Classification, clinical features, and genetics of neural tube defects

Neural tube defects [NTDs] constitute a major health burden [0.5-2/1000 pregnancies worldwide], and remain a preventable cause of still birth, neonatal, and infant death, or significant lifelong handicaps. The malformations result from failure of the neural folds to fuse in the midline, and form the neural tube between the third and the fourth week of embryonic development. This review article discusses their classification, clinical features, and genetics. Most NTDs are sporadic and both genetic, and non- genetic environmental factors are involved in its etiology. Consanguinity was suggested to contribute to the high incidence of NTDs in several countries, including Saudi Arabia. Syndromes, often associated with chromosomal anomalies, account for >10% of all NTDs; but a higher proportion [20%] has been documented in Saudi Arabia. Genetic predisposition constitutes the major underlying risk factor, with a strong implication of genes that regulate folate one- carbon metabolism and planar cell polarity.

Epidemiology, prenatal management, and prevention of neural tube defects

This review article discusses the epidemiology, risk factors, prenatal screening, diagnosis, prevention potentials, and epidemiologic impact of neural tube defects [NTDs]. The average incidence of NTDs is 1/1000 births, with a marked geographic variation. In the developed countries, the incidence of NTDs has fallen over recent decades. However, it still remains high in the less-developed countries in Latin America, Africa, the Middle East, Asia, and the Far East [>1 to 11/1000 births]. Recognized NTDs risks include maternal diabetes, obesity, lower socioeconomic status, hyperthermia, and exposure to certain teratogens during the periconceptional period. Periconceptional folic acid supplementation decreased the prevalence of NTDs by 50-70%, and an obligatory folic acid fortification of food was adopted in several countries to reach women with unplanned pregnancies and those facing social deprivation. Prevention of NTDs can be accelerated if more, especially low income countries, adopted fortification of the staple food in their communities.

Epidemiology of neural tube defects

To find the prevalence of neural tube defects [NTDs], and compare the findings with local and international data, and highlight the important role of folic acid supplementation and flour fortification with folic acid in preventing NTDs. This is a retrospective study of data retrieved from the medical records of live newborn infants admitted to the Neonatal Intensive Care Unit [NICU], Security Forces Hospital [SFH], Riyadh, Saudi Arabia with NTDs spanning 14 years [1996-2009]. All pregnant women on their first antenatal visit to the primary care clinic were prescribed folic acid 0.5 mg daily, or 5 mg if there is a family history of NTD. The pre-fortification prevalence is compared to post-fortification, before and after excluding syndromic, genetic, and chromosomal causes. The results were compared with reports from other parts of Saudi Arabia and internationally, through a literature search using MEDLINE. The prevalence of NTDs during the period was 1.2 per 1000 live births. The pre-fortification of flour with folic acid prevalence was 1.46 per 1000 live births. The post-fortification prevalence was 1.05 [p=0.103]. After excluding syndromic, genetic, and chromosomal causes from calculation of the prevalence, there was a significant reduction in the prevalence, from 1.46 to 0.81 per 1000 live births [p=0.0088]. Syndromic, genetic, and chromosomal causes were identified in 20 cases [19.4%]. Only 2% of mothers received preconception folic acid, and only 10% of them received it during the first 4 weeks of gestation. Conclusion: Despite the implementation of fortification of flour with folic acid since 2001, the prevalence of NTDs in the Kingdom of Saudi Arabia is still high. This is due to the impact of genetic, syndromic, and chromosomal causes of NTD not preventable by folic acid. Other factors like unplanned pregnancy and lack of awareness of the role of folic acid in preventing nonsyndromic causes, play a significant role.

Sirenomelia and severe caudal regression syndrome

To describe cases of sirenomelia and severe caudal regression syndrome [CRS], to report the prevalence of sirenomelia, and compare our findings with the literature. Retrospective data was retrieved from the medical records of infants with the diagnosis of sirenomelia and CRS and their mothers from 1989 to 2010 [22 years] at the Security Forces Hospital, Riyadh, Saudi Arabia. A perinatologist, neonatologist, pediatric neurologist, and radiologist ascertained the diagnoses. The cases were identified as part of a study of neural tube defects during that period. A literature search was conducted using MEDLINE. During the 22-year study period, the total number of deliveries was 124,933 out of whom, 4 patients with sirenomelia, and 2 patients with severe forms of CRS were identified. All the patients with sirenomelia had single umbilical artery, and none were the infant of a diabetic mother. One patient was a twin, and another was one of triplets. The 2 patients with CRS were sisters, their mother suffered from type II diabetes mellitus and morbid obesity on insulin, and neither of them had a single umbilical artery. Other associated anomalies with sirenomelia included an absent radius, thumb, and index finger in one patient, Potter's syndrome, abnormal ribs, microphthalmia, congenital heart disease, hypoplastic lungs, and diaphragmatic hernia. The prevalence of sirenomelia [3.2 per 100,000] is high compared with the international prevalence of one per 100,000. Both cases of CRS were infants of type II diabetic mother with poor control, supporting the strong correlation of CRS and maternal diabetes.

Split cord malformation associated with spinal open neural tube defect

To illustrate the clinical and radiological findings of split cord malformation [SCM] in patients with spinal open neural tube defect [SONTD], and report the outcome of their treatment. A retrospective study of the clinical and radiological findings of 11 patients diagnosed with SCM, identified among 83 patients with SONTD at King Khalid University Hospital, in Riyadh, Saudi Arabia between 1995 and 2010. There were 6 girls and 5 boys; their age ranged from less than a year to 9 years [mean 4.2 years]. Six patients had type I SCM, and 5 patients type II SCM. The CT and MRI imaging showed characteristic bony, cartilaginous, or fibrous septum, and other SONTD-associated anomalies. Seven patients were graded A and B according to the Frankel grading score, and none of them required surgery, while worsening neurology led to surgical intervention in 3 patients, with clinical improvement after surgery, and one patient that underwent cord untethering remained stable. Split cord malformation is not uncommon among patients with SONTD. It tends to involve mainly the lumbar spine, and female predominance is more remarkable in type I. Neurological manifestations of SCM may be superimposed with SONTD. Surgery is effective for symptomatic patients, and not indicated in the severely disabled.

Genetic, chromosomal, and syndromic causes of neural tube defects

To ascertain the incidence, and describe the various forms of neural tube defects [NTDs] due to genetic, chromosomal, and syndromic causes. We carried out a retrospective analysis of data retrieved from the medical records of newborn infants admitted to the Neonatal Intensive Care Unit with NTDs and their mothers spanning 14 years [1996-2009] at the Security Forces Hospital, Riyadh, Saudi Arabia. The cases were ascertained by a perinatologist, neonatologist, geneticist, radiologist, and neurologist. The literature was reviewed via a MEDLINE search. Only liveborn babies were included. Permission from the Educational Committee at the Security Forces Hospital was obtained prior to the collection of data. Out of 103 infants with NTDs admitted during this period, 20 [19.4%] were found to have an underlying genetic syndromic, chromosomal and/or other anomalies. There were 5 cases of Meckel-Gruber syndrome, 2 Joubert syndrome, one Waardenburg syndrome, one Walker-Warburg syndrome, 2 chromosomal disorders, 2 caudal regression, one amniotic band disruption sequence, one associated with omphalocele, one with diaphragmatic hernia, and 4 with multiple congenital anomalies. There is a high rate of underlying genetic syndromic and/or chromosomal causes of NTDs in the Saudi Arabian population due to the high consanguinity rate. Identification of such association can lead to more accurate provisions of genetic counseling to the family including preimplantation genetic diagnosis or early termination of pregnancies associated with lethal conditions.

Agenesis of the corpus callosum associated with spinal open neural tube defect

To ascertain the incidence and clinical implications of agenesis of the corpus callosum [ACC] in spinal open neural tube defects [SONTD]. All cases of SONTD registered at the Spina Bifida Clinic in King Khalid University Hospital, Riyadh, Saudi Arabia between 1995 and 2010 were retrospectively reviewed, and mid-sagittal MRI of the corpus callosum [CC] area was analyzed in each case. Neurodevelopmental outcome was classified as poor in children with seizures, severe neurodevelopmental impairment, or death. Thirty-eight patients [45.8%] with ACC were identified among 83 cases with SONTD. Patients' age ranged between one and 16 years. Total ACC was found in 10 patients, partial ACC in 25, and in 3 patients, the CC was hypoplastic. Active hydrocephalus was an associated finding in 9 out of 10 patients with total ACC, 22 out of 25 with partial ACC, and in all patients with hypoplasia of the CC. Thirteen patients [34.2%] had normal intellectual function, whereas 24 patients presented with learning disability, epilepsy, or poor intellectual function; and one patient died of respiratory failure. Agenesis of the corpus callosum is found in a significant portion of patients with SONTD. When associated with hydrocephalus, its presence affects neuro-developmental outcome.

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, lowmolecular-weight heparins, aspirin or warfarin, or both. Specialized stroke care and follow-up are needed for children with stroke, as well as their families.

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

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.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. 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%]. 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

To explore the hematologic risk factors for stroke in a cohort of Saudi children. 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 [SCO], and Duplex scan. Hemostatic assays included coagulation screening tests, tests of thrombin generation and fibrinolysis, coagulation inhibitors, and activated protein C resistance. 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 SC beta-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. The study strongly highlights the importance of prothrombotic disorders and the severe phenotype of SCD as risk factors for stroke in Saudi children.

Perinatal stroke in Saudi children. Clinical features and risk factors

To describe the clinical features and presentations of perinatal stroke in a prospective and retrospective cohort of Saudi children and ascertain the risk factors. 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. 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. 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 childern

To report on the role of infectious and inflammatory disorders as risk factors for stroke in a prospective and retrospective cohort of Saudi children. 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. 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. 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.

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

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. 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. 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. 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

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. 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. 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 - 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. 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.

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

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. 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. 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-B-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. 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.

Stroke due to mitochondrial disorders in Saudi children

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. 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. 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. 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

To report on the prognosis, neurologic outcome, and recurrences of stroke in Saudi children. 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. 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. 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

Stroke from systemic vascular disorders in Saudi children. the devastating role of hypernatremic dehydration

Systemic vascular disorders, leading to childhood stroke, include volume depletion or systemic hypotension and hypernatremic dehydration. We describe 3 cases of stroke following systemic vascular disorders. These were diagnosed during a prospective and retrospective study on childhood stroke, which included 104 patients. Post-gastroenteritis hypernatremic dehydration is an important, potentially preventable, cause of stroke in Saudi children