cared for by private obstetricians and 471 cared for by certified nurse-midwives. At intake, all women qualified for nurse-midwifery care. They were retained in their original group for analysis, even if they were later referred to physicians. Infant and maternal mortality, 30 clinical indicators, satisfaction with care, and monetary charges were studied. The study site's history and philosophy of honoring consumer choice of provider precluded random assignment, but multivariate analyses minimized the effects of multiple confounding factors. The statistical power was adequate for the study design. RESULTS: Significant differences (P < .05) between the obstetrician and nurse-midwife groups were found for seven clinically important outcomes: infant abrasions (7 versus 4%), infant remaining with mother for the entire hospital stay (15 versus 27%), third- or fourth-degree perineal laceration (23 versus 7%), number of complications (0.7 versus 0.4), satisfaction with care, average hospital charges ($5427 versus $4296), and average professional fee charges ($3425 versus $3237). When maternal risk, selection bias, and the medical intensiveness of care were controlled, the provider group did not continue to have an independent effect on infant abrasions, hemorrhage, and professional fee charges; when women's preferences were added, the difference in hospital charges disappeared. However, the provider group continued to have significant independent effects on the other four outcomes. Interaction effects were not significant. CONCLUSION: Although most outcomes were equally good, important differences between obstetrician and nurse-midwife care remained after multivariate analysis.

The role of ultrasound in screening patients referred for sialography: a possible protocol.

In a prospective study, ultrasound examination of the salivary glands was performed in 31 consecutive patients referred for sialography. Good correlation between ultrasound and digital sialography was observed in 26 patients with only one false negative ultrasound in a patient with significant sialectasis. We recommend initial ultrasound examination in patients with symptoms suggesting an inflammatory lesion in the salivary glands. If this is normal or reveals a solid mass, sialography is not indicated. If ultrasound examination demonstrates the presence of calculi, duct dilatation, cystic elements or an enlarged gland, digital sialography should be performed to identify lesions in the main duct such as strictures or obstructing calculi.

Osteomyelitis of the skull base: the role of high resolution CT in diagnosis.

Osteomyelitis of the skull base (involving the temporal, occipital or sphenoid bones) is an uncommon condition occurring in elderly diabetic patients which was almost always fatal in the pre-antibiotic era. Despite the advent of effective antibiotics against the usual causative organism, Pseudomonas aeruginosa, the mortality remains high and is related to delay in diagnosis and inappropriate treatment. We report three cases of osteomyelitis of the skull base, in order to illustrate the difficulties encountered in diagnosis and management. The CT scan appearances, which would appear to be typical for the disease, are described and the pathogenesis of skull base osteomyelitis is discussed.

Bilateral communicating bronchopulmonary foregut malformations in an infant with multiple congenital anomalies.

Communicating bronchopulmonary foregut malformations (BPFMs) are uncommon congenital lesions which usually present in infancy with respiratory distress, which is exacerbated during feeding. We present an unusual case of bilateral oesophageal BPFM in an infant with multiple congenital anomalies.

Diarrhea associated with Aeromonas species in children in day care centers.

Outbreaks of diarrhea caused by enteropathogens have been reported in day care centers (DCC), but Aeromonas species have not been implicated. This study evaluated 381 children involved in 51 outbreaks in four DCC to determine the association of Aeromonas species with diarrhea and to characterize the isolates. The organism was identified in two outbreaks of diarrhea. In one, Aeromonas species were isolated from 6 (24%) of 25 children and in the other from 5 (21%) of 24 children. Seven other Aeromonas strains from children in DCC were studied. Fourteen (78%) of 18 were Aeromonas caviae and 15 were from children with diarrhea. Of the isolates, 75% did not have plasmids detected; all others had unique plasmid patterns. All strains had different DNA content. Twenty-two control isolates of Aeromonas from children with diarrhea in Mexico and Dallas had different chromosomal DNA patterns. Most Aeromonas infections were associated with symptoms. Chromosomal DNA patterns differentiated Aeromonas strains better than did plasmid DNA patterns. The outbreaks of diarrhea were unusual in that several different Aeromonas genospecies were involved in each outbreak.

Acute renal failure in bone marrow transplantation.

Acute renal failure (ARF) is a serious complication in clients who have undergone bone marrow transplantation (BMT). The majority of cases develop as a result of intrarenal damage. Renal ischemia or nephrotoxic drugs, free hemoglobin, and free myoglobin contribute to acute tubular necrosis (ATN), which is the most likely cause of ARF in BMT clients. Nursing care of hospitalized BMT clients is directed toward the prevention of ARF by identifying clients who are at risk, the early diagnosis of renal impairment, and the administration of comprehensive treatment. Nurses play a vital role in the early diagnosis of renal impairment by assessing the client's fluid status, serum and urine electrolyte levels, and daily weights. The nursing role in managing clients with ARF includes preventing drug nephrotoxicity, maintaining fluid and electrolyte balance, preventing infection, and providing emotional support.