Olivier Rouyer

Cannabis Use, Ischemic Stroke, and Multifocal Intracranial Vasoconstriction: A Prospective Study in 48 Consecutive Young Patients

Background and Purpose— Our objective was to evaluate the relationship between cannabis use and ischemic stroke in a young adult population. Methods— Forty-eight consecutive young patients admitted for acute ischemic stroke participated in the study. First-line screening was performed, including blood tests, cardiovascular investigations, and urine analysis for cannabinoids. If no etiology was found, 3D rotational angiography and cerebrospinal fluid analysis were performed. A control was planned through neurovascular imaging within 3 to 6 months. Results— In this series, there was multifocal intracranial stenosis associated with cannabis use in 21% (n=10). Conclusions— Multifocal angiopathy associated with cannabis consumption could be an important cause of ischemic stroke in young people.

Cannabis-related Stroke Myth or Reality?

Cannabis, which is the most widely used recreational substance in the world, is considered by many consumers as safe with few negative side effects.1 This opinion is somehow strengthened by the fact that cannabis was also shown to have therapeutic applications.2 Cannabis is obtained from the plant Cannabis sativa and its varieties Cannabis indica and Cannabis americana .3 The 2 main preparations derived from cannabis are marijuana and hashish.2 The principal psychoactive cannabinoid in cannabis is delta 9 tetrahydrocannabinol4, and the potency of different preparations of cannabis that relates to tetrahydrocannabinol content is extremely variable.3 The plasma half-life of tetrahydrocannabinol isμ56 hours in occasional users and 28 hours in chronic users.5 Psychopharmacological acute effects associated with cannabis use are euphoria, increased self-confidence, relaxation, and a general sense of well being.3 Except for nausea associated with cancer chemotherapy, most of the potential beneficial effects are not approved by many administrations around the world. Indeed, the more common effects described as beneficial are glaucoma, analgesia, appetite in AIDS patients, tremor, Parkinson disease, spasticity in multiple sclerosis, epilepsia, anxiolytic, or antidepressive actions.1,3 However, several important negative side effects associated with cannabis are also observed. Indeed, in selected patients, acute psychiatric and behavioral abnormalities, such as anxiety, panic, and attentional abnormalities, have been reported.3,6 Risk of psychotic disorders or symptoms is higher in regular users of cannabis.6 Furthermore, psychological and physical dependence are described as chronic effects of cannabis use.6 As for other drugs, cannabis withdrawal syndrome, including anxiety, depressed mood, and sleep difficulties, may occur in heavy users on cessation.6,7 Also, somatic negative effects, such as cardiovascular complications (myocardial infarction, ventricular tachycardia, and sudden death), peripheral events (peripheral arteritis and kidney infarction), and …

Tetrahydrocannabinol Induces Brain Mitochondrial Respiratory Chain Dysfunction and Increases Oxidative Stress: A Potential Mechanism Involved in Cannabis-Related Stroke

Cannabis has potential therapeutic use but tetrahydrocannabinol (THC), its main psychoactive component, appears as a risk factor for ischemic stroke in young adults. We therefore evaluate the effects of THC on brain mitochondrial function and oxidative stress, key factors involved in stroke. Maximal oxidative capacities V max (complexes I, III, and IV activities), V succ (complexes II, III, and IV activities), V tmpd (complex IV activity), together with mitochondrial coupling (V max/V 0), were determined in control conditions and after exposure to THC in isolated mitochondria extracted from rat brain, using differential centrifugations. Oxidative stress was also assessed through hydrogen peroxide (H2O2) production, measured with Amplex Red. THC significantly decreased V max (−71%; P < 0.0001), V succ (−65%; P < 0.0001), and V tmpd (−3.5%; P < 0.001). Mitochondrial coupling (V max/V 0) was also significantly decreased after THC exposure (1.8±0.2 versus 6.3±0.7; P < 0.001). Furthermore, THC significantly enhanced H2O2 production by cerebral mitochondria (+171%; P < 0.05) and mitochondrial free radical leak was increased from 0.01±0.01 to 0.10±0.01% (P < 0.001). Thus, THC increases oxidative stress and induces cerebral mitochondrial dysfunction. This mechanism may be involved in young cannabis users who develop ischemic stroke since THC might increase patients vulnerability to stroke.

Ischaemic Strokes with Reversible Vasoconstriction and without Thunderclap Headache: A Variant of the Reversible Cerebral Vasoconstriction Syndrome?

Background: Reversible vasoconstriction (RV) may cause ischaemic stroke (IS) in the absence of any other defined stroke aetiology. The three objectives of our study were to evaluate the frequency of RV in a prospective series of young IS patients, to describe the detailed clinical-radiological features in the patients with RV and IS, and to compare these characteristics with those of reversible cerebral vasoconstriction syndrome (RCVS). Methods: We identified between October 2005 and December 2010, 159 consecutive young patients (<45 years) hospitalized for an acute IS confirmed by cerebral magnetic resonance imaging. An extensive diagnostic work-up was performed including toxicological urinary screening for cannabis, cocaine and amphetamines, and the usual biological, cardiac and vascular investigations for an IS in the young. We specifically studied patients with IS and RV, which was defined as multifocal intracranial arterial stenoses confirmed by intracranial arterial imaging that resolved within 3-6 months. Results: Out of 159 patients with IS, 21 (13%, 12 males, 9 females; mean age 32 years) had multifocal cerebral arterial stenoses that were fully reversible at 3-6 months, and no other cause for stroke. IS were located on posterior territory in 71% of cases, and vasoconstriction predominated on posterior cerebral and superior cerebellar arteries. Precipitating factors of IS and RV were the use of cannabis resin (n = 14), nasal decongestants (n = 2) and triptan (n = 1). Most cases (74%) had unusual severe headache, but none had thunderclap headache. None of 21 cases had reversible posterior leukoencephalopathy, cortical subarachnoid or intracerebral haemorrhage. Conclusion: RV was the sole identified cause of IS in 13% of our cohort. These young patients with IS and RV may have a variant of RCVS, related to an increased susceptibility to vasoactive agents in some individuals. RV in our patients differs from the classical characteristics of RCVS by the absence of thunderclap headache, reversible brain oedema and subarachnoid or intracranial haemorrhage. Intracranial arteries should be looked for, by appropriate vascular imaging, in young patients with IS at the acute stage and during the follow-up period.

High Frequency of Intracranial Arterial Stenosis and Cannabis Use in Ischaemic Stroke in the Young

Background: Leading aetiologies of ischaemic stroke in young adults are cervico-cerebral arterial dissections and cardio-embolism, but the causes remain undetermined in a considerable proportion of cases. In a few reports, intracranial arterial stenosis has been suggested to be a potential cause of ischaemic stroke in young adults. The aim of our work was to evaluate the frequency, characteristics and risk factors of intracranial arterial stenosis in a prospective series of young ischaemic stroke patients. Methods: The study was based on a prospective consecutive hospital-based series of 159 patients aged 18-45 years who were admitted to our unit for an acute ischaemic stroke from October 2005 to December 2010. A structured questionnaire was used in order to assess common vascular risk factors such as hypertension, diabetes, hypercholesterolemia, use of tobacco, alcohol and illicit drugs, migraine, and, in women, oral contraceptive use. A systematic screening was performed, including the following: brain magnetic resonance imaging or, if not feasible, brain computed tomography scan, carotid and vertebral Duplex scanning and trans-cranial Doppler sonography, 3D time-of-flight magnetic resonance cerebral angiography or cerebral computed tomography angiography. Long-duration electrocardiography, trans-thoracic and trans-oesophageal echocardiography were performed and laboratory blood investigations were extensive. Urine samples were screened for cannabinoids, cocaine, amphetamine and methylene-dioxy-methamphetamine. When this initial work-up was inconclusive, trans-femoral intra-arterial selective digital subtraction angiography with reconstructed 3D images was performed. Results: In this series, 49 patients (31%) had intracranial arterial stenosis. Other defined causes were found in 91 patients (57%), including cardio-embolism in 32 (20%), cervical dissection in 23 (14%), extracranial atherosclerosis in 7 (4%), haematological disorders in 7 (4%), small vessel disease in 1, and isolated patent foramen ovale in 21 (13%); in 19 patients (12%), ischaemic stroke was related to an undetermined aetiology. Comparing risk factors between patients with intracranial arterial stenosis and those with other definite causes showed that there were only two significant differences: a lower age and a higher frequency of vasoactive substances (especially cannabis) in patients with intracranial arterial stenosis. All intracranial arterial stenosis in patients who used vasoactive substances were located in several intracranial vessels. Conclusions: Intracranial arterial stenosis may be an important mechanism of stroke in young patients and it should be systematically investigated using vascular imaging. Strong questioning about illicit drug consumption (including cannabis) or vasoactive medication use should also be performed. It should be emphasized for health prevention in young adults that cannabis use might be associated with critical consequences such as stroke.

Effect of angiotensin‐converting enzyme inhibition on skeletal muscle oxidative function and exercise capacity in streptozotocin‐induced diabetic rats

Since exercise capacity is related to the mitochondrial respiration rate in skeletal muscle and both parameters are potentially modulated by the onset of diabetes and by inhibition of the angiotensin‐converting enzyme (ACE), we investigated whether skeletal muscle oxidative functions and exercise capacities are impaired in chronic streptozotocin‐induced diabetic (STZ) rats and whether ACE inhibition could reverse such abnormalities. The ACE inhibitor perindopril (2 mg kg−1 day−1) was given for a period of 5 weeks to 7‐month‐old STZ rats (DIA‐PE, n= 8) whose haemodynamic function, skeletal muscle mitochondrial function and exercise capacity were compared with those of untreated diabetic (DIA, n= 8) and control rats (CONT, n= 8). Increased arterial blood pressure (157 ± 12 versus 130 ± 6 mmHg, P < 0.05) and reduced exercise capacity (29 ± 2 versus 91 ± 2 min, respectively, P < 0.01) were observed in DIA compared with CONT. The oxidative capacity of the gastrocnemius muscle was significantly reduced in DIA compared with CONT rats (5.4 ± 0.5 versus 10.6 ± 0.7 μmol O2 min−1(g dry weight)−1, respectively, P < 0.001). Moreover, the coupling between oxidation and phosphorylation was significantly impaired in DIA (−52%, P < 0.001). Angiotensin‐converting enzyme inhibition (ACEi) normalized blood pressure without improving mitochondrial function (4.3 ± 0.8 μmol O2 min−1 (g dry weight)−1 in DIA‐PE rats) but reduced exercise capacity to even lower levels (10 ± 1 min, P < 0.01). Exercise capacity correlated positively with blood pressure in DIA‐PE (r= 0.79, P < 0.05). In experimental type 1 diabetic rats, both skeletal muscle mitochondrial respiration and exercise capacity are impaired. The ACEi failed to restore the muscular function and worsened exercise capacity. Further studies will be useful to determine whether an inadequate muscular blood flow secondary to the reduction in mean systemic blood pressure can explain these results.

Improving exercise capacity, 6 wk training tends to reduce circulating endothelin after heart transplantation

Abstract:  Short‐term survival is no longer the pivotal issue after heart transplantation but, most heart‐transplant (Htx) patients still present with increased circulating endothelin‐1 (ET) and reduced exercise capacity. ET‐1 limits both exercise‐induced vasodilation and blood flow redistribution toward acting muscles and might be accessible to training. This study was performed to investigate the effect of training on ET‐1 and whether an eventual training‐induced improvement in exercise capacity may be related to reduced baseline or exercise circulating ET‐1 in Htx patients. Five Htx patients performed a maximal bicycle exercise test and an endurance exercise test before and after a training program of 18 exercises sessions during 6 wk. ET‐1 was determined by radioimmunoassay at rest, end endurance exercise and 30 min recovery, before and after training. Training improved significantly Htxs maximal oxygen uptake (+13.1 ± 4.8%; p < 0.05) and also reduced significantly the endurance exercise‐induced heart rate increase. Resting ET‐1 was increased in Htx (5.98 ± 1.88 vs. 1.61 ± 0.25 pmol/L in controls; p < 0.01) but although ET‐1 modulation might participate in training‐induced beneficial effects, training failed to modulate either resting or exercise ET‐1 plasma level. Training‐induced improvement in exercise capacity might not mainly due to decreased ET‐1 after heart transplantation. Further supporting the usefulness of training, these preliminary data suggest that improved exercise capacity may not be mainly due to decreased ET‐1 in Htx patients. Further, larger scale studies will be needed to investigate whether an impaired nitric oxide pathway stimulation might explain such results and whether a longer training program can reduce local ET‐1, arising from working muscles after heart transplantation.

l-Arginine supplementation improves exercise capacity after a heart transplant

BACKGROUND Endothelial dysfunction is associated with the decreased exercise capacity observed in heart-transplant (HTx) recipients. L-arginine supplementation (LAS) stimulates the nitric oxide (NO) pathway and restores endothelial function. OBJECTIVE We compared exercise capacity in healthy subjects and HTx patients and investigated whether chronic LAS might improve exercise capacity and NO/endothelin balance after an HTx. DESIGN Clinical, echocardiographic, and exercise characteristics were measured in 11 control subjects and 22 HTx recipients. In a prospective, double-blind study, the 22 HTx recipients performed a 6-min exercise [6-min-walk test (6MWT)] and a maximal bicycle exercise test before and after a 6-wk period of placebo intake or LAS. Endothelial function was measured by analyzing blood NO metabolites, endothelin, and the resulting NO/endothelin balance. RESULTS Exercise capacity decreased after transplantation. Unlike with the placebo intake, 6 wk of LAS improved quality of life in HTx recipients (mean +/- SEM Minnesota Score: from 15.3 +/- 1.3 to 10.6 +/- 1.1; P < 0.001) and their submaximal exercise capacity. The distance walked during the 6MWT increased (from 525 +/- 20 to 580 +/- 20 m; P = 0.002), and the ventilatory threshold during the incremental test was delayed by 1.2 min (P = 0.01). Central factors such as resting stroke volume, systolic pulmonary arterial pressure, cardiac systolodiastolic functions, and heart-rate reserve were not modified, but LAS significantly increased the NO:endothelin ratio (from 2.49 +/- 0.38 to 3.31 +/- 0.39; P = 0.03). CONCLUSION Oral LAS may be a useful adjuvant therapeutic to improve quality of life and exercise tolerance in HTx recipients.

Does circulating BNP normalize after heart transplantation in patients with normal hemodynamic and right and left heart functions

Abstract:  Background:  Increased brain natriuretic peptide (BNP) in cardiovascular disease is thought to be a compensatory protective mechanism allowing to delay the occurrence of terminal heart failure. Heart transplantation should normalize the neuroendocrine balance but BNP remains elevated in stable heart‐transplant recipients (Htx). Such increase has been related to persistent endothelial and cardiac dysfunctions. The purpose of this study was to determine whether selected Htx, presenting with normal hemodynamic and cardiac systolic and diastolic functions on both side of the heart, show a normalization of their BNP plasma values.

Stroke Mimics in a Stroke Care Pathway Based on MRI Screening.

Background: Since the use of tissue plasminogen activator for acute ischemic stroke (IS), stroke care pathways have been developed for patients with suspicion of acute stroke. The aim of this prospective observational study was to analyze the stroke mimic (SM) characteristics in patients who were part of our stroke care pathway. Methods: All consecutive patients admitted in the code stroke within a 1-year period were prospectively enrolled in this study. Patients with a sudden onset of neurological focal deficit in a time window less than 4H30 as indicated for intravenous thrombolysis, had been accepted in the pathway by a neurologist who was directly contactable by the prehospital emergency medical service 24 h per day. Patients arrived directly on the MRI site without passing by the emergency department. A clinical neurological evaluation and a brain MRI with tri-dimensional time-of-flight magnetic resonance angiography were performed. The FAST score was calculated a posteriori. The final discharge diagnosis was concluded either immediately after both neurological examination and cerebrovascular neuroimaging or after other relevant investigations. We classified the discharge diagnosis into neurovascular diseases (NVDs) and into SM. Results: There were 1,361 consecutive patients admitted for suspicion of acute stroke. Sixty-two percent (n = 840) had an NVD including IS (n = 529), transient ischemic attacks (n = 236), intracranial hemorrhages (n = 68), cerebral venous thrombosis (n = 3) and neurovascular medullar pathologies (n = 4). SM represented 38% of cases (n = 521) and the most frequent discharge diagnosis was defined as headaches (18.6%), psychological disorders (16.7%), peripheral vertigo (11.9%) and epilepsy (10.6%). The comparison between the characteristics of the NVD and those of the SM groups showed some significant differences: in the SM group, women were more represented, patients were younger and the NIHSS was lower than in the NVD group. All cardiovascular risk factors were more represented in the NVD group. Concerning the symptoms, motor deficit, speech disturbances, homonymous lateral hemianopia and head and gaze deviation were more represented in the NVD group, whereas vertigo, non-systematized visual trouble, headache, confusion, weakness, neuropsychological symptoms, seizure and chest pain were significantly more frequent in the SM group. The negative predictive value of the FAST score was 64% and the positive predictive value was 76%. Conclusions: A rate of SM up to 38% of the code stroke system confirms the difficulty to distinguish clinically a stroke from another diagnosis. In this study, using cerebral MRI in first intention was of special interest in patients with acute neurological symptoms to differentiate an NVD from an SM.