Successful thrombolysis following enoxaparin therapy in two pediatric patients with congenital heart disease presenting with intracardiac and cerebral thrombosis.

Enoxaparin displays fibrinolytic activity through stimulation of endothelial release of tissue plasminogen activator. Moreover, enoxaparin increases the release of tissue factor pathway inhibitor, which inhibits coagulation activity. However, there are only few reports regarding the use of enoxaparin for the treatment of children with thrombosis complicating congenital heart disease. We report the clinical findings from two patients, one child with an A. cerebri media infarction and another with a left ventricular thrombus. In both cases successful thrombolysis was obtained by intravenous administration of enoxaparin. The first patient was a 12-year-old girl with an atrioventricular septal defect, who underwent biventricular repair at the age of 8 months. She presented with right-sided middle cerebral artery infarction. Thrombolysis was contraindicated, because she was beyond the therapeutic window recommended by accepted guidelines. Enoxaparin 2.5 mg/kg/d was administered as a continuous intravenous infusion (CII). The MRI 10 days later revealed a reopened middle cerebral artery and she experienced complete remission of the neurological signs. The second patient was a 16-year-old boy who had tetralogy of Fallot corrected in late infancy. He presented with severe heart failure and a mural thrombus in the left ventricular apex. Enoxaparin was administered and resulted in complete disappearance of the thrombus within a week. According to our experience, CII of enoxaparin was safe and well tolerated without secondary bleeding and resulted in complete dissolution of the thrombi without secondary embolization. Therefore, CII of enoxaparin may be a possible alternative for the treatment of thrombotic complications in children with contraindications against conventional thrombolytic therapy.

Possible effect of corticoids on hemiplegic attacks in severe hemiplegic migraine.

BACKGROUND: Sporadic and familial hemiplegic migraines are rare paroxysmal disorders characterized by transient hemiparesis and headache. The distinction is based on whether other family members are affected. In 50% of cases, these migraines are caused by CACNA1 A missense mutations. PATIENTS: We describe a boy with a particularly severe phenotype and a de novo R1349Q mutation of the CACNA1 A gene. RESULTS: The patient suffered from early-onset profound mental retardation, epileptic seizures, cerebellar ataxia, and progressive cerebellar atrophy. He experienced prolonged attacks of migraine with hemiparesis, seizures, altered consciousness, and fever resulting from minor head traumas. A prolonged hemiplegic attack improved following a 5-day treatment of 100 mg/d methylprednisolone. CONCLUSION: R1349Q mutation of the CACN1 A gene may be associated with a severe phenotype. Corticoids might be beneficial in prolonged hemiplegic attacks.

Acute encephalopathy with unilateral cortical-subcortical lesions in two unrelated kindreds treated with glucocorticoids prenatally for congenital adrenal hyperplasia due to 21-hydroxylase deficiency: established facts and novel insight.

BACKGROUND: Prenatal glucocorticoid (GC) treatment of the female fetus with 21-hydroxylase deficiency (21-OHD) may prevent genital virilization and androgen effects on the brain, but prenatal GC therapy is controversial because of possible adverse effects on fetal programming, the cardiovascular system and the brain. CASE REPORTS: We report 2 patients with congenital adrenal hyperplasia (CAH) due to 21-OHD who were treated prenatally with dexamethasone, suffered from an acute encephalopathy and showed focal and multifocal cortical and subcortical diffusion restrictions in early MRI and signs of permanent alterations in the follow-up neuroimaging studies. Both patients recovered from the acute episode. Whereas the first patient recovered without neurological sequelae the second patient showed hemianopsia and spastic hemiplegia in the neurological follow-up examination. CONCLUSION: These are 2 children with CAH, both treated prenatally with high doses of dexamethasone to prevent virilization. The question arises whether prenatal high-dose GC treatment in patients with CAH might represent a risk factor for brain lesions in later life. Adverse effects/events should be reported systematically in patients undergoing prenatal GC treatment and long-term follow-up studies involving risk factors for cerebrovascular disease should be performed.

12q24.33 deletion: report of a patient with intellectual disability and review of the literature.

Deletions of chromosome band 12q24.33 are rare. We report on a 17-year-old male patient with intellectual disability but no major malformations or dysmorphic features in whom a de novo interstitial 660 kb deletion in 12q24.33 was detected by SNP array analysis. This deletion was secondary to a translocation t(12;14)(q24.3;q13)dn that also led to a small deletion in 14q21.1 and a small duplication in 2p23.1. The deletion overlaps with two previously published larger deletions in patients who suffered from intellectual disability, obesity, and polycystic kidney disease, indicating that haploinsufficiency of one or several of the genes in the deleted interval of the patient reported here causes intellectual deficits, but not obesity or renal problems. The 14 RefSeq genes that are harbored by this deletion include P2RX2, which had previously been proposed as a candidate gene for intellectual disability. Thus, the patient reported here broadens our knowledge of the phenotypic consequences of deletions in 12q24.33 and facilitates genotype-phenotype correlations for chromosome aberrations of this region.

Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum.

BACKGROUND: Mutations in SACS, leading to autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), have been identified as a frequent cause of recessive early-onset ataxia around the world. Here we aimed to enlarge the spectrum of SACS mutations outside Quebec, to establish the pathogenicity of novel variants, and to expand the clinical and imaging phenotype. METHODS: Sequencing of SACS in 22 patients with unexplained early-onset ataxia, assessment of novel SACS variants in 3.500 European control chromosomes and extensive phenotypic investigations of all SACS carriers. RESULTS: We identified 11 index patients harbouring 17 novel SACS variants. 9/11 patients harboured two variants of at least probable pathogenicity which were not observed in controls and, in case of missense mutations, were located in highly conserved domains. These 9 patients accounted for at least 11% (9/83) in our series of unexplained early onset ataxia subjects. While most patients (7/9) showed the classical ARSACS triad, the presenting phenotype reached from pure neuropathy (leading to the initial diagnosis of Charcot-Marie-Tooth disease) in one subject to the absence of any signs of neuropathy in another. In contrast to its name "spastic ataxia", neither spasticity (absent in 2/9=22%) nor extensor plantar response (absent in 3/9=33%) nor cerebellar ataxia (absent in 1/9=11%) were obligate features. Autonomic features included urine urge incontinence and erectile dysfunction. Apart from the well-established MRI finding of pontine hypointensities, all patients (100%) showed hyperintensities of the lateral pons merging into the (thickened) middle cerebellar peduncles. In addition, 63% exhibited bilateral parietal cerebral atrophy, and 63% a short circumscribed thinning of the posterior midbody of the corpus callosum. In 2 further patients with differences in important clinical features, VUS class 3 variants (c.1373C>T [p.Thr458Ile] and c.2983 G>T [p.Val995Phe]) were identified. These variants were, however, also observed in controls, thus questioning their pathogenic relevance. CONCLUSIONS: We here demonstrate that each feature of the classical ARSACS triad (cerebellar ataxia, spasticity and peripheral neuropathy) might be missing in ARSACS. Nevertheless, characteristic MRI features - which also extend to supratentorial regions and involve the cerebral cortex - will help to establish the diagnosis in most cases.

The effect of vasospasm on cerebral perfusion: a colour duplex study of the extra- and intracranial cerebral arteries.

To assess whether middle cerebral artery (MCA) vasospasm reduces the flow volume in the corresponding extracranial internal carotid artery (ICA) or global cerebral blood flow volume (CBFV) in subarachnoid haemorrhage (SAH) patients, a colour duplex ultrasound study of the intra- and extracranial cerebral arteries was performed. MCA vasospasm was defined as a time-averaged maximum flow velocity (TAMX) exceeding 120 cm/s. ICA flow volumes and CBFV, were compared in each patient at maximum TAMX recorded in one MCA ("maximum-vasospasm") and when TAMX in the same vessel was closest to mean reference values ("no-vasospasm"). Additionally, the CBFV course during the first 3 weeks after SAH was evaluated longitudinally. Data from age- and gender-matched healthy test persons served as control. In 28 patients with MCA vasospasm, 337 measurements were completed. Global CBFV was significantly reduced starting from day 3 after SAH. ICA flow volumes and CBFV were not different when comparing at "maximum-vasospasm" and "no-vasospasm". Compared with the control group, both were lower at either condition. Thus, in SAH patients, vasospasm even severe, in general does not further diminish ICA flow volumes and global CBFV, which are reduced already before the onset of vasospasm.

A longitudinal study of cerebral blood flow over the first 30 months.

To investigate prospectively the development of cerebral perfusion during infancy, serial quantitative measurements of cerebral blood flow (CBF) volume were performed in two healthy children from birth up to the age of 30 mo. A total of 28 CBF volume measurements were done in either of the children. Absolute flows were measured in the internal carotid and vertebral arteries on both sides. Blood flow was calculated as the product of angle-corrected time-averaged flow velocity and the cross-sectional area of the vessel. Starting from 67 and 80 mL/min, respectively, at birth an almost 10-fold increase of CBF volume was observed in both children during the examination period. Half of this rise occurred during the first 6 mo, probably reflecting the steep metabolic incline during this period of synaptogenesis. The continuous increase in CBF volume after the sixth month of life mainly corresponds to brain growth. Estimated CBF (based on estimated brain weights) increased from 21 and 23 mL 100 g(-1) min(-1), respectively, after birth to 46 and 53 mL 100 g(-1) min(-1), respectively, during the first 6 mo of life in both children, remaining stable thereafter. This study is the first to provide longitudinal data of CBF during the first 30 mo after birth.

Vessel wall contrast enhancement: a diagnostic sign of cerebral vasculitis.

PURPOSE: Inflammatory stenoses of cerebral arteries cause stroke in patients with florid vasculitis. However, diagnosis is often difficult even with digital subtraction angiography (DSA) and biopsy. The purpose of this study was to establish the value of contrast-enhanced MRI, proven to be sensitive to extradural arteritis, for the identification of intracranial vessel wall inflammation. PATIENTS AND METHODS: Twenty-seven patients with a diagnosis of cerebral vasculitis affecting large brain vessels were retrieved from the files: 8 children (2-10 years, 7 female, 1 male) and 19 adults (16-76 years, 10 female, 9 male). Diagnosis was based on histological or serological proof of vasculitis or on clinical and imaging criteria. All MRI examinations included diffusion-weighted imaging, time-of-flight magnetic resonance angiography (TOF-MRA) and contrast-enhanced scans. MRI scans were assessed for the presence of ischemic brain lesions, arterial stenoses, vessel wall thickening and contrast uptake. RESULTS: Ischemic changes of the brain tissue were seen in 24/27 patients and restricted diffusion suggestive of recent ischemia in 17/27; 25/27 patients had uni- or multifocal stenoses of intracranial arteries on TOF-MRA and 5/6 had stenoses on DSA. Vessel wall thickening was identified in 25/27, wall enhancement in 23/27 patients. CONCLUSION: Wall thickening and intramural contrast uptake are frequent findings in patients with active cerebral vasculitis affecting large brain arteries. Further prospective studies are required to determine the specificity of this finding.

Prenatal multicystic encephalomalacia due to anomaly of the aortic arch.

Multicystic encephalomalacia (ME) usually results from severe hypoxic-ischemic brain damage occurring during the late third trimester of gestation and birth. We report on a case of congenital ME due to a congenital anomaly of the aortic origin of brachiocephalic vessels resulting in subclavian steal syndrome. A 5-day-old term neonate presented with microcephaly and overlapping cranial sutures. Both arms were developed normally. Magnetic resonance imaging of the brain showed extensive bilateral supratentorial ME. Color duplex sonography of the aortic arch and the intracranial and extracranial vessels revealed a stenosis at the origin of the left common carotid artery and atresia of the origin of the left subclavian artery resulting in left-sided subclavian steal syndrome and retrograde perfusion of the basilar artery. Total cerebral blood flow volume was reduced to 22 mL/min. Severely reduced cerebral blood flow volume resulted from left carotid artery stenosis and atresia of the origin of the left subclavian artery with consecutive subclavian steal. Infratentorial brain structures and the left arm remained intact, but supratentorial brain structures were severely affected with ME.

Development of cerebral blood flow volume in preterm neonates during the first two weeks of life.

To investigate the postnatal development of cerebral perfusion in preterm neonates with normal brains over the first 2 wk of life, a prospective longitudinal study was designed. Quantitative measurement of cerebral blood flow (CBF) volume was performed using ultrasound flowmetry of the extracranial, brain-feeding arteries in 32 preterm infants of 28-35 wk gestational age. Measurements were done in the internal carotid and vertebral arteries of both sides on d 1, 2, 3, 7, and 14 after birth. A 10.0-MHz linear transducer of a computed sonography system (Acuson 128/XP10) was used. Intravascular flow volumes were calculated as the product of angle-corrected time-averaged flow velocity and the cross-sectional area of the vessel. Mean CBF volume increased markedly over the first 2 wk. One-third of this rise already occurred from the first to the second postnatal day, thereafter there was a continuous increase from d 2 to d 14 of life. Whereas the absolute level of CBF volume was primarily determined by postmenstrual age, the pattern of postnatal changes in CBF volume was found to be independent of gestational age. Arterial carbon dioxide tension, mean arterial blood pressure, and hematocrit had no influence on the development of CBF volume. The pronounced increase of CBF volume from d 1 to d 2 is likely to represent a normal adaptive response of the cerebral circulation to postnatal life. The data presented here may serve as the basis for further studies to investigate whether deviations from this adaptive response are associated with an increased risk of brain injury.

Volume measurement of cerebral blood flow: assessment of cerebral circulatory arrest.

BACKGROUND: Cerebral blood flow (CBF) volume can be measured at bedside by color duplex flowmetry of the extracranial cerebral arteries. In neurointensive care patients, we prospectively tested the hypothesis that a CBF volume <100 ml/min indicates imminent cerebral circulatory arrest. METHODS: CBF volume was determined as sum of flow volumes in the internal carotid and vertebral arteries of both sides. In 192 neurointensive care patients, 829 measurements were taken. When CBF volume fell short of 100 ml/min, common carotid and external carotid artery flow volumes were also measured, and transcranial color-coded duplex sonography (TCCD) of basal cerebral arteries was performed. Results were compared with actual clinical conditions, outcome, and previously published reference data. RESULTS: All 41 patients with CBF volume <100 ml/min (range, 0-89 ml/min) were officially declared brain dead 2-126 hours after the measurement (median, 23 hours). TCCD revealed signs of cerebral circulatory arrest in all patients with a patent acoustic bone window. External carotid artery flow volumes were normal. The lowest CBF volume rate recorded in a surviving patient was 208 ml/min. CONCLUSIONS: Early confirmation of cerebral circulatory arrest is of decisive importance if the patient is a potential organ donor. CBF volume measurement allows confirming the arrest of cerebral circulation even in patients without a patent acoustic bone window for TCCD. Because the critical lower threshold for survival appears to lie at 200 ml/min, bedside monitoring of CBF volume in neurointensive care patients may indicate a therapeutic window before irreversible circulatory arrest occurs.

Cerebral blood flow volume measurements with ultrasound: Interobserver reproducibility in preterm and term neonates.

Cerebral blood flow (CBF) volume can be measured quantitatively by colour duplex sonography. To test the reliability of CBF volume measurements in newborns, two "blinded" examiners performed a prospective test-retest study in 32 neonates (postmenstrual age 32 to 42 weeks). Measurements were done in the internal carotid and vertebral arteries. Intravascular flow volumes (FV) were calculated as the product of angle-corrected time-averaged flow velocity and the cross-sectional area of the vessel. The CBF volumes measured by the two examiners were very close (mean +/- SD, 62.6 +/- 20.6 vs. 62.1 +/- 21.2 mL/min, NS; coefficient of variation, 6.3%; intraclass correlation coefficient, 0.98). The 95% limits of agreement, according to Bland and Altman, ranged from -7.3 to +8.4 mL/min. In comparison with other test-retest studies, the reproducibility of quantitative CBF measurements reported here is among the best ever found. We conclude that CBF volume can be measured reliably even in preterm neonates.

The development of haemodynamics in the extracranial cerebral arteries of healthy preterm and term neonates.

To investigate the development of cerebral haemodynamics in healthy preterm and term newborns, a prospective colour duplex sonography study was performed in 113 neonates at 32 to 42 weeks of postmenstrual age. In the extracranial internal carotid arteries (ICAs) and vertebral arteries (VAs), luminal diameters and angle-corrected flow velocities were measured. Flow volumes and waveform parameters were calculated. There were no side-to-side or gender-related differences for any of the parameters measured. A marked increase of luminal diameters, end-diastolic and time-averaged flow velocities and flow volumes with postmenstrual age was found in both ICA and VA (p

Complete asymptomatic thrombosis and resorption of a congenital giant intracranial aneurysm.

Intracranial aneurysms in infants are rare, but are associated with a high risk of rupture and subarachnoid hemorrhage. The authors report a case of an incidentally diagnosed, probably congenital, asymptomatic giant aneurysm of the posterior communicating artery in a 9-month-old girl, which completely thrombosed following a diagnostic superselective angiography without any neuropathological incident. Follow-up magnetic resonance imaging revealed that the aneurysm decreased further in size and was largely resorbed within 3 years after the initial finding. In single cases the natural history of congenital giant aneurysms may be better than previously assumed.

Neonatal cerebral infarction diagnosed by diffusion-weighted MRI: pseudonormalization occurs early.

BACKGROUND: Seizures in the neonatal period may be the single symptom of acute ischemic cerebral infarction. It may be difficult to establish the diagnosis in the acute phase by the use of ultrasound, CT, and conventional MRI because of the high water content of the immature brain. Diffusion-weighted (DW) MRI is a very sensitive and fast imaging modality to visualize acute ischemic stroke in infants even before conventional MR images become abnormal. Signal abnormality in DW MRI, however, seems to follow a different time course than in older patients. CASE DESCRIPTION: DW MRI became falsely negative 1 week after stroke (pseudonormalization) in 2 newborn patients during persistence of signal abnormalities on turbo spin-echo images, whereas the so-called pseudonormalization in adults normally occurs within 10 to 14 days. CONCLUSIONS: T2-weighted sequences should supplement DW images to reliably detect subacute ischemic infarctions in the neonatal period.