Longitudinal assessment of visual development in non-syndromic craniosynostosis: a 1-year pre- and post-surgical study.

OBJECTIVE: to investigate visual function pre- and post surgery in children with single-suture non-syndromic craniosynostosis DESIGN: Twenty-nine infants (12 with sagittal synostosis, 10 with trigonocephaly and 7 with anterior plagiocephaly) were longitudinally evaluated using a battery of tests assessing various aspects of visual function, including ocular behaviour, acuity, visual fields and fixation shift. All infants were assessed before surgery and 2, 6 and 12 months after surgery. RESULTS: Before surgery only 16% of infants had completely normal visual function, while on the assessment performed 12 months after surgery, the number with normal results on all the tests increased to 65%. The only abnormalities found 12 months after surgical correction were mainly found on abnormal oculomotor behaviour in infants with plagiocephaly. CONCLUSION: Abnormalities of visual function were not frequent in infants with non-syndromic craniosynostosis who underwent surgical correction. Approximately half of the patients had some visual abnormalities before surgery, which subsequently improved, showing a delayed visual maturation rather than persistent abnormalities.

Visual function in infants with non-syndromic craniosynostosis.

The aim of this study was to assess various aspects of visual function in children with single-suture, non-syndromic craniosynostosis. Thirty-eight infants (28 males, 10 females; age range 3.5-13mo, mean age 7mo, 11 with plagiocephaly, 12 with trigonocephaly, and 15 with scaphocephaly), were assessed with a battery of tests specifically designed to assess various aspects of visual function in infancy. Thirty-two of the 38 infants had at least one abnormality on one of the aspects of visual function assessed. Abnormal eye movements were found in eight infants of the whole cohort and were mainly found in infants with plagiocephaly (6/11), who also had frequent visual field abnormalities (5/11). In contrast, fixation shift, an aspect of visual function related to the integrity of parietal lobes, was more frequently abnormal in patients with scaphocephaly. Our results suggest that the presence and severity of visual impairment is related to the type of craniosynostosis. Follow-up studies after surgical correction are needed to evaluate the possible beneficial effects of reconstructive surgery on visual function.

Anisotropic constitutive equations and experimental tensile behavior of brain tissue.

The present study deals with the experimental analysis and mechanical modeling of tensile behavior of brain soft tissue. A transversely isotropic hyperelastic model recently proposed by Meaney (2003) is adopted and mathematically studied under uniaxial loading conditions. Material parameter estimates are obtained through tensile tests on porcine brain materials accounting for regional and directional differences. Attention is focused on the short-term response. An extrapolation of tensile test data to the compression range is performed theoretically, to study the effect of the heterogeneity in the tensile/compressive response on the material parameters. Experimental and numerical results highlight the sensitivity of the adopted model to the test direction.

[Prolonged ICP monitoring in children with sylvian fissure arachnoid cysts]. / Monitoraggio prolungato della pressione intracranica (PIC) nei bambini affetti da cisti aracnoidee della scissura di Silvio.

BACKGROUND: The decision making process for patients with sylvian fissure arachnoid cysts still represents a challenge for the neurosurgeon. A high proportion of the patients is indeed asymptomatic, in spite of neuroimaging signs of apparently increased intracranial pressure (ICP). The aim of the present study was to evaluate the usefulness of prolonged ICP recording in the preoperative work-out. METHODS: Twelve children (11 M/1 F) harboring temporal arachnoid cysts were investigated (men age 6.3 years). According to Galassi classification they were subdivided into 3 groups. Group I included 3 patients with Type I cysts; group II comprised 6 children with Type II cysts; group III consisted of 3 children with Type III cysts. An extensible silicone microprocessor (Codman ), developed for continuous ICP recording, was implanted intraparenchymally, adjacent to the major extension of the cyst. The collected information was cable unloaded to a PC and stored. All the patients underwent a minimum of 48 hours to a maximum of 72 hours ICP continuous check. Ten mmHg was arbitrarily chosen as the upper normal limit of ICP in resting conditions and the patients were classified according to the percentile distribution of their ICP daily and nightly pressure values. RESULTS: ICP recordings were in the normal range in all the 3 children with Type I cysts (49-86% <10 mmHg during the entire recording), in spite of the fact that 2 of them were apparently symptomatic. Three of the 6 children with a Type II temporal cyst had elevated ICP values (69-99% >10 mmHG), even though they had an incidental (1 case) or prenatal (2 cases) diagnosis. The remaining 3 patients had normal ICP values for more than 70% of the recording time period. Two of the 3 patients with type III temporal arachnoid cysts had almost constantly abnormal ICP values (95=99% >10 mmHg); conversely the third patient showed normal ICP values for more than 80% of the recording time period. Five patients were operated on; in 4 of them the surgical indication was based on ICP recordings (2 of the 3 children with a Type II cyst and increased ICP and the 2 patients with a Type III cyst and increased ICP). The last child, harboring a Type I cyst, was operated on under parents request, as a preventive measure. At a mean follow-up of 10.1 months all the patients operated on are in excellent clinical conditions; 1 of them (Type II cyst) initially submitted to craniotomy and cystic membrane excision needed a subdural-peritoneal shunt implant 3 months after surgery for the appearance of a symptomatic subdural hygroma on the side of the cyst. Postoperative CT showed signs of brain expansion in the 2 patients operated on for a Type III cyst, and in the patients operated on for a Type I cyst. CONCLUSIONS: With the limit of the relatively small series here presented, prolonged ICP recording appeared to be an important preoperative tool to rule out the necessity of operating on children with Type I cysts. Furthermore, it was particularly useful in the decision-making process for children with Type III cysts. In cases of Type II lesions, the investigation resulted less discriminating, though the ICP monitoring contributed to find out those patients in whom surgery was indicated in spite of the absence of symptoms.

The influence of hemocoagulative disorders on the outcome of children with head injury.

BACKGROUND: Although disseminated intravascular coagulation (DIC) and other hemocoagulative abnormalities are severe complications of head injury, their effect on clinical outcome remains unclear, particularly among children. OBJECTIVES: To evaluate the frequency of hemocoagulative abnormalities and their influence on outcome among children with head injury. STUDY DESIGN: We conducted a prospective observational study among 60 children with head injury, immediately evaluating severity of head injury (Glasgow Coma Scale, GCS); cerebral axial tomography; prothrombin time; activated partial thromboplastin time (aPTT); fibrinogen level; concentration of fibrin-fibrinogen degradation products (FDP), and platelet count. Two months after injury, we applied the Glasgow Outcome Score (GOS). Associations with GOS were evaluated using univariate and multivariate logistic models. RESULTS: Among children with severe head injury, 22.2% (6/27) developed DIC, all of whom died and had shown severe brain edema. Among those with severe head injury yet without DIC, the mortality was only 14.2%. A low GOS was significantly and independently associated with a low GCS, multiple trauma, delayed aPTT, low fibrinogen level, elevated FDP and low platelet count. Brain edema was also associated with a low GOS, though not significantly. CONCLUSIONS: In addition to GCS, type of trauma, type of brain lesion and certain coagulation abnormalities are predictors of GOS.

Spontaneous regression of a symptomatic pineal cyst after endoscopic third-ventriculostomy.

With the advent of modern diagnostic tools for neuroimaging, the incidental detection of pineal cysts in asymptomatic subjects has increased. Only rarely do pineal cysts present with the clinical signs and symptoms of increased intracranial pressure or with neurological deficits in relation to compression and distortion of the adjacent nervous structures and cerebrospinal fluid pathways. While asymptomatic cysts are considered to be normal variants for which no further investigations are usually required, surgical treatment is suggested for symptomatic cysts, with the goal of eliminating the block in the cerebrospinal fluid circulation and/or the mass effect exerted by the lesion. In this report we describe a pediatric case of symptomatic pineal cyst, revealed by repeated episodes of headache caused by secondary obstructive hydrocephalus. Following an endoscopic third-ventriculostomy, serial magnetic resonance imaging studies demonstrated that not only had the ventriculomegaly resolved but also that the pineal cyst had regressed over time. A to-and-fro movement of fluid through the cyst wall, the direction of which depends on the equilibrium existing between the inner pressure of the cyst and the outer cerebrospinal fluid pressure, is suggested as a possible mechanism accounting for this unexpected result--to our knowledge, the first reported in literature.

Safety and efficacy of remifentanil in craniosynostosis repair in children less than 1 year old.

Few studies on analgesia with remifentanil (Rf) in children are available, and there are no data on the use of this drug in pediatric neurosurgery. Rf is a new mu-receptor opioid agonist, acting through the activation of pain inhibitory mechanisms. We conducted a prospective trial on the analgesic effects of Rf in 20 children less than 1 year of age undergoing a neurosurgical procedure for craniosynostosis repair. Rf was administered at doses of 0.25 microgram/kg/min, by continuous infusion, 1 h after admission to the pediatric intensive care unit (PICU). The treatment was prolonged for 12 h after the operation. The postoperative pain was evaluated in our PICU, comparing the changing of behavioral (AFS and CHEOPS score) and hemodynamic (heart rate, respiratory rate, systolic and diastolic blood pressure, oxygen saturation, O(2) and CO(2) partial pressure) parameters, before and after treatment with Rf. This drug showed a satisfactory pain control in all the children treated. No significant side effects were noticed, except for one episode of urinary retention. In conclusion, Rf appears to be safe and effective for the treatment of acute pain in the very young child submitted to craniosynostosis repair.

Blood salvage in craniosynostosis surgery.

In the history of surgery, every single step forward in the development of complex surgical techniques has been sustained by the acquisition of more reliable and effective methods for controlling hemostasis. For many years, in fact, uncontrolled hemorrhages, together with infections, represented the most deadly hazard of surgical procedures. In the last century, technical advances in surgical hardware and homologous blood transfusions have been utilized to counteract operative and postoperative anemia and hypovolemia. At the end of this millennium, however, new revelations about the infective and noninfective risks of allogeneic blood transfusions have led to a new acceleration in patients' and physicians' demands for autologous transfusions and more efficient blood conservation techniques. Specific surgical protocols, based on the preoperative administration of r-HuEPO, preoperative autologous blood donation, acute preoperative normovolemic hemodilution and intraoperative blood salvage techniques, have been designed by pediatric neurosurgeons to minimize the exposure of patients affected by craniosynostoses to allogeneic blood and blood components even when the surgical procedure is to be realized at an early age. In spite of the evolution expected in this area in the immediate future, the implementation of these blood concentration methodologies may prove to be highly effective only when associated with a concerned attitude of the surgeon toward blood-sparing intraoperative strategies.

Fibroblast growth factor receptor mutational screening in newborns affected by metopic synostosis.

A number of craniosynostotic disorders have recently been ascribed to mutations in genes coding for the fibroblast growth factor receptors(FGFRs). The common feature of these FGFR-associated conditions is the unilateral or bilateral premature ossification of the coronal suture. One distinct craniosynostotic condition is trigonocephaly, which results from the premature fusion of the metopic suture. Trigonocephaly mostly occurs as isolated cranial defect; however, the premature closure of the metopic suture may represent a feature of more complex craniosynostotic conditions in which a progressive involvement of other cranial sutures with age is observed. The possible involvement of mutated FGFRs in trigonocephaly was investigated in nine newborns affected by isolated premature synostosis of the metopic suture. All except one of these cases carried no mutations in the FGFR1-3 domains indicated as hot spots for craniosynostosis-associated mutations. A T(978)C transition in the FGFR2 exon IIIa was found in a patient who had a phenotype that apparently fitted the trigonocephalic condition at birth, but showed additional facial anomalies, which worsened progressively with age towards a Crouzon-like profile. The present finding points out the importance, from both diagnostic and prognostic points of view, of early FGFR mutational screening in craniosynostotic conditions, even in forms that apparently do not involve closure of the coronal suture at birth.

Decreased proliferation and altered differentiation in osteoblasts from genetically and clinically distinct craniosynostotic disorders.

Craniosynostoses are a heterogeneous group of disorders characterized by premature fusion of cranial sutures. Mutations in fibroblast growth factor receptors (FGFRs) have been associated with a number of such conditions. Nevertheless, the cellular mechanism(s) involved remain unknown. We analyzed cell proliferation and differentiation in osteoblasts obtained from patients with three genetically and clinically distinct craniosynostoses: Pfeiffer syndrome carrying the FGFR2 C342R substitution, Apert syndrome with FGFR2 P253R change, and a nonsyndromic craniosynostosis without FGFR canonic mutations, as compared with control osteoblasts. Osteoblasts from craniosynostotic patients exhibited a lower proliferation rate than control osteoblasts. P253R and nonsyndromic craniosynostosis osteoblasts showed a marked differentiated phenotype, characterized by high alkaline phosphatase activity, increased mineralization and expression of noncollagenous matrix proteins, associated with high expression and activation of protein kinase Calpha and protein kinase Cepsilon isoenzymes. By contrast, the low proliferation rate of C342R osteoblasts was not associated with a differentiated phenotype. Although they showed higher alkaline phosphatase activity than control, C342R osteoblasts failed to mineralize and expressed low levels of osteopontin and osteonectin and high protein kinase Czeta levels. Stimulation of proliferation and inhibition of differentiation were observed in all cultures on FGF2 treatment. Our results suggest that an anticipated proliferative/differentiative switch, associated with alterations of the FGFR transduction pathways, could be the causative common feature in craniosynostosis and that mutations in distinct FGFR2 domains are associated with an in vitro heterogeneous differentiative phenotype.

Intraventricular streptokinase infusion in acute post-haemorrhagic hydrocephalus.

Neonatal post-haemorrhagic hydrocephalus is a clinical condition with a high mortality and long-term morbidity. Its clinical management is difficult and not well standardized. We describe the case of a term baby suffering from acute intracranial hypertension caused by an intraventricular and thalamic haemorrhage. In this case, the external ventricular drain inserted to control intracranial pressure was ineffective because of repeated obstructions due to blood clots. Continuous intraventricular infusion of streptokinase of 20,000 U/day allowed quick lysis of the clots, drainage of the cerebrospinal fluid and relief from the coma. Although it did not prevent a permanent ventriculoperitoneal shunt, we obtained reabsorption of the intraventricular haemorrhage without rebleeding complications. We suggest the use of low-dose fibrinolytic infusion through an external drain for the treatment of acute intracranial hypertension following intraventricular haemorrhage in term infants.

"No allogeneic blood transfusion" protocol for the surgical correction of craniosynostoses. II. Clinical application.

The authors describe the results obtained in 13 consecutive cases of craniosynostosis operated on according to a protocol devised at avoiding allogeneic blood transfusion. The protocol is based on pre- and postoperative treatment with erythropoietin, preoperative autologous blood donation, preoperative normovolemic hemodilution and intraoperative blood salvage. Nine subjects were affected by simple forms of craniosynostosis, whereas the remaining 4 presented with oxycephaly or craniofacial syndromes. Five of the 13 children were under 7 months and a further 3, under 10 months of age at the time of the surgical operation. Seven children weighed less than 10 kg. Allogeneic blood transfusion was avoided in 11 of the 13 children considered. Two failures - defined as the necessity to reinfuse the patient with an allogeneic blood transfusion - were recorded, 1 of them resulting from an unexpected hemorrhage during surgery. The results obtained indicate that this protocol designed to avoid allogeneic blood transfusion can be safely applied in the great majority of children with craniosynostosis, even when the surgical correction is carried out early in life.

"No allogeneic blood transfusion" protocol for the surgical correction of craniosynostoses. I. Rationale.

Improved anesthesiological and surgical care has resulted in a progressively declining need for allogeneic blood transfusion. In infants with craniosynostosis, however, allogeneic blood transfusion is still performed as a routine procedure. In the present paper, the authors describe a protocol they have devised with the aim of limiting or even avoiding allogeneic blood transfusion even in very young patients, consequently avoiding the risks of infective or immunologic reactions associated with the procedure. The protocol is based on stimulation of the hematopoietic system with erythropoietin, selection of an appropriate age for operation when a favorable balance between fetal and adult-type hemoglobin is established (that is after 4-6 months), preoperative preparation of the autologous blood supply, and intraoperative blood salvage.

Trp290Cys mutation in exon IIIa of the fibroblast growth factor receptor 2 (FGFR2) gene is associated with Pfeiffer syndrome.

Pfeiffer syndrome is a skeletal disorder characterized by craniosynostosis associated with foot and hand anomalies. Mutations in the genes encoding fibroblast growth factor receptors 1 and 2 (FGFR1 and FGFR2) have recently been implicated in the aetiology of such a syndrome, as well as of other craniosynostotic conditions. We now report a novel missense mutation, a G to C transversion at position 1049 (exon IIIa) of FGFR2, detected in a patient with severe Pfeiffer clinical features. The mutation results in the substitution of a cysteine for tryptophan-290 in the third immunoglobulin-like domain and affects both spliceoforms of FGFR2. Mutations causing replacement of tryptophan-290 have also been reported previously in Crouzon syndrome, a similar but clinically distinct craniosynostotic disorder. This finding confirms the involvement of mutations of FGFR2 exon IIIa in Pfeiffer syndrome, and emphasizes both the extensive heterogeneity of the FGFR2 mutations that result in the Pfeiffer phenotype and the perturbations caused by unpaired cysteine residues in receptor dimerization and transduction of the FGFs signal.

Failure of fibrinolytic endoventricular treatment to prevent neonatal post-haemorrhagic hydrocephalus. A case-control trial.

Post-haemorrhagic hydrocephalus is assumed to result from obstruction of the cerebrospinal fluid (CSF) pathways by blood clots and subsequent chronic infiltration with collagen. The aim of this work was to evaluate the possibility of preventing permanent shunt dependence by enhancing the endoventricular fibrinolysis by means of an endoventricular streptokinase infusion in babies affected by posthaemorrhagic ventricular dilation. A case-control trial was carried out in 12 neonates affected by intraventricular haemorrhage and subsequent progressive ventriculomegaly. Six of them were treated with 20,000 U/day of streptokinase infused over 96 h through a percutaneous ventricular catheter. Our results show that the percentage of shunted babies was identical in treated and control patients despite the enhancement of endoventricular fibrinolysis obtained in all treated patients. On the basis of our results we do not recommend intraventricular streptokinase infusion for routine use in post-haemorrhagic ventricular dilatation.

Jackson-Weiss syndrome: identification of two novel FGFR2 missense mutations shared with Crouzon and Pfeiffer craniosynostotic disorders.

Jackson-Weiss syndrome is a rare skeletal disorder characterized by craniosynostosis associated with foot malformations. This condition is inherited as an autosomal dominant trait with complete penetrance and wide phenotypic heterogeneity. Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been recently identified as causes of this syndrome and of at least four other craniosynostotic disorders, namely the Apert, Beare-Stevenson cutis gyrata, Crouzon and Pfeiffer syndromes. We report two novel FGFR2 missense mutations associated with phenotypes consistent with Jackson-Weiss syndrome. Both nucleotide changes predict a serine for cysteine-342 substitution in the second half of the third immunoglobulin-like domain. The replacement of Cys342 with arginine has previously been reported in one of the three Jackson-Weiss cases investigated. Interestingly, both Cys342Ser and Cys342Arg substitutions have been found to be associated with the Crouzon and Pfeiffer phenotypes; a phenotypic heterogeneity, Crouzon vs Jackson-Weiss clinical features, has been also observed for Gln289Pro and Ala344Gly amino-acid changes. This finding indicates the genetic homogeneity of the "heterogeneous" Jackson-Weiss phenotype and a common molecular basis for these apparently "clinically distinct" craniosynostotic disorders.

Combined management of intracranial vascular malformations in children.

UNLABELLED: We have reviewed 39 cases of intracranial vascular malformations, observed in the Section of Paediatric Neurosurgery of the Catholic University of Rome between 1980 and 1995 (age 1-15 years). Diagnosis was of parenchimal AVM in 26 cases, in 7 cases of AVM of the Galen region, in 5 cases of dural AVM and in 1 case of venous angioma. RESULTS AND CONCLUSIONS: Haemorrhage was the prevalent clinical onset in patients with parenchimal AVMs (57.7% of cases). Only one patient with a Galen region AVM presented cardiovascular symptoms, while 2/5 children observed for a dural AVM complained a congestive heart failure. Total surgical excision was performed in 17 of the 26 patients with parenchimal AVMs; moreover surgery was combined with preoperative endovascular embolization in 2 cases and with radiosurgery in 1 patient; we think that surgery is still the treatment of choice in patients with parenchimal AVMs. Endovascular treatment and radiosurgery have mainly an adjuvant role; nevertheless we agree that a preoperative endovascular management of parenchimal AVMs reduces the surgical risk, especially in cases of huge AVMs or AVMs localized in eloquent areas of the brain. Radiosurgery may be an alternative choice for complex or deeply sited AVMs; however in most cases, a combination with surgery or endovascular treatment is necessary to reduce the "target" size. AVM embolization was the only treatment in 2 of the 6 cases of dural AVMs; dural AVM embolization was combined with surgery in 1 case. Endovascular AVM exclusion is the treatment of choice in these patients. Surgery may be combined with endovascular treatment in case of a partial persistence of the AVM, or if signs of revascularization are present on control angiography. A conservative management is justified in patients with carotido-cavernous fistulae; in fact a complete spontaneous thrombosis is very frequent in these cases. A high rate of cardiovascular symptoms is reported in patients with Galen region AVMs diagnosed in the 1st year of life, but only 1 of our patients complained of congestive cardiac symptoms. Surgical treatment of Galen region AVMs is associated with a high morbidity and mortality. Actually a transarterial embolization of afferent vessels represents the treatment of choice in these patients; it can be combined with transvenous approach in case of complex AVMs and/or a non complete AVM exclusion.

Metopic synostosis: in favour of a "simplified" surgical treatment.

Metopic synostosis is a relatively simple form of craniosynostosis, resulting from premature fusion of the metopic suture. In this pathology different degrees of dysmorphia of the anterior cranial fossa and the presence of associated anomalies of the skull might enable specific subgroups to be identified. Since most functional and cosmetic anomalies benefit from early surgical treatment, over the last few years neurosurgeons have been forced to elaborate less drastic, but nonetheless effective, surgical techniques. In the present report we analyze the surgical results obtained in a series of 62 infants with trigonocephaly operated on within their 1st year of life. Patients were subdivided into two groups (group I: 8 patients; group II: 54 patients) according to the specific dysmorphic characteristics of the frontal bone and anterior cranial fossa, and the presence of compensatory deformities affecting the anterior cranial base and temporo-parietal region. All the patients were treated using one of two relatively simple surgical techniques (procedure A: inversion of two hemifrontal bone flaps--48 cases; procedure B: the "shell" operation--14 cases). Both surgical procedures appeared to be effective, allowing adequate functional and cosmetic correction of the cranial deformity. In patients operated on following procedure B surgical time and blood loss were dramatically reduced. Long-term outcomes were satisfactory in all cases, irrespective of the surgical technique used. In the group II patients, however, progressive normalization of the interorbital distance was constantly observed, suggesting a different degree of stenotic involvement at the level of the anterior cranial base in these patients.