Laparoscopic Roux-en-Y feeding jejunostomy as a long-term solution for severe feeding problems in children.

Enteral feeding is a common problem in children with gastric emptying disorders. Traditional feeding methods in these patients often show a high rate of complications and maintenance issues. Laparoscopic Roux-en-Y feeding jejunostomy (LRFJ) has been described in a few patients as a minimal invasive option for enteral access in these children. The aim of this study is to evaluate the outcomes of the LRFJ procedure in our tertiary referral center. We conducted a retrospective case-series including all patients, aged 0-18 years old, that underwent a LFRJ procedure between August 2011 and December 2020 for the indication of oral feeding intolerance due to delayed gastric emptying. Outcomes evaluated were complications (short and long term) and parenteral satisfaction. In total, 12 children were identified that underwent LRFJ for the indication of oral feeding intolerance due to delayed gastric emptying. A total of 16 complications were noted in 8/12 patients (67%). Severity classified by Clavien-Dindo were grade I (n = 13), grade II (n = 1), and grade IIIB (n = 2). In 11/12 patients, parents were satisfied with the results. CONCLUSIONS: Although minor complications after LRFJ are common in our patients, this technique is a safe solution in patients with gastric emptying disorders leading to a definitive method of enteral feeding and high parenteral satisfaction. WHAT IS KNOWN: • Traditional tube feeding in children (duodenal, PEG-J-tubes) with severe delayed gastric emptying can be challenging with a high rate of complications and maintenance issues. • Open loop jejunostomy and Roux-en-Y jejunostomy are alternative, permanent methods of feeding but either invasive or are accompanied by severe complications. Little is known in the literature about laparoscopic Roux-en-Y feeding jejunostomy. WHAT IS NEW: • Laparoscopic Roux-en-Y feeding jejunostomy is a permanent, safe and minimal invasive alternative option for enteral feeding in children with severe delayed gastric emptying..

Review: Sporadic Parkinson's disease: development and distribution of α-synuclein pathology.

The development of α-synuclein immunoreactive aggregates in selectively vulnerable neuronal types of the human central, peripheral, and enteric nervous systems is crucial for the pathogenesis of sporadic Parkinson's disease. The presence of these lesions persists into the end phase of the disease, a process that is not subject to remission. The initial induction of α-synuclein misfolding and subsequent aggregation probably occurs in the olfactory bulb and/or the enteric nervous system. Each of these sites is exposed to potentially hostile environmental factors. Once formed, the aggregates appear to be capable of propagating trans-synaptically from nerve cell to nerve cell in a virtually self-promoting pathological process. A regional distribution pattern of aggregated α-synuclein emerges that entails the involvement of only a few types of susceptible and axonally interconnected projection neurons within the human nervous system. One major route of disease progression may originate in the enteric nervous system and retrogradely reach the dorsal motor nucleus of the vagal nerve in the lower brainstem. From there, the disease process proceeds chiefly in a caudo-rostral direction through visceromotor and somatomotor brainstem centres to the midbrain, forebrain, and cerebral cortex. Spinal cord centres may become involved by means of descending projections from involved lower brainstem nuclei as well as by sympathetic projections connecting the enteric nervous system with postganglionic peripheral ganglia and preganglionic nuclei of the spinal cord. The development of experimental cellular and animal models is helping to explain the mechanisms of how abnormal α-synuclein can undergo aggregation and how transmission along axonal connectivities can occur, thereby encouraging the initiation of potential disease-modifying therapeutic strategies for sporadic Parkinson's disease.

[Pathogenesis and prevention of Alzheimer's disease: when and in what way does the pathological process begin?]. / Pathogenese und Prävention des M. Alzheimer: Wann und auf welche Weise beginnt der pathologische Prozess?

Abnormal tau lesions (e.g., pretangles, neuropil threads, and neurofibrillary tangles) that develop in a few types of nerve cells in the central nervous system are essential to the pathogenesis of Alzheimer's disease. Pretangles begin to occur in puberty and even during early childhood in the locus coeruleus. Evolutionally speaking, the propensity to develop tau lesions may be related to late developing and maturing nerve cell types in the human brain.

[Pathophysiology of sporadic Parkinson's disease]. / Pathophysiologie des sporadischen Morbus Parkinson.

Sporadic Parkinson's disease is a multisystem disorder that involves predisposed nerve cell types in circumscribed regions of the entire human nervous system (peripheral, enteric, and central nervous systems). A recent staging procedure for the pathological process proposes that, in the brain, the formation of intraneuronal Lewy bodies and Lewy neurites begins at two sites and continues in a topographically predictable sequence in 6 stages, during which components of the olfactory, autonomic, limbic, and somatomotor systems become progressively involved. In stages 1 - 2, the Lewy body pathology is confined to the medulla oblongata/pontine tegmentum and anterior olfactory structures. In stages 3 - 4, the substantia nigra, other nuclei of the basal mid- and forebrain, and the mesocortex become the focus of initially subtle and, then, severe changes. During this phase, the illness probably becomes clinically manifest. In the final stages 5 - 6, the lesions appear in the neocortex.

[Transcraniel ultrasound in the differential diagnosis of Parkinson's disease]. / Stellenwert der Hirnparenchym-Sonografie in der Differenzial- und Frühdiagnose des Parkinson-Syndroms.

Imaging of the brain structure with transcranial ultrasound has become an important tool for the diagnosis and differential diagnosis of Parkinson's Disease. In up to 90 % of parkinsonian patients abnormal echogenity of the substantia nigra could be demonstrated. Particularly in the early diagnosis in subjects with only very mild extrapyramidal features and in the differential diagnosis to other neurodegenerative disorders with parkinsonian features, such as the parkinsonian variant of multisystematrophy (MSA-P) and progressive supranuclear paralysis (PSP) ultrasound has a high diagnostic yield. Because of a prevalence of about 10 % in the normal population, the evidence of an abnormal echogenity of the substantia nigra has to be interpreted carefully in the context of a clinical examination. Although there are a number of studies indicating that in some of these subjects a vulnerability of the nigrostriatal system can be found, the meaning of an abnormal echogenicity of the substantia nigra in the healthy population needs to be further elucidated in already ongoing research projects.

Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease.

REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of normal skeletal muscle atonia during REM sleep with prominent motor activity accompanying dreaming. The terminology relating to RBD, and mechanisms underlying REM sleep without atonia and RBD based on data in cat and rat are presented. Neuroimaging data from the few published human cases with RBD associated with structural lesions in the brainstem are presented, in which the dorsal midbrain and pons are implicated. Pharmacological manipulations which alter RBD frequency and severity are reviewed, and the data from human neuropathological studies are presented. An anatomic framework and new schema for the pathophysiology of RBD are proposed based on recent data in rat regarding the putative flip-flop switch for REM sleep control. The structure in man analogous to the subcoeruleus region in cat and sublaterodorsal nucleus in rat is proposed as the nucleus (and its associated efferent and afferent pathways) crucial to RBD pathophysiology. The association of RBD with neurological disease ('secondary RBD') is presented, with emphasis on RBD associated with neurodegenerative disease, particularly the synucleinopathies. The hypothesized pathophysiology of RBD is presented in relation to the Braak staging system for Parkinson's disease, in which the topography and temporal sequence of synuclein pathology in the brain could explain the evolution of parkinsonism and/or dementia well after the onset of RBD. These data suggest that many patients with 'idiopathic' RBD are actually exhibiting an early clinical manifestation of an evolving neurodegenerative disorder. Such patients may be appropriate for future drug therapies that affect synuclein pathophysiology, in which the development of parkinsonism and/or dementia could be delayed or prevented. We suggest that additional clinicopathological studies be performed in patients with dementia or parkinsonism, with and without RBD, as well as in patients with idiopathic RBD, to further elucidate the pathophysiology and also characterize the clinical and pathophysiological relevance of RBD in neurodegenerative disease. Furthermore, longitudinal studies in patients with idiopathic RBD are warranted to characterize the natural history of such patients and prepare for future therapeutic trials.

Parkinson's disease: premotor clinico-pathological correlations.

Parkinsonism is a clinical syndrome characterized by bradykinesia, hypo-/ akinesia, muscular rigidity, and resting tremor, mainly caused by Parkinson's disease (PD). Progressive loss of nigral neurons with Lewy bodies is considered an essential neuropathological feature. Recent studies, however, indicate that nigral degeneration is only a part of this synucleinopathy, and clinical symptoms go far beyond motor parkinsonism. Olfactory disturbances, autonomic dysfunction, pain, sleep fragmentation, depression, and dementia with or without psychosis are frequently seen. The variability in the expression of these signs and symptoms suggests multiple causes and/or pathogeneses within the present diagnostic disease entity. In this article, a recently proposed staging of PD-related brain pathology will be correlated with the various clinical expressions. It will be argued that the specific topographical sequence of the pathology, depending on the extent and progression of the degenerative process at defined sites, may explain the individually variable expression of this disease.

Critical appraisal of brain pathology staging related to presymptomatic and symptomatic cases of sporadic Parkinson's disease.

Clinical Parkinson's disease (PD) is a well-characterised syndrome that benefits significantly from dopamine replacement therapies. A staging procedure for sporadic PD pathology was developed by Braak et al. assuming that the abnormal deposition of alpha-synuclein indicates the intracellular process responsible for clinical PD. This paradigm has merit in corralling patients with similar cellular mechanisms together and determining the potential sequence of events that may herald the clinical syndrome. Progressive pathological stages were identified--1) preclinical (stages 1-2), 2) early (stages 3-4, 35% with clinical PD) and 3) late (stages 5-6, 86% with clinical PD). However, preclinical versus early versus late-stage cases should on average be progressively older at the time of sampling, a feature not observed in the cohort analysed. In this cohort preclinical cases would have developed extremely late-onset PD compared with the other types of cases analysed. While the staging scheme is a valuable concept, further development is required.

Pathology associated with sporadic Parkinson's disease--where does it end?

Parkinson's disease (PD) is a multisystem disorder in which predisposed neuronal types in specific regions of the human peripheral, enteric, and central nervous systems become progressively involved. A staging procedure for the PD-related inclusion body pathology (i.e., Lewy neurites and Lewy bodies) in the brain proposes that the pathological process begins at two sites and progresses in a topographically predictable sequence in 6 stages. During stages 1-2, the inclusion body pathology remains confined to the medulla oblongata, pontine tegmentum, and anterior olfactory structures. In stages 3-4, the basal mid- and forebrain become the focus of the pathology and the illness reaches its symptomatic phase. In the final stages 5-6, the pathological process is seen in the association areas and primary fields of the neocortex. To date, we have staged a total of 301 autopsy cases, including 106 cases with incidental pathology and 176 clinically diagnosed PD cases. In addition, 163 age-matched controls were examined. 19 of the 301 cases with PD-related pathology displayed a pathological distribution pattern of Lewy neurites and Lewy bodies that diverged from the staging scheme described above. In these cases, olfactory structures and the amygdala were predominantly involved in the virtual absence of brain stem pathology. Most of the divergent cases (17/19) had advanced concomitant Alzheimer's disease-related neurofibrillary changes (stages IV-VI).

Alzheimer's disease: striatal amyloid deposits and neurofibrillary changes.

Sensitive silver methods were employed for the examination of extracellular amyloid and intraneuronal neurofibrillary changes in the striatum of Alzheimer's disease patients. Numerous amyloid deposits were present in the striatum whereas neuritic (senile) plaques were only rarely encountered. Many large and a few medium-sized nerve cells had neurofibrillary tangles within their somata and according to morphological criteria corresponded to local circuit neurons. Numerous argyrophilic threads in the neuropil were scattered throughout the nuclear gray matter. The striatum of non-demented individuals was virtually devoid of amyloid and neurofibrillary changes.

Isocortical pathology in type C Niemann-Pick disease. A combined Golgi-pigmentoarchitectonic study.

A case of Niemann-Pick disease was examined with Golgi preparations and a transparent Golgi impregnation counterstained for intraneuronal pigment deposits. There was a specific type of storage of unmetabolized substrate restricted to certain nerve cell types. The most conspicuous changes in the isocortex were: 1) dilated axonal segments in layer IIIab pyramidal cells filled with storage material; the volume of these axonal expansions often exceeded that of the soma; 2) distension of layer IIIc, layer V, and layer VIa pyramidal cell perikarya with storage material; 3) new formation, elongation, and vertical orientation of basal dendrites in layer V pyramidal cells; 4) well-preserved pyramidal cells almost devoid of storage material and generally small in size were frequently found in layers II and IV, and to a lesser extent in layers III, V, and VI; 5) severe numerical reduction of small pigment-laden stellate cells in layers II and III; and 6) reduction of stellate cells devoid of lipofuscin pigment. These cells only occasionally contained small amounts of storage material.

Filamentous tau pathology in nerve cells, astrocytes, and oligodendrocytes of aged baboons.

Intracellular filamentous inclusions containing abnormally phosphorylated tau protein are hallmarks of several human neurodegenerative disorders. This study reveals tau-positive cytoskeletal abnormalities in neurons and glial cells of aged baboons. The brains of four baboons (Papio hamadryas, 20-30 yr of age) were examined using the Gallyas silver technique for neurofibrillary changes and phosphorylation-dependent anti-tau antibodies (AT8, AT100, AT270, PHF-1, TG-3). Conspicuous changes were noted in two animals, 26 and 30 yr of age. In both animals, a combination of neuronal and glial cytoskeletal pathology was seen preferentially affecting limbic brain areas, including the hippocampal formation. In the 30-yr-old animal, numerous tau-positive inclusions were seen in the granule cells of the fascia dentata. These cells even exhibited an accumulation of argyrophilic neurofibrillary tangles. The glial changes affected both astrocytes and oligodendrocytes. Tau-positive astrocytes were seen in perivascular, subpial, and subependymal locations. Tau-positive oligodendrocytes preferentially occurred in limbic fiber tracts including the entorhinal perforant path. Ultrastructurally, tau-positive straight filaments (10-14 nm) in both neurons and glial cells were revealed by anti-tau immunoelectron microscopy. This study thus indicates the potential usefulness of aged baboons for experimental investigation of neuronal and glial filamentous tau pathology. This nonhuman primate species may provide valuable information pertinent to the broad spectrum of human tauopathies.

Fleecy amyloid deposits in the internal layers of the human entorhinal cortex are comprised of N-terminal truncated fragments of Abeta.

The deposition of amyloid in the brain is a hallmark of Alzheimer disease (AD). Amyloid deposits consist of accumulations of beta-amyloid (Abeta), which is a 39-43 amino-acid peptide cleaved from the Abeta-protein precursor (APP). Another cleavage product of APP is the P3-peptide, which consists of the amino acids 17-42 of the Abeta-peptide. In order to study the deposition of N-terminal truncated forms of Abeta in the human entorhinal cortex, serial sections from 16 autopsy cases with AD-related pathology were immunostained with antibodies against Abeta1-40, Abeta1-42, Abeta17-23, and Abeta8-17, as well as with the Campbell-Switzer silver impregnation for amyloid. In the external entorhinal layers (pre-beta and pre-gamma), sharply delineated diffuse plaques were seen. They were labeled by silver impregnation and by all Abeta-antibodies used. By comparison, in the internal layers (pri-alpha, pri-beta, and pri-gamma) blurred, ill-defined clouds of amyloid existed, in addition to sharply delineated diffuse plaques. These clouds of amyloid were termed "fleecy amyloid." Immunohistochemically, fleecy amyloid was stained by Abeta17-23 and Abeta1-42 antibodies, but not with antibodies against Abeta8-17 and Abeta1-40. Using the Campbell-Switzer technique, the fleecy amyloid deposits were found to be fine argyrophilic amyloid fibrils. Thus, the internal entorhinal layers are susceptible to a distinct type of amyloid, namely fleecy amyloid. This fleecy amyloid obviously corresponds to N-terminal truncated fragments of Abeta1-42, probably representing the P3-peptide. These N-terminal truncated fragments of Abeta are capable of creating fine fibrillar "amyloid."

Sequence of Abeta-protein deposition in the human medial temporal lobe.

The deposition of Abeta protein (Abeta) and the development of neurofibrillary changes are important histopathological hallmarks of Alzheimer disease (AD). In this study, the medial temporal lobe serves as a model for the changes in the anatomical distribution pattern of different types of Abeta-deposits occurring in the course of AD, as well as for the relationship between the development of Abeta-deposition and that of neurofibrillary pathology. In the first of 4 phases of beta-amyloidosis, diffuse non-neuritic plaques are deposited in the basal temporal neocortex. The same plaque type appears in the second phase within the external entorhinal layers pre-beta and pre-gamma, and fleecy amyloid deposits occur in the internal entorhinal layers pri-alpha, pri-beta, pri-gamma, and in CA1. In the third phase, Abeta-deposits emerge in the molecular layer of the fascia dentata, and band-like Abeta-deposits occur in the subpial portion of the molecular layer of both the entorhinal region and the temporal neocortex. In addition, confluent lake-like Abeta-deposits appear in the parvopyramidal layer of the presubicular region. The fourth phase is characterized by diffuse and core-only plaques in CA4. Diffuse plaques evolve sporadically in the external entorhinal layer pre-alpha. Parallel to the evolution of beta-amyloidosis as represented by the 4 phases, neuritic plaques gradually make their appearance in the temporal neocortex, entorhinal region, CA1, the molecular layer of the fascia dentata, and CA4. A prerequisite for their development is the presence of Abeta and the presence of neurofibrillary tangles in neurons targeting the regions where neuritic plaques evolve. Each of the different types of Abeta-deposits, including neuritic plaques, plays a specific role in the distinct developmental sequence as represented by the 4 phases so that the medial temporal lobe inexorably becomes involved to an ever greater extent. The step-for-step involvement of connected anatomical subfields highlights the importance of the entorhino-hippocampal pathways for the expansion of beta-amyloidosis. The 4 phases in the evolution of beta-amyloidosis correlate significantly with the stages of the neurofibrillary pathology proposed by Braak and Braak.

Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes.

Accumulation of paired helical filaments (PHFs) in neurofibrillary tangles, neuropil threads, and dystrophic neurites is one of the major neuropathological hallmarks of Alzheimer disease (AD). The principal protein subunit of PHFs is the abnormally hyperphosphorylated tau. Glycogen synthase kinase 3beta (GSK-3beta) is one of the candidate kinases involved in PHF-tau formation. To play a role in PHF-tau formation, it would be expected that GSK-3beta is active in tangle bearing neurons. In the present study, we investigated the regional and intracellular distributions of active and inactive forms of GSK-3beta in brains staged for neurofibrillary changes. We found that neurons with tangle-like inclusions positive for active, but not inactive, GSK-3beta appear initially in the Pre-alpha layer of the entorhinal cortex and extend to other brain regions, coincident with the sequence of the development of neurofibrillary changes. Active, but not inactive, GSK-3beta was found to initially accumulate in the cytoplasm of pretangle neurons. These data provide direct in situ evidence that is consistent with the involvement of GSK-3beta in PHF-tau formation.

Neuropathology of cognitively normal elderly.

Despite general agreement about the boundaries of Alzheimer disease (AD), establishing a maximum limit for Alzheimer-type pathology in cognitively intact individuals might aid in defining more precisely the point at which Alzheimer pathology becomes clinically relevant. In this study, we examined the neuropathological changes in the brains of 39 longitudinally followed. cognitively normal elderly individuals (24 women, 15 men; age range 74-95, median 85 years). Neuropathological changes of the Alzheimer type were quantified by determining neurofibrillary tangle (NFT) staging by the method of Braak and Braak and by quantification of the abundance of diffuse, cored, and neuritic plaque burden using the scheme developed by the Consortium to Establish a Registry for Alzheimer Disease (CERAD). Vascular, Lewy body, and argyrophilic grain pathology were also assessed. We found 34 subjects (87%) with a Braak stage

Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections.

Selective and sensitive silver staining of extracellular amyloid deposits and intraneuronal neurofibrillary changes can be applied to 50-150 microns thick polyethylene glycol sections and/or 5-15 microns thick paraffin sections. The silver techniques take advantage of physical development of the nucleation sites thus permitting tight control of the entire procedure. Both techniques can be applied to routinely fixed autopsy material. They do not require particular skills and considerably facilitate processing of large numbers of sections through entire hemispheres of the human brain.

Evolution of the neuropathology of Alzheimer's disease.

Our knowledge of the etiology and pathogenesis of Alzheimer's disease is limited. The most conspicuous changes seen in the brain are deposits of insoluble proteins in both extracellular and intraneuronal locations. The extracellular deposits consist primarily of a specific A4 amyloid protein. The significance of these deposits remains to be determined, as they are often found in the cerebral cortex of non-demented elderly persons. More telling is the gradual accumulation of insoluble fibrous material within some neurons that consists mainly of abnormally phosphorylated tau protein. Six stages of increasingly severe cortical destruction can be distinguished. Stages I and II are characterized by neurofibrillary changes that are largely confined to the transentorhinal region, whereas stages III and IV are marked by severe involvement of both the entorhinal and transentorhinal regions. Isocortical destruction occurs during stages V and VI. This progression in cortical pathology correlates with the gradual worsening of clinical symptoms.

Frequency of stages of Alzheimer-related lesions in different age categories.

Alzheimer's disease is a relentlessly progressing dementing disorder. Major pathological hallmarks include extracellular deposits of amyloid protein and intraneuronal neurofibrillary changes. No remissions occur in the course of the disease. Initial amyloid deposits develop in poorly myelinated areas of the basal neocortex. From there, they spread into adjoining areas and the hippocampus. Deposits eventually infiltrate all cortical areas, including densely myelinated primary fields of the neocortex (stages A-C). Intraneuronal lesions develop initially in the transentorhinal region, then spread in a predictable manner across other areas (stages I-VI). At stages I-II, neurofibrillary changes develop preferentially in the absence of amyloid deposits. A proportion of cases shows early development of amyloid deposits and/or intraneuronal changes. Advanced age is thus not a prerequisite for the evolution of the lesions. Alzheimer's disease is an age-related, not an age-dependent disease. The degree of brain destruction at stages III-IV frequently leads to the appearance of initial clinical symptoms. The stages V-VI representing fully developed Alzheimer's disease are increasingly prevalent with increasing age. The arithmetic means of the stages of both the amyloid-depositing and the neurofibrillary pathology increase with age. Age is a risk factor for Alzheimer's disease.

Diagnostic criteria for neuropathologic assessment of Alzheimer's disease.

Prior to any evaluation of morphologic brain changes, a decision must be made whether a given alteration is associated with aging or with disease. Patients with disease-related lesions may be in a clinically silent phase of a disease or show overt symptoms. Neurofibrillary tangles and neuropil threads are the hallmarks of Alzheimer's disease. They should not be considered to be age-related changes, even when they are present only in small numbers. In general, the initial changes consist of neurofibrillary tangles and neuropil threads. Plaques (amyloid deposits and/or neuritic plaques) are consistently present in the end stage of the disease. Initial neurofibrillary tangles and neuropil threads develop at specific cortical predilection sites. The changes then spread in a predictable, nonrandom manner across other portions of the telencephalic cortex. The sequential changes in the distribution pattern of the lesions provide the basis for a staging procedure that takes the slow and gradual progression of the destructive process into consideration. The staging procedure provides accurate diagnoses in the initial stages and even reveals brain changes developing prior to the appearance of clinical symptoms. It is thus advantageous in characterizing nondemented controls. The staging procedure can be carried out easily and does not require knowledge of clinical data, quantitative assessments, or adjustments for the age of the patients. Application of advanced silver techniques (Gallyas, Campbell-Switzer) to demonstrate Alzheimer's disease-related lesions also allows recognition of the hallmarks of other disorders, such as Lewy body disease (Parkinson's disease) and dementia with argyrophilic grains, which frequently co-occur with Alzheimer's disease.