A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies

Leukodystrophies (LD) and genetic leukoencephalopathies (gLE) are disorders that result in white matter abnormalities in the central nervous system (CNS). Magnetic resonance (MR) imaging (MRI) has dramatically improved and systematized the diagnosis of LDs and gLEs, and in combination with specific clinical features, such as Addison’s disease in Adrenoleukodystrophy or hypodontia in Pol-III related or 4H leukodystrophy, can often resolve a case with a minimum of testing. The diagnostic odyssey for the majority LD and gLE patients, however, remains extensive – many patients will wait nearly a decade for a definitive diagnosis and at least half will remain unresolved. The combination of MRI, careful clinical evaluation and next generation genetic sequencing holds promise for both expediting the diagnostic process and dramatically reducing the number of unresolved cases. Here we present a workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis, including salient clinical features suggesting a specific diagnosis, neuroimaging features and molecular genetic testing. We also discuss recommendations on the use of broad-spectrum next-generation sequencing in instances of ambiguous MRI or clinical findings. We conclude with a proposal for systematic trials of genome-wide agnostic testing as a first line diagnostic in LDs and gLEs given the increasing number of genes associated with these disorders

The impact of laxative use upon symptoms in patients with proven slow transit constipation

<p>Abstract</p> <p>Background</p> <p>Constipation severity is often defined by symptoms including feelings of complete evacuation, straining, stool frequency and consistency. These descriptors are mostly obtained in the absence of laxative use. For many constipated patients laxative usage is ubiquitous and long standing. Our aim was to determine the impact of laxative use upon the stereotypic constipation descriptors.</p> <p>Methods</p> <p>Patients with confirmed slow transit constipation completed 3-week stool diaries, detailing stool frequency and form, straining, laxative use and pain and bloating scores. Each diary day was classified as being under laxative affect (laxative affected days) or not (laxative unaffected days). Unconditional logistic regression was used to assess the affects of laxatives on constipation symptoms.</p> <p>Results</p> <p>Ninety four patients with scintigraphically confirmed slow transit constipation were enrolled in the study. These patients reported a stool frequency of 5.6 ± 4.3 bowel motions/week, only 21 patients reported <3 bowel motions/week. Similarly, 21 patients reported a predominant hard stool at defecation. The majority (90%) of patients reported regular straining. A regular feeling of complete evacuation was reported in just 7 patients. Daily pain and/or bloating were reported by 92% of patients. When compared with laxative unaffected days, on the laxative affected days patients had a higher stool frequency (OR 2.23; <it>P </it><0.001) and were more likely to report loose stools (OR 1.64; <it>P </it><0.009). Laxatives did not increase the number of bowel actions associated with a feeling of complete evacuation. Laxative use had no affect upon straining, pain or bloating scores</p> <p>Conclusions</p> <p>The reporting of frequent and loose stools with abdominal pain and/or bloating is common in patients with slow transit constipation. While laxative use is a significant contributor to altering stool frequency and form, laxatives have no apparent affect on pain or bloating or upon a patients feeling of complete evacuation. These factors need to be taken into account when using constipation symptoms to define this population.</p

Surgical Outcomes after Total Colectomy with Ileorectal Anastomosis in Patients with Medically Intractable Slow Transit Constipation

Purpose: The aim of this study was to evaluate outcomes of a total colectomy with ileorectal anastomosis in patients with slow transit constipation. Methods: A retrospective review of 37 consecutive patients with slow transit constipation who underwent a total colectomy between 1994 and 2008 was undertaken. Preoperative and postoperative Wexner’s constipation scores were collected and used to evaluate the outcomes after surgical treatment. Also patients ’ postoperative satisfaction scores were collected using a 4-point scale. Results: The 37 patients consisted of 31 women and 6 men, with a median age of 41 years (range, 17 to 71 years). Pre- and post-operative Wexner’s scores were collected from 33 patients (89.1%), and the mean preoperative Wexner’s score was 19.3 (range, 11 to 24), which decreased to an average post-operative score of 2.3 (range, 0 to 8). Neither intraoperative complications nor postoperative mortalities were noted. Five patients (13.5%) had early postoperative complications, and the most common complication was postoperative ileus (10.8%). Seven patients (18.9%) had late postoperative complications, and postoperative ileus (10.8%) was also the most common. Twenty seven of 33 patients were satisfied with their surgical outcome (81.8%). Conclusion: A total colectomy with ileorectal anastomosis might be an effective surgical procedure with acceptable morbidity to treat medically intractable slow transit constipation

Tunable SIM: observation at varying spatiotemporal resolutions across the FOV

To date, imaging systems have generally been designed to provide an even spatiotemporal resolution across the field of view (FOV). However, this becomes a fundamental limitation when we aim to simultaneously observe varying dynamics at different parts of the FOV. In conventional imaging systems, to capture fast dynamics occurring at only a small portion of the FOV, the entire imaging system&apos;s sampling rate must be increased. This is a major problem if different parts of the FOV must rather be imaged at high spatial resolutions beyond the diffraction limit and require a sacrifice in temporal resolution. To answer this unmet challenge, we propose tunable SIM, which enables adaptive modulation of spatiotemporally varying structured illumination across different parts of the FOV. Using tunable SIM, we exploit the varying and designable spatiotemporal resolution to demonstrate simultaneous measurements of subdiffraction-limited changes in the actin fine structure of U87MG-EGFP-CD9 cells and the fast viscous flow inducing these structural changes. (c) 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreemen

Constipation : symptoms and findings in relation to structural and functional abnormalities

The aim of this study was to increase the knowledge about functional constipation with special reference to symptoms analysis, laboratory investigations and histopathology findings. 155 consecutive patients with intractable constipation underwent anorectal manometry, electromyography (EMG), balloon expulsion test, colonic transit time, and defecography. All investigations were completed by 134 patients. Whole-gut transit time was delayed in 55 patients (41%) and pelvic floor dysfunction (PFD) was diagnosed in 59 patients (44%) but in 35% of the patients both transit time and pelvic floor function were normal. It was concluded that about two thirds of patients with constipation have objective evidence of either colonic or pelvic floor dysfunction. Symptoms were good predictors of transit time but less good predictors of pelvic floor function in patients with constipation. Self-administered questionnaires were used to assess quality of life (Psychological General Well-Being Index, PGWB) and severity of gastrointestinal symptoms (Gastrointestinal Symptom Rating Scale, GSRS) in 84 patients with constipation. The overall mean score and confidence interval (CI) for quality of life in our patient material was 85.5 (CI: 80.9-89.9), which indicates that the well-being of patients with constipation is impaired compared to the normal population which exhibits an average index score of 102.9 (CI: 102.1-103.8). Patients with normal whole-gut transit time scored lower values in the total PGWB (median 82, interquartile range 69.5-96.5) than did patients with slow transit (median 94, interquartile range 77.8-105.8). The overall PGWB index was strongly corTelated with the total GSRS and with each of its three dimensions, dyspeptic syndrome, indigestion syndrome and bowel dysfunction syndrome. Symptom severity was negatively correlated with the perceived quality of life. Twenty consecutive patients with slow transit constipation underwent antroduodenal manometry. Twelve patients [60%] had one or more abnormal patterns of motor activity indicating motor abnormalities. This study concluded that a significant proportion of patients with slow transit constipation have manometric findings which indicate a generalised motor disorder of the gut. Bowel specimens were obtained from 16 patients with slow transit constipation. 13 colonic and 14 small bowel tissue were available for inummohistochernical study. All patients studied had abnormalities of intestinal neuromuscular structures. The majority of our patients had neuropathic changes both in the colon and in the small bowel but some had findings indicating a primary visceral myopathy. It was concluded that intrinsic neuromuscular abnormalities and defects in the interstitial cells of CaJal may underlie the colonic hypornotility that can be seen in patients with STC and hence contribute to their constipation. Twenty-six patients with paradoxical puborectalis contraction PPC were retrained by either of two feedback modes: anal pressure using a manometry probe, or anal sphincter electromyography (EMG) using surface electrodes. In the global assessment, 14 out of 20 patients who completed the therapy (6 in the manometry group, 8 in the EMG group) considered that their symptoms had improved after biofeedback therapy. The overall efficacy was maintained at follow-up 6 months later. It was concluded that alteration of an abnormal EMG pattern by biofeedback therapy could lead to long-standing improvement of symptoms and bowel function. We found no difference in the efficacy of biofeedback between the use of manometry or EMG for feedback