Etiologic Workup in Cases of Cryptogenic Stroke

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Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

METHODS
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.

91-93
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

94-103
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. Table 1 153-161 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).

n/a
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
Tables II -VIII in appendix Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.

172-202
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15).  Domain score (%) 1. The overall objective(s) of the guideline is (are) specifically described. 2. The health question(s) covered by the guideline is (are) specifically described. 3. The population (patients, public, etc.) to whom the guideline is meant to apply is specifically described. Domain score (%) 7. Systematic methods were used to search for evidence. 8. The criteria for selecting the evidence are clearly described. 9. The strengths and limitations of the body of evidence are clearly described. 10. The methods for formulating the recommendations are clearly described. 11. The health benefits, side effects, and risks have been considered in formulating the recommendations. 12. There is an explicit link between the recommendations and the supporting evidence. 13. The guideline has been externally reviewed by experts prior to its publication. 14. A procedure for updating the guideline is provided.  Domain score (%) 18. The guideline describes facilitators and barriers to its application. 19. The guideline provides advice and/or tools on how the recommendations can be put into practice. 20. The potential resource implications of applying the recommendations have been considered. 21. The guideline presents monitoring and/or auditing criteria. Totals Bespoke system/ no reference for system provided GRADE A1 (RGA1): Evidence demonstrates at least moderate certainty of at least moderate net benefit. GRADE A2 (RGA2): Evidence demonstrates a net benefit, but of less than moderate certainty, and may consist of a consensus opinion of experts, case studies, and common standard care. GRADE B (RGB): Evidence is insufficient, conflicting, or poor and demonstrates an incomplete assessment of net benefit vs harm; additional research is recommended. GRADE C1 (RGC1): vidence demonstrates a lack of net benefit; additional research is recommended.

GRADE C2 (RGC2):
Evidence demonstrates potential harm that outweighs benefit; additional research is recommended.

RECOMMENDATION OF THE GDG (R-GDG):
LEVEL 1 (L1): Meta-analyses; randomised controlled trials with meta-analysis; randomised controlled trials; systematic reviews. The wording used in the recommendations in the guideline (for example, words such as 'offer' and 'consider') denotes the certainty with which the recommendation is made (the strength of the recommendation). No explicit statement about establishing stroke etiology.

HIGH LEVEL:
Two relevant recommendations related to brain imaging in diagnostic workup (see Table II). Explicit statement about the need to conduct further investigation of stroke mechanism if not established through initial investigation.
In about a quarter of people with stroke, and more commonly in younger age groups, no cause is evident on initial investigation. Other causes that should be considered include paroxysmal atrial fibrillation (PAF), intracranial arterial disease, cervical artery dissection, antiphospholipid syndrome and other prothrombotic conditions, and patent foramen ovale (PFO The guideline provides a stroke pathophysiology algorithm which details the potential underlying causes of a stroke which merit investigation and provides two extensive lists detailing investigations that are mandatory and those which should be completed in selection patients, one for general stroke cases and one for cases of stroke in young adults. There were no relevant formal recommendations identified in this guideline as the focus of such recommendations tended to be on treatment, with the content on establishing stroke etiology presented in the main text and appendices. Explicit statements about the need to identify underlying cause of the stroke during evaluation with a view to guiding secondary prevention.
Initial evaluation of a suspected stroke patient entails checking vital signs and stabilisation of the patient, followed by assessment of neurological deficit and co-morbidities. Goals of this assessment include: • determining whether patient has had a stroke • identifying whether or not the patient is a suitable candidate for emergency interventional therapy with agents such as tPA Explicit statements about the need to identify underlying cause of the stroke during evaluation with a view to guiding secondary prevention.
The results of assessment and investigation should answer the following questions: (1) Is this a vascular event, i.e. a stroke or transient ischaemic attack (TIA)?
(2) Which part of the brain is affected?
(3) Is it an ischaemic or haemorrhagic vascular event?
(4) What is the cause of the vascular event?
(5) What functional and social problems does this cause the patient?
(6) What other medical problems co-exist with and affect the management of the stroke? Statements about the need to identify underlying cause of the stroke during evaluation with a view to guiding secondary prevention.
Patient history should be comprehensive and should be taken within 5 minutes. The overall aim of collecting patient history is not only to identify a possible stroke but also to exclude stroke mimics (conditions with strokelike symptoms, e.g., primary tumor of brain, metastatic neoplasm of brain, meningoencephalitis, thyrotoxicosis, hypoglycemia [ Conventional CT of the head is the examination most frequently used for the emergent evaluation of patients with acute stroke because of its wide availability and usefulness.

[Class II, Level B]
In conjunction with MRI and magnetic resonance angiography (MRA), perfusion and diffusion MR are very helpful for the evaluation of patients with acute ischaemic stroke.

[Class I, Level A]
Magnetic resonance imaging has a higher sensitivity than conventional CT and results in lower inter-rater variability in the diagnosis of ischaemic stroke within the first hours of stroke onset.  CTA including extracranial and intracranial vasculature from aortic arch to vertex, which can be performed at the time of initial brain CT, is recommended as an ideal way to assess both the extracranial and intracranial circulation.

[Level B]
Vascular imaging is recommended to identify significant symptomatic extracranial carotid artery stenosis for which patients should be referred for possible carotid revascularization.

[Level A]
Carotid ultrasound (for extracranial vascular imaging) and MR angiography are acceptable alternatives to CTA, and selection should be based on immediate availability, and patient characteristics. All patients with suspected acute ischemic stroke who arrive within 6 h and are potentially eligible for EVT (refer to criteria in Box 4B and Section 5) should undergo immediate brain imaging non-contrast CT and CT angiography (CTA) without delay, from arch-tovertex including the extra-and intra-cranial circulation, to identify large vessel occlusions eligible for endovascular thrombectomy.

Ministry of Public Health (2016) Stroke and transient ischemic attack [Qatar]
Carotid artery imaging: • All people with suspected anterior circulation stroke or TIA, who after specialist assessment are considered as candidates for carotid endarterectomy. • Carotid duplex ultrasound should be performed within 24-48 hours.
• In selected patients, carotid endarterectomy can also be performed in patients with stenosis of 60-70%. For patients who are outside the time window for acute reperfusion therapies (4.5 hours at sites where only IV tPA is being considered; 8 hours at sites where endovascular therapy is considered) and for patients with TIAs, emphasis is on secondary prevention and their imaging work-up should be focused on vascular imaging (CTA, MRA or Dopplerultrasound [DUS]) to assess carotid arteries as a possible cause of the ischemic stroke, with secondary prevention in mind. If MRA is obtained, it makes sense to concurrently obtain MR imaging with DWI, FLAIR, and GRE/SWI. Echocardiography should also be obtained to assess for cardiac sources.
In acute stroke patients, vascular imaging should be performed to evaluate the mechanism of stroke and assess risk of future stroke. Overall, vascular imaging with DUS, CTA, MRA, or DSA has good agreement. It is important to evaluate the extracranial vasculature soon after the onset of acute cerebral ischemia to aid in the determination of the mechanism of the stroke, and thus potentially prevent a recurrence. In addition, CEA or angioplasty/stenting is occasionally performed acutely, which requires appropriate imaging  For patients being investigated for an acute embolic ischemic stroke or TIA, ECG monitoring for more than 24 h is recommended as part of the initial stroke work-up to detect paroxysmal atrial fibrillation in patients who would be potential candidates for anticoagulant therapy.

[Level A]
For patients being investigated for an acute embolic ischemic stroke or TIA of undetermined source whose initial short-term ECG monitoring does not reveal atrial fibrillation but a cardioembolic mechanism is suspected, prolonged ECG monitoring for at least two weeks is recommended to improve detection of paroxysmal atrial fibrillation in selected patients aged 55 years who are not already receiving anticoagulant therapy but would be potential anticoagulant candidates. [ The following laboratory investigations should be routinely considered for patients with transient ischemic attack or nondisabling ischemic stroke as part of the initial evaluation: a. Initial bloodwork: hematology (complete blood count), electrolytes, coagulation (aPTT, INR), renal function (creatinine, e-glomerular filtration rate), random glucose or hemoglobin A1c, and troponin. [Level C] b. Subsequent laboratory tests may be considered during patient encounter or as an outpatient, including a lipid profile (fasting or nonfasting); and, screening for diabetes with either a fasting plasma glucose, or 2-hour plasma glucose, or glycated hemoglobin (A1C), or 75 g oral glucose tolerance test. Not addressed as a formal recommendation but it is suggested that "Routine investigations should include full blood count, electrolytes, erythrocyte sedimentation rate, C-reactive protein, renal function, cholesterol and glucose levels, although direct evidence is lacking for each of these investigations." Oliveira-Filho et al. (2012) Guidelines for acute ischemic stroke treatment -part I [Brazil] Thus, it is well established the requirement, on admission, of exams, such as complete blood count, blood glucose and glycozilated hemoglobin (in cases of hyperglycemia), creatinine, urea, electrolytes, arterial blood gas analysis and coagulation, as well as electrocardiogram and cardiac enzymes, due to the common comorbidity of acute myocardial infarction.[Grade D, Level 5] Exams to be requested in the sub-acute phase: lipid profile, serology for Chagas' disease and syphilis, and, in young patients, in addition to the ones already mentioned, evaluation of autoimmune diseases, arteritis, homocysteine levels, AVM research, coagulopathy and genetic profile for thrombophylia. In the ED setting, laboratory tests should be obtained and processed rapidly to facilitate rapid assessment of the stroke patient, especially one who is a candidate for rtPA. At a minimum, the following tests should be performed: CBC, including platelets, blood chemistries, and coagulation studies (PT, aPTT, and INR). [Class I, Level A]