The role of ICP overnight monitoring (ONM) in children with suspected craniostenosis.

PURPOSE: Secondary craniostenosis is a relevant problem pediatric neurosurgeons are confronted with and poses challenges regarding reliable diagnosis of raised ICP, especially in case of absent or questionable papilledema. How to identify children with elevated ICP is still controversial and diagnostics vary. We report on our experience with computerized ICP ONM in relation to imaging derived parameters. METHODS: Thirty-four children with primary or secondary craniostenosis and clinical suspicion of raised ICP were investigated. We compared clinical signs, history, and radiographic assessment with the results of computerized ICP ONM. Differences were significant at a p < 0.05. RESULTS: Baseline ICP was significantly higher in patients with combined suture synostosis, who also had a higher rate of questionable papilledema. Children with narrowed external CSF spaces in MRI had significantly higher ICP levels during REM sleep. Mean RAP was significantly elevated in patients with multi-suture synostosis, indicating poor intracranial compensatory reserve. Syndromal craniostenosis was associated with elevated ICP, RAP was significantly lower, and skull X-rays showed more impressions (copper beaten skull). RAP increased with more severe impressions only to decline in most severe abnormalities, indicating exhaustion of cerebrovascular reserve at an upper ICP breakpoint of 23.9 mmHg. Headaches correlated to lower ICP and were not associated with more severe X-ray abnormalities. CONCLUSION: Narrowed external CSF spaces in MRI seem to be associated to elevated ICP. Skull X-rays can help to identify patients at risk for chronically elevated ICP. Severe X-ray changes correlate with exhausted cerebrovascular reserve as indicated by RAP decline. Only ICP monitoring clearly identifies raised ICP and low brain compliance. Thus, in cases with ambiguous imaging, ONM constitutes an effective tool to acquire objective data for identification of surgical candidates.

Avoiding CT scans in children with single-suture craniosynostosis.

INTRODUCTION: During the last decades, computed tomography (CT) has become the predominant imaging technique in the diagnosis of craniosynostosis. In most craniofacial centers, at least one three-dimensional (3D) computed tomographic scan is obtained in every case of suspected craniosynostosis. However, with regard to the risk of radiation exposure particularly in young infants, CT scanning and even plain radiography should be indicated extremely carefully. MATERIAL AND METHODS: Our current diagnostic protocol in the management of single-suture craniosynostosis is mainly based on careful clinical examination with regard to severity and degree of the abnormality and on ophthalmoscopic surveillance. Imaging techniques consist of ultrasound examination in young infants while routine plain radiographs are usually postponed to the date of surgery or the end of the first year. CT and magnetic resonance imaging (MRI) are confined to special diagnostic problems rarely encountered in isolated craniosynostosis. The results of this approach were evaluated retrospectively in 137 infants who were referred to our outpatient clinic for evaluation and/or treatment of suspected single suture craniosynostosis or positional deformity during a 2-year period (2008-2009). RESULTS: In 133 (97.1%) of the 137 infants, the diagnosis of single-suture craniosynostosis (n = 110) or positional plagiocephaly (n = 27) was achieved through clinical analysis only. Two further cases were classified by ultrasound, while the remaining two cases needed additional digital radiographs. In no case was CT scanning retrospectively considered necessary for establishing the diagnosis. Yet in 17.6% of cases, a cranial CT scan had already been performed elsewhere (n = 16) or had been definitely scheduled (n = 8). CONCLUSION: CT scanning is rarely necessary for evaluation of single-suture craniosynostosis. Taking into account that there is a quantifiable risk of developing cancer in further lifetime, every single CT scan should be carefully indicated.

Neurosurgery in Würzburg until World War II.

The institution of German neurosurgery as an autonomous surgical specialty, starting in Würzburg in 1934, is closely linked to the names of Fritz König and Wilhelm Tönnis. They were acting at a time when the global economic crisis and a consolidating Nazi dictatorship caused a cascade of alarming changes in political and social life. On the one hand it is fascinating to see how the restless work and energy of Tönnis managed to build up the first independent neurosurgical unit in Germany and to tighten efficient international connections all over the world within a few years. On the other hand-from a present-day perspective-it is difficult to understand how his strive towards a specialist's success, in contrast to that of Otfrid Foerster, was barely affected by the threatening political development, until the Second World War stopped his plans and ideas for many years.

[Hypophosphatasia]. / Hypophosphatasie.

Hypophosphatasia (HP) is an inborn error of bone metabolism transmitted predominantly as an autosomal-recessive trait. It is characterized by a reduced activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSAP) and elevated concentrations of its substrates, including pyrophosphates. Clinical symptoms include defective bone mineralisation with bone deformities, fractures and as recently defined chronic non-bacterial osteomyelitis. Renal damage due to calcification, craniosynostosis and dental abnormalities with premature loss of dentition are further symptoms, which have been described as characteristic in the ESPED inquiry of 2004. Knowledge about the mechanisms underlying cell activation leading to inflammation and tissue destruction is still limited in HP. Recent investigations have provided evidence that calcium pyrophosphate crystals are essentially involved in activating inflammatory signal transduction pathways via different receptors of the innate immune system. Laboratory assays, genetic counselling and testing, and radiologic imaging can confirm the diagnosis. Because symptoms are highly variable in their clinical expression, patients should be followed by a HP-experienced multidisciplinary team (paediatrician, radiologist, orthopedist, neurosurgeon, dentist). At the moment symptomatic support and treatment is most important because a causative therapy, e. g. enzyme replacement therapy, is not yet available.

Neurosurgical aspects of childhood hypophosphatasia.

OBJECTIVE: Hypophosphatasia (HPP; MIM241510) is a rare inborn error of bone metabolism of recessive inheritance. It is caused by mutations in the gene encoding the tissue-nonspecific alkaline phosphatase. Apart from problems in bone mineralization, growth failure, and premature loss of decidual teeth, the infantile and the childhood types of HPP are associated with premature fusion of cranial sutures. PATIENTS: We report on seven children affected with infantile and childhood HPP who presented with craniosynostosis. RESULTS: Neurosurgical intervention was necessary in four of them because of intracranial hypertension. In one of these, severe dural calcification posed an unexpected problem during surgery. Secondary ectopia of the cerebellar tonsils were detected in five of the seven patients and caused hydrosyringomyelia in one of them. CONCLUSIONS: Since cranial sutures are frequently involved in infantile and childhood HPP, a multidisciplinary approach for the clinical care is necessary, including long-term neurosurgical surveillance.

Morphometric analysis of untreated adult skulls in syndromic and nonsyndromic craniosynostosis.

The aim of this study was to perform a morphometric analysis of untreated adult skulls displaying syndromic and nonsyndromic craniosynostosis. We analyzed, in detail, 42 adult craniosynostoses (18 scaphocephaly, 11 anterior plagiocephaly, 2 trigonocephaly, 9 oxycephaly, and 2 brachycephaly) from archeological (three skulls) and pathoanatomical samples (39 skulls). The univariate and bivariate measurements from the pathological skulls were compared with 40 anatomical skulls with normal cranial vault morphology. Bony signs of chronic elevated intracranial pressure (ICP) are (1) diffuse beaten copper pattern, (2) dorsum sellae erosion, (3) suture diastasis, and (4) abnormalities of venous drainage that particularly affect the sigmoid-jugular sinus complex. The mean cranial length was significantly greater in scaphocephaly than in anatomical skulls (20.3 vs 18.0 cm), and the sagittal suture was also longer (14.3 vs 11.8 cm). There were three types of suture course in the bregma region in scaphocephaly: anterior spur (28%), normal configuration (61%), and posterior spur (11%). The plagiocephaly measurements showed nonsignificant differences, and there was no correlation between the length of the anterior and middle skull base (ipsilateral anterior-posterior shortening of the skull) and incomplete or complete suture synostosis. Bony signs of chronic elevated ICP were found in 82% of cases of oxycephaly and brachycephaly. In three such cases of oxycephaly, we found a marked (1.8-2.1 cm) elevation of bregma region. One skull (Saethre-Chotzen syndrome) yielded human DNA sufficient for polymerase chain reaction (PCR)-based amplification procedures. Mutation analyses in the FGFR3 gene revealed nucleotide alterations located in the mutational hot spot at amino acid residue 250 (g.C749). The mean cranial length in adult scaphocephaly was 12% greater than anatomical skulls. A unilateral complete or incomplete coronal synostosis can be found with or without plagiocephalic deformation. Elevation of the bregma region is a bony sign of chronic elevated ICP. These data on adult craniosynostosis could be of interest for physicians dealing with craniosynostotic children.

Contiguous gene deletions involving EFNB1, OPHN1, PJA1 and EDA in patients with craniofrontonasal syndrome.

Craniofrontonasal syndrome (CFNS [MIM 304110]) is an X-linked malformation syndrome characterized by craniofrontonasal dysplasia and extracranial manifestations in heterozygous females. In the majority of patients CFNS is caused by mutations in the EFNB1 gene (MIM 300035). We identified three girls with classical CFNS and mild developmental delay harboring de novo deletions of the EFNB1 gene. Applying haplotype analysis, Southern blot hybridization and array-comparative genomic hybridization, deletion of EFNB1 was found to be part of contiguous gene deletions in the patients. In one patient the deletion interval includes the genes for oligophrenin-1 (OPHN1 [MIM 300127]) and praja 1 (PJA1 [MIM 300420]). In the second patient the deletion includes OPHN1, PJA1 and the gene for ectodysplasin A (EDA [MIM 300451]). In the third patient EFNB1 gene deletion may include deletion of regulatory regions 5' of OPHN1. Previously, the OPHN1 gene has been shown to be responsible for recessive X-linked mental retardation. Although it is too early to predict the future cognitive performance of the two infant patients with contiguous gene deletions of OPHN1-EFNB1-PJA1, mild learning disabilities have been recognized in the older, third patient. It is important for genetic counseling to be aware that their male offspring may not only be carriers of CFNS but may also be affected by mental retardation and anhidrotic ectodermal dysplasia.

Management of hydrocephalus in children with plasminogen deficiency.

Congenital plasminogen deficiency is an infrequent disorder, which usually becomes symptomatic as ligneous conjunctivitis. However, pseudomembranous lesions in the mucosa of the pharynx, tracheobronchial tree, and the peritoneum may likewise occur. An accompanying hydrocephalus is extremely rare; only 16 cases have been reported to date. The reports indicate that hydrocephalus, even if treated by ventriculoperitoneal (VP) cerebrospinal fluid (CSF) shunting, worsens the prognosis substantially. Thus, VP CSF shunting does not seem to be the optimal therapy for hydrocephalic children with plasminogen deficiency. We add two cases to the literature, and, on the base of our experience, we propose a management strategy for the hydrocephalus. We report the case history of two children with plasminogen deficiency and associated hydrocephalus. Both children initially were treated with VP shunts and had a very similar clinical course with multiple shunt malfunctions due to nonabsorption by the peritoneum. In the first child, the attempt to treat the hydrocephalus with a ventriculoatrial (VA) shunt failed due to catheter thrombosis. Finally, a ventriculocholecystic shunt was placed in both children, which worked well. In patients with plasminogem deficiency and associated hydrocephalus, special care must be taken in the management of hydrocephalus. The absorptive capacity of the peritoneum is reduced by pseudomembrane formation, which results in VP shunt malfunction. The plasminogen deficiency results in early thrombus formation if atrial catheters are used. Therefore, the authors believe that ventriculocholecystic shunting should be considered early on in the course of the disease.

[Radiographic changes in non-operated isolated sagittal suture synostosis]. / Radiologische Veränderungen bei nichtoperierter isolierter Sagittalnahtsynostose.

PURPOSE: To characterize the spontaneous clinical course of isolated sagittal synostosis based on planar skull radiography. MATERIALS AND METHODS: In this retrospective analysis we evaluated a total of 155 radiographs of 55 children 2 weeks to 9 years old. The sagittal, coronal and lambdoid sutures were evaluated on the basis of pairs of ap and lateral radiographs. The sutures were examined with respect to their boundary, activity, and conspicuity to be visualized (based on a 3-grade score system). Six selected points on the skull X-ray defined eight measured distances, three angles, and a width-length index. To document changes over time, the measurements were correlated to normal values. In addition, a correlation between suture activity and selected parameters was evaluated. RESULTS: The sagittal suture could be continuously or partially depicted in more then half of all radiographs taken during the first year of life, The measured distances and angles were concordant with results from the literature. With increasing age, the width-length index deviated from standard values while other parameters approximated the norm. CONCLUSION: In the case of children younger than twelve months, the sagittal suture appears radiologically open in many cases despite clear-cut scaphocephaly. Definite signs of progressive plurisutural fusion were not found in this series. The dolichocephalic deformity remained unchanged while some signs of scaphocephalic appearance actually improved.

Effective NSAID treatment indicates that hyperprostaglandinism is affecting the clinical severity of childhood hypophosphatasia.

BACKGROUND: Hypophosphatasia (HP) is an inborn error of bone metabolism characterized by a genetic defect in the gene encoding the tissue-nonspecific alkaline phosphatase (TNSALP). There is a lack of knowledge as to how the variability and clinical severity of the HP phenotype (especially pain and walking impairment) are related to metabolic disturbances or impairments, subsequent to the molecular defect. METHODS: We analyzed the changes in clinical symptoms and the prostaglandin (PG) metabolism in response to treatment with non-steroidal anti-inflammatory drugs (NSAIDs) in six children affected by childhood HP. In addition, by exposing HP fibroblasts to pyridoxal phosphate and/or calcium pyrophosphate in vitro, we analyzed whether the alterations in PG levels are sequelae related to the metabolic defect. RESULTS: Childhood HP patients, who often complain about pain in the lower limbs without evident fractures, have systemic hyperprostaglandinism. Symptomatic anti-inflammatory treatment with NSAIDs significantly improved pain-associated physical impairment. Calcium pyrophosphate, but not pyridoxal phosphate, induced cyclooxygenase-2 (COX-2) gene expression and PG production in HP and normal fibroblasts in vitro. CONCLUSION: Clinical features of childhood HP related to pain in the lower legs may be, at least in part, sequelae related to elevated PG levels, secondary to the primary metabolic defect. Consequently, NSAID treatment does improve the clinical features of childhood HP.

Cutaneous lesions in occult spinal dysraphism--correlation with intraspinal findings.

OBJECTS: This study was conducted to investigate the frequency and type of cutaneous stigmata in different forms of occult spinal dysraphism (OSD) and their correlation to the underlying malformation. METHODS: Fourteen different forms of spinal malformations were identified in 358 operated patients with OSD. Most frequent findings (isolated or in combinations) were spinal lipoma, split cord malformation, pathologic filum terminale, dermal sinus, meningocele manqué, myelocystocele and caudal regression. Stigmata were present in 86.3% of patients, often in various combinations. Using a binary logistic regression analysis, significant correlations with distinct malformations were found for subcutaneous lipomas, skin tags, vascular nevi, pori, hairy patches, hypertrichosis, meningoceles and "cigarette burn" marks. CONCLUSIONS: Cutaneous markers in a high percentage accompany spinal malformations. Due to the correlations of different stigmata to distinct malformations, they can aid the clinician in further diagnostic and therapeutic work.

Hydrocephalus in craniosynostosis: a review.

INTRODUCTION: Ventricular dilatation in the presence of primary craniosynostosis is a unique condition with respect to pathogenesis, clinical significance, and morphological appearance. It is rarely observed in nonsyndromic craniosynostosis, and in these cases usually attributable to coincidental disorders. Conversely, it is a common feature of syndromic craniosynostosis, affecting at least 40% of patients with Crouzon's, Pfeiffer's or the Apert syndrome. Shunt-dependent hydrocephalus is predominantly associated with Crouzon or Pfeiffer syndrome while in the Apert syndrome the usual finding is nonprogressive ventriculomegaly which, however, may also occur in some cases of Crouzon syndrome. PATHOGENESIS: The pathogenesis of progressive hydrocephalus remains somewhat obscure, a hypoplastic posterior fossa and a venous outlet occlusion at the skull base being the main causative factors discussed in literature. Ventriculomegaly may reflect primary brain maldevelopment or in some cases even a compensated state of increased cerebrospinal fluid (CSF) outflow resistance. CLINICAL EVALUATION: Clinical evaluation is mainly aimed at identifying progressive hydrocephalus, but diagnosis is hampered by the fact that classical clinical signs may be absent, and that ventricular dilatation will often become evident only after decompressive cranial surgery. Moreover, mild ventriculomegaly may in some cases coexist with intracranial hypertension from craniostenosis. Therefore, careful monitoring of intracranial pressure and ventricular size in the pre- and postoperative period is a diagnostic mainstay. CONCLUSION: In true hydrocephalus ventriculo-peritoneal shunting is currently the single promising mode of treatment.

[Pioneers of neurosurgery: Emil Heymann (4/15/1878-1/11/1936)]. / Aus der Pionerzeit der Neurochirurgie: Emil Heymann (15.4.1878-11.1.1936).

Following Fedor Krause and Otfrid Foerster, pioneers of neurosurgery in Germany, Emil Heymann was one of the outstanding promoters of the young surgical section, before it emerged as an independent specialty. As successor to Fedor Krause at the Augusta-Hospital, Berlin, he consistently improved techniques of investigation and operative treatment of intracranial and spinal tumors. Because of his Jewish parents he was persecuted by the Nazi regime, who nearly succeeded that his name fall into oblivion.

Immunolocalization of urokinase and its receptor in prematurely fused cranial sutures of infants.

In cranial sutural samples derived from five children with premature cranial suture fusion we have performed immunostaining for the urokinase plasminogen activator (uPA) and urokinase receptor (uPAR). We have found a strong reactivity for cell- or matrix-bound uPA and uPAR in the sutural connective tissue and associated with the osteoblasts and osteocytes lining the calvarial bone. The sutural tissue itself showed a banding with different intensity of urokinase and uPAR staining concerning connective tissue. It is proposed that the components of the plasminogen activating system are involved in tissue turnover of sutural tissue and in sutural growth.

Surgical management of tethered spinal cord in adults: report of 54 cases.

OBJECT: The clinical features specific to tethered cord syndrome (TCS) in adults as well as factors determining outcome and prognosis have rarely been addressed systematically. The authors studied 56 patients, 54 of whom were treated surgically over the last 16 years. METHODS: In 17 patients who had been asymptomatic during childhood, TCS was diagnosed 8 years after onset of symptoms. Tethered cord syndrome was diagnosed 4 years after worsening in 39 patients with neurological signs or symptoms since childhood. The patients were followed for an average of 8 years. Features specific to adult-age presentation included nondermatomal pain aggravated by movement in 34 patients and conditions such as pregnancy and childbirth (in five of 11 pregnant patients). The most frequent tethering lesions were lipoma in 32, tight terminal filum in 28, and split cord malformation and secondary adhesions in 12 patients, respectively. Improvement or stabilization of symptoms at 6 months after surgery was noted in 46 (85%) of 54 patients. Improvement in pain status was most frequent (86%) followed by improvements in spasticity (71%), bladder dysfunction (44%), and sensorimotor deficits (35%). Factors associated with adverse outcome included preoperative duration of neurological deficits more than 5 years and incomplete untethering. On average, 8 (80%) of 10 patients with incomplete untethering developed recurrent symptoms 5 years after surgery compared with only seven (16%) of 44 patients in whom complete untethering was achieved. Seven patients underwent reoperation and in five of them stabilization of symptoms was attained. At a mean follow up of 8 years, 46 (85%) of the 54 surgically treated patients were in stable neurological condition, including those in whom reoperation was performed. CONCLUSIONS: Surgery for TCS is as beneficial in adults as it is in children. Its success depends on early diagnosis and complete untethering of the spinal cord.

Standardized evaluation and documentation of findings in patients with craniosynostosis.

Surgical correction of craniosynostosis is usually performed according to standard procedures. However, a standard for clinical examination and report of findings for patients with craniosynostosis does not exist as yet. To compare findings from different hospitals, a documentation system was developed by a national craniosynostosis group. This system comprises a two-page document, clinical photographs, radiographs, CT scans, anthropometric measurements and molecular genetic findings. Data from craniosynostosis patients collected from participating hospitals are stored in a database, which facilitates online access. The documentation system was developed in cooperation with the group during 3 years since 1996. It was evaluated as being practicable and reliable and enables a comparability of findings reported in different hospitals. Molecular genetic analysis was found to support the investigation of patients with craniosynostosis and should therefore be integrated in the clinical evaluation.

Clustering of FGFR2 gene mutations inpatients with Pfeiffer and Crouzon syndromes (FGFR2-associated craniosynostoses).

A cohort of 36 unrelated German patients with craniosynostosis syndromes of the Crouzon and Pfeiffer type were analyzed for FGFR mutations. Mutations in FGFR2 were identified in 25 Crouzon and 5 Pfeiffer syndrome patients, whereas no sequence alterations were found in the remaining patients, even after screening of the relevant parts of FGFR1, FGFR3, and TWIST. Mutations in FGFR2 clustered at two critical cysteine residues, 278 and 342, which were involved in 18 of 30 cases (60%). These two mutational hot spots, therefore, are prime targets for an efficient mutation-screening strategy. The spectrum of mutations overlapped the two syndromes and thus reflected the phenotypic similarities observed in both patient groups. In 21 families, the origin of the mutation could be traced by analyzing parents and relatives. Eleven mutations arose de novo, indicating a high mutation rate for FGFR2. In the 10 familial cases, the clinical presentation varied considerably within the pedigree, but both syndromes "bred true," i.e., a Pfeiffer syndrome phenotype was never observed in a Crouzon syndrome family and vice versa.

An unusual FGFR1 mutation (fibroblast growth factor receptor 1 mutation) in a girl with non-syndromic trigonocephaly.

Non-syndromic trigonocephaly is a heterogeneous entity; in most cases the origin is unknown. Rare cases with autosomal dominant and recessive inheritance exist. Here the mutational screening of ten patients in the FGFR1, 2, and 3 genes and the TWIST gene causative of autosomal dominant craniosynostosis syndromes was reported. In one girl an unusual FGFR1 mutation was found.

[Long-term outcome after corrective surgery of the neuro- and viscerocranium of patients with simple and syndrome-related premature craniosynostosis]. / Langzeitergebnisse nach Korrekturoperationen am Neuro- und Viszerokranium von Patienten mit einfachen und syndromalen prämaturen Kraniosynostosen.

A retrospective and partly prospective study was conducted to analyse both clinically and cephalometrically the craniofacial growth pattern of patients with isolated and syndrome-related premature craniosynostosis after standardized fronto-orbital and midface advancement. The file data of 293 children with fronto-orbital advancement were evaluated over an average period of 4.4 years. In addition, lateral teleradiographies of 117 patients from this group were cephalometrically analysed. Moreover, late results of 36 children and 8 adults with midface-advancement with an average follow-up period of 4.5 years were assessed. In contrast to linear craniectomy and so-called lateral canthal advancement, in only 8.2% of cases (24 out of 293 patients) were relapses requiring reoperation found in this study after fronto-orbital advancement. The evaluations indicate that with simple forms of craniosynostosis such as trigonocephaly and plagiocephaly predominantly very good or good growth can be observed. Cephalometric evaluation confirmed the limited potential of growth in the area of the anterior skull base and in the midface in the presence of syndrome-related faciocraniosynostoses. In such cases the cephalometrically confirmed maxillary hypoplasia, which increases in severity in the following order of syndromes 'Saethre-Chotzen-Crouzon-Apert-Pfeiffer', could be influenced only to a limited degree by fronto-orbital advancement. For this reason midface advancement is of secondary importance in children with very severe anomalies. In the present evaluation, a high rate of relapse of midfacial hypoplasia was to be found in children and adolescents after this operation in accordance with other references. Therefore, the indication for Le Fort III osteotomy in the growth period should be limited.