Melissa Cambron

Vascular aspects of multiple sclerosis

Three types of vascular dysfunction have been described in multiple sclerosis (MS). First, findings from epidemiological studies suggest that patients with MS have a higher risk for ischaemic stroke than people who do not have MS. The underlying mechanism is unknown, but might involve endothelial dysfunction secondary to inflammatory disease activity and increased plasma homocysteine concentrations. Second, patients with MS have global cerebral hypoperfusion, which might predispose them to the development of ischaemic stroke. The widespread decrease in perfusion in normal-appearing white matter and grey matter in MS seems not to be secondary to axonal degeneration, but might be a result of reduced axonal activity, reduced astrocyte energy metabolism, and perhaps increased blood concentrations of endothelin-1. Data suggest that a subtype of focal MS lesions might have an ischaemic origin, and there seems to be a link between reduced white matter perfusion and cognitive dysfunction in MS. Third, the pathology of MS might be the consequence of a chronic state of impaired venous drainage from the CNS, for which the term chronic cerebrospinal venous insufficiency (CCSVI) has been coined. A number of recent vascular studies do not support the CCSVI theory, but some elements of CCSVI might be explained by slower cerebral venous blood flow secondary to the reduced cerebral perfusion in patients with MS compared with healthy individuals.

White-matter astrocytes, axonal energy metabolism, and axonal degeneration in multiple sclerosis

In patients with multiple sclerosis (MS), a diffuse axonal degeneration occurring throughout the white matter of the central nervous system causes progressive neurologic disability. The underlying mechanism is unclear. This review describes a number of pathways by which dysfunctional astrocytes in MS might lead to axonal degeneration. White-matter astrocytes in MS show a reduced metabolism of adenosine triphosphate-generating phosphocreatine, which may impair the astrocytic sodium potassium pump and lead to a reduced sodium-dependent glutamate uptake. Astrocytes in MS white matter appear to be deficient in β2 adrenergic receptors, which are involved in stimulating glycogenolysis and suppressing inducible nitric oxide synthase (NOS2). Glutamate toxicity, reduced astrocytic glycogenolysis leading to reduced lactate and glutamine production, and enhanced nitric oxide (NO) levels may all impair axonal mitochondrial metabolism, leading to axonal degeneration. In addition, glutamate-mediated oligodendrocyte damage and impaired myelination caused by a decreased production of N-acetylaspartate by axonal mitochondria might also contribute to axonal loss. White-matter astrocytes may be considered as a potential target for neuroprotective MS therapies.

Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1

Decreased cerebral blood flow (CBF) may contribute to the pathology of multiple sclerosis (MS), but the underlying mechanism is unknown. We investigated whether the potent vasoconstrictor endothelin-1 (ET-1) is involved. We found that, compared with controls, plasma ET-1 levels in patients with MS were significantly elevated in blood drawn from the internal jugular vein and a peripheral vein. The jugular vein/peripheral vein ratio was 1.4 in patients with MS vs. 1.1 in control subjects, suggesting that, in MS, ET-1 is released from the brain to the cerebral circulation. Next, we performed ET-1 immunohistochemistry on postmortem white matter brain samples and found that the likely source of ET-1 release are reactive astrocytes in MS plaques. We then used arterial spin-labeling MRI to noninvasively measure CBF and assess the effect of the administration of the ET-1 antagonist bosentan. CBF was significantly lower in patients with MS than in control subjects and increased to control values after bosentan administration. These data demonstrate that reduced CBF in MS is mediated by ET-1, which is likely released in the cerebral circulation from reactive astrocytes in plaques. Restoring CBF by interfering with the ET-1 system warrants further investigation as a potential new therapeutic target for MS.

Prehospital Unassisted Assessment of Stroke Severity Using Telemedicine A Feasibility Study

Background and Purpose— We evaluated the feasibility and the reliability of remote stroke severity quantification in the prehospital setting using the Unassisted TeleStroke Scale (UTSS) via a telestroke ambulance system and a fourth-generation mobile network. Methods— The technical feasibility and the reliability of the UTSS were studied in healthy volunteers mimicking 41 stroke syndromes during ambulance transportation. Results— Except for 1 issue, high-quality telestroke assessment was feasible in all scenarios. The mean examination time for the UTSS was 3.1 minutes (SD, 0.4). The UTSS showed excellent intrarater and interrater variability (&rgr;=0.98 and 0.97; P<0.001), as well as excellent internal consistency and rater agreement. Adequate concurrent validity can be derived from the strong correlation between the UTSS and the National Institutes of Health Stroke Scale (&rgr;=0.90; P<0.001). Conclusions— Remote assessment of stroke severity in fast-moving ambulances using a system dedicated to prehospital telemedicine, 4G technology, and the UTSS is feasible and reliable.

Astrocyte loss and astrogliosis in neuroinflammatory disorders

Neuroinflammation can lead to either damage of astrocytes or astrogliosis. Astrocyte loss may be caused by cytotoxic T cells as seen in Rasmussen encephalitis, auto-antibodies such as in neuromyelitis optica (aquaporin-4 antibodies), or cytokines such as TNF-α in major depressive disorder. Interleukins-1 and -6 appear to be important molecular mediators of astrogliosis. Chronic focal lesions in multiple sclerosis are characterized by a very dense astrogliosis. Other mechanisms, such as astrocytic β2 adrenergic receptor deficiency, upregulation of endothelin-1 and tissue transglutaminase, may contribute to astroglial scarring in multiple sclerosis.

Reliable measurements of brain atrophy in individual patients with multiple sclerosis

As neurodegeneration is recognized as a major contributor to disability in multiple sclerosis (MS), brain atrophy quantification could have a high added value in clinical practice to assess treatment efficacy and disease progression, provided that it has a sufficiently low measurement error to draw meaningful conclusions for an individual patient.

Cerebral white matter blood flow and energy metabolism in multiple sclerosis

Background: Cerebral blood flow (CBF) is reduced in normal-appearing white matter (NAWM) of subjects with multiple sclerosis (MS), but the underlying mechanism is unknown. Objective: The objective of this article is to assess the relationship between reduced NAWM CBF and both axonal mitochondrial metabolism and astrocytic phosphocreatine (PCr) metabolism. Methods: Ten healthy controls and 25 MS subjects were studied with 3 Tesla magnetic resonance imaging. CBF was measured using pseudo-continuous arterial spin labeling. N-acetylaspartate/creatine (NAA/Cr) ratios (axonal mitochondrial metabolism) were obtained using 1H-MR spectroscopy and PCr/β-ATP ratios using 31P-MR spectroscopy. In centrum semiovale NAWM, we assessed correlations between CBF and both NAA/Cr and PCr/β-ATP ratios. Results: Subjects with MS had a widespread reduction in CBF of NAWM (centrum semiovale, periventricular, frontal and occipital), and gray matter (frontoparietal cortex and thalamus). Compared to controls, NAA/Cr in NAWM of the centrum semiovale of MS subjects was decreased, whereas PCr/β-ATP was increased. We found no correlations between CBF and PCr/β-ATP. CBF and NAA/Cr correlated in controls (p = 0.02), but not in MS subjects (p = 0.68). Conclusions: Our results suggest that in MS patients there is no relationship between reduced CBF in NAWM and impaired axonal mitochondrial metabolism or astrocytic PCr metabolism.

Intravenous thrombolysis with recombinant tissue plasminogen activator in a stroke patient treated with apixaban

Apixaban is increasingly used in clinical practice (1), but data on the bleeding risk in patients treated with recombinant tissue plasminogen activator (rt-PA) while taking apixaban are nonexistent. A 74-year-old right-handed man presented with abrupt onset of global aphasia. He was known with a partial right hemianopsia secondary to a left occipital intracerebral hemorrhage five-years earlier and with paroxysmal nonvalvular atrial fibrillation treated with apixaban 5 mg bid. The National Institutes of Health Stroke Scale (NIHSS) score was 8. Noncontrast computed tomography (CT) of the brain showed no signs of acute intracranial pathology. Perfusion-CT revealed hypoperfusion in the territory of the left middle cerebral artery (Fig. 1a). An ostial stenosis of the left internal carotid artery was diagnosed on CT angiography (Fig. 1b). After informed consent by proxy, i.v. rt-PA therapy (0·9 mg/kg; total dose 81 mg) was administered at 4·5 h after symptom onset and 8·5 h after apixaban intake. Platelet count, prothrombin time, activated partial thromboplastin time, and fibrinogen levels were normal, as was creatinine clearance. The patient experienced an excellent recovery (NIHSS score 1) without signs of new infarction or intracranial hemorrhage on repeat CT. As apixaban is commonly used in patients with elevated stroke risk (1), therapeutic decision-making with regard to thrombolytic therapy may not uncommonly pose problems in the near future. Our case report illustrates that further study on the safety of rt-PA in this patient population is justified. Ann De Smedt*, Melissa Cambron, Koenraad Nieboer, Maarten Moens, Robbert-Jan Van Hooff, Laetitia Yperzeele, Kristin Jochmans, Jacques De Keyser, and Raf Brouns

Fluoxetine in Progressive Multiple Sclerosis (FLUOX-PMS): study protocol for a randomized controlled trial

BackgroundCurrently available disease-modifying treatments acting by modifying the immune response are ineffective in progressive multiple sclerosis (MS), which is caused by a widespread axonal degeneration. Mechanisms suspected to be involved in this widespread axonal degeneration are reduced axonal energy metabolism, axonal glutamate toxicity, and reduced cerebral blood flow. Fluoxetine might theoretically reduce axonal degeneration in MS because it stimulates energy metabolism through enhancing glycogenolysis, stimulates the production of brain-derived neurotrophic factor, and dilates cerebral arterioles. The current document presents the protocol of a clinical trial to test the hypothesis that fluoxetine slows down the progressive phase of MS.Methods/DesignThe FLUOX-PMS trial is a multi-center, randomized, controlled and double-blind clinical study. A total of 120 patients with the diagnosis of either secondary or primary progressive MS will be treated either by fluoxetine (40 mg daily) or placebo for a total period of 108 weeks. The primary endpoint is the time to confirmed disease progression defined as either at least a 20% increase in the timed 25-Foot Walk or at least a 20% increase in the 9-Hole Peg Test. Secondary endpoints include the Hauser ambulation index, cognitive changes, fatigue, magnetic resonance imaging of the brain, and in a small subgroup optical coherence tomography.DiscussionThe FLUOX-PMS trial will gives us information as to whether fluoxetine has neuroprotective effects in patients with progressive MS.Trial RegistrationEudra-CT: 2011-003775-11

β2-Adrenergic receptors protect axons during energetic stress but do not influence basal glio-axonal lactate shuttling in mouse white matter

In vitro studies have demonstrated that β2-adrenergic receptor activation stimulates glycogen degradation in astrocytes, generating lactate as a potential energy source for neurons. Using in vivo microdialysis in mouse cerebellar white matter we demonstrate continuous axonal lactate uptake and glial-axonal metabolic coupling of glutamate/lactate exchange. However, this physiological lactate production was not influenced by activation (clenbuterol) or blocking (ICI 118551) of β2-adrenergic receptors. In two-photon imaging experiments on ex vivo mouse corpus callosum subjected to aglycemia, β2-adrenergic activation rescued axons, whereas inhibition of axonal lactate uptake by α-cyano-4-hydroxycinnamic acid (4-CIN) was associated with severe axonal loss. Our results suggest that axonal protective effects of glial β2-adrenergic receptor activation are not mediated by enhanced lactate production.