INFECTI0N AS A RISK FACTOR OF STROKE

Osama A. RagabNeurology, MD

2016

• Although established risk factors for stroke exist, some infectious pathogens might confer additional risk either by aggravating theses factors or having a direct causal role.

• Several findings suggest a possible association between systemic infection and stroke. • Some patients who had stroke lack traditional cerebrovascular

risk factors.• stroke incidence rises during cold months, which leads to

speculation that infections contribute to this seasonal fluctuation

MECHANISM OF STROKE RELATED INFECTION

• Stimulation of the inflammatory response is thought to be the predominant mechanism linking ischaemic stroke with infection .• Inflammatory cascades promote atherosclerosis, plaque rupture, and

thrombosis, leading to ischaemic stroke. • High-sensitivity C-reactive protein in the blood might be an independent

predictor of ischaemic stroke, but its precise association is unsettled.• A systemic inflammatory response to infection can injure vascular

endothelial cells and predispose patients to intracranial haemorrhage.

INFECTIONS CAUSING STROKEBACTERIALVIRALFUNGALPARASITES

BACTERIAL INFECTIONS

INFECTIVE ENDOCARDITIS

• Stroke occurred in 17% of adult inpatients with infective endocarditis enrolled in a study done in 25 countries.

• The risk of stroke was highest at presentation of infective endocarditis and declined within 1–2 weeks after antibiotics were initiated.

• S aureus, β-haemolytic streptococci, and Streptococcus viridans are the most frequently identified pathogens in infective endocarditis complicated by intracranial haemorrhage. • Degradation of the arterial wall by bacteria or septic embolisation

causes abnormal dilatations or mycotic aneurysms. • These aneurysms can be numerous and occur at distal portions of

the middle cerebral artery, and their rupture is associated with a high mortality rate.

INFECTIVE ENDOCARDITIS

• Transesophageal echocardiogram at the level of the midesophagus demonstrating a large vegetation on the left atrial side of the mitral valve (arrow). The patient reported no neurological symptoms, and a detailed neurological examination was normal. Right, Axial MRI of the brain using a fluid-attenuation inversion recovery sequence. The bright lesion in the left frontal cortex (arrow) represents ABE. LV indicates left ventricle.

• T2* cerebral magnetic resonance imaging shows corticomeningeal small black dots related to microhemorrhages (A). At the corresponding site of a left frontal microhemorrhage (white arrow), axial and sagittal magnetic resonance angiography views (B and C) suggest the presence of a fusiform mycotic aneurysm; arterial origin was confirmed by using cerebral angiography (D)

BACTERIAL MENINGITIS• Brain infarction occurred in (25%) of patients with bacterial meningitis. • venous infarction also complicates bacterial meningitis in 3–5% of patients. • One prominent mechanism for arterial infarction is vasculitis, most

commonly associated with inflammation of large and medium cerebral blood vessels.

• Concentrations of interleukin-6 were notably elevated in the cerebrospinal fluid of the patients.

• Reactive oxygen species and reactive nitrogen intermediates have been identified as critical mediators of the pathogenesis of bacterial meningitis related stroke.

• Bacterial meningitis may be complicated by intracranial haemorrhage in 1–3% of patients.

• Causative bacteria include S pneumoniae in 67% of patients, S aureus in 21% of patients, and Pseudomonas aeruginosa or Listeria monocytogenes in a few patients .

• Intracranial haemorrhage might be evident at presentation, but in about two-thirds of cases, the haemorrhage is diagnosed later in the clinical course.

• the most frequent types of cerebral haemorrhage are intraparenchymal (42%) and subarachnoid (21%), followed by haemorrhagic transformation of infarction (17%) and microhaemorrhages (13%).

BACTERIAL MENINGITIS

• D, Apparent diffusion coefficient maps showing an acute ischemic lesion involving the complete MCA stroke territory.

• E ,MR angiography reveals a severe stenosis and reduced flow within the right distal internal carotid artery and the proximal MCA (arrow) of the same patient.

• H, Ischemic infarct involving left posterior, inferior temporal, and occipital lobe. Additional involvement of the splenium of the corpus callosum

• A 36 year old lady with meningitis showing A) normal cranial MRI but her B) MR venography shows thrombosis of superior sagittal sinus (white arrow).

• Cerebral CT scan without contrast showing a hematoma in the basal ganglia in a patient with meningitis due to S. pneumoniae.

TUBERCULOSIS• In tuberculous meningitis, a necrotising meningoencephalitis

develops with leptomeningeal exudates that surround the brainstem and infiltrate the walls of arteries and veins.• The hypercoagulable state might be associated with low blood

concentrations of protein S and increased concentrations of factor VIII. • The sites that are susceptible to cerebral infarction in patients

with TB meningitis are the basal ganglia, internal capsule, thalamus, cerebral cortex, pons, and cerebellum• Aneurysmal dilatation, ruptured mycotic aneurysm, and

granulomatous septic embolism have also been noted.

• Stroke occurs in 45% of patients with TBM both in early and later stage, mostly in basal ganglia region, and predicts pooroutcome at 3 months.

• Stroke was significantly related to stage of meningitis, hydrocephalus, exudate, and hypertension.

• Cranial MRI of patient with Tuberculosis meningitis (TBM) shows cortical and subcortical infarcts in Diffusion weighted Imaging (DW1) (A) and T2 images (B).

VIRUSES

HERPES SIMPLEX

• HSV-1, when causing meningoencephalitis, can lead to petechial cerebral haemorrhages and intracranial haemorrhage in severe cases.

• Disruption of the blood–brain barrier, cerebral oedema, and necrosis, particularly involving the temporal lobe, orbital gyrus, insula, and angular cortex are well described.

• The outcome of fulminant cerebral haemorrhage in the setting of HSV encephalitis is generally poor, even with antiviral therapy .

• Areterial ischaemic stroke may occur but less frequent than haemorrhage.

An axial T2W MRI image shows an area of left medial temporal lobe encephalitis (left). On the right, an axial CT image without contrast shows the presence of bleeding in the same encephalitic area, with brainstem compression and obliteration of the lateral ventricle horn

• Brain MRI (T1 post-IV contrast) showing enhancement in the area of the ischemic stroke.

VZV can spread to arteries in the central nervous system and cause hemorrhagic or ischemic complications due to an inflammatory vasculopathy.

VARICELLA ZOSTER VIRUS

Their findings provide evidence that HZ carries an increased risk of stroke or TIA and that the effect of HZ on stroke decreases with increasing age.

• VaricStrokes related to VZV infection tend to affect the deep structures of the brain, including the basal ganglia and internal capsules, as well as the cerebral cortex supplied by the branches of the middle cerebral artery.

VARICELLA ZOSTER VIRUS

• Hepatitis C virus (HCV) could increase the long-term risk of stroke and stroke death. • This increase might occur either through cryoglobulinaemia, which

leads to a rise in deposition of immune complexes in the vessel wall or atherosclerosis provoked by inflammation.• It has been demonstrated that HCV lives and replicates within carotid

plaque and the virus enters and replicates inside human brain endothelial cells • It is important to consider that a significant number of patients with

HCV and stroke did not show liver disease or had only a moderate disease.

HEPATITIS C VIRUS

CNS vasculitis in a patient with HCV infection. Brain MRI showed a left caudate nucleus and lenticulocapuslar recent ischemic lesion in DWI (a); an old infarction in, the right ACA territory, and other white matter changes were visible in FLAIR (b). Time of flight MR angiography revealed multiple intracranial stenosis in the proximal ACA, left ACP and basilar artery segments (c). Conventional cerebral angiography documented right ACA occlusion (d), critical stenosis at the left A1/A2 segment (e), and occlusion of the inferior 1/3 and of the distal segment of right vertebral artery (f),

HIV• HIV can directly invade the CNS as early as 8 days after systemic infection,

producing increased inflammatory markers in CSF and brain parenchymal inflammation.

• Thinning of the arterial media layer and fragmentation of internal elastic lamina occurs in patients with chronic HIV .

• Several case series have reported aneurysmal and non-aneurysmal dilatation of arteries.

• Protein S deficiency is often identified in HIV, • Other coagulopathies, namely antiphospholipid antibody syndrome, have

been reported.

FUNGI

FUNGI• Fungal meningitis typically cause vasculopathy of the large

vessels traversing the subarachnoid space, • venous outflow obstruction, and endarteritis mechanistically

account for stroke. • Fungi can also form focal brain parenchymal abscesses

associated with haemorrhage. • The highly destructive organisms can invade the walls of major

intracranial arteries, including the basilar artery, predisposing to stroke and aneurysmal rupture.

• Sagittal T2 and postcontrast sagittal and axial T2 images showing heterogeneous T2 signal intensity lesion in the sphenoid sinus destroying the posterior wall and with enhancing soft tissue extending into prepontine cisterns encasing basilar artery and causing basilar artery thrombosis.

PARASITES

CHAGAS DISEASE

• Chagas disease, caused by the Trypanosoma cruzi, is the third most common parasitic infection worldwide, with the largest infected population living in South America, Africa and Iraq.

• Chagas disease is associated with cardioembolic stroke. • Cerebral embolism most commonly occurs to the middle cerebral artery

territory, affecting 70% of patients with Chagas cardiomyopathy.

• Brain scans of patients with Chagas disease• (A) MRI (fluid-attenuated inversion recovery sequence) showing several previous

ischaemic strokes in the territory of both middle cerebral arteries in a 37-year-old man. (B) MRI (T2 sequence) showing cerebellar ischaemic infarction (in region of the posterior inferior cerebellar artery) in a 32-year-old man.

NEUROCYSTICERCOSIS

• CNS infection with Taenia solium occurs when cysticerci lodge in the subarachnoid space, brain parenchyma, or cerebral ventricles, causing local inflammation.

• Neurocysticerci can remain for years before undergoing degeneration, which stimulates an inflammatory reaction with surrounding leptomeningeal deposition of exudative material. This stage of infection is generally associated with seizure activity, increased intracranial pressure, and ischaemic and haemorrhagic infarcts.

• (A) MRI fast imaging employing steady state acquisition (FIESTA) axial image showing intra-ventricular cystic lesions with ipsilateral ventricular dilatation. (B) MRI T2W coronal image displaying a left side temporo-parietal infarction. (C) Computer tomography angiography shows decrease blood flow through LMCA (dotted arrow) and contralateral ICA aneurism (white arrow). (D) Digital substraction angiography confirmation of right ICA aneurism (black arrow).

SCHISTOSOMIASIS• Cerebrovascular events can occur during any stage of schistosomiasis, but

occur most often in the subacute and chronic stages. • Schistosomal ectopic eggs reach the CNS through retrograde flow through

the venous plexus. • Eosinophil-mediated toxicity may lead to vasculitis and small-vessel

thrombosis in acute schistosome vasculitis.• Cerebral haemorrhage typically occurs in the setting of a meningitic

granulomatous reaction around schistosomal ova.

MALARIA• the mechanical theory claims that the obstruction of the capillaries and cerebral venules

by parasitized erythrocytes is caused by direct action of the parasite on the erythrocyte, distorting its morphology.

• The results are thrombosis, anoxia, stroke, and tissue necrosis. In more serious cases, further endothelial damage produces increase in capillary permeability and even hemorrhages.

• There is also a discoloration of the cortex due to hemozoine (malarial pigment). Malaria digest haemoglobin and release high quantities of free heme, which is the non-protein component of hemoglobin. Free heme is toxic to cells, so the parasites convert it into an insoluble crystalline form called hemozoin. Since the formation of hemozoin is essential to the survival of these parasites, it is an attractive target for developing drugs .Several currently used antimalarial drugs, such as chloroquine and mefloquine, are thought to kill malaria parasites by inhibiting haemozoin biocrystallization.

• Cerebral malaria can cause cerebral edema, diffuse or focal compromise of the subcortical white matter, and cortical, cerebellar and pontine infarctions .

• Brain vessels from four different cases of fatal falciparum malaria showing accumulations of different parasite stages. A, late trophozoites, B, schizonts with abundant pigment; C, mid-stage trophozoites; D; ring forms containing no intraerythrocytic pigment.

WHEN TO INVESTIGATE FOR INFECTIOUS CAUSES

• Patients who have had strokes caused by infection might be misdiagnosed if lumbar puncture is not done.

• However, lumbar puncture is not indicated when evaluating a typical patient (an elderly person with atherosclerotic risk factors with sudden-onset focal neurological deficits).

• The clinical symptoms that might indicate infectious causes include a history of antecedent fever, rash, and known prior infections.

• For immunocompromised patients, the suspicion should be higher and CSF should be obtained in immunosuppressed patients.

• Meningeal enhancement or multifocal infarctions, particularly ones that do not respect traditional arterial or venous territories, could raise the suspicion for infectious or inflammatory pathologies.

TREATMENT• Treatment of systemic infections that precede or accompany stroke requires

prompt initiation of effective antimicrobial therapy.• The treatment of specific pathogens should generally follow established

guidelines wherever they exist. • The role of oral or intravenous steroids alongside antibiotics with infections

and new stroke is also unclear.• Infection is not an official contraindication for thrombolytic therapy;

however, formal recommendations for treatment cannot be made because of insufficient clinical data.

• No convincing evidence proves that anticoagulation prevents embolisation in either native or prosthetic valve-related infectious endocarditis; in fact, the risk of intracranial haemorrhage is probably increased with anticoagulation.

• Stable, unruptured, cerebral aneurysms are often sufficiently treated with antimicrobials alone; however, surgery or endovascular therapy can be considered for ruptured aneurysms or enlarging unruptured aneurysms.

TREATMENT

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