Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy

Mitochondrial neurogastrointestinal encephalomyopathy is a rare multisystemic autosomic recessive disorder characterized by: onset typically before the age of 30 years; ptosis; progressive external ophthalmoplegia; gastrointestinal dysmotility; cachexia; peripheral neuropathy; and leucoencephalopathy. The disease is caused by mutations in the TYMP gene encoding thymidine phosphorylasethymine phosphorylase. Anecdotal reports suggest that allogeneic haematopoetic stem cell transplantation may be beneficial for mitochondrial neurogastrointestinal encephalomyopathy, but is associated with a high mortality. After selecting patients who fulfilled the clinical criteria for mitochondrial neurogastrointestinal encephalomyopathy and had severe thymidine phosphorylase deficiency in the buffy coat (<10% of normal activity), we reviewed their medical records and laboratory studies. We identified 102 patients (50 females) with mitochondrial neurogastrointestinal encephalomyopathy and an average age of 32.4 years (range 11–59 years). We found 20 novel TYMP mutations. The average age-at-onset was 17.9 years (range 5 months to 35 years); however, the majority of patients reported the first symptoms before the age of 12 years. The patient distribution suggests a relatively high prevalence in Europeans, while the mutation distribution suggests founder effects for a few mutations, such as c.866A>G in Europe and c.518T>G in the Dominican Republic, that could guide genetic screening in each location. Although the sequence of clinical manifestations in the disease varied, half of the patients initially had gastrointestinal symptoms. We confirmed anecdotal reports of intra- and inter-familial clinical variability and absence of genotype–phenotype correlation in the disease, suggesting genetic modifiers, environmental factors or both contribute to disease manifestations. Acute medical events such as infections often provoked worsening of symptoms, suggesting that careful monitoring and early treatment of intercurrent illnesses may be beneficial. We observed endocrine/exocrine pancreatic insufficiency, which had not previously been reported. Kaplan–Meier analysis revealed significant mortality between the ages of 20 and 40 years due to infectious or metabolic complications. Despite increasing awareness of this illness, a high proportion of patients had been misdiagnosed. Early and accurate diagnosis of mitochondrial neurogastrointestinal encephalomyopathy, together with timely treatment of acute intercurrent illnesses, may retard disease progression and increase the number of patients eligible for allogeneic haematopoetic stem cell transplantation

A review of the diagnosis and management of vertebral basilar (posterior) circulation disease

We have reviewed the English literature published in the last 70 years on Diseases of the Vertebral Basilar Circulation, or Posterior Circulation Disease (PCD). We have found that errors have been made in the conduct and interpretation of these studies that have led to incorrect approaches to the management of PCD. Because of the difficulty in evaluating the PC, the management of PCD has been incorrectly applied from anterior circulation disease (ACD) experience to PCD. PCD is a common form of stroke affecting 20-40% patients with stroke. Yet, the evidence is strong that the Anterior Circulation (AC) and Posterior Circulations (PC) differ in their pathology, in their clinical presentations, in the rapidity of development of symptoms, in optimal imaging methods, and in available treatments. There appears to be two categories of patients who present with PCD. The first, acute basilar artery occlusion has a more rapid onset. The diagnosis must be made quickly and if imaging proves a diagnosis of Basilar Artery Occlusion (BAO), the treatment of choice is Interventional removal of the basilar artery thrombosis or embolus. The second category of PCD and the most commonly seen PCD disease process presents with non-specific symptoms and early warnings of PCD that now can be related to ischemic events in the entire PC vessels. These warning symptoms and signs occur much earlier than those in the AC. IA angiography is still the gold standard of diagnosis and is superior in definition to MR and CT angiography which are commonly used as a convenient screening imaging tool to evaluate PCD but are both inferior to IA angiography in definition for lesions below 3-4 mm. In at least two reported studies 7T MR angiography appears superior to other imaging modalities and will become the gold standard of imaging of PCD in the future. Medical treatments applied to the ACD have not been proven of value in specific forms of PCD. Interventional therapy was promising but of unproven value in Randomized Controlled Trials (RCT) except for the treatment of Basilar Artery Occlusion (BAO). Surgical revascularization has been proved to be highly successful in patients, who are refractory to medical therapy. These studies have been ignored by the scientific community basically because of an incorrect interpretation of the flawed EC-IC Bypass Trial in 1985 as applying to all stroke patients. Moreover, the EC-IC Bypass Study did not include PCD patients in their study population, but the study results were extrapolated to patients with PCD without any scientific basis. This experience led clinicians to an incorrect bias that surgical treatments are of no value in PCD. Thus, incorrectly, surgical treatments of PCD have not been considered among the therapeutic possibilities for PCD. QMRA is a new quantitative MR technique that measures specific blood flow in extra and intracranial vessels. QMRA has been used to select those patients who may benefit from medical, or interventional, or surgical treatment for PCD based on flow determinations with a high success rate. QMRA accurately predicts the flows in many large and small vessels in the PC and AC and clearly indicates that both circulations are intimately related. From medical and surgical studies, the longer one waits for surgical treatment the higher the risk of a poor outcome results. This observation becomes obvious when the rapidity of development of PCD is compared with ACD. Recent advances in endovascular therapy in the treatment of acute basilar thrombosis is a clear sign that early diagnosis and treatment of PCD will reduce the morbidity and mortality of these diseases. In this review it is evident that there are multiple medical and surgical treatments for PCD depending upon the location of the lesion(s) and the collateral circulation demonstrated. It is clear that the AC and PC have significant differences. With the exception of the large population studies from Oxford England, the reported studies on the management of PCD in the literature represent small selected subsets of the universe of PC diseases, the information from which is not generalizable to the universe of PCD patients. At this point in the history of PCD, there are not large enough databases of similar patients to provide a basis for valid randomized studies, with the exception of the surgical studies. Thus, a high index of suspicion of the early warning symptoms of PCD should lead to a rapid individual clinical assessment of patients selecting those with PCD. Medical, interventional, and/or surgical treatments should be chosen based on knowledge presented in this review. Recording the results in a national Registry on a continuing basis will provide the data that may help advance the management of PCD based on larger data bases of well documented patient information to guide the selection of future therapies for PCD treatments. It is also clear that the management of patients within the complex of diseases that comprise PCD should be performed in centers with expertise in the imaging, medical, interventional and surgical approaches to diseases of the PCD

Immediate effects of a single session of physical exercise on cognition and cerebral blood flow : A randomised controlled study of older adults

Background Regular physical activity is beneficial for cognitive performance in older age. A single bout of aerobic physical exercise can transiently improve cognitive performance. Researchers have advanced improvements in cerebral circulation as a mediator of long-term effects of aerobic physical exercise on cognition, but the immediate effects of exercise on cognition and cerebral perfusion are not well characterized and the effects in older adults are largely unknown. Methods Forty-nine older adults were randomized to a 30-minutes aerobic exercise at moderate intensity or relaxation. Groups were matched on age and cardiovascular fitness (VO2 max). Average Grey Matter Blood Flow (GMBF), measured by a pulsed arterial-spin labelling (pASL) magnetic resonance imaging (MRI) acquisition, and working memory performance, measured by figurative n-back tasks with increasing loads were assessed before and 7 minutes after exercising/resting. Results Accuracy on the n-back task increased from before to after exercising/resting regardless of the type of activity. GMBF decreased after exercise, relative to the control (resting) group. In the exercise group, higher n-back performance after exercise was associated with lower GMBF in the right hippocampus, left medial frontal cortex and right orbitofrontal cortex, and higher cardiovascular fitness was associated with lower GMBF. Conclusion The decrease of GMBF reported in younger adults shortly after exercise also occurs in older adults and relates to cardiovascular fitness, potentially supporting the link between cardiovascular fitness and cerebrovascular reactivity in older age.Träning för äldres hjärnhäls