Stroke, the third leading cause of death and disability worldwide, is undergoing a change in perspective with the emergence of new ideas on neurodegeneration The concept that stroke is a disorder solely of blood vessels has been expanded to include the effects of a detrimental interaction between glia, neurons, vascular cells, and matrix components, which is collectively referred to as the neurovascular unit Following the acute stroke, the majority of which are ischemic, there is secondary neuroinflammation that both promotes further injury, resulting in cell death, but conversely plays a beneficial role, by promoting recovery The proinflammatory signals from immune mediators rapidly activate resident cells and influence infiltration of a wide range of inflammatory cells (neutrophils, monocytes/macrophages, different subtypes of T cells, and other inflammatory cells) into the ischemic region exacerbating brain damage In this review, we discuss how neuroinflammation has both beneficial as well as detrimental roles and recent therapeutic strategies to combat pathological responses Here, we also focus on time-dependent entry of immune cells to the ischemic area and the impact of other pathological mediators, including oxidative stress, excitotoxicity, matrix metalloproteinases (MMPs), high-mobility group box 1 (HMGB1), arachidonic acid metabolites, mitogen-activated protein kinase (MAPK), and post-translational modifications that could potentially perpetuate ischemic brain damage after the acute injury Understanding the time-dependent role of inflammatory factors could help in developing new diagnostic, prognostic, and therapeutic neuroprotective strategies for post-stroke inflammation

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Neuroinflammation: friend and foe for ischemic stroke

Inflammation is a hallmark of stroke pathology. The cytokines, tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6, modulate tissue injury in experimental stroke and are therefore potential targets in future stroke therapy. The effect of these cytokines on infarct evolution depends on their availability in the ischemic penumbra in the early phase after stroke onset, corresponding to the therapeutic window (<4.5 hours), which is similar in human and experimental stroke. This review summarizes a large body of literature on the spatiotemporal and cellular production of TNF, IL-1, and IL-6, focusing on the early phase in experimental and human stroke. We also review studies of cytokines in blood and cerebrospinal fluid in stroke. Tumor necrosis factor and IL-1 are upregulated early in peri-infarct microglia. Newer literature suggests that IL-6 is produced by microglia, in addition to neurons. Tumor necrosis factor- and IL-1-producing macrophages infiltrate the infarct and peri-infarct with a delay. This information is discussed in the context of suggestions that neuronal sensitivity to ischemia may be modulated by cytokines. The fact that TNF and IL-1, and suppossedly also IL-6, are produced by microglia within the therapeutic window place these cells centrally in potential future stroke therapy.

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.2012.88

Inflammatory cytokines in experimental and human stroke

Neuroinflammatory mediators play a crucial role in the pathophysiology of brain ischemia, exerting either deleterious effects on the progression of tissue damage or beneficial roles during recovery and repair. Within hours after the ischemic insult, increased levels of cytokines and chemokines enhance the expression of adhesion molecules on cerebral endothelial cells, facilitating the adhesion and transendothelial migration of circulating neutrophils and monocytes. These cells may accumulate in the capillaries, further impairing cerebral blood flow, or extravasate into the brain parenchyma. Infiltrating leukocytes, as well as resident brain cells, including neurons and glia, may release pro-inflammatory mediators, such as cytokines, chemokines and oxygen/nitrogen free radicals that contribute to the evolution of tissue damage. Moreover, recent studies have highlighted the involvement of matrix metalloproteinases in the propagation and regulation of neuroinflammatory responses to ischemic brain injury. These enzymes cleave protein components of the extracellular matrix such as collagen, proteoglycan and laminin, but also process a number of cell-surface and soluble proteins, including receptors and cytokines such as interleukin-1beta. The present work reviewed the role of neuroinflammatory mediators in the pathophysiology of ischemic brain damage and their potential exploitation as drug targets for the treatment of cerebral ischemia.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1742-4658.2008.06766.x

Post‐ischemic brain damage: pathophysiology and role of inflammatory mediators

The Orthopaedic Section of the American Physical Therapy Association (APTA) has an ongoing effort to create evidence-based practice guidelines for orthopaedic physical therapy management of patients with musculoskeletal impairments described in the World Health Organization's International Classification of Functioning, Disability, and Health (ICF). The purpose of these revised clinical practice guidelines is to review recent peer-reviewed literature and make recommendations related to neck pain. J Orthop Sports Phys Ther. 2017;47(7):A1–A83. doi:10.2519/jospt.2017.0302

Neck Pain: Revision 2017

CNS lymphoma consists of 2 major subtypes: secondary CNS involvement by systemic lymphoma and PCNSL. Contrast-enhanced MR imaging is the method of choice for detecting CNS lymphoma. In leptomeningeal CNS lymphoma, representing two-thirds of secondary CNS lymphomas, imaging typically shows leptomeningeal, subependymal, dural, or cranial nerve enhancement. Single or multiple periventricular and/or superficial contrast-enhancing lesions are characteristic of parenchymal CNS lymphoma, representing one-third of secondary CNS lymphomas and almost 100% of PCNSLs. New CT and MR imaging techniques and metabolic imaging have demonstrated characteristic findings in CNS lymphoma, aiding in its differentiation from other CNS lesions. Advanced imaging techniques may, in the future, substantially improve the diagnostic accuracy of imaging, ultimately facilitating a noninvasive method of diagnosis. Furthermore, these imaging techniques may play a pivotal role in planning targeted therapies, prognostication, and monitoring treatment response.

http://www.ajnr.org/content/ajnr/32/6/984.full.pdf

Central Nervous System Lymphoma: Characteristic Findings on Traditional and Advanced Imaging

Objectives –  Inflammation plays an important role in the pathophysiology of stroke. We correlated interleukin (IL)-6, IL-10, C-reactive protein (CRP) and T-lymphocyte subtype levels in acute ischemic stroke patients with stroke volume and clinical outcome.



Materials and methods –  Blood samples were obtained from 11 patients at defined intervals during 1 year. Nine healthy age-matched subjects served as controls. IL-6, IL-10 and CRP were quantified by enzyme-linked immunosorbent assay and T lymphocytes by flow cytometry. Volume measurement was carried out by computed tomography or magnetic resonance imaging and clinical outcome was scored by the European stroke scale (ESS) and Barthel index (BI).



Results –  IL-6 levels were increased in the acute phase of stroke compared with healthy controls (P = 0.002) and correlated with larger stroke volume (P = 0.012) and less favorable prognosis after 1 year, measured by ESS (P = 0.014) and BI (P = 0.006). IL-10, CRP and T-lymphocyte subtypes in the acute phase were not correlated with stroke volume or clinical outcome.



Conclusion –  IL-6 seems to be a robust early marker for outcome in acute ischemic stroke.

IL-6: an early marker for outcome in acute ischemic stroke.

Our aim was to characterise and classify structural changes in the alar ligaments in the late stage of whiplash injuries by use of a new MRI protocol, and to evaluate the reliability and the validity of this classification We studied 92 whiplash-injured and 30 uninjured individuals who underwent proton density-weighted MRI of the craniovertebral junction in three orthogonal planes Changes in the alar ligaments (grades 0-3) based on the ratio between the high signal area and the total cross-sectional area were rated twice at a 4-month interval, independently by three radiologists Inter- and intraobserver statistics were calculated by ordinary and weighted kappa Cases classified differently were reviewed to identify potential causes for disagreement The alar ligaments were satisfactorily demonstrated in all cases (244 ligaments in 122 individuals) The lesions, 2-9 years after the injury, varied from small high-signal spots to high signal throughout the cross-sectional area Signal was highest near the condylar insertion in 82 of 94 ligaments, indicating a lesion near that insertion, and near the dental insertion in eight, indicating a medial lesion No grade 2 or 3 lesion was found in the control group At least two observers assigned the same grade to 214 ligaments (877%) on the second occasion In 30 ligaments (123%) this agreement was not obtained Pair-wise interobserver agreement (weighted kappa) was fair to moderate (031-054) in the first grading, improving to moderate (049-057) in the second Intraobserver agreement (weighted kappa) was moderate to good (043-070) Whiplash trauma can cause permanent damage to the alar ligaments, which can be shown by high-resolution proton density-weighted MRI Reliability of classification of alar ligament lesions needs to be improved

MRI assessment of the alar ligaments in the late stage of whiplash injury--a study of structural abnormalities and observer agreement.

BACKGROUND AND PURPOSE: Studying imaging findings of non–acquired immunodeficiency syndrome (AIDS) primary central nervous system lymphoma (PCNSL), we hypothesized that the imaging presentation has changed with the increasing incidence of PCNSL and is related to clinical factors (eg, time to diagnosis and the patient9s being diagnosed alive or at postmortem examination). MATERIALS AND METHODS: Chart and histologic reviews of patients recorded as having PCNSL during 1989–2003 in the Norwegian Cancer Registry identified 98 patients with non-AIDS PCNSL; 75 had available imaging. CT and MR images from the first diagnostic work-up after onset of symptoms but before histologic diagnosis were reviewed. RESULTS: CT and/or MR imaging in the 75 patients revealed no lesion in 10 (13%), a single focal lesion in 34 (45%), multiple focal lesions in 26 (35%), and disseminated lesions in 5 (7%) patients. All together, we identified 103 focal lesions (single/multiple): 63% in white matter, 56% abutting the ventricular surface, and 43% in the frontal lobes); 100% (102/102 lesions evaluated with contrast) showed contrast enhancement. The median time from imaging to diagnosis for patients with no, single, multiple, or disseminated lesions was 32, 3, 5, and 3 weeks, respectively (P = .01). Patients with no or disseminated lesions were more often diagnosed at postmortem examination (P = .06). Imaging findings were practically unchanged during the consecutive 5-year periods. CONCLUSIONS: White matter periventricular contrast-enhancing single or multiple focal lesions were typical of non-AIDS PCNSL. No or disseminated lesions heightened the risk of delayed or postmortem diagnosis. Although the incidence of non-AIDS PCNSL has increased, its presentation at imaging remains unchanged.

http://www.ajnr.org/content/ajnr/30/4/744.full.pdf

CT and MR Imaging Features of Primary Central Nervous System Lymphoma in Norway, 1989-2003

Study Design. Review article. Objectives. To review the literature on soft tissue lesions of the upper cervical spine in whiplash trauma with focus on imaging. of Background Data. Whiplash injury is associated with chronic impairment in a substantial number of patients. There are different opinions as to the nature and prognosis of this condition, and the role of diagnostic imaging is debated. Methods. Review the literature on the anatomic source of the chronic whiplash syndrome. Review the literature on imaging of the upper cervical spine, emphasizing on the author's own research. Results. MRI shows structural changes in ligaments and membranes after whiplash injury, and such lesions can be assessed with reasonable reliability. Lesions to specific structures can be linked with specific trauma mechanisms. There is a correlation between clinical impairment and morphologic findings. Conclusion. Whiplash trauma can damage soft tissue structures of the upper cervical spine, particularly the alar ligaments. Structural lesions in this area contribute to the understanding of the chronic whiplash syndrome.

Magnetic Resonance Imaging Assessment of Craniovertebral Ligaments and Membranes After Whiplash Trauma

We have established an imaging protocol in order to characterise the normal ligamentous structures in the craniovertebral junction. Thirty volunteers without a history of car accident or head or neck trauma underwent MR imaging with 2-mm-thick proton-density-weighted sections in three orthogonal planes. The alar ligaments were clearly seen in every case and had three different configurations in cross-section: round, ovoid or wing-like. A broadening from lateral to medial in the coronal plane was observed in all cases. The transverse ligament was clearly demonstrated in 26 out of 30 cases. The ligament was flattened where it arched across the dens. Towards the insertions the ligament twisted into an oblique-horizontal orientation. The lower tectorial membrane had a median portion merging with the dura, and a lateral portion separated from it. Between the dens and clivus this membrane either merged totally with dura or was partly separated from it by a thin layer of fat. The posterior atlanto-occipital membrane was clearly demonstrated. It either merged with the dura or was partly or totally separated from it by a fat layer. The anterior atlanto-occipital membrane was inconsistently seen and could not be evaluated. Our refined MR protocol improves the visualisation of the craniovertebral ligamentous structures, and may in the future give new insight into post-traumatic neck disorders up to now poorly understood.

Jostein Kråkenes

Papers

IL-6: an early marker for outcome in acute ischemic stroke.

MRI assessment of the alar ligaments in the late stage of whiplash injury--a study of structural abnormalities and observer agreement.

CT and MR Imaging Features of Primary Central Nervous System Lymphoma in Norway, 1989-2003

Magnetic Resonance Imaging Assessment of Craniovertebral Ligaments and Membranes After Whiplash Trauma

MRI assessment of normal ligamentous structures in the craniovertebral junction.