Comparison of the hypoglycemic and antithrombotic (anticoagulant) actions of whole bovine and camel milk in streptozotocin-induced diabetes mellitus in rats.

People with diabetes are at higher risk of fatal thromboembolic accidents in the cerebral and coronary circulations, especially stroke and ischemic heart disease. We have previously described the hypoglycemic, hypolipidemic, and anticoagulant activity of orally administered camel milk in streptozotocin-induced diabetic rats. In the present study in the same animal model, we extended these observations by comparing camel milk and the more available and widely consumed bovine milk with respect to their antidiabetic and antithrombotic actions. Rats were rendered diabetic by intraperitoneal streptozotocin (65 mg/kg), and then camel milk or bovine milk was administered orally for 8 wk. We evaluated the changes in body weight, fasting blood glucose, glucose tolerance, blood coagulation profile, and platelet function. Diabetic rats developed weight loss, hyperglycemia, glucose intolerance, inhibition of platelet aggregation responses to arachidonic acid and adenosine diphosphate, a marked decrease (>50%) in plasma fibrinogen levels, and short activated partial thromboplastin time. Treatment with camel milk or bovine milk reversed these abnormalities, resulting in weight gain, decreased blood glucose levels, and improved glucose tolerance. Despite the more remarkable antidiabetic action of camel milk, treatment with bovine milk was more effective in correcting plasma fibrinogen levels and restoring inhibited platelet aggregation responses. Long-term administration of camel milk or bovine milk counteracted streptozotocin-induced metabolic manifestations in rats, maintained platelet function, and abolished coagulopathy-associated fibrinogen consumption. Notably, the antidiabetic effect of camel milk was more pronounced than that of bovine milk, but bovine milk exhibited more potent anticoagulant activity than camel milk. These findings should encourage further clinical trials to assess the efficiency of camel milk and bovine milk or their derived peptides as food supplements or potential nonpharmacological therapies for dysglycemia and the vascular complications of diabetes mellitus.

Hepatitis C virus genotypes in Saudi Arabia: a future prediction and laboratory profile.

BACKGROUND: Hepatitis C virus (HCV) genotypes and subtypes are considered an important tool for epidemiological and clinical studies and valuable markers for disease progression and response to antiviral therapy. The aim of this study was to identify the prevalence of HCV genotypes and their relation to socio-demographic factors particularly age and sex, various biochemical profiles and viral load. METHODS: The records (630) of Saudi patients positive for HCV (2007-2011) reported in the system of the Molecular Pathology Laboratory at a tertiary reference hospital in Riyadh, Saudi Arabia were analyzed. Socio-demographic characteristics, liver biochemical profile, viral load and co-infection with HBV and HIV were retrieved from the hospital database. The associations of continuous and categorical variables with genotypes were analyzed. RESULT: The overall mean age of the surveyed patients was 59 years ±0.5 years (21% were <50 years (p = 0.02). The rate of infection is lower in males than in females (47.6% vs. 52.4%). HCV genotype 4 was the most prevalent (60.7%), followed by genotype 1 (24.8%). However, genotype 1 and 3 were found more in males (29.7% vs. 20.3% and 6% vs. 2.1%, respectively, p = 0.001), while genotype 2 and 4 were more among females (4.8% vs. 2% and 68.5% vs. 52.3%, respectively). In addition, genotype 1 was found dominant in younger males (33.8%). Biochemical parameters across gender showed significant variation in particular for the ALT (p = 0.007). The mean viral load was significantly higher in genotype 1 than genotype 4 (4,757,532 vs. 1,435,012, p = <001). There is a very low overall percentage of co-infection of HBV or HIV in this study (around 2% for each). CONCLUSION: Although HCV genotype 4 shows an overall high prevalence in this study, a clear decline in the rate of this genotype was also demonstrated in particular among the younger age group who displayed increasing trends toward the global trend of genotype 1, rather than genotype 4. This finding would be of clinical interest in relation to future planning of the therapy for HCV infected patient.

A 23 years audit of packed red blood cell consumption in a university hospital in a developing country.

BACKGROUND: There is paucity of information on the blood transfusion practice in developing countries. The current audit aims to find out the long term trend in the consumption of packed red blood cells (PRBCs) in a large Saudi teaching hospital in Riyadh MATERIALS AND METHODS: We analyzed the annual consumption of PRBCs from 1985 to 2007 in seven major hospital divisions (Medicine, General Surgery, Pediatrics, Obstetrics and Gynecology, Cardiac Surgery, Accident and Emergency and Renal Dialysis Unit) at the 850-bed King Khalid University Hospital (KKUH), Riyadh. RESULTS: Grand total consumption of PRBCs was 345,642 units. The consumption increased gradually and peaked in the year 1994, dropped to 30.4% 6 years later and then increased gradually thereafter, due to the expansion in the number of patients cared for in the Departments of Medicine, Cardiac Surgery and Accident and Emergency, while in the Department of Pediatrics the drop in consumption continued unabated. In the Renal Dialysis Unit consumption was minimal with the use of erythropoietin therapy. The crossmatch:transfusion ratio uncovered gross over-ordering of PRBCs and wastage of blood bank resources in most hospital divisions most notably in the Department of Obstetrics and Gynecology. CONCLUSION: The results obtained indicate clearly that there has been overuse of blood products that dropped markedly in years coinciding with the worldwide apprehension about the safety of transfusion therapy particularly HIV transmission. This factor in addition to the current implementation of strict guidelines is gradually improving transfusion practices in our institute.

Tissue plasminogen activator and plasminogen activator inhibitor-1 levels in patients with acute myocardial infarction and unstable angina.

OBJECTIVE: To compare levels of tissue plasminogen activator and plasminogen activator inhibitor-1 levels in patients with acute myocardial infarction and unstable angina in order to understand the use of high sensitivity C-reactive protein (hsCRP), coagulation and fibrinolysis markers for cardiovascular risk assessment. METHODS: The cross-sectional case-control study compared circulating concentrations of high sensitivity C reactive protein (hsCRP), fibrinogen, tissue-type plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) between patients of acute myocardial infarction (AMI) (n = 67), Unstable Angina Pectoris (UA) (n = 35) and healthy control subjects (n = 39) at the King Khalid University Hospital, Riyadh, Saudi Arabia, from June 2006 to August 2007. RESULTS: The patients had significantly higher hsCRP (1.06 +/- 0.11 vs 0.52 +/- 0.14, p < 0.01), fibrinogen (426.21 +/- 24.09 vs 329.32 +/- 13.93, p < 0.05), PAL-1 (44.02 +/- 6.05 vs 19.35 +/- 3.94, p < 0.01) and tPA (12.31 +/- 1.16 vs 9.49 +/- 0.86, p < 0.05) compared to the controls. Fibrinogen (329.32 +/- 13.93) and PAL-1 (19.35 +/- 3.94) were higher in both angina and infarction groups compared to the healthy subjects (p < 0.01). Between the two categories of patients the difference between Fibrinogen (449.60 +/- 52.98 vs 419.46 +/- 23.42) and PAL-1 (52.00 +/- 17.34 vs 43.19 +/- 6.10) levels were non-significant. Also, the difference in tPA levels between the controls and angina patients was nonsignificant (9.49 +/- 0.86 vs 9.91 +/- 1.24 p > 0.05). It was higher in infarction patients (14.79 +/- 3.14) compared to angina patients and the controls, (p < 0.05). Compared to the controls, hsCRP levels were significantly higher in both the patient groups (0.52 +/- 0.14, 1.05 +/- 0.28, 1.40 +/- 0.20, p < 0.01). Moreover, they were significantly higher in infarction patients than those suffering from angina (p < 0.05). CONCLUSIONS: CAD patients had a procoagulant state and presented with higher levels of hsCRP compared to the healthy individuals. Moreover, there were significant differences in coagulation markers and hsCRP between angina and infarction patients.

Haemostatic and cytokine changes in gestational diabetes mellitus.

BACKGROUND: Limited data indicate the existence of a hypercoagulable state and the possible involvement of pro-inflammatory cytokines in the pathogenesis of gestational diabetes mellitus (GDM). AIM: To characterise the coagulation inhibitor and cytokine profiles in women with GDM. METHODS: Two groups of women in the third trimester of pregnancy were studied: GDM (n = 150) and controls: women with normal pregnancy (n = 100); GDM in their first post-delivery day (n = 52). LABORATORY ASSAYS: Plasma fibrinogen, antithrombin (AT), protein C, total and free protein S, interleukins-2, 6 and 8 (IL-2, 6, 8). RESULTS: During pregnancy, the only significant alterations noted were higher levels of body mass index, fibrinogen and total protein S in women with GDM when compared to normal pregnancy. In the post-delivery group, there was further elevation in the levels of plasma fibrinogen and significant drop in the level of total protein S, protein C and AT. Significant elevation of IL-2 and IL-6 levels was recorded only in post-delivery group. CONCLUSION: In GDM, the only indicator of a tendency towards hypercoagulability is the higher fibrinogen levels as compared to normal pregnancy. This feature along with the higher body mass index and presumed associated insulin resistance suggests that GDM may be a mild form of the metabolic syndrome. The lack of significant change in the levels of pro-inflammatory cytokines do not support the existence of an inflammatory state in GDM.

Prevalence and Risk Factors for Diabetic Peripheral Neuropathy Among Saudi Hospitalized Diabetic Patients: A Nested Case-Control Study.

OBJECTIVE: To determine the prevalence and the risk factors of diabetic peripheral neuropathy (DPN) in hospitalized adult Saudi diabetics. METHODS: This is a retrospective, nested case-control study conducted at King Abdulaziz Medical City (KAMC) in Riyadh, Saudi Arabia. All diabetic patients admitted to the hospital between the January 1, and December 31, 2018 were considered for inclusion in the study. Patients with DPN were identified and three controls per case were randomly selected from the remaining diabetic patients without peripheral neuropathy (PN). RESULTS: A total of 2,096 adult diabetic patients were identified during the study period. Of these, 73 patients (3.5%) were confirmed to be suffering from DPN and 219 were included as controls. When comparing diabetic with the control cases, DPN cases were significantly older (p=0.002), had a significantly higher proportion of type 2 diabetes (p=0.023), chronic kidney disease (p<0.0001), cerebral vascular stroke (p=0.027), hypertension (p=0.005), dyslipidemia (p=0.002), peripheral vascular disease (p<0.0001), osteoarthritis (p=0.034), diabetic ketoacidosis (p=0.003), foot ulcers (p=0.006), gangrene (p=0.001), lower limb ischemia (p=0.001), increased duration with diabetic disease (p=0.031), increased BMI (p=0.003), higher serum creatinine (p<0.001) and lower serum albumin levels (p=0.035). In the multivariate logistic regression, only older age {odds ratio (OR) 1.02, 95% CI 1.01-1.04, p=0.031}, chronic kidney disease (OR 2.39, 95% CI 1.23-4.64, p=0.010) and peripheral vascular disease (OR 3.14, 95% CI 1.39-7.13, p=0.006) were independently associated with DPN. CONCLUSION: This study identified several risk factors that contributed to the development of DPN in Saudis. These must be considered in strategies and campaigns aimed at risk reduction of cardiovascular and chronic diseases, and consequently progression of DPN.

Natural anticoagulants and fibrinolytic activity following interferon therapy in chronic viral hepatitis.

Chronic liver disease is accompanied by derangement of hepatocyte function including the synthesis of haemostastic factors. It is, however, not known whether the improvement in liver functions as a result of interferon (IFN)-alpha therapy would be reflected in the plasma levels of these factors. To evaluate the effect of IFN-alpha therapy on the plasma levels of natural anticoagulants and on the fibrinolytic parameters, in patients with chronic viral hepatitis. Twenty one patients with chronic viral hepatitis (B and C) were treated with IFN-alpha, and were studied before commencement of therapy (first sample) 3 (second sample) and 6 months (third sample) later. The coagulation screening tests: activated partial thromboplastin time, prothrombin time, thrombin time, reptilase time and plasma fibrinogen and the natural anticoagulants: antithrombin, Protein C and free and total protein S as well as fibrinolytic parameters (tissue type plasminogen activator, plasminogen activator inhibitor type-1 and plasminogen) were measured. An increase in the levels of total protein S at 3 and 6 months after the commencement of IFN therapy was noted but the increase was statistically significant in the latter period. Reptilase time was prolonged in the first (pretreatment) and in the second samples and then began to decrease in the third sample but remained higher than the pretreatment level. Fibrinogen level increased in the second and third samples. No remarkable changes were noted in other haemostatic parameters. Total protein S level is a good marker of response to IFN therapy. IFN therapy does not affect other natural anticoagulants or fibrinolytic parameters. More detailed studies need to be done to confirm these findings.

Effects of heat on camel platelet structure and function-a comparative study with humans.

Camels and many other desert animals are uniquely adapted to conserve water and other fluids in order to survive intense heat for long periods. Earlier studies have suggested that human platelets may be the trigger for the coagulopathy involved in heat prostration and stroke. The present study has compared the resistance of camel and human platelets to heat in order to see if they might help to protect camels from the effects of high body temperature for prolonged periods. The findings demonstrate that camel platelets are significantly less sensitive to heat than human platelets. Temperatures (43 degrees C-45 degrees C) that cause human cells to undergo marked structural alterations and lose their ability to spread and aggregate have no effect on camel platelets. Even higher temperatures (50 degrees C) that destroy human platelets have minor effects on camel cells and do not seriously compromise their function. Temperatures of 55 degrees C do destroy camel platelets and their functional capability. The resistance of camel platelets to heat may help protect camels from the effects of extreme body temperature and dehydration, which are everyday conditions in the desert.

Long-term audit of the use of fresh frozen plasma in a university hospital.

OBJECTIVES: There is universal concern about the inappropriate use of fresh frozen plasma (FFP). This study aimed to determine the extent of the inappropriate use of FFP at a university hospital in KSA. METHODS: Medical records on the annual use of FFP were analysed from 1986 to 2007. Then, the results of the coagulation screening tests were extracted from the medical records of 531 consecutive patients in various departments of the hospital. RESULTS: As many as 68,480 FFP units were used during the 22 year study period. Consumption increased and then plateaued in 1995, but dropped dramatically by 30.9% and reached its lowest level in 2000. There was also a concomitant and overlapping drop in both FFP usage and the hospital mortality rate per patient admission. One-thousand-six-hundred-twenty FFP units were issued for 531 patients. Coagulation testing, before and after infusion, was adopted in almost all patients in the Department of Obstetrics and Gynaecology, in 90% of patients in the Department of Surgery and in approximately 70% of patients in other departments. CONCLUSIONS: Significant inappropriate use of FFP at our institute has been made evident by examining the remarkable drop in use following the universal "HIV scare" of the early 1990s. The resulting drop in the hospital mortality rate, accompanying the simultaneous drop in FFP use, reflects the benefits of resorting to the use of less blood therapy. Coagulation testing was used to a satisfactory extent. Transfusion audits and educational programs could result a better use of FFP.

Diagnostic approach and management strategy of childhood stroke.

Prompt recognition and early intervention, with pertinent management and medication, may reduce subsequent neurologic deficits in stroke, which constitutes a devastating event in children. This is due to the tasking and demanding consequences including death or residual neurological deficits, which may last for many decades, in over 60% of survivors. Evidence-based treatment for children with stroke is still lacking, reflecting scarcity in baseline epidemiological data on pediatric stroke, the multitude of underlying risk factors, and the ethical and practical challenges incurred in conducting clinical trials. Based on the experience we gained from a combined prospective and retrospective study on childhood stroke (covering 10 years and 7 months and involving a cohort of 104 Saudi children), a diagnostic algorithm, which outlines the approach to a child with suspected stroke/cerebrovascular lesion, was designed. This algorithm might also be of use for managing other children with stroke from the Arabian Peninsula and Middle Eastern Region with similar demographic, socioeconomic, and ethnic backgrounds. Underlying risk factors, which need special attention, include thrombophilia and hypercoagulable states and sickle cell disease (SCD), which contrary to previous studies from Saudi Arabia, were found to constitute a common risk factor with severe manifestations. Other risk factors include infections (especially neurobrucellosis), cardiac diseases, and hypernatremic dehydration. Recognition of an identifiable syndrome or inherited metabolic cause may unravel an underlying cerebrovascular disease. This is particularly important in this region, given the large pool of autosomal recessive diseases and the high rate of consanguinity. In the evaluation of a suspected case of stroke, important imaging modalities include cranial CT, MRI (including diffusion-weighted images), magnetic resonance angiography (MRA), magnetic resonance venography (MRV) and conventional angiography. Transcranial Doppler sonography of the intracranial vessels and Duplex scan of the neck are valuable modalities for detecting large vessel vasculopathy, which occur in SCD, moyamoya syndrome, arterial dissection, and stenosis. Antithrombotic drugs are increasingly being used in the acute phase of childhood ischemic stroke. These include unfractionated heparin, low-molecular-weight heparins, aspirin or warfarin, or both. Specialized stroke care and follow-up are needed for children with stroke, as well as their families.

Perinatal stroke in Saudi children. Clinical features and risk factors.

OBJECTIVES: To describe the clinical features and presentations of perinatal stroke in a prospective and retrospective cohort of Saudi children and ascertain the risk factors. METHODS: Patients with perinatal stroke were identified from within a cohort of 104 Saudi children who were evaluated at the Division of Pediatric Neurology at King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia from July 1992 to February 2001 (retrospective study) and February 2001 to March 2003 (prospective study). Neuroimaging for suspected cases of stroke consisted of cranial CT, MRI, or both. RESULTS: During the study period, 23 (22%) of 104 children (aged one month to 12 years) were diagnosed to have had perinatal stroke. The male:female ratio was 1.6:1. Ten (67%) of the 15 children who had unilateral ischemic involvement had their lesion in the left hemisphere. The presentation of the ischemic result was within 24-72 hours of life in 13 (57%) patients, and in 6 children (26%), motor impairment was recognized at or after the age of 4 months. Nine children (39%) had seizures at presentation. Pregnancy, labour, and delivery risk factors were ascertained in 18 (78%) cases. The most common of these included emergency cesarean section in 5 cases, and instrumental delivery in another 5. Screening for prothrombotic risk factors detected abnormalities in 6 (26%) patients on at least one test carried out between 2 months and 9 years of age. Four children (17%) had low protein C, which was associated with low protein S and raised anticardiolipin antibodies (ACA) in one patient, and low antithrombin III in another. Low protein S was detected in a 42-month-old boy. The abnormality in the sixth child was confined to raised ACA. CONCLUSIONS: The present study highlights the non-specific features by which stroke presents during the neonatal period. The data are in keeping with the potential role for inherited and acquired thrombophilia as being the underlying cause. However, the high prevalence of additional acquired antenatal and perinatal risk factors support a multifactorial disorder.

Infectious and inflammatory disorders of the circulatory system as risk factors for stroke in Saudi children.

OBJECTIVE: To report on the role of infectious and inflammatory disorders as risk factors for stroke in a prospective and retrospective cohort of Saudi children. METHODS: Children, who presented with stroke, were evaluated at the Division of Pediatric Neurology or admitted to King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia during the periods July 1992 to February 2001 (retrospective study) and February 2001 to March 2003 (prospective study). Investigations for suspected cases included hemostatic assays, microbiological and serological tests. Neuroimaging included cranial CT, MRI, magnetic resonance angiography (MRA), magnetic resonance venography (MRV) and single photon emission computed tomography (SPECT) brain scan. RESULTS: Of the 104 Saudi children with stroke, seen during the combined study periods of 10 years and 7 months, infectious and inflammatory disorders of the circulatory system were the identified risk factor in 18 (17.3%). Five children had stroke following acute bacterial meningitis at ages ranging between 5-21 months. The causative organism was identified in 3 of them and consisted of Haemophilus influenzae (in a 5-month-old girl), Streptococcus pneumoniae (in a 21-month-old girl complicated by subdural empyema and sinovenous thrombosis), and Staphylococcus aureus in a 6-month-old boy who had an underlying chronic granulomatous disease. Unspecified meningitis/meningoencephalitis affected 4 patients, whereas 3 children had an underlying congenital infection as a cause for their stroke. Two of the latter 3 children were diagnosed to have congenital toxoplasmosis, and the third had congenital rubella syndrome. Two girls had stroke following septicemia at ages of one and 2 months. Neurobrucellosis caused stroke in 2 boys at the ages of 4 1/2 and 4 years. In both patients, neuroimaging revealed lacunar and other infarcts involving mainly the deep cerebral nuclei, secondary to occlusion of small penetrating end arteries. Two patients presented with cerebrovascular disease following systemic lupus erythematosus. These were a 12-year-old girl and a 5-year-old boy. CONCLUSIONS: Several of the infectious diseases that caused stroke in this cohort of Saudi children are potentially preventable through childhood immunization programs or other maternity health programs. In particular, immunogenic conjugate vaccines against the 3 most common organisms causing acute bacterial meningitis (Haemophilus influenzae type b, Neisseria meningitidis and defined serotypes of Streptococcus pneumoniae) are needed to protect the young (<2 years) who are mostly affected.

Stroke due to mitochondrial disorders in Saudi children.

OBJECTIVE: To report on the clinical and biochemical features of patients who presented with stroke due to mitochondrial disorders amongst a prospective and retrospective cohort of Saudi children. METHODS: Children, who presented with stroke, were evaluated at the Division of Pediatric Neurology, or admitted to King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia, during the periods July 1992 to February 2001 (retrospective study) and February 2001 to March 2003 (prospective study). Open muscle biopsies were obtained from patients suspected to have mitochondrial disorders, and examined using conventional histological and histochemical techniques. Biochemical, molecular pathological investigations, or both, of muscle could be arranged for only some of the patients. RESULTS: Mitochondrial disorders were the underlying risk factor for stroke in 4 (3.8%) of 104 children (aged one month to 12 years). Three patients (one male and 2 females) had Leigh syndrome (LS) and one had mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). At the time of stroke, the 3 children with LS were 11 months, 15 months, and 7 years old. They presented with psychomotor regression and seizures. Muscle histology and histochemistry showed mild non-specific changes but no ragged red fibers. Biochemical analysis of muscle (in one patient) revealed deficiency of pyruvate dehydrogenase complex. Analysis of mitochondrial DNA (mtDNA), [the other 2 patients] was negative for the 2 point mutations (T-G and T-C) at nucleotide position 8993, and for two T-C point mutations (at positions 8851 and 9176 of the ATPase 6 gene) that have been described in patients with LS. The girl with MELAS syndrome presented with a stroke-like episode at the age of 29 months and had focal brain lesions in the medial aspect of the left occipital and temporal lobes, and in the posteromedial aspect of the left thalamus, which resolved within 7 weeks. She had raised cerebrospinal fluid lactate but no ragged red fibers on muscle histochemistry. Biochemical assay of muscle homogenate showed reduction in respiratory chain complexes I, III and IV. Mutation screening of mtDNA at nucleotides 3243 (tRNA(Leu(UUR))) and 8344 (tRNA(Lys)) was negative. CONCLUSIONS: Mitochondrial disorders constitute a risk factor for stroke in Saudi children. However, demanding and highly specialized investigations are needed to confirm the diagnosis. These are better performed at supraregional centers where facilities for clinical, biochemical and molecular work-up are available.

Outcome of stroke in Saudi children.

OBJECTIVE: To report on the prognosis, neurologic outcome, and recurrences of stroke in Saudi children. METHODS: We evaluated a cohort of 104 Saudi children with stroke at the Division of Pediatric Neurology at King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia from July 1992 to February 2001 (retrospective study) and February 2001 to March 2003 (prospective study). We analyzed the salient clinical, neuroimaging, neurophysiological, neuropsychological and laboratory data following retrieval from a specialty designed comprehensive protocol. RESULTS: Of the 104 children in the cohort (aged one month to 12 years), 5 (4.8%) died during the study period and 9 (8.7%) were lost to follow-up. The mean duration of follow-up for the remaining 90 children was 40 months (median 33 months). Recovery was judged complete in 6 (6.7%) of these 90 children. We detected residual hemiparesis (irrespective of its effect on daily functions) in 73 (81%) and this was combined with other motor deficits in 45 children (50%). Forty-one children (46%) had residual dysphasia or language deficits, whereas 45 (50%) were judged to have had cognitive deficit. Psychometry revealed an abnormal intelligence quotient test (<70) in 19 of 26 (73%) children. Other neurologic sequelae included epilepsy in 52 (58%), recurrent headaches in 13 (14%) and hydrocephalus in 4 (4.4%) patients. Six of the 95 (6.3%) children, who were ascertained to have died or kept their follow-up, had one or more recurrences, one month to 5 years after the initial stroke (median 23 months). Patients who had recurrent strokes were significantly more likely to be the product of consanguineous marriages (p=0.04). Regarding the group of 23 children with perinatal stroke, neither deaths nor recurrences occurred during the follow-up period. However, 20 (87%) of them had significant delays in their developmental milestones. CONCLUSIONS: The toll of stroke in Saudi children is demanding, with most children demonstrating persistent neurologic or cognitive deficits. Primary prevention for recurrences is feasible through informed genetic counseling.

Congenital and genetic cerebrovascular anomalies as risk factors for stroke in Saudi children.

OBJECTIVE: To explore the role of and report on congenital and genetic cerebrovascular anomalies as risk factors for stroke in a prospective and retrospective cohort of Saudi children. METHODS: Children with stroke were evaluated at the Division of Pediatric Neurology (DPN), or were seen as inpatients in the Pediatric Wards at King Khalid University Hospital (KKUH), Riyadh, Kingdom of Saudi Arabia during the periods July 1992 to February 2001 (retrospective study) and February 2001 to March 2003 (prospective study). Stroke work-up for each suspected case included hemostatic assays, serological, biochemical and neurophysiological tests. Neuroimaging modalities included routine skull x-rays, CT, MRI, magnetic resonance angiography (MRA) and conventional cerebral angiography. RESULTS: Of 104 children with stroke, congenital and genetic cerebrovascular anomalies were the underlying risk factor in 7 (6.7%). The patients were evaluated at the DPN at a mean age of 66 months (range = 8 months to 11 years, median = 6 years); and they had stroke at a mean age of 48 months (range = 2 months to 10 years, median = 8 months). Four patients had stroke in association with neurocutaneous syndromes. Two had Sturge-Weber syndrome (SWS), one had Klippel-Trenaunay syndrome associated with SWS, and the fourth had neurofibromatosis type 1. Two patients had intracranial hemorrhage secondary to ruptured aneurysm. A girl (aged 9 years and 4 months) had left posterior cerebral artery aneurysm. She was diagnosed to have autosomal dominant polycystic kidney disease following renal ultrasonography. She died 5 months later despite surgical intervention (clipping of aneurysm). The second child was an 8-month-old boy who presented with subarachnoid and intraventricular hemorrhage (IVH) following ruptured anterior communicating artery aneurysm. He recovered with no residual symptoms following successful clipping of the aneurysm. Arteriovenous malformation (AVM) caused IVH in a 7-year-old boy who reported to hospital 5 hours after onset of headache, vomiting, drowsiness, and dizziness. Following drainage of the IVH and stabilization of the patient, the AVM was successfully embolized 6 weeks later. CONCLUSIONS: As a group, congenital and genetic cerebrovascular anomalies constitute a significant risk factor for stroke in Saudi children. Recognition of these diseases is important since some are treatable and because other family members may be at risk.

Cardiac diseases as a risk factor for stroke in Saudi children.

OBJECTIVE: To ascertain the role of cardiac diseases as a risk factor for stroke in a cohort of Saudi children who were evaluated in a retrospective and prospective study. METHODS: Children with cardiac diseases were identified from within a cohort of 104 Saudi children who presented with stroke. They were seen as inpatients in the Pediatric Wards or evaluated at the Outpatient Clinics of the Division of Pediatric Neurology (DPN), and the Division of Pediatric Cardiology at King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia during the periods July 1992 to February 2001 (retrospective study) and February 2001 to March 2003 (prospective study). A comprehensive form for clinical, neuroimaging, neurophysiological and laboratory data retrieval was designed and completed for each patient. Cardiac evaluation included 12-lead ECG and serial echocardiograms. Cardiac catheterization and 24-hour ambulatory ECG (Holter) were conducted on clinical discretion. RESULTS: Cardiac diseases were the underlying risk factor for stroke in 6 (5.8%) of the 104 children (aged one month to 12 years). The patients (4 males and 2 females) were evaluated at the DPN at a mean age of 5.3 years (range = 1-8 years; median 6.5 years). Onset of stroke was at a mean age of 34 months (range = 4 months-8 years; median = 30 months). Five patients had stroke in association with congenital heart disease (CHD), whereas the sixth had restrictive cardiomyopathy. The identified CHD consisted of membranous ventricular septal defect in a 5-year-old boy who had moyamoya syndrome and sickle cell beta(0)-thalassemia, asymptomatic patent ductus arteriosus (PDA) in a 17-month-old girl, atrioventricular canal defect and PDA in an 8-year-old boy who also had Down syndrome, partial anomalous pulmonary venous drainage in a one-year-old boy, and Tetralogy of Fallot in an 8-year-old boy. The latter patient developed hemiparesis secondary to a septic embolus, which evolved into brain abscess involving the right fronto-parietal region. This was successfully managed surgically. The sixth patient was an 8 1/2-year-old girl who had hemiparesis and complex partial seizure in association with restrictive cardiomyopathy. Serial echocardiograms depicted resolution of the cardiac abnormalities within 5 years and subsequent normal findings. CONCLUSIONS: Cardiac diseases, as a group, constitute a significant risk factor for stroke in Saudi children. Early diagnosis of these diseases is important to prevent further recurrences of stroke, and because some of them are potentially curable.

Stroke in Saudi children. Epidemiology, clinical features and risk factors.

OBJECTIVES: To describe the epidemiology and clinical features of stroke in a prospective and retrospective cohort of Saudi children and ascertain the causes, pathogenesis, and risk factors. METHODS: The Retrospective Study Group (RSG) included children with stroke who were evaluated at the Division of Pediatric Neurology, or admitted to King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia during the period July 1992 to February 2001. The Prospective Study Group (PSG) included those seen between February 2001 and March 2003. RESULTS: During the combined study periods of 10 years and 7 months, 117 children (61 males and 56 females, aged one month-12 years) were evaluated; the majority (89%) of these were Saudis. The calculated annual hospital frequency rate of stroke was 27.1/100,000 of the pediatric (1 month-12 years) population. The mean age at onset of the initial stroke in the 104 Saudi children was 27.1 months (SD = 39.3 months) and median was 6 months. Ischemic strokes accounted for the majority of cases (76%). Large-vessel infarcts (LVI, 51.9%) were more common than small-vessel lacunar lesions (SVLL, 19.2%). Five patients (4.8%) had combined LVI and SVLL. Intracranial hemorrhage was less common (18.2%), whereas sinovenous thrombosis was diagnosed in 6 (5.8%) patients. A major risk factor was identified in 94 of 104 (89.4%) Saudi children. Significantly more hematologic disorders and coagulopathies were identified in the PSG compared to the RSG (p=0.001), reflecting a better yield following introduction of more comprehensive hematologic and coagulation laboratory tests during the prospective study period. Hematologic disorders were the most common risk factor (46.2%), presumed perinatal ischemic cerebral injury was a risk factor in 23 children (22.1%) and infectious and inflammatory disorders of the circulatory system in 18 (17.3%). Congenital and genetic cerebrovascular anomalies were the underlying cause in 7 patients (6.7%) and cardiac diseases in 6 (5.8%). Six patients (5.8%) had moyamoya syndrome, which was associated with another disease in all of them. Inherited metabolic disorders (3.8%) included 3 children with Leigh syndrome and a 29-month-old girl with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. Systemic vascular disease was a risk factor in 3 children (2.9%) including 2 who had hypernatremic dehydration; and post-traumatic arterial dissection was causative in 3 cases (2.9%). Several patients had multiple risk factors, whereas no risk factor could be identified in 11 (10.6%). CONCLUSION: Due to the high prevalence and importance of multiple risk factors, a comprehensive investigation, including hematologic, neuroimaging and metabolic studies should be considered in every child with stroke.

Hematologic risk factors for stroke in Saudi children.

OBJECTIVE: To explore the hematologic risk factors for stroke in a cohort of Saudi children. METHODS: We evaluated children at the Division of Pediatric Neurology at King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, during the periods July 1992 to February 2001 (retrospective study) and February 2001 to March 2003 (prospective study). Investigations for suspected cases included neuroimaging, transcranial Doppler (TCD) for cases of sickle cell disease (SCD), and Duplex scan. Hemostatic assays included coagulation screening tests, tests of thrombin generation and fibrinolysis, coagulation inhibitors, and activated protein C resistance. RESULTS: During the study period, 104 Saudi children (aged one month to 12 years) with stroke were seen. The mean age of the cohort was 27.1 months (SD = 39.3 months) and median was 6 months. Ischemic strokes accounted for the majority of cases (76%). A major risk factor was identified in 93 of 104 cases of stroke (89.4%). Hematologic disorders were the most common (46.2%), followed by prothrombic disorders (31.7%); microcytic hypochromic anemia (26%); sickle cell disease (SCD), or SCbeta(0)-thalassemia, (11.5%), and factor IX deficiency (2.9%). Raised anticardiolipin antibodies (13/49, 26.5%) was the most frequent abnormality. Deficiencies of the natural anticoagulants (protein S, protein C and antithrombin III) were as follows: protein S (15/70, 21.4%); protein C (15/70, 21.4%) and combined deficiency of 2 or more inhibitors (9/70, 12.9%). Activated protein C resistance has not been detected. Contrary to the findings of previous studies from Saudi Arabia, SCD is a common risk factor and is severe, as it resulted in multiple strokes. Moyamoya syndrome was diagnosed in 2 patients with SCD, one of whom had revascularization surgery (encephaloduroarteriosynangiosis). Assessment of children with SCD at risk of stroke was helped by the introduction of TCD followed by neuroimaging, using MRI and magnetic resonance angiography. CONCLUSIONS: The study strongly highlights the importance of prothrombotic disorders and the severe phenotype of SCD as risk factors for stroke in Saudi children.

Moyamoya syndrome as a risk factor for stroke in Saudi children. Novel and usual associations.

OBJECTIVE: To report on moyamoya syndrome (MMS) as a risk factor for stroke in a prospective and retrospective cohort of Saudi children. The usual and novel associations of MMS in this cohort will also be described. METHODS: Children with stroke were evaluated at the Division of Pediatric Neurology at King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia during the periods July 1992 to February 2001 (retrospective study) and February 2001 to March 2003 (prospective study). Investigations for suspected cases included hemostatic assays, biochemical, and serological tests. Neuroimaging included CT, MRI, magnetic resonance angiography (MRA), single photon computerized tomography (SPECT) brain scan and conventional cerebral angiography. RESULTS: Moyamoya syndrome was the underlying risk factor for stroke in 6 (5.8%) of the 104 children (aged one month to 12 years). They were 4 females and 2 males. Their first cerebral ischemic event occurred at a mean age of 45 months (median = 44 months, range 17-66 months). In all 6 cases, MMS was associated with an underlying hematologic abnormality or other diseases. Protein C deficiency was identified in one girl and protein S deficiency in another. Two patients had respectively, sickle cell disease (SCD) and sickle cell-beta-thalassemia (S beta-thalassemia), which had been associated in the latter with membranous ventricular septal defect. Adams-Oliver syndrome (AOS, OMIM 100300) was associated with MMS in an 18-month-old girl. A 4-year-old boy had wrinkly skin syndrome (WSS, OMIM 278250) phenotype. The association of MMS and protein C deficiency was first reported in this cohort of patients, whereas the association of the syndrome with WWS and AOS has not, hitherto, been described. The 3 patients who had MMS associated with protein C deficiency, SCD, and AOS underwent successful revascularization surgery in the form of encephaloduroarteriosynangiosis. CONCLUSIONS: Moyamoya syndrome constitutes an important risk factor of stroke in Saudi children. Comprehensive clinical evaluation and investigations, including screening for thrombophilia and neuroimaging studies, are required for the primary diagnosis of the disease and for unraveling other diseases associated with MMS. This will help in managing these patients and in guiding genetic counseling for their families.

The Levels of Tissue Factor Pathway Inhibitor in Sepsis Patients Receiving Prophylactic Enoxaparin.

OBJECTIVE: Sepsis syndrome is usually accompanied by activation of blood coagulation mechanisms. Earlier studies found deficiencies of the 3 main natural anticoagulants, antithrombin, protein C, and protein S. However, none of these inhibitors block tissue factor, the prime trigger of coagulation during sepsis that is controlled specifically by the tissue factor pathway inhibitor (TFPI). The aim of this study was to characterize the fluctuations in the levels of natural anticoagulants, particularly TFPI, in the course of sepsis and to find out their association with the anticoagulant action of the low-molecular-weight heparin enoxaparin. MATERIALS AND METHODS: We studied 51 consecutive patients with sepsis. Blood samples were collected from patients at baseline (0 h) and at 4, 12, and 24 h after enoxaparin administration. The following assays were undertaken using commercial kits: activated partial thromboplastin time, prothrombin time, thrombin time, total and free TFPI, protein C and protein S, antithrombin, fibrinogen, and anti-factor Xa. RESULTS: Before enoxaparin administration, there was significant prolongation of the prothrombin time and activated partial thromboplastin time, and this remained the case in the 3 subsequent samples. There was marked reduction in the levels of antithrombin, protein C, and total and free protein S to below control values throughout the study. In contrast, plasma levels of both total and free TFPI were markedly elevated and increased after enoxaparin therapy. Anti-factor Xa levels were within the therapeutic range throughout. There was no difference in TFPI levels between those patients who died and those who survived. CONCLUSION: Sepsis triggered marked release of TFPI from endothelial cells. This persisted and was increased further following the administration of enoxaparin. In contrast, there was marked consumption of the natural coagulation inhibitors antithrombin, protein C, and protein S. These results go some way towards explaining why the therapeutic use of recombinant TFPI fails to correct sepsis-associated coagulopathy.