STROKE

Definitions:

Stroke:

The following definition of stroke is taken from the WHO MONICA Manual - http://www.ktl.fi/publications/monica/manual/part4/iv-2.htm#Introduction:

 

Stroke is defined as rapidly developed clinical signs of focal (or global1) disturbance of cerebral function lasting more than 24 hours (unless interrupted by surgery or death), with no apparent cause other than a vascular origin: it includes patients presenting clinical signs and symptoms suggestive of subarachnoid haemorrhage, intracerebral haemorrhage or cerebral ischaemic necrosis. It does not include transient cerebral ischaemia or stroke events in cases of blood disease (e.g. leukaemia, polycythaemia vera), brain tumour or brain metastases. Secondary stroke caused by trauma should also be excluded. A diagnosis of ischemic stroke is made only if the patient has a clinical diagnosis of stroke and if a CT scan or MR of the brain done after onset of symptoms either is normal or shows the relevant infarct. Patients with hemorrhagic transformation of an infarct remain eligible.

Time of stroke onset:

It is defined as the time when the subject was last noted to be at baseline neurologic status. If the patient awoke with stroke symptoms, the time of onset is taken as the last time the patient was known to be awake and without any symptoms of stroke.

Note1 : Global: this applies to patients with subarachnoid haemorrhage or deep coma but excluding coma of systemic vascular origin such as shock, Stokes-Adams syndrome or hypertensive encephalopathy.

 

Important Terminology:

 

  • stroke or cerebrovascular accident (CVA): permanent ischemic neurological deficit
  • Transient ischemic attack (TIA):

    The following definition is taken from the National Clinical Guidelines for Stroke (2nd edition) prepared by the UK Intercollegiate Stroke Working Party 2004 - http://www.rcplondon.ac.uk/pubs/books/stroke/stroke_guidelines_2ed.pdf

    Transient ischaemic attack (TIA) is a clinical syndrome characterised by an acute loss of focal cerebral or ocular function with symptoms lasting less than 24 hours. It is thought to be due to inadequate cerebral or ocular blood supply as a result of low blood flow, thrombosis, or embolism associated with diseases of the blood vessels, heart, or blood (Hankey & Warlow 1994).

 

 

DATA COLLECTION:

 

Variables of data collection for an Ischemic Stroke Genetics Study:

  • Structured interview

  • Demographics

  • Medications

  • Family history

  • Past medical history

  • Social and behavioural history

  • QVSS

  • Vital signs

  • Medical records

  • Blood sample

  • Laboratory tests

  • Head imaging

  • Vascular imaging

  • Treatments

 

STROKE DIAGNOSIS:

 

Stroke Diagnosis:

Definite focal signs - reproduced from the WHO MONICA Manual - http://www.ktl.fi/publications/monica/manual/part4/iv-2.htm#Introduction:

Not acceptable as sole evidence of focal dysfunction - although strokes can present in this way, these signs are not specific and cannot therefore be accepted as definite evidence for stroke - reproduced from the WHO MONICA Manual - http://www.ktl.fi/publications/monica/manual/part4/iv-2.htm#Introduction:

  • Dizziness, vertigo

  • Localized headache

  • Blurred vision of both eyes

  • Dysarthria (slurred speech)

  • Impaired cognitive function (including confusion)

  • Impaired consciousness

  • Seizures

Diagnostic Categories - reproduced from the WHO MONICA Manual - http://www.ktl.fi/publications/monica/manual/part4/iv-2.htm#Introduction:

 

There are the following three categories:

(1) = Definite stroke
(4) = Not stroke
(5) = Definite stroke associated with Definite myocardial infarction
(9) = Insufficient data

Insufficient data should be mainly used for fatal cases, especially for cases of sudden death without necropsy.

All patients having insufficient supporting evidence of stroke, but for whom the diagnosis of stroke cannot be entirely excluded, should be classified as insufficient data, e.g. cases with no necropsy, no documented history of focal neurologic deficits and no other diagnosis. Living patients can be classified into this category if:

  1. it is impossible to say whether the symptoms were from stroke or from some other disease, e.g. epilepsy, or

  2. patients with symptoms and clinical findings otherwise typical for a stroke but the duration remaining uncertain.

 

Confirmation of given subjects being stroke-free:

 

 

Stroke Risk Factors, Warning Signs, And Symptoms:

 

Several risk factors have been identified for stroke. Risk factors may be categorized into those that are not modifiable and those that are changeable or controllable.

Non-modifiable Risk Factors:

 

 

Modifiable or Controllable Risk Factors:

 

  • Elevated Cholesterol:

Cholesterol test - http://www.nlm.nih.gov/medlineplus/ency/article/003492.htm

            Code of best practice for the measurement of blood glucose and cholesterol - http://www.health.nsw.gov.au/public-health/ehb/general/skinpen/cobp_bg_bc.pdf

CRMLN (Cholesterol Reference Method Laboratory Network ) Member Laboratories – International - http://www.cdc.gov/labstandards/crmln_member_labs_international.htm

International Clinical Laboratories Certified for Total Cholesterol measurement - http://www.cdc.gov/labstandards/pdf/crmln/Web_TCCert_International_Report.pdf

  • Smoking:

Smoking questionnaire to collect data for research purposes and for service development - http://www.scsrn.org/research_resources.html

Conduction of a smoking prevalence survey - http://factsheets.globalink.org/en/prevalence.shtmlink

  • Atrial fibrillation & other cardiac diseases:

Overview of atrial fibrillation / flutter - http://www.nlm.nih.gov/medlineplus/ency/article/000184.htm

Active and passive tests done to diagnosis atrial fibrillation and to determine its severity - http://www.mayoclinic.org/atrial-fibrillation/diagnosis.html

  • Obesity (patients have more hypertension, lipid abnormalities, etc.):

Anthropometric measurements in the context of obesity as per the WHO MONICA report - http://www.ktl.fi/publications/ehrm/product1/section6.htm

Definition of obesity - http://www.cdc.gov/nccdphp/dnpa/obesity/defining.htm

Body Mass Index (BMI) definition, BMI formula and BMI calculator - http://www.nhlbisupport.com/bmi/, http://www.cdc.gov/nccdphp/dnpa/bmi/index.htm

BMI table - United States Department of Health and Human Services - http://www.cdc.gov/nccdphp/dnpa/bmi/00binaries/bmi-adults.pdf

Important statistics related to overweight and obesity; why do statistics about overweight and obesity differ - http://win.niddk.nih.gov/statistics/index.htm

  • Sedentary lifestyle.

  

Warning Signs:


The five warning signs of stroke are:  

  1. Sudden numbness or weakness of face, arm or leg, especially on one side of the body

  2. Sudden confusion, trouble speaking or understanding

  3. Sudden trouble seeing in one or both eyes

  4. Sudden trouble walking or experiencing dizziness, loss of balance or coordination.

  5. Sudden headache with no known cause.

Measures to asses the severity of neurological deficit in a stroke patient: Measures to asses the severity of neurological deficit in a stroke patient:

 

Measures to asses the severity of neurological deficit in a stroke patient:

NIH Stroke Scale (NIHSS): for assessing the severity of the neurological deficit:

 

Measures for Stroke Subtyping: Measures for Stroke Subtyping:

 

Measures for stroke subtyping:

 

Types of stroke:

 

Management and prognosis of different stroke subtypes differ. For any stroke study, it is therefore imperative to establish the exact stroke subtype in the studied subjects.

Subarachnoid Haemorrhage ICD 8 or 9 43 - http://www.nlm.nih.gov/medlineplus/ency/article/000701.htm

Symptoms:

Abrupt onset of severe headache or unconsciousness or both. Signs of meningeal irritation (stiff neck, Kernig and Brudzinski signs). Focal neurological deficits are usually not present.

Signs:

At least one of the following must be present additional to typical symptoms.

  1. Necropsy - recent subarachnoid haemorrhage and an aneurysm or arteriovenous malformation

  2. CT - blood in the Fissura Sylvii or between the frontal lobes or in the basal cistern or in cerebral ventricles

  3. Cerebrospinal fluid (liquor) bloody (>2 000rbc per cmm) and an aneurysm or an arteriovenous malformation found on angiography

  4. Cerebrospinal fluid (liquor) bloody (>2 000rbc per cmm) and xanthochromic and the possibility of intra-cerebral haemorrhage excluded by necropsy or CT-examination.

Intracerebral haemorrhage ICD 8 or 9 431 - http://www.emedicine.com/emerg/topic557.htm

Symptoms:

Usually sudden onset during activities. Often rapidly developing coma, but small haemorrhage presents no consciousness disturbance.

Signs:

Cerebrospinal fluid often, but not always bloody or xanthochromic. Often severe hypertension present. Haemorrhage must be confirmed by necropsy or by CT-examination.

Brain infarction due to occlusion of precerebral arteries ICD 9 433 ICD 8 432

Symptoms:

May vary.

Signs:

The occlusion must be confirmed by angiography or ultrasound or necropsy.

Brain infarction due to cerebral thrombosis ICD 9 434 ICD 8 433 - http://www.emedicine.com/emerg/topic558.htm

Symptoms:

No severe headache, if at all. Onset acute, sometimes during sleep. Often gradual progression of focal neurologic deficits. Usually, no, or only slight, disturbance of consciousness. TIA can often be detected in history. Often other symptoms of atherosclerosis (CHD, peripheral arterial disease) or underlying diseases (hypertension, diabetes).

Signs:

Brain infarction in the necropsy or in the CT-examination and no evidence for an embolic origin.
 

OR

 

CT scan of satisfactory quality shows no recent brain lesion although clinical criteria of stroke are fulfilled.

Embolic brain infarction ICD 9 434 ICD 8 434 - http://www.emedicine.com/emerg/topic558.htm

Symptoms:

Abrupt onset, usually completion of the neurologic deficits within a few minutes. Disturbance of consciousness absent or only slight at the onset.

Signs:

As in brain infarction due to cerebral thrombosis, but in addition a source of the embolus must be detectable. The most common origins are:

  • arrhythmia (atrial flutter and fibrillation)

  • valvular heart disease (mitral)

  • recent AMI (within previous 3 months).

 

Pathophysiology:  Pathophysiology:   

Thorough understanding of the underlying mechanisms involved in the pathogenesis of stroke is important in order to correctly select the candidate genes for any study considering the polymorphisms associated with stroke.

 

On the macroscopic level: ischemic strokes are mostly either thrombotic (thrombus developing in some intracerebral vessel) or embolic (an embolus coming from heart etc and occluding some of the intracerebral blood vessel).

 

On the cellular level: Ischemic of the brain tissue ensues a cascade of events that ultimately terminates in tissue death. All ATP-generating pathways that are dependent on continuous supply of oxygen stop. The obvious consequence would be failure of all ATP-dependent cellular processes - the most important being the active ionic transport across the cellular membrane. Failure of this transport causes massive influx of calcium from ECF to ICF, which in turn activates many degradative enzymes  which cause destruction of essential cellular structures like cell membrane. In essence one can say that the ATP-dependent ionic transport across the cell membrane is essential for the maintenance of cell membrane integrity. Once this integrity is lost, many of the cytoplasmic organelles will leak into the ECF culminating to the death of the individual cells.

 

Another important ill-effect of calcium influx is the consequent release of a number of excitatory neurotransmitters (like glutamate) from the ischemic cells, which stimulate excitatory receptors on surrounding cells (like N-methyl-D-aspartate (NMDA)) causing their depolarization and thus consequent influx of calcium and activation of degradation enzymes in these surrounding cells as well. In this way, ischemic death of a given pocket of cells will in turn culminate in the death of some of the surrounding pockets of cells as well.

 

Moreover, ischemia causes generation and release of such degradative factors like free radicals, arachidonic acid, and nitric oxide, which cause further neuronal damage.

 

Within hours to days after a stroke, specific genes are activated, leading to the formation of cytokines and other factors that in turn cause further inflammation and microcirculatory compromise.

 

The cumulative effect of all the afore-mentioned cellular processes is neuronal death and infarction within hours of the onset of the stroke.

 

Likely interventions to block the ischemic cascade: Based on our understanding of the different cellular processes that ensue following ischemia and culminate in neuronal death, different interventional strategies have been proposed, like blocking the calcium channels and thus inhibiting calcium influx or antagonising the glutamate receptor with some other agent.

 

Genetics and Pathobiology of Stroke: Genetics and Pathobiology of Stroke:

Hypertension, DM, smoking and hypercholesterolemia are considered as the major risk factors for stroke. It is a well-established fact that conditions like hypertension, DM and hypercholesterolemia have strong genetic basis. Even the effects of exposure to toxins contained in cigarette smoke, and infectious agents are modified by an individual's genetic make-up. In this way, it can be safely said that stroke (atherosclerosis, precisely speaking) has a strong genetic component in its pathobiology.

Infection:

 

Since host defences are modified by genes, an individual's susceptibility to develop infection is very much governed, at least in part, by his genetic make-up. An example being the strong association of certain human leukocyte antigen (HLA) classes to autoimmune responses. A ubiquitous infectious agent thus may cause an inflammatory response in some but not others.  Hegele et al, (2000) found that some polymorphisms of the mannose-binding lectin gene, which codes for a protein designed to help facilitate phagocytosis, increase the risk of infection in humans. These polymorphisms also were found to correlate with the presence and size of carotid atherosclerotic plaques.

 

The pro-inflammatory genotype, although helps in wound healing and eradication of infections, may contribute to atherosclerosis and insulin resistance. Many genes coding for molecules involved in inflammatory mechanisms may thus have possible connection to atherosclerotic disease.

Common sporadic strokes - a consequence of polygenic or multifactorial influences:

 

Most strokes appear to be sporadic. There is considerable evidence that suggests that sporadic stroke is due in part to genetic influences. Rather than being due to a highly penetrant single gene disorder however, common sporadic strokes are thought to arise as a consequence of polygenic or multifactorial influences whereby multiple genes each exert a small influence or risk on phenotype - http://www.acnr.co.uk/pdfs/volume4issue4/v4i4reviewartstroke.pdf

Monogenic stroke - http://brain.oxfordjournals.org/cgi/content/full/123/9/1784

Although, majority of cases of ischaemic stroke are multifactorial in aetiology, mutations in the Notch 3 gene is increasingly appreciated as a cause of familial subcortical stroke. Single-gene defect as a cause of stroke should be considered in the differential diagnosis of any young patient presenting with stroke, or a young or middle-aged adult who lacks the usual risk factors, particularly in the presence of a family history of young-onset stroke.

  • Single-gene disorders that cause cardioembolic stroke - http://stroke.ahajournals.org/cgi/content/full/strokeaha;32/12/2762 In cases of embolic stroke, the usual source of embolus is heart. Many cardiac ailments that predispose to thromboembolic phenomenon are single-gene disorders e.g. familial atrial myxomas, hereditary cardiac conduction defects and inherited cardiomyopathies. The latter may present as a primary cardiac disorder (e.g. hypertrophic obstructive cardiomyopathy) or be secondary to a neuromuscular disorder (e.g. Duchenne muscular dystrophy) or one of the inborn errors of metabolism (e.g. Menkes disease).

  • Single-gene disorders that cause large artery disease:  Important single-gene disorders include homocysteinuria and dyslipidaemias. The molecular genetic basis of homocysteinuria has been well characterized. The cystathione -synthase gene maps to chromosome 21q22.3 (Kraus et al., 1993), and there are several relatively common mutations. The I278T and A114V mutations are widely distributed and frequently found in pyridoxine responders, whilst the G307S and A1224–2C mutations occur more frequently in northern European populations and are associated with a lack of pyridoxine responsiveness (Sebastio et al., 1995). As regards dyslipidaemias, a link has been reported in several disorders, including familial hypoalphalipoproteinaemia, familial hypercholesterolaemia (homozygous form), type II and type IV hyperlipidaemia and Tangier's disease (Brown et al., 1983; Third et al., 1984; Natowicz and Kelley, 1987).

  • Single-gene disorders that cause haematological disorders: Haemoglobinopathies, including sickle cell disease and various inherited coagulopathies (deficiency of the natural anticoagulants protein C and protein S) predispose to thrombosis of the cerebral vasculature, in particular in the young. In cases with a positive family history of young-age thrombosis the association is likely to be causal (Kohler et al., 1990; Barinagarrementeria et al., 1994). In elderly individuals, the relationship between the levels of protein C and protein S and stroke appears to be weak (Markus and Hambley, 1998).

  • CADASIL - http://ghr.nlm.nih.gov/condition=cadasil: Cases of familial vascular dementia began to appear in the literature in 1977 and since then have been given a number of names. In 1993, the acronym CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) was adopted to designate a form of this disorder as specified by genetic homogeneity (Tournier-Lasserve et al., 1993). The underlying pathology of this condition is non-arteriosclerotic, non-amyloid angiopathy involving the media of the cerebral small vessels.The underlying genetic mutation was identified using a linkage strategy. A sequence of 8 cM (centimorgans) was defined in CADASIL (Joutel et al., 1996; Dichgans et al., 1996), within which the human equivalent of the mouse Notch 3 gene was identified. This was proposed as a candidate gene on the basis of similarity between another gene involved in Notch signalling, Sel 12, and S 182, a gene implicated in Alzheimer's disease (Levitan and Greenwald, 1995). Identification of deleterious mutations confirmed Notch 3 as the causative gene.

  • Mitochondrial encephalomyelopathy, lactic acidosis and stroke-like episodes (MELAS - http://www.emedicine.com/ped/topic1406.htm): It is a mitochondrial encephalopathy. Muscle biopsy usually reveals abnormal mitochondria and ragged red fibres. The underlying cause of this disorder is mutations in the mitochondrial DNA. MELAS, like many mitochondrial disorders, demonstrates the phenomenon of heteroplasmy.  MELAS mutations usually lie within the tRNA-leu gene (UUR). Most frequently reported is an AG transition at position 3243 (Enter et al., 1991) and a TC transition at position 3271 (Sakuta et al., 1993). It has been proposed that mutations at position 3243 may result in somatic mutations accumulating in the mitochondrial DNA, leading to progressive mitochondrial dysfunction (Kovalenko et al., 1996).

Genes confer susceptibility to Vascular Cognitive Impairment (VCI):

Genes which confer susceptibility to vascular cognitive impairment can be divided into two categories:

  1. Genes that confer susceptibility to cerebrovascular disease.

  2. Genes that determine brain tissue responses to cerebrovascular disease (i.e. render parenchymal tissue more or less susceptible to injury or able to repair itself after injury).

Although some progress has been made in identifying genes of the first class, little has been done to explore genes of the second class.

 

Atherosclerosis -  an inflammatory process: Atherosclerosis -  an inflammatory process:

http://content.nejm.org/cgi/content/extract/340/2/115

Atherosclerosis is indeed an inflammatory process. When endothelium is damaged or becomes dysfunctional, a cascade leading to atherogenesis is precipitated, initiating a cycle of injury, immunologic induction, and amplification. Genetics may influence atherosclerosis in numerous ways. For example, genes control the development of inflammatory mediators involved in atherogenesis. In this way genes influence the extent of the pro-inflammatory response or its specificity. Likewise, some other genes are incriminated in influencing the ischemic vulnerability of the tissue and also the ability of the tissue to recover following an ischemic attack. Risk-factors leading to endothelial damage / dysfunction, triggering the inflammatory cascade, include the following:

  • Hypertension.
  • Diabetes Mellitus (DM).
  • Smoking
  • Low-density lipoprotein
  • Homocysteine
  • Infection
    • Chlamydia
    • Herpes

Role of hypertension and Angiotensin II in the pathogenesis of stroke:

 

Hypertension increases the stroke-risk (risk of atherogenesis) by 3-5 fold  (Benson and Sacco, 2000). Hypertension can result in mechanical injury to endothelium, thereby increasing the number of endothelial adhesion molecules, which attract monocytes and lymphocytes. Angiotensin II, in addition to being a potent vasoconstrictor, can lead to smooth muscle hypertrophy, extracellular matrix production, and induction of cytokines. Expression of angiotensin-converting enzyme (ACE) has been demonstrated in macrophages, lymphocytes, and microvessels neighboring carotid plaques (Fukuhara et al, 2000). Independent of the effects of angiotensin II, hypertension has been shown in animals to increase formation of hydrogen peroxide and free radicals, which in turn can increase leukocyte adhesion (Ross; Swei et al). Thus additional pathophysiologic studies are needed.

 

American Heart Association Updates Recommendations for Blood Pressure Measurements - http://www.medscape.com/viewarticle/496270

Standard suggestions for measuring blood pressure to use in populations surveys - http://publications.paho.org/english/Vol.14_5_Special.pdf

 

Diabetes mellitus (DM):

 

Diabetes mellitus increases stroke-risk by 1.5-3 fold. DM by causing endothelial damage accelerates atherosclerosis. It induces both microangiopathic changes and large-vessel atherosclerosis.

 

Code of best practice for the measurement of blood glucose and cholesterol - http://www.health.nsw.gov.au/public-health/ehb/general/skinpen/cobp_bg_bc.pdf

 

Smoking:

 

Smoking almost doubles the risk of stroke. This is thought to occur by multiple mechanisms. Smoking leads to decreased arterial wall compliance, increased platelet aggregation, increased fibrinogen levels, and decreased HDL cholesterol levels. Smokers show a lower production of endogenous tissue plasminogen activator (tPA) antigen secondary to substance P infusion, suggesting an impairment of endogenous fibrinolysis in smokers (Newby et al, 1999). Physiologically, endogenous t-PA is released by endothelial cells in order to lyse subclinical clots, which develop on denuded areas on the surface of atherosclerotic plaques. An attenuated tPA production thus worsens atherogenesis.

 

Interestingly, serum t-PA levels have a diurnal pattern with the trough in the morning. This contrasts with levels of the most significant endogenous t-PA inactivator, plasminogen activator inhibitor 1 (PAI-1), which peaks in the morning. Elevated PAI-1 levels can be seen with hypertension, increased age, and insulin resistance. In one study, PAI-1 activity was higher in patients with stroke than in a control group (Lindgren et al, 1996). Nicotine also may increase levels of PAI-1, as shown in endothelial cells in culture, thus inactivating t-PA (Zidovetzki et al, 1999). This may represent another mechanism by which endogenous fibrinolysis is impaired in smokers.

Homocysteine:

 

Those with genetic enzyme disorders, such as deficiencies in cystathionine beta-synthase, have elevated homocysteine levels and accelerated atherosclerosis associated with the disease homocysteinuria. Interestingly, raised homocysteine levels have been found even in those individuals with no enzymatic defect. In this way, elevated homocysteine level should be considered as an independent risk factor for vascular disease regardless of the presence or absence of an enzymatic defect.

 

Homocysteine also has been postulated to cause a release of reactive oxygen species. Elevations of both homocysteine and lipid peroxide have been found in patients with acute stroke, while low levels of ascorbic acid (a potent antioxidant) have been detected. This suggests depletion of ascorbic acid in the setting of increased oxidative stress (El Kossi et al, 2000).

 

An association may exist between elevated homocysteine levels and large- and small-vessel strokes, but not with cardioembolic infarcts, lending support to the contribution of homocysteine in atherogenesis rather than as another mechanism of increased stroke risk (Eikelboom et al, 2000).

 

Overview of Homocystinuria - http://www.nlm.nih.gov/medlineplus/ency/article/001199.htm

DTT (dithiothreitol) method is a simple and inexpensive assay for homocysteine determination in human plasma for research application - http://medind.nic.in/iaf/t03/i2/iaft03i2p106.pdf

 

Infection:

 

Since inflammatory cells play a major role in the pathogenesis of atheroma plaques, a past history of chronic or even acute infection may be regarded as one of the predispositions for vascular disease. The antecedent infection may have very much triggered the inflammatory cascade, which originally initiated the fatty streak formation in the vasculature. Another clue to the involvement of an infectious agent in the pathogenesis of atheromatous plaques comes from the observation of increased mRNA coding for complement proteins in plaques (Yasojima et al, 2001).

 

Role of C-reactive protein (CRP):

 

CRP is nowadays considered as a marker for vascular disease. Raised CRP levels in patients of myocardial infarction (MI) and stroke generally means poor prognosis. In addition to the suggestion that CRP is likely a marker for an ongoing inflammatory/infectious process, there is evidence to suggest that CRP actually has a pathogenic role in the progression of atherosclerosis (plaques have a higher expression of CRP mRNA than normal arteries - Yasojima et al, 2001).

 

Overview of C-reactive protein testing - http://www.nlm.nih.gov/medlineplus/ency/article/003356.htm

 

Chlamydia:

 

C pneumoniae has been implicated as a possible causative agent for atherosclerosis more than any other infectious pathogen.

 

Chlamydia serology - what test to ask?

Chlamydia pneumoniae serology: comparing a commercial enzyme immunoassay and microimmunofluorescence test in patients with cardiovascular disease:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12716394&dopt=Abstract

Importance of Methodology in Determination of Chlamydia pneumoniae Seropositivity in Healthy Subjects and in Patients with Coronary Atherosclerosis:

http://jcm.asm.org/cgi/content/abstract/41/9/4049?ijkey=a4c3b328f6110d35e0a5bfd0a466bfdac825b0a0&keytype2=tf_ipsecsha

Early Carotid Atherosclerosis and Chlamydia pneumoniae Seropositivity: Are There Arguments to Treat With Antibiotics?

http://circ.ahajournals.org/cgi/content/full/110/7/e74


Herpes:

 

Viruses have been hypothesized to play a pathogenic role in atherosclerosis as well. Although results have been mixed, some prospective studies have failed to find an association between IgG and cytomegalovirus (CMV), herpes simplex virus (HSV), and subsequent stroke (Danesh et al, 1999; Nicholson and Hajjar, 1998; Ridker et al, 1998).

 

Diagnostics tests for herpes - http://www.herpesalliance.org/diagnostics.htm

 

 

Lab Studies:  Lab Studies:   

 

         Complete blood count (CBC), basic blood chemistry, coagulation profile and cardiac biomarkers should be obtained in most patients. Normal haematological reference values-       http://en.wikipedia.org/wiki/Reference_ranges_for_common_blood_tests):

o       Interestingly, a test as simple as CBC can very much reveal the underlying cause for the stroke (e.g. polycythemia, thrombocytosis, thrombocytopenia, leukaemia). Even when the other parameters are normal, it can provide the evidence of a concurrent illness like anaemia.

o       Chemistry panel can reveal conditions which can clinically simulate stroke like hypoglycaemia, hyponatremia. It can also provide evidence of concurrent illness (e.g. diabetes, renal insufficiency). Code of best practice for the measurement of blood glucose and cholesterol - http://www.health.nsw.gov.au/public-health/ehb/general/skinpen/cobp_bg_bc.pdf

o       The purpose of asking the coagulation profile is to rule out coagulopathy. This is important before instituting thrombolytics or anticoagulants in a stroke patient. WHO International Standards (IS) for the measurement of blood coagulation factors and inhibitors in plasma - http://www.who.int/bloodproducts/ivd/coagulation_disorders/en/

o       Some authors recommend cardiac biomarkers because of the association of cerebral vascular disease and coronary artery disease. Overview of cardiac biomarkers - American Association for Clinical Chemistry - http://www.labtestsonline.org/understanding/analytes/cardiac_biomarkers/glance.html

o       Recommendations of the National Academy of Clinical Biochemistry (NACB), Laboratory Medicine Practice Guidelines for the use of cardiac markers in coronary artery diseases:

http://www.nacb.org/lmpg/cardiac_lmpg.stm

         Toxicology screens may be useful in selected patients. Recommendations of the National Academy of Clinical Biochemistry (NACB), Laboratory Medicine Practice Guidelines for the use of laboratory tests in poisoned patients:

http://www.nacb.org/lmpg/emtox_lmpg.stm

 

Imaging Studies: Imaging Studies:

 

  • Head CT scan: In every stroke patient, it is mandatory to go for a noncontrast CT scan head as early as possible. There are at least three pertinent aims of asking CT scan (a) to find out that whether the cause of stroke is vascular occlusion (thrombosis / embolism) or hemorrhage, (b) to delineate the anatomic distribution of stroke. Recall that the patients with thromboembolism as a cause of stroke may be the candidates to receive  thrombolytic therapy, instituting the same therapy in patients with hemorrhagic stroke practically means iatrogenic killing, (c) CT scans also may rule out other life-threatening processes, such as hematomas, neoplasms, and abscesses.
  • Findings: In a stroke patient, the radiological findings on CT scan change with time. These are usually normal within the initial 06 hours. After 6-12 hours, sufficient oedema is recruited into the stroke area to produce a regional hypodensity on CT scan. Other radiologic clues to acute ischemic infarction include the insular ribbon sign, the hyperdense MCA sign, obscuration of the lentiform nucleus, sulcal asymmetry, and loss of gray-white matter differentiation.
  • Shortcomings: Unfortunately, as many as 05% of patients with subarachnoid haemorrhages have normal CT scans. This is the reason why, if subarachnoid hemorrhage is suspected clinically, but CT scan comes out to be normal, lumbar puncture should be done. CT scans also may fail to demonstrate some parenchymal haemorrhages smaller than 1 cm.

 

Useful links regarding CT scan:

  

       Standardized criteria for measuring the infarct size using the first CT or MRI scan –

       An update on the preparation and execution of CT scan head; interpretation of the abnormal results, risks and special considerations: http://www.nlm.nih.gov/medlineplus/ency/article/003786.htm)

       Standardized methods of measuring for diagnostic X-ray exposures published by the American Institute of Physics - http://www.aapm.org/pubs/reports/rpt_31.pdf

       Acute stroke: usefulness of early CT findings before thrombolytic therapy -  http://radiology.rsnajnls.org/cgi/content/abstract/205/2/327

 

  • Non-invasive arterial studies:

 

    • Carotid duplex scanning: It is reserved for patients with acute ischemic stroke in whom carotid artery stenosis or occlusion is suspected.
    • Transcranial Doppler ultrasound: It is useful for evaluating more proximal vascular anatomy, including the MCA, intracranial carotid artery, and vertebrobasilar artery.
    • Results of these studies may guide the decision to initiate anticoagulation or to perform carotid endarterectomy.

Useful links regarding carotid duplex scanning:

         Technical aspects and interpretation of the results of carotid duplex imaging - http://www.gehealthcare.com/usen/ultrasound/products/msucmecd.html

http://www.nlm.nih.gov/medlineplus/ency/article/003774.htm

         Before, during and after the Transcranial Doppler ultrasound:

http://www.clevelandclinic.org/health/health-info/docs/0100/0159.asp?index=4998&src=news

  

  • Echocardiography:

 

         Echocardiography is reserved for patients with acute ischemic stroke in whom heart as a source of embolism is suspected.

         Transesophageal echocardiography is useful for detecting thoracic aortic dissection, and transthoracic echocardiography may assist in the diagnosis of acute MI: http://stroke.ahajournals.org/cgi/content/abstract/strokeaha;24/12/1865

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8195520&dopt=Citation

         Since early anticoagulation of patients with cardioembolic stroke is controversial, emergent echocardiography is indicated when it will lead to a change in the patient's ED management.

Useful links regarding echocardiography:

  •   Preparation, execution, interpretation, risks and special considerations regarding echocardiography:

http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm

         Transesophageal echocardiography in the detection of potential cardiac source of embolism in stroke patients -http://stroke.ahajournals.org/cgi/content/abstract/strokeaha;22/6/727

 

  • Magnetic resonance imaging:

 

    • MRI is superior to CT scan in terms of showing cerebellar stroke or lacunar pathology.
    • Disadvantages include its high cost, lack of ready availability, and insensitivity for detecting early haemorrhages.

Useful links regarding MRI:

  •   A Standardized MRI Stroke Protocol:

http://stroke.ahajournals.org/cgi/content/full/strokeaha;30/4/765

         Practice guideline for the performance and interpretation of magnetic resonance imaging (MRI) of the brain:

http://www.acr.org/s_acr/bin.asp?TrackID=&SID=1&DID=12250&CID=542&VID=2&DOC=File.PDF

         Comparison of diffusion-weighted MRI and CT in acute stroke - http://neurology.org/cgi/content/abstract/54/8/1557

 

Other Tests: Other Tests:

 

         Electrocardiogram: ECG should be obtained on all patients with acute stroke The cause is obvious. In as many as 60% of all cardiogenic emboli patients, some intrinsic cardiac pathology like atrial fibrillation or acute MI is found. To rule out these pathologies, it is mandatory to ask for ECG examination.

         Continuous cardiac monitoring: It has been recommended by some for all patients. The aim is to rule out the presence of life-threatening arrhythmias during the course of their illness (present in 04% cases!), and concurrent MI (present in 03% cases!) - http://stroke.ahajournals.org/cgi/content/abstract/strokeaha;16/6/950

Useful links regarding ECG:

         ACC/AHA Clinical Competence Statement on Electrocardiography and Ambulatory Electrocardiography:

http://www.acc.org/clinical/competence/ecg/III_electrocardiogram.htm

         ECG – an overview:

http://www.webmd.com/hw/heart_disease/hw213248.asp.

 

 Procedures:  Procedures:

 

  • Angiography:
    • Angiography is useful for patients with subtle occlusive diseases (e.g., fibromuscular dysplasia, vasculitis) or arterial dissection. In such patients delineation of cerebral vasculature can have therapeutic bearings (the treating doctor may decide to go for surgery instead of instituting conservative therapy). 
    • In all surgery candidates for carotid artery disease, angiography is done as an important preoperative evaluation tool.

   Useful links regarding carotid angiography:

  •   Carotid Angiography and Stenting – an overview:

http://www.clevelandclinic.org/heartcenter/pub/guide/tests/procedures/carotidstent.htm

  •   Cerebral angiography – before, during and after the test:

http://www.nlm.nih.gov/medlineplus/ency/article/003799.htm

        Racial variations in the rates of carotid angiography and endarterectomy in patients with stroke and transient ischemic attack:

http://archinte.ama-assn.org/cgi/content/abstract/153/24/2781

Genetic Data:Genetic Data:

Measures for data analysis: Measures for data analysis:

       Hosmer DW Jr, Lemeshow S: Applied Logistic Regression

New York, Wiley 1989

       Simple Methods for Analyzing Three-Factor Interaction in Contingency Tables -

http://www.jstor.org/view/01621459/di985877/98p0224i/0?frame=noframe&userID=984e06de@soton.ac.uk/01cc99339700507d1d3&dpi=3&config=jstor

 

 


 


Document Provenance and History

Document Author: Dr. Fazal Danish

Document Created: 4th July 2006

Document Edits: