Laboratory Diagnosis in Neurology, 1 Ed.

12 Cerebral Ischemia and Hemorrhage

E. Stolz, P. Oschmann

Stroke is the third most common cause of death in the Western industrialized world, and it is now the most common cause of long-term disability. Laboratory analysis plays an important role in the etiological classification and treatment of this disease.

Ischemic Cerebral Infarction

Laboratory Analysis in the Acute Phase of Cerebral Infarction

Basic laboratory tests. Laboratory analysis in the acute phase of cerebral infarction is restricted in most cases to basic tests for the following parameters: blood count (including thrombocyte counts), serum glucose, coagulation (aPTT, TT, INR), electrolytes, liver enzymes, renal function, and blood gas analysis (BGA). These parameters usually suffice when systemic fibrinolytic therapy is planned.

Exclusion of other diseases. Particularly when consciousness is severely impaired and specific focal neurological signs are absent, other diseases should be excluded. Intoxication is responsible for 30–40% of comas of nontraumatic origin. Table 12.1 summarizes some important differential diagnoses and the contribution of laboratory analysis. Of course, the clinical context governs which laboratory tests are requested.

Monitoring. In the acute phase of the disease, serum glucose should be closely monitored and kept below 200 mg/dL because hyperglycemia negatively affects the prognosis. Monitoring of serum osmolarity (< 320 mOsm/L) is necessary when osmotherapeutics are used to treat increased intracranial pressure, as uncontrolled osmotherapy may lead to acidosis, renal failure, and hemolysis. Similarly, coagulation markers must be monitored during anticoagulation treatment with heparin (partial thromboplastin time, PTT) or with phenprocoumon or warfarin (international normalized ratio, INR). During heparin therapy, thrombocyte counts should be monitored every 2nd day as a decline indicates heparin-induced thrombocytopenia, which may trigger thromboembolism.

Laboratory Analysis to Determine the Etiology of Cerebral Infarction

Thrombophilic factors. The majority of cerebral infarctions are caused by embolism originating from the heart or aortic arch, or from local arteriosclerosis. Here, laboratory analysis has no essential information to contribute. General screening for thrombophilic factors is not recommended; according to current data, it only makes sense in patients under the age of 50, or when embolism due to a right–left shunt is suspected. In the case of congestive infarction due to cerebral venous thrombosis, screening is obligatory because about 30% of the patients have thrombophilia. Table 12.2 summarizes the coagulation factors which on the basis of several studies are assumed to be associated with an increased risk of thrombosis. Numerous other coagulation factors are currently considered, such as plasminogen activator inhibitor I (PAI I), tissue factor pathway inhibitor (TFPI), factor XIII, β-fibrinogen polymorphisms, and factor VIII concentration. However, their significance is still unclear.

Vasculitis. Systemic vasculitis and pathogen-induced vasculitis are rare causes of cerebral infarction (Chap. 10, “Systemic Vasculitis and Connective Tissue Diseases”), the diagnosis of which is largely dependent on laboratory tests together with the clinical picture and pattern of organ involvement (Table 12.2). As a rule, mild lymphocytic pleocytosis (< 200 cells/μL) is shown in these diseases if intracranial vessels or the brain parenchyma are involved. ESR, CRP, and blood counts (anemia, thrombocytosis, eosinophilia) can serve as screening variables, except in the case of Takayasu's syndrome (aortic arch arteritis):

Table 12.1 Laboratory analysis to distinguish acute cerebral infarction from other diseases

Disease

Diagnostic test

Hypoglycemia

Serum glucose

Hyperglycemia

Serum glucose, ketone bodies, lactate, osmolarity, K+, BGA

Hepatic coma

NH3, GOT, GPT, bilirubin, BGA

Renal failure

Urea, creatinine, electrolytes, BGA

Thyrotoxic/hypothyroid crisis

T3, T4, TSH

Addisonian crisis, hypophyseal coma

Na+, K+, Cl, glucose, cortisol, TSH, BGA

Postictal confusion

CK, prolactin

Sepsis

CRP, ESR, coagulation, Na+, K+, creatinine, urea

Severe electrolyte imbalance

Na+, K+, Ca2+

CO intoxication

COHb

Alcohol intoxication

Ethanol in the serum

Substance intoxication (recreational and pharmaceutical drugs)

Direct detection in the serum and/or urine

Table 12.2 Contribution of laboratory analysis to determining the etiology of cerebral infarction

Thrombophilia

• Protein C activity

• Protein S activity

• Activated protein C resistance (factor V Leiden mutation)

• Antithrombin III concentration

• Plasminogen concentration

• Prothrombin polymorphism

• Lupus anticoagulant

• Anti-cardiolipin antibodies

Hematological diseases

• Essential thrombocythemia: thrombocyte count →

• Polycythemia vera: erythrocyte count →, Hct → Hb →

• Lymphoma: idiopathic thrombocytopenic purpura, acquired von Willebrand-Jürgens disease

• Sickle cell anemia: hypochromic anemia, differential blood count, Hb electrophoresis

Systemic vasculitis

• Chap. 10, “Systemic Vasculitis and Connective Tissue Diseases”

Pathogen-induced vasculitis

• Hepatitis B serology, perhaps HBV PCR

• Hepatitis C serology, perhaps HCV PCR

• HIV test

• Varicella antibody index if varicella-associated vasculitis is suspected, perhaps VZV PCR

• Syphilis diagnosis in the serum and CSF if syphilitic vasculitis is suspected (Chap. 10, “Neurosyphilis”)

• Diagnostic tests for Borrelia in serum and CSF if Borrelia-associated vasculitis is suspected (Chap. 10, “Neuroborreliosis”)

• Mycobacterium tuberculosis PCR if tuberculous vasculitis is suspected

• Cerebral mycosis: lymphocytic CSF pleocytosis, direct detection in the CSF and/or serological findings

• Cerebral cysticercosis: lymphocytic CSF pleocytosis, CSF protein →, serology

Isolated angiitis of the CNS

There may be mild CSF pleocytosis and/or blood–brain barrier dysfunction

Genetically determined arteriopathy

• CADASIL: skin biopsy and/or molecular genetic confirmation

• MELAS: serum and CSF lactate →, aerobic lactate ischemia test, molecular genetics

• Vascular dissection in Marfan's syndrome and Ehlers-Danlos syndrome

Other rare causes

• Homocystinuria: homocysteine in serum and urine →, methionine load test

• Heparin-induced thrombocytopenia: thrombocytes decreased under heparin therapy, detection by antibody diagnosis

• Temporal arteritis: There are no specific laboratory parameters for temporal arteritis, which in rare cases can also involve the extracranial arteries supplying the brain. Raised ESR, increased CRP level, and thrombocytosis are indicative; the diagnosis is made by biopsy.

• Immune complex-mediated forms of vasculitis: These include cryoglobulinemic vasculitis, hypersensitivity vasculitis, infection-associated endoperiarteritis, systemic lupus erythematosus, rheumatoid arthritis, and Sharp's syndrome. They often cause hypocomplementemia.

• Isolated angiitis: Isolated angiitis of the CNS is extremely rare. In most cases (about 60%) headache occurs; otherwise the manifestations are very varied, and include encephalopathy, focal neurological deficits, and cranial nerve dysfunction. Laboratory results for systemic markers are normal. In about 90% of cases, CSF exhibits mild lymphocytic pleocytosis with elevated protein and normal glucose levels. In some cases, positive oligoclonal bands have been reported. Diagnosis is on the basis of meningeal biopsy, since in up to 50% of cases even angiography reveals no abnormalities.

Thrombocythemia, plasmacytoma. The risk of cerebral infarction is markedly increased in essential thrombocythemia and polycythemia vera, whereas leukemic diseases (with the exception of plasmacytoma) carry a much lower risk. In addition to the patient's history and clinical findings, changes in the blood count results may show thrombocythemia and polycythemia, whereas a raised ESR usually indicates plasmacytoma.

Homocystinuria. Homocystinuria is caused by a rare autosomal recessive defect (incidence 1:40 000 to 1:330 000). Severe juvenile atherosclerosis unassociated with any known risk factor suggests the heterozygous form of homocystinuria; homozygous carriers usually die in childhood of atherothrombotic complications. The characteristic symptoms are excessively high homocysteine levels in the serum (> 100 mmol/L) and the presence of homocysteine in the urine. The methionine load test (oral administration of 0.1 g/kg methionine followed by determination of the homocysteine concentration in the serum after 4–6 hours) may be used to screen for heterozygous carriers. Homocystinuria is caused by defects in methionine and vitamin B12 metabolism and can be detected by molecular genetic analysis. There are three types of the disease, the most common being a defect in cystathionine synthetase (type 1).

Table 12.3 Laboratory analysis of treatable risk factors in primary and secondary stroke prevention

Risk factor

Target value

Hypercholesterolemia

 

Primary prevention

 

• Slightly elevated global risk: no CHD, 0–1 risk factors

• Moderately elevated global risk: no CHD and ≥ 2 risk factors

• High global risk: no CHD, ≥ 2 risk factors, and peripheral occlusive arterial disease

• LDL cholesterol ≤ 160 mg/dL

• LDL cholesterol ≤ 130 mg/dL

• LDL cholesterol ≤ 100 mg/dL

Secondary prevention

 

• Very high global risk: manifest CHD or secondary prevention

• After cerebral infarction or TIA or diabetes

• LDL cholesterol ≤ 100 mg/dL

• HDL cholesterol ≥ 40 mg/dL

• Triglycerides < 200 mg/dL

Diabetes

 

Fasting blood sugar

≤ 100 mg/dL

Blood sugar 1 hour postprandial

≤ 135 mg/dL

Urinary glucose

0 mg/dL

Glycohemoglobin (HbA1c)

<6.5%

Hyperhomocysteinemia

 

Normal range

11.15 ± 2.15 mmol/L

Risk factors: age > 45 years (men) or > 55 years (women), family history of early CHD, smoking, arterial hypertension, diabetes mellitus, HDL cholesterol < 35 mg/dL, trunk obesity.

Genetically determined arteriopathies. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and mitochondrial encephalopathy with lactic acidosis and strokelike episodes (MELAS) are very rare diseases that can be detected by neurogenetic analysis. Skin biopsy is also highly sensitive in detecting CADASIL, while for MELAS the elevated lactate levels in serum and CSF, and a three- to four-fold increase in lactate levels after low-load aerobic exercise testing (< 100 W) on a bicycle ergometer, can be used as a screening test.

CSF Analysis in Cerebral Infarction

Acute phase. In the acute phase of an ischemic stroke, CSF analysis is rarely indicated. It is absolutely contraindicated if there is increased intracranial pressure. In some cases it can be used to distinguish between a stroke and septic focal encephalitis (CSF pleocytosis up to 200 cells/μL, predominantly granulocytic, elevated protein and lactate levels, decrease in CSF glucose) or herpes encephalitis (Chap. 10, “Viral Infections of the Nervous System”). Otherwise, CSF analysis is normal during the acute phase. Not until day 2–4 can a mild to moderate blood–brain barrier dysfunction be shown. Mild mixed-cell pleocytosis (< 30 cells/μL) may occur later as a sign of a nonspecific cellular immune response.

Postacute phase. In the postacute phase and, in large infarcts, after normalization of the cranial pressure, CSF analysis plays an important role in the establishing the etiology of a stroke when vasculitis is included in the differential diagnosis (Table 12.2).

Primary and Secondary Stroke Prevention

Laboratory tests play an important role in primary and secondary stroke prevention (Table 12.3). The focus is on recognizing treatable risk factors. Hyperhomocysteinemia can be treated with 1 mg vitamin B12 and 400 mg folic acid per day. However, to date, no critical threshold value is known for homocysteine, and evidence is still lacking that the risk of stroke can actually be reduced by treatment. For diabetes mellitus, too, there are not intervention studies specifically targeting stroke. In some cases, it can be helpful to monitor patient compliance by laboratory tests: carboxyhemoglobin (COHb) for smoking; liver enzymes, mean corpuscular volume (MCV), and carbohydrate-deficient transferrin (CDT) for alcohol abuse.

image

Fig. 12.1 a–c Markers of neuronal destruction: temporal dynamics in different diseases.

a Serum concentration of S 100B after ischemic territorial infarction. The serum levels on days 2–4 correlate with the volume of infarcts in the territory of the middle cerebral artery (n = 26). The error bars show the standard deviation, and the blue area represents normal values (see Büttner et al., 1997).

b Serum concentration of S 100B after cardiopulmonary bypass surgery with autotransfusion of blood from the aspiration system (n = 90). The error bars show the standard error of the mean. The profile is markedly different from the one shown in a (see Jönsson et al., 1999).

c Serum concentration of NSE after hypoxic brain damage. The temporal dynamics in patients with severe handicap, persistent coma, or vegetative state (black line) differ in a prognostically useful way from those seen in patients with a favorable prognosis (blue line). The error bars show the standard deviation (see Schoerkhuber et al., 1999).

Markers of Neuronal Destruction

On days 2–4 after a cerebral territorial infarct, serum and CSF concentrations of neuron-specific enolase (NSE) and S 100B correlate with the size of the infarct and with the extent of neurological deficits (Fig. 12.1 ac).

The use of these markers to estimate the extent of neurological damage after heart surgery should be viewed more critically, since S 100B increases after sternotomy anyway, and both S 100B and NSE are influenced by autotransfusion, hemolysis, hemodilution, or renal failure. The temporal dynamics of these markers are very different from those seen after cerebral territorial infarction (Fig. 12.1 b).

Intracerebral Hemorrhage

Acute phase. About 10–15% of all strokes are caused by intracerebral hemorrhage. In the acute phase of the disease, the basic laboratory tests listed above (“Ischemic Cerebral Infarction”) suffice. CSF analysis is usually not indicated because intracranial pressure is increased after massive hemorrhage. In some cases, however, CSF analysis may be helpful in excluding hemorrhagic encephalitis, particularly HSV-induced encephalitis and septic focal encephalitis. CSF findings in intracerebral hemorrhage correspond roughly to those in subarachnoid hemorrhage (see above, “Subarachnoid hemorrhage”), and blood–brain barrier dysfunction is usually present.

Postacute phase. CSF analysis is required in the postacute phase in the search for the cause of the hemorrhage, to diagnose vasculitis, which is a rare cause of intracerebral hemorrhage. Extensive coagulation tests are necessary in patients without known risk factors and with a positive family or personal history of recurrent hemorrhages (Table 12.4). Blood count, differential blood count, liver enzymes, aPTT, TT, INR, and Duke's bleeding time may provide the first clues.

Table 12.4 Laboratory diagnosis of hemorrhagic diathesis in patients with intracerebral hemorrhage

Congenital bleeding disorders

 

Hemophilia A and B

PTT →, factor VIII and IX activity ↓

Von Willebrand's disease

Factor VIII activity ↓, factor VIII-associated antigen ↓, bleeding time →, thrombocyte aggregation ↓

Protein Z deficiency

Bleeding time →, Rumpel-Leede test positive, protein Z concentration ↓

Bernard-Soulier syndrome (giant platelet syndrome, hemorrhagiparous thrombocytic dystrophy)

Bleeding time →, platelet function test

Glanzmann's disease (thrombasthenia)

Bleeding time →, platelet function test

Osler's disease (hereditary hemorrhagic telangiectasia)

Skin lesions, Rumpel-Leede test positive

Rare disorders: dysfibrinogenemia, deficiency in factors I, II, V, VII, X, XI, XIII

Acquired bleeding disorders

 

• Acquired von Willebrand's disease (associated with autoantibodies; e. g., in patients with lymphoma)

• Thrombopenia associated with leukemia, tumor invasion, radiation, and chemotherapy, parainfectious thrombopenia; thrombotic thrombocytopenic purpura (Moschcowitz’ disease) with hemolytic anemia

• Liver diseases: INR →, transaminases →, thrombocytes ↓, protein C ↓, antithrombin III ↓

• Pharmaceuticals: e. g., phenprocoumon, acetylsalicylic acid, antiphlogistics

• Consumptive coagulopathy

Subarachnoid Hemorrhage

Clinical Features

The characteristic clinical symptom of subarachnoid hemorrhage is a severe, sudden headache. A stiff neck, impaired consciousness, and focal neurological deficits, which may be present right at the beginning, or they may appear later.

Diagnosis

Cranial CT. The most important diagnostic investigation is cranial CT, which has a diagnostic sensitivity of 98% within the first 12 hours after the event. The sensitivity drops as the delay increases, however, and also depends on whether the scan is interpreted by a neuroradiologist or a general radiologist. In practice, therefore, the sensitivity is much lower.

CSF analysis. According to expert opinion, lumbar puncture is the next best diagnostic tool when the clinical picture fits but CT findings are negative. The following are helpful in the diagnosis of subarachnoid hemorrhage:

• Three-glass test: During the first 12 hours after the event, the three-glass test is the most commonly used method. Other CSF markers depend on processes of production, degradation, and phagocytosis. In subarachnoid hemorrhage, unlike in traumatic lumbar puncture, the admixture of blood does not change during the puncture (Table 12.5). Accordingly, when CSF is collected in fractionated portions, erythrocyte counts remain the same in each, whereas in traumatic puncture they decrease. After more than 2 hours in CSF, erythrocytes undergo autolytic changes, and the presence of deformed erythrocytes (echinocytes) essentially excludes traumatic lumbar puncture as the source of the blood. No threshold value exists for erythrocyte counts, so absolute erythrocyte counts are therefore of no diagnostic importance. If doubts remain concerning the source of the blood, lumbar puncture should be repeated at one intervertebral level up or down; if subarachnoid hemorrhage is present, the erythrocyte counts will be the same.

Table 12.5 Distinguishing between traumatic lumbar puncture and subarachnoid hemorrhage

Parameter

Traumatic lumbar puncture

Subarachnoid hemorrhage

Opening pressure

Normal

Increased in 60% of cases

Three-glass test

CFS initially bloody, decreasing blood content

No decrease in blood content

Lumbar puncture one level up or down

Usually clear

Bloody

Xanthochromia after centrifugation

Clear

Xanthochromic (may be absent < 12 h)

Leukocyte count

Proportional to blood

Initially proportional to blood; relative increase later

Erythrocyte count

Decreasing in three-glass test

Unchanged in three-glass test

Spectrophotometry

No Hb degradation products

Hb degradation products

CSF ferritin

≤ 15 ng/mL

>15 ng/mL

D-dimer

Not detectable

Detectable

Erythrophages

Not detectable

Detectable (from 12 h onward)

Siderophages

Not detectable

Detectable (from day 3 onward)

image

Fig. 12.2 Colorless CSF (left) and xanthochromic CSF (right).

• Xanthochromia: Xanthochromia is yellowish discoloration of the CSF, which is primarily caused by degradation of hemoglobin via oxyhemoglobin to bilirubin (Fig. 12.2). It occurs 8–12 hours after hemorrhage. The CSF should be centrifuged and compared to water against a white background. False-positive results are caused by severe icterus, increased protein levels in the CSF (bilirubin binding), rifampicin therapy, carotene, and melanoma metastases or leptomeningeal spread. The minimum concentration of bilirubin for xanthochromia to be generated is 10–15 mg/dL. Xanthochromia has a characteristic time course: out of 49 patients with subarachnoid hemorrhage, all had a pathological three-glass test within 6 hours, but only 10 (20%) had xanthochromic CSF; while in the 6–12 hour period, out of 40 patients, all had a pathological three-glass test and 26 (65%) had xanthochromic CSF. Spectrophotometry may help quantify the absorption of light by bilirubin, thus increasing sensitivity. However, the wavelengths of oxyhemoglobin (413–415 nm) and methemoglobin (405 nm)—which may be present after traumatic lumbar puncture—are close to that of bilirubin absorption (459 nm), thus leading to false-positive results.

• CSF cytology: In acute subarachnoid hemorrhage, erythrocytes are initially present in huge numbers (Fig. 12.3 a), turning into echinocytes within a short period of time. During the early phase, leukocyte counts are proportional to erythrocyte counts (at a ratio of about 1:700), and all types of peripheral blood cells are found. However, hemorrhage triggers meningeal inflammation which may lead to pleocytosis (up to 500 cells/μL). Initially, neutrophilic granulocytes predominate, but as early as 12 hours after hemorrhage a few macrophages are seen phagocytosing erythrocytes: the engulfed erythrocytes begin to look like empty vacuoles in the cytoplasm of macrophages (erythrophages, Fig. 12.3 b). After about 3 days, the first hemosiderin granules appear in the cytoplasm of macrophages (siderophages, Fig. 12.3 c). Renewed appearance of erythrophages is a sign of a secondary bleeding. As a next step, the phagocytosed hemoglobin is deposited in the cytoplasm as iron-free hematoidin granules; some is also deposited in the form of crystals. Pappenheim's stain is usually sufficient for cytodiagnosis; if in doubt, hemosiderin and hematoidin can be specifically detected with the Prussian blue reaction. Siderophages are found in CSF up to 6 months after subarachnoid hemorrhage.

• CSF chemistry: So far, the following chemical tests are available for CSF analysis:

– D-Dimer: In 1994 Page et al. reported on determination of D-dimers in the CSF of patients with subarachnoid hemorrhage. In this study, 12 out of 23 patients (52%) were positive for D-dimers, and there were no false-negative findings. However, these results have not been replicated in other studies.

– Ferritin: CSF macrophages produce large quantities of ferritin, and ferritin measurement can be used to confirm or exclude subarachnoid hemorrhage. With 15 ng/mL as the threshold value, the test has a sensitivity of 95%, and a specificity of 95% (Wick et al., 1999). However, the results should be assessed in the clinical context, since increased ferritin levels have also been found in meningitis, leptomeningeal spread, and dementia. Ferritin levels remain high for months after subarachnoid hemorrhage.

So long as the temporal dynamics of changes are taken into account, CSF analysis is very reliable in confirming subarachnoid hemorrhage when CT is negative. The most common differential diagnosis is traumatic lumbar puncture (Table 12.5).

image

Fig. 12.3 a–c CFS cytology in subarachnoid hemorrhage (Pappenheim's stain).

a Acute subarachnoid hemorrhage. Erythrocytes dominate the cytology. Plenty of granulocytes and some lymphocytes are also present, at about the same ratio as one would expect in blood.

b About 12 hours after subarachnoid hemorrhage. Plenty of erythrocyte ghosts are still visible, but already some macrophages are seen with phagocytosed erythrocytes, recognizable as vacuoles in the cytoplasm (erythrophages, arrow).

c About 36 hours after subarachnoid hemorrhage. Erythrocytes are rarely found. Macrocytic phagocytosis has progressed to a point where iron granules are seen in the cytoplasm (siderophages, arrow). Also present are macrophages with phagocytosed erythrocytes and some cytoplasmic iron granules.

Cerebral Hypoxia

Etiology and Clinical Features

The most common cause of cerebral hypoxia is life-threatening cardiac arrhythmias, meaning that most of these patients are treated in medical or cardiac intensive care units where instrumental neurological examinations are often not possible. Frequently, purely clinical findings are not usable because the patients are ventilated and under analgesia/sedation.

Diagnosis

Neuron-specific enolase. In the case of cardiac arrythmia, the serum concentration of NSE is a sensitive marker of the prognosis. The temporal dynamics are characteristic: NSE concentration rises 24 h after hypoxia, peaks on days 2–3, and then falls again slowly over several days (Fig. 12.1 c). It is therefore advisable to determine a base value on admission. NSE concentration on days 2–3 has a sensitivity of 90–100% in predicting persistent coma or vegetative state (Schaarschmidt et al., 1994). According to recent studies, threshold values on day 2 range between 33 and 43 mg/mL (Madl et al., 2002; Zingler et al., 2003). What is clear is: the sharper the rise, the worse the prognosis. In the case of patients with cardiac arrest and resuscitation, the NSE concentration in blood increases within a few hours to several hundred μg/L. Values above 120 μg/L which last several days are not compatible with a recovery of the patient's cognitive functions (Schaarschmidt et al., 1994, Reiber 2003). In head/brain trauma the NSE values decrease within few hours to normal values (< 30 μg/L).

S 100B protein. The diagnostic value of S 100B in the serum is low, due to the low sensititvity compared to NSE.

Somatosensory evoked potentials. When neurophysiological examinations are possible, bilateral loss of the N20 signal upon eliciting somatosensory evoked potentials (SEP) on days 2–7 has a positive predictive value for death or persisting coma, with a specificity of 100%.

References

Büttner T, Weyers S, Postert T, et al. S-100 protein: serum marker for focal brain damage after ischemic territorial MCA infarction. Stroke 1997;28:1961–1965

Jönsson H, Johnsson P, Alling C, et al. S 100β after coronary artery surgery: release pattern, source of contamination, and relation to neuropsychological outcome. Ann Thorac Surg 1999;68:2202–2208

Madl C, Hasibeder W, Lechleitner P, et al. Empfehlungen zur Prognosebeurteilung bei cerebraler Hypoxie nach kardiopulmonaler Reanimation. Österreichische interdisziplinäre Konsensuskonferenz. Intensivmed 2002;39:117–124

Page KB, Howell SJ, Smith CM, et al. Billirubin, ferritin, D-dimers, and erythrophages in the cerebrospinal fluid of patients with suspected subarachoid haemorrage but negative computed tomography scans. J Clin Pathol 1994;47:986–989

Reiber H. Proteins in cerebrospinal fluid and blood: Barriers, CSF flow rate, and source-related dynamics. Restorative Neurology and Neuroscience 2003;21:79–96

Schaarschmidt H, Prange H, Reiber H. Neuron specific enolase concentrations in blood as a prognostic parameter in cerebrovascular diseases. Stroke 1994;24:558–565

Schoerkhuber W, Kittler H, Sterz F, et al. Time course of serum neuronspecific enolase. A predictor of neurological outcome in patients resuscitated from cardiac arrest. Stroke 1999;30:1598–1603

Wick M, Wick M, Fink W, Pfister HW. Ferritin im Liquor – ein lokal synthetisiertes Protein. Aktuelle Neurologie 1999;26(Suppl):S 2–S 3

Zingler VC, Krumm B, Bertsch T, et al. Early prediction of neurological outcome after cardiopulmonary resuscitation: a multimodal approach combining neurobiochemical and electrophysiological investigations may provide high prognostic certainty in patients after cardiac arrest. Eur Neurol 2003;49:79–84

Further Reading

Bogousslavsky J, Caplan L, eds. Uncommon causes of stroke. Cambridge: Cambridge University Press; 2001

Edlow JA, Wyer PC. How good is a negative cranial computed tomographic scan result in excluding subarachnoid hemorrhage? Ann Emerg Med 2000;36:507–516

Foot C, Merfield E. Suspected subarachnoid haemorrhage with a negative CT head scan: what next? Emerg Med 2000;12:212–217

National Heart, Lung, and Blood Institute, National Institutes of Health. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). NIH publication No. 01–3670; 2001

Shah KH, Edlow JA. Clinical laboratory in emergency medicine. Distinguishing traumatic lumbar puncture from true subarachnoid hemorrhage. J Emerg Med 2002;23:67–74

Wolf PA, Clagett GP, Easton D, et al. Preventing ischemic stroke in patients with prior stroke and transient ischemic attack. A statement for healthcare professionals from the Stroke Council of the American Heart Association. Stroke 1999;30:1991–1994