POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism

Objective: Mitochondrial dysfunction plays a key role in the pathophysiology of neurodegenerative disorders such as ataxia and Parkinson's disease. We describe an extended Belgian pedigree where seven individuals presented with adult-onset cerebellar ataxia, axonal peripheral ataxic neuropathy, and tremor, in variable combination with parkinsonism, seizures, cognitive decline, and ophthalmoplegia. We sought to identify the underlying molecular etiology and characterize the mitochondrial pathophysiology of this neurological syndrome. Methods: Clinical, neurophysiological, and neuroradiological evaluations were conducted. Patient muscle and cultured fibroblasts underwent extensive analyses to assess mitochondrial function. Genetic studies including genome-wide sequencing were conducted. Results: Hallmarks of mitochondrial dysfunction were present in patients' tissues including ultrastructural anomalies of mitochondria, mosaic cytochrome c oxidase deficiency, and multiple mtDNA deletions. We identified a splice acceptor variant in POLG2, c.970-1G>C, segregating with disease in this family and associated with a concomitant decrease in levels of POLG2 protein in patient cells. Interpretation: This work extends the clinical spectrum of POLG2 deficiency to include an overwhelming, adult-onset neurological syndrome that includes cerebellar syndrome, peripheral neuropathy, tremor, and parkinsonism. We therefore suggest to include POLG2 sequencing in the evaluation of ataxia and sensory neuropathy in adults, especially when it is accompanied by tremor or parkinsonism with white matter disease. The demonstration that deletions of mtDNA resulting from autosomal-dominant POLG2 variant lead to a monogenic neurodegenerative multicomponent syndrome provides further evidence for a major role of mitochondrial dysfunction in the pathomechanism of nonsyndromic forms of the component neurodegenerative disorders

Quantitative signal intensity in Fluid-Attenuated Inversion Recovery and treatment effect in the WAKE-UP trial

Background and Purpose: Relative signal intensity of acute ischemic stroke lesions in fluid-attenuated inversion recovery (fluid-attenuated inversion recovery relative signal intensity [FLAIR-rSI]) magnetic resonance imaging is associated with time elapsed since stroke onset with higher intensities signifying longer time intervals. In the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke Trial), intravenous alteplase was effective in patients with unknown onset stroke selected by visual assessment of diffusion weighted imaging fluid-attenuated inversion recovery mismatch, that is, in those with no marked fluid-attenuated inversion recovery hyperintensity in the region of the acute diffusion weighted imaging lesion. In this post hoc analysis, we investigated whether quantitatively measured FLAIR-rSI modifies treatment effect of intravenous alteplase. Methods: FLAIR-rSI of stroke lesions was measured relative to signal intensity in a mirrored region in the contralesional hemisphere. The relationship between FLAIR-rSI and treatment effect on functional outcome assessed by the modified Rankin Scale (mRS) after 90 days was analyzed by binary logistic regression using different end points, that is, favorable outcome defined as mRS score of 0 to 1, independent outcome defined as mRS score of 0 to 2, ordinal analysis of mRS scores (shift analysis). All models were adjusted for National Institutes of Health Stroke Scale at symptom onset and stroke lesion volume. Results: FLAIR-rSI was successfully quantified in stroke lesions in 433 patients (86% of 503 patients included in WAKE-UP). Mean FLAIR-rSI was 1.06 (SD, 0.09). Interaction of FLAIR-rSI and treatment effect was not significant for mRS score of 0 to 1 (P=0.169) and shift analysis (P=0.086) but reached significance for mRS score of 0 to 2 (P=0.004). We observed a smooth continuing trend of decreasing treatment effects in relation to clinical end points with increasing FLAIR-rSI. Conclusions: In patients in whom no marked parenchymal fluid-attenuated inversion recovery hyperintensity was detected by visual judgement in the WAKE-UP trial, higher FLAIR-rSI of diffusion weighted imaging lesions was associated with decreased treatment effects of intravenous thrombolysis. This parallels the known association of treatment effect and elapsing time of stroke onset

Subtypes classification and prediction of outcome in acute cerebral ischemia using spect imaging

Cerebrovascular diseases represent the third leading cause of death in the industrialized countries and lead to major disability in many patients. Our knowledge of stroke risk factors, diagnosis, and treatment of ischemic stroke has grown substantially during the last decade. New acute treatments mainly based in the ischemic penumbra concept are now investigated in the setting of stroke care units. Early therapeutic interventions aim to reverse the ischemic process, thereby salvaging the ischemic brain tissue before its transformation into irreversible infarct. Standard treatment include general measures, such as maintaining adequate blood pressure and cardiac outflow, increase of cerebral perfusion with hypercolemic hemodilution, and treatment of cerebral edema and intracranial hypertension. However, the main challenging therapeutic avenues are reperfusion treatment with thrombolytic agents, antithrombotic therapy, neuroprotective agents, growth factor, and therapy modulating the early gene expression. Because it is not likely that one treatment will be effective for all patients, the pathological mechanism underlying ischemia should be clarified in the acute stage using appropriate investigations. This requires individual evaluation of the location and extent of the ischemic lesion, arterial occlusion site, residual blood flow in the infarct core, extent of the penumbral zone with persistent viable tissue, critical duration of ischemia, and the anastomotic collateral systems. The time window for acute therapeutic interventions is universally accepted to be 6 hours. However, this time interval remains controversial. It may be shorter or longer in some patients according to the above pathophysiological factors. Thus, clinical investigations should help define which treatment to give, which type of brain ischemia to treat, which time interval for successful intervention, and which outcome may be expected. The currently available imaging techniques in acute ischemic stroke are PET, SPECT, brain CT, MRI, Mr-angiography, utlrasonography, and arterial angiography. Each has advantages and limitations and some of them only give partial informations on the pathophysiological determinants. SPECT is a non-invasive functional imaging technique, which is readily available in emergency conditions to assess the brain tissue perfusion. The present work demonstrates that SPECT can depict the ischemic lesion with a higher sensitivity than CT in the acute phase. With its high sensitivity, SPECT can be used for early characterization of stroke subtypes. It can also determine the extent of ischemia, the residual perfusion in the ischemic core, the cerebral tissue viability, and the collateral supply in the peri-infarct area. SPECT can add useful additional informations to ultrasonography on the arterial occlusion site and the related hemodynamic consequences. The present work also shows that SPECT indices such as the degree and size of hypoperfusion and clinical indices can reliably predict outcome. However, functional status and mortality are better predicted with the size of hypoperfusion and the Canadian Neurological Score, respectively. Thus, different clinical and SPECT indices with threshold values should be appropriately chosen according to the outcome end point. Early thrombolytic therapy can improve functional status. However, despite stringent exclusion criteria, fibrinolysis increases mortality and the rate of symptomatic hemorrhagic transformation of the cerebral infarct. Thus, additional criteria should allow more refined selection of patients likely to benefit from this therapy with a lower risk of hemorrhage. In this respect, SPECT can add informations on stroke subtypes, extent of ischemia, collateral supply, and remaining perfusion, which have been shown to be correlated with outcome after thrombolysis. In the future, some PET tracers fit for high resolution gamma cameras should allow most hospitals to monitor the stroke evolution o the clinical setting. Patients with transient ischemic attack have different vascular risk factors, etiology, and accordingly different risk for early or late stroke recurrence. Similarly to TIA patients with cerebral infarct, categorization of patients with persistent hypoperfusion may have important therapeutic impact. However, the present work shows no significant differences in vascular risk and etiological factors and risk for stroke recurrence between the patients with or without focal prolonged hypoperfusion. Thus, SPECT does not seem to be useful in the management of TIA patients, but further studies, using high resolution cameras and vasoreactivity tests, should reevaluate its potential role in larger populations of patients. Measurements of the cerebrovascular reserve capacity may be helpful in patients with TIA or minor stroke due to carotid occlusive disease. Early identification of exhausted cerebrovascular reserve is needed to plan acute medical interventions and carotid surgery. This can be achieved with SPECT studies using acetazolamide challenge. >BR> The encouraging results described above do not mean that SPECT is the single investigation to perform in ischemic cerebral diseases. Indeed, it does not give informations about the arterial occlusion site and the ischemic or hemorrhagic nature of stroke. Thus, in spite of improvement in SPECT or PET technologies, they must be added to brain CT or MRI to exclude cerebral hemorrhage and techniques imaging the vascular tree, such as ultrasonography, angiography, or MR-angiography, to localize the occlusion site. Because performing consecutively several techniques is time consuming, the main limitations of SPECT or PET is the potential delay for an early therapeutic intervention within the 6-hour limit. the new MRI techniques, such as diffusion-weighted and perfusion imaging and MR-spectroscopy, are promising to enhance the capacity for detecting ischemic stroke in the very early phase, assessing the brain tissue viability, and evaluating the metabolic evolution of cerebral ischemia. In combination with MR-angiography, this very sensitive technique is likely to become the single investigation to perform in the acute phase, which will allow to save time for early therapeutic interventions such as thrombolysis. However, this will also imply rapid access to MRI in emergency and medical expertise at any time of the day. In conclusion, the SPECT findings can guide the therapeutic strategy, even when performed beyond the 6-hour therapeutic window. However, the place of this functional cerebral imaging in cerebrovascular diseases should be reevaluated once the new MRI technologies will be available and validated in routine clinical practice. Indeed, T1- and T2-weighted imaging, will be probably the first –choice, single examination to perform to get all the needed informations about the ischemic process. On the other hand, if MRI is not available or cannot be performed due to the patient’s status, SPECT should be then performed in addition to the CT scan and ultrasonographyThèse d'agrégation de l'enseignement supérieur (Faculté de médecine) -- UCL, 199

Cost of acute stroke. A review.

The annual incidence of cerebrovascular diseases in Belgium is between 200 and 230/100,000 inhabitants. Mortality after stroke is about 21% and approximately 30% of stroke patients will be dependent on others. Cost is mainly related to the length of hospital stay but also to outpatient care. Length of stay is dependent on stroke severity at entry, stroke location (total infarct in the anterior circulation costs twice as much as small lacunar infarcts), and the social status (patients living alone or in a nursing home have a longer length of stay gene-rating a higher cost). Stroke units by using rationalized acute stroke therapy (including thrombolysis) reduce death and disability and decrease the length of stay by acting on stroke severity and co-morbidities. Stroke units also facilitate early discharge by coordinating outpatient care with the general practitioners, rehab centers, and nursing home. A global stroke-based prospective payment should be implemented in Belgium

Risk and benefit of statins in stroke secondary prevention.

Statin is now recommended in secondary prevention after stroke or transient ischemic attacks to reduce the risk of a new stroke or major cardiovascular events. However, some issues about the extent of the benefit in some stroke patients and the risk of cerebral hemorrhage remain debated. This review shows that statins are significantly effective in decreasing the risk of further strokes despite an increase in the risk of brain hemorrhage. A significant benefit was observed in men and women, in aged patients and possibly to a greater extent in patients with carotid artery stenosis. Intensive statin therapy lowering the LDL-cholesterol beyond the cut-off value of 1.8 mmol/L (70 mg/dl) seems to be more effective than less intensive treatment and without an increased risk of side effects. Overall, statins are well tolerated. Further prospective studies should clarify whether the effect is of the same magnitude in small vessel disease and how to select the patients to reduce the risk of cerebral hemorrhage