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Craniosynostosis constitutes one of the most common congenital cranial malformations, affecting approximately 6/10,0000 live births. A genetic etiology has long been known for several forms of syndromic craniosynostosis, including pathogenic variants in TWIST1 and FGFR3 in children with Saethre-Chotzen and Muenke syndrome. Over the last decade, reports of genetic aberrations in TCF12 in children with craniosynostosis have emerged, in particular in cases with premature closure of the coronal suture(s). In this study, we, therefore, systematically reviewed the rapidly growing knowledge of TCF12-related coronal craniosynostosis, clearly illustrating its high degree of genotype and phenotype variability. With the two novel cases presented, at least 113 cases of TCF12-related coronal craniosynostosis have currently been reported. By pooling data from several prospectively collected undifferentiated craniosynostosis cohorts (ntotal = 770), we estimate a prevalence of pathogenic TCF12 variants of at least 2%. Overall, pathogenic germline variants in TCF12 are relatively frequent in children with coronal craniosynostosis, accounting for â¼10-20% of TWIST1- and FGFR1/2/3-negative cases, with even higher rates for bicoronal and syndromic cases. Genetic counseling is recommended for all children with craniosynostosis, and involvement of the coronal suture(s) should precipitate TCF12 testing.
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INTRODUCTION: We present a unique case of monozygotic female twins with virtually identical clinical and radiological presentations of supratentorial hydrocephalus and cystic formations from the suprasellar cistern. DISCUSSION: Evaluating genetic predispositions and prenatal exposures is crucial for hydrocephalus in twins. Familial cases imply a genetic contribution to the development of these anomalies, including chromosomal abnormalities and specific variants linked to arachnoid cyst formation in various syndromes. Extensive genetic analyses found no pathogenic variants in the twins. Prenatal exposure to anti-epileptic medication was known during pregnancy and may be associated with fetal abnormalities, but not central nervous system (CNS) malformations, and was therefore not considered the cause of the condition in the twins. The twins presenting simultaneously with hydrocephalus caused by suprasellar cysts (SAC) underwent a two-step surgical management: initial ventriculoperitoneal shunt (VPS) placement followed by fenestration. Postoperative imaging showed cyst reduction, but a secondary VPS was necessary in both cases. CONCLUSION: Genetic analysis is less likely to identify a monogenic etiology in non-syndromic cases of SACs, which are assumed to be multifactorial. There is no established evidence linking a teratogenic effect of anti-epileptic drugs to CNS malformations. Moreover, the surgical treatment of this complex condition constitutes a point of discussion.
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Quistes Aracnoideos , Hidrocefalia , Embarazo , Femenino , Humanos , Hidrocefalia/diagnóstico por imagen , Hidrocefalia/genética , Hidrocefalia/cirugía , Anticonvulsivantes , Predisposición Genética a la Enfermedad , Periodo PosoperatorioRESUMEN
Background: Anterior communicating artery (AcomA) represents the most common location for ruptured intracranial aneurysms (rIAs). Approximately 50% of all rIAs are smaller than 7 mm, but factors that lead to rupture are multifactorial. The study investigates whether AcomA location represents an independent risk factor for small size at time of rupture (<7 mm) in a cohort of aneurysmal subarachnoid hemorrhage (aSAH) when controlling for known risk factors. Methods: The aSAH cohort was retrospectively searched from our institution charts. The cohort was dichotomized into small aneurysms (<7 mm) or large aneurysms (≥7 mm). Risk factors for rupture were identified according to the unruptured intracranial aneurysm treatment score (UIATS). These were sex, age, location, smoking, hypertension, alcohol abuse, aneurysm morphology, multiplicity, previous SAH, and family history. With size as independent variable, a multiple regression analysis was performed including UIATS risk factors. Results: One-hundred and seventy-six patients were included in the study. About 49.4% of the aneurysms were <7 mm. Multiple regression analysis demonstrated that aneurysms located at AcomA and posterior communicating artery (PcomA) was significantly more frequent smaller than 7 mm, compared to middle cerebral artery (P = 0.006), internal carotid artery (other than PcomA) (P = 0.013), and posterior circulation (P = 0.017), when controlling for risk factors. Conclusion: Ruptured AcomA and PcomA aneurysms are more frequent smaller than 7 mm compared to other locations. Patients with unruptured UIA at either AcomA or PcomA may be at increased risk of rupture even if the size of the aneurysm is small. Further studies are needed to confirm this finding.
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Meningiomas are benign lesion although anot insignificant number experiences recurrences despite Simpson grade 1 removal. FG001 is a compound with a fluorophore (ICG) that binds to a urokinase-type plasminogen activator receptor (uPAR) and is currently investigated at our institution in a first-in-human trial. The patient presented with a plausible malignant glioma but proved to be a grade 1 meningioma. FG001 could delineated the tumor not only on the surface but supplementary in the cavity to remove safely the dural attachment. We present FG001 as a new promising tool for improved surgical radicality beyond the intended indication, provided that a prospective validation in a consecutive meningioma cohort demonstrates similar results.
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Glioma , Neoplasias Meníngeas , Meningioma , Niño , Colorantes Fluorescentes , Humanos , Neoplasias Meníngeas/diagnóstico por imagen , Neoplasias Meníngeas/cirugía , Meningioma/diagnóstico por imagen , Meningioma/cirugía , Receptores del Activador de Plasminógeno Tipo UroquinasaRESUMEN
OBJECTIVE: Placement of a subdural drain reduces recurrence and death after evacuation of chronic subdural hematoma (CSDH), but little is known about optimal drainage duration. In the present national trial, the authors investigated the effect of drainage duration on recurrence and death. METHODS: In a randomized controlled trial involving all neurosurgical departments in Denmark, patients treated with single burr hole evacuation of CSDH were randomly assigned to 24 hours or 48 hours of postoperative passive subdural drainage. Follow-up duration was 90 days, and the primary study outcome was recurrent hematoma requiring reoperation. Secondary outcome was death. In addition, complications and length of hospital stay were recorded and analyzed. RESULTS: Of the 420 included patients, 212 were assigned 24-hour drainage and 208 were assigned 48-hour drainage. The recurrence rate was 14% in the 24-hour group and 13% in the 48-hour group. Four patients died in the 24-hour group, and 8 patients died in the 48-hour group; this difference was not statistically significant. The ORs (95% CIs) for recurrence and mortality (48 hours vs 24 hours) were 0.94 (0.53-1.66) and 2.07 (0.64-7.85), respectively, in the intention-to-treat analysis. The ORs (95% CIs) for recurrence and mortality per 1-hour increase in drainage time were 1.0005 (0.9770-1.0244) and 1.0046 (0.9564-1.0554), respectively, in the as-treated sensitivity analysis that used the observed drainage times instead of the preassigned treatment groups. The rates of surgical and drain-related complications, postoperative infections, and thromboembolic events were not different between groups. The mean ± SD postoperative length of hospital stay was 7.4 ± 4.3 days for patients who received 24-hour drainage versus 8.4 ± 4.9 days for those who received 48-hour drainage (p = 0.14). The mean ± SD postoperative length of stay in the neurosurgical department was significantly shorter for the 24-hour group (2 ± 0.9 days vs 2.8 ± 1.6 days, p < 0.001). CONCLUSIONS: No significant differences in the rates of recurrent hematoma or death during 90-day follow-up were identified between the two groups that randomly received either 24- or 48-hour passive subdural drainage after burr hole evacuation of CSDH.
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BACKGROUND: Upregulation of vasoconstrictor receptors in cerebral arteries, including endothelin B (ETB) and 5-hydroxytryptamine 1B (5-HT(1B)) receptors, has been suggested to contribute to delayed cerebral ischemia, a feared complication after subarachnoid hemorrhage (SAH). This receptor upregulation has been shown to be mediated by intracellular signalling via the mitogen activated protein kinase kinase (MEK1/2)--extracellular regulated kinase 1/2 (ERK1/2) pathway. However, it is not known what event(s) that trigger MEK-ERK1/2 activation and vasoconstrictor receptor upregulation after SAH.We hypothesise that the drop in cerebral blood flow (CBF) and wall tension experienced by cerebral arteries in acute SAH is a key triggering event. We here investigate the importance of the duration of this acute CBF drop in a rat SAH model in which a fixed amount of blood is injected into the prechiasmatic cistern either at a high rate resulting in a short acute CBF drop or at a slower rate resulting in a prolonged acute CBF drop. RESULTS: We demonstrate that the duration of the acute CBF drop is determining for a) degree of early ERK1/2 activation in cerebral arteries, b) delayed upregulation of vasoconstrictor receptors in cerebral arteries and c) delayed CBF reduction, neurological deficits and mortality. Moreover, treatment with an inhibitor of MEK-ERK1/2 signalling during an early time window from 6 to 24 h after SAH was sufficient to completely prevent delayed vasoconstrictor receptor upregulation and improve neurological outcome several days after the SAH. CONCLUSIONS: Our findings suggest a series of events where 1) the acute CBF drop triggers early MEK-ERK1/2 activation, which 2) triggers the transcriptional upregulation of vasoconstrictor receptors in cerebral arteries during the following days, where 3) the resulting enhanced cerebrovascular contractility contribute to delayed cerebral ischemia.
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Isquemia Encefálica/etiología , Isquemia Encefálica/metabolismo , Receptor de Endotelina B/metabolismo , Receptor de Serotonina 5-HT1B/metabolismo , Hemorragia Subaracnoidea/complicaciones , Regulación hacia Arriba/fisiología , Análisis de Varianza , Animales , Antipirina/análogos & derivados , Área Bajo la Curva , Presión Sanguínea/fisiología , Isquemia Encefálica/mortalidad , Butadienos/farmacología , Isótopos de Carbono , Arterias Cerebrales/metabolismo , Circulación Cerebrovascular/fisiología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Flujometría por Láser-Doppler , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Actividad Motora/fisiología , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/prevención & control , Nitrilos/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Endotelina B/genética , Receptor de Serotonina 5-HT1B/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
OBJECTIVES: The objective of this study was to identify prognostic factors for clinical outcome in patients with non-traumatic, angiographically negative subarachnoid hemorrhage. Furthermore, the aim was to investigate if patients on anticoagulant therapy may have a more unfavorable outcome than patients not receiving anticoagulant therapy. MATERIALS AND METHODS: This study contains a retrospective analysis of 95 patients with non-traumatic, non-aneurysmal subarachnoid hemorrhage who were admitted to our institution in the period 2000-2011. The patients were classified according to risk factors, clinical presentation at admission, anticoagulant therapy at the time of hemorrhage and complications. The outcome was assessed with modified Rankin Score at discharge. RESULTS: Patients who were exposed to risk factors combined with a higher WFNS score at admission had an unfavorable outcome according to the modified Rankin Score at discharge. Unfavorable outcome was evaluated in relation to sex, anticoagulant therapy, hypertension, smoking and alcohol abuse. A strong correlation with anticoagulant therapy, smoking and alcohol abuse was found. None of the patients who developed vasospasms in this study were receiving anticoagulant therapy. CONCLUSION: There is a correlation between antithrombotic state at admission and unfavorable outcome for patients with non-traumatic, non-aneurysmal subarachnoid hemorrhage. The results from this study indicate that patients on anticoagulant therapy have a higher risk of developing complications after non-aneurysmal angiographically negative subarachnoid hemorrhage compared to patients who were not receiving anticoagulant therapy.
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Angiografía Cerebral/métodos , Hemorragia Subaracnoidea/diagnóstico por imagen , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alcoholismo/complicaciones , Anticoagulantes/efectos adversos , Niño , Interpretación Estadística de Datos , Femenino , Fibrinolíticos/efectos adversos , Humanos , Hipertensión/complicaciones , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Factores Sexuales , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Derivación Ventriculoperitoneal , Adulto JovenRESUMEN
OBJECTIVE: To summarize the current knowledge of the mechanisms leading to rebleeding and the prevention of rebleeding after subarachnoid hemorrhage (SAH). METHODS: A literature search was performed to investigate factors associated with rebleeding after SAH. RESULTS: The review of the literature revealed that rebleeding is a complex and multifactorial event involving hemostasis, pathophysiologic, and anatomic factors. Administration of antifibrinolytics has been shown to have a dramatic effect on the rebleeding rate, so changes in coagulation and fibrinolysis must be involved in rebleeding. CONCLUSIONS: Further studies are warranted before the exact mechanisms leading to rebleeding are established and the optimal preventive measures are made available. At the present time, antifibrinolytic therapy remains the only realistic protective measure during the initial 6 hours after SAH during which the rebleeding rate is highest.
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Hemorragia Subaracnoidea/etiología , Hemorragia Subaracnoidea/fisiopatología , Antifibrinolíticos/uso terapéutico , Presión del Líquido Cefalorraquídeo , Hemostasis , Humanos , Factores de Riesgo , Prevención Secundaria , Hemorragia Subaracnoidea/terapiaRESUMEN
OBJECT: Delayed cerebral ischemia after subarachnoid hemorrhage (SAH) remains a major cause of death and disability. It has been hypothesized that cerebrovascular upregulation of vasoconstrictor receptors is a key step in the development of delayed cerebral ischemia. Upregulation of endothelin-B (ET(B)) and 5-hydroxytryptamine 1B (5-HT(1B)) receptors has been demonstrated in cerebral artery smooth muscles in the delayed ischemic phase after experimental SAH, and intracellular signaling via the mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase 1/2 pathway has been shown to be involved in this upregulation. The aim in the present study was to determine whether treatment with the MEK1/2 inhibitor U0126 can prevent cerebrovascular receptor upregulation and improve functional outcome after experimental SAH in rats. METHODS: Subarachnoid hemorrhage was induced in male Sprague-Dawley rats by the injection of 250 µl of autologous blood into the basal cisterns. Either U0126 or vehicle was intracisternally administered at 6, 12, 24, and 36 hours after SAH. Smooth muscle ET(B) and 5-HT(1B) receptor upregulation was studied in isolated cerebral artery segments through immunohistochemical and myographic studies of contractile responses to receptor-specific agonists. Gross sensorimotor function in the rats after SAH was assessed using a rotating pole test. RESULTS: Contractile concentration-response curves for middle cerebral artery (MCA) and basilar artery (BA) segments to endothelin-1 (ET-1) and 5-carboxamidotryptamine (5-CT) were shifted leftward for SAH-induced compared with shamoperated rats due to enhanced contractile responses to individual doses of the agonists (for example, contractile responses of the BA to 3 × 10(-10) M of ET-1 and 3 × 10(-7) M of 5-CT were 9.98 ± 5.01% and 16.75 ± 3.62% of the maximal contractile capacity, respectively, in sham-operated rats and 62.78 ± 9.9% and 45.44 ± 10.62%, respectively, in SAH-induced rats). In vivo treatment with 0.19 µg/kg U0126 normalized responses in the SAH-induced rats to levels in the sham-operated rats. Protein expression of ET(B) and 5-HT(1B) receptors in cerebrovascular smooth muscles from SAH-induced rats was increased to 175 ± 33.17% and 167.7 ± 24.74%, respectively, of the levels in sham-operated rats. Endothelin-B and 5-HT(1B) expression levels in U0126-treated SAH-induced rats were at the levels in sham-operated rats (101.9 ± 13.38% and 91.44 ± 16.75%, respectively). In a rotating pole test used to assess gross sensorimotor function on the 2nd day after surgery, sham-operated rats achieved an average score of 5.37 ± 0.23, SAH-induced rats scored 3.35 ± 0.67, and SAH-induced U0126-treated rats scored 5.00 ± 0.4. CONCLUSIONS: The authors demonstrated that experimental SAH induces upregulation of ET(B) and 5-HT(1B) receptors in cerebrovascular smooth muscles and that treatment with the MEK1/2 inhibitor U0126 abolishes this receptor upregulation. They also demonstrated that experimental SAH results in sensorimotor deficits as assessed by a rotating pole test. These deficits were alleviated by U0126 treatment, suggesting that cerebrovascular receptor upregulation is critical for the functional outcome of delayed cerebral ischemia. The authors suggest that inhibition of MEK1/2 may be a promising new SAH treatment strategy.
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Butadienos/uso terapéutico , Antagonistas de los Receptores de la Endotelina B , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 2/antagonistas & inhibidores , Nitrilos/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor de Serotonina 5-HT1B/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Hemorragia Subaracnoidea/tratamiento farmacológico , Animales , Conducta Animal/efectos de los fármacos , Arterias Cerebrales/patología , Inmunohistoquímica , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/psicología , Equilibrio Postural/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Serotonina/análogos & derivados , Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Hemorragia Subaracnoidea/enzimología , Hemorragia Subaracnoidea/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Vasoconstricción/efectos de los fármacosRESUMEN
INTRODUCTION: Rebleeding from subarachnoid haemorrhage (SAH) usually occurs within the first six hours after the initial bleeding. Rebleeding can be prevented effectively with tranexamic acid (TXA). Although a broad consensus has evolved that SAH should be treated as an emergency, it is likely that delays do exist in the diagnosis and treatment of SAH patients. The aim of this study was to prospectively assess the interval between symptom onset, emergency room (ER) admission, initial diagnosis and treatment, and final closure of the aneurysm. MATERIAL AND METHODS: We prospectively studied the time course from the initial bleeding to ER admission, computed tomography (CT), TXA treatment, referral to the neurosurgical department, and to the final closure of the aneurysm. RESULTS: A total of 133 patients with SAH due to ruptured intracranial aneurysms were admitted to two neurosurgical units in Copenhagen, Denmark, during a one-year period. The median time to admission was 60 min. The median delay from admission to CT scan was 55 min. Long pre-hospital delay (p = 0.03) and high Glasgow Coma Scale score on arrival (p = 0.0006) were associated with a longer time to CT scan. The median time from CT scan to initiation of TXA treatment was 50 min. The median time from initial insult to final closure of the aneurysm was 30 hours. CONCLUSION: The present study demonstrates that considerable diagnostic delays exist in connection with CT and TXA treatment after patients' arrival to the ER.