Different interpretation of additional evidence for HTA by the commissioned HTA body and the commissioning decision maker in Germany: whenever IQWiG and Federal Joint Committee disagree.

BACKGROUND: The purpose of this study was to analyse the impact of commissioned addenda by the Federal Joint Committee (FJC) to the HTA body (IQWiG) and their agreement with FJC decisions and to identify potential additional decisive factors of FJC. METHODS: All available relevant documents up to end of 2017 were screened and essential content extracted. Next to descriptive statistics, differences between IQWiG and FJC were tested and explored by agreement statistics (Cohen's kappa and Fleiss' kappa) and ordinal logistic regression. RESULTS: Most of the 90 addenda concerned oncological products. In all contingent comparisons, positive changes in added benefit or evidence level on a subpopulation basis (n = 124) prevailed negative ones. Fleiss' ordinal kappa for agreement of assessments, addenda, and appraisals reached a moderate strength for added benefit (0.474, 95%-CI, 0.408-0.540). Overall agreement between addenda and appraisals on a binary nominal basis is poor for added benefit (Cohen's kappa 0.183; 95%-CI: 0.010-0.357) ranging from "less than by chance" (respiratory diseases) to "perfect" (neurological diseases). The OR of the selected regression model showed that i) mortality, ii) unmet need, the positions of iii) the physicians' drug commission and iv) medical societies, and v) the annual therapeutic costs of the appropriate comparative therapy had a high influence on FJC's appraisals deviating from IQWiG's addenda recommendation. CONCLUSIONS: IQWiG's addenda have a high impact on decision-maker's appraisals offering additional analyses of supplementary evidence submitted by the manufacturers. Nevertheless, the agreement between addenda and appraisals varies, highlighting different decisive factors between IQWiG and FJC.

Recruitment of the sensorimotor cortex--a developmental FMRI study.

INTRODUCTION: The growing mastery of motor tasks is one of the most visible changes in the developing child. The cortex is known to play a central role in learning, planning, and performance of motor tasks. We investigated the age dependency of motor cortex activation using functional magnetic resonance imaging (fMRI). METHODS: Thirty-two right-handed subjects were studied: 11 children (median age 9 years, range 6 - 10 years), 10 adolescents (median age 13 years, range 11 - 15 years), and 11 adults (median age 27 years, range 23 - 42 years). The subjects performed a simple, paced unilateral motor task (repetitive squeezing of a ball with the right hand). Also, we set up a control experiment (visual stimulation using an alternating checkerboard pattern) in which no age-related differences were expected. RESULTS: Compared to children, adults showed significantly increased activation of the bilateral sensorimotor cortex, parietal areas, the supplementary motor area, and the cerebellum. In the visual stimulation experiment there were no age-related differences. CONCLUSION: Children show a significant difference in the degree of cortical activation compared to adults when performing a simple motor task. The change in fMRI activation patterns may reflect a maturation process of primary and secondary motor areas.

Determination of hemisphere dominance for language: comparison of frontal and temporal fMRI activation with intracarotid amytal testing.

The reliability of frontal and temporal fMRI activations for the determination of hemisphere language dominance was evaluated in comparison with intracarotid amytal testing (IAT). Twenty-two patients were studied by IAT (bilateral in 13, unilateral in 9 patients) and fMRI using a paradigm requiring semantic decisions. Global and regional (frontal and temporoparietal) lateralisation indices (LI) were calculated from the number of activated (r>0.4) voxels in both hemispheres. Frontolateral activations associated with the language task were seen in all patients, temporoparietal activations in 20 of 22. Regional LI corresponded better with IAT results than global LI. Frontolateral LI were consistent with IAT in all patients with bilateral IAT (including three patients with right dominant and one patient with bilateral language representation) and were not conflicting in any of the patients with unilateral IAT. Temporoparietal LI were discordant with IAT in two patients with atypical language representation. In the determination of hemisphere dominance for language, regional analysis of fMRI activation is superior to global analysis. In cases with clear-cut fMRI lateralisation, i.e. consistent lateralised activation of frontal and temporoparietal language zones, IAT may be unnecessary. FMRI should be performed prior to IAT in all patients going to be operated in brain regions potentially involved in language.

The morphological effects of a radio frequency lesion adjacent to the dorsal root ganglion (RF-DRG)--an experimental study in the goat.

Radiofrequency (RF) lesions adjacent to the dorsal root ganglion (DRG) are increasingly used in the treatment of intractable chronic pain of spinal origin. Opinions differ on which nerve fibres are affected by these lesions. Morphological studies have been carried out to assess the effects of radiofrequency lesions on nervous tissue. Interpretation has been difficult, since most studies have been performed under circumstances which are not comparable to the clinical situation. This study was undertaken to investigate morphological effects of RF lesions as they develop in the normal clinical situation. In two goats 22 G 100 mm SMK electrodes with a 5 mm active tip (Radionics) were positioned posterior to the lumber dorsal root ganglia (DRG). Sixty-second 67;C lesions were made on one side. The contralateral side was used as sham operation. The goats were sacrificed 2 weeks after the procedure. The lesions were studied for size as well as for effects on proliferation and regeneration using Ki-67 (MIB-1). Lesions made inside the DRG (23) were 1.8-2.0 mm in size. In these lesions there was a total loss of myelinated fibres. In lesions made adjacent to the DRG there was a significantly higher MIB-1 labelling on the treated side as compared to the sham-treated side. An RF lesion inside the DRG destroys myelinated fibres. A lesion adjacent to the DRG increases MIB-1 activity, indicating proliferation and regeneration after 2 weeks, despite the fact that the lesion was made outside the ganglion.

Surgical treatment of aspergillus spondylodiscitis.

Four cases of aspergillus spondylodiscitis were treated with operative debridement and fusion. In this rarely encountered mycotic infection of the spine in immunocompromised patients rapid destruction of the intervertebral disc and vertebral bodies can occur. In advanced cases antimycotic drug therapy is thought to be ineffective and a forcing indication for surgery exists when the destruction is progressive and spinal cord compression is imminent or manifest. Spinal instrumentation can be of help in maintaining or restoring spinal stability and maintaining spinal alignment. In our four patients the aspergillus spondylodiscitis was successfully eradicated and fusion achieved. In two of three patients with a neurologic deficit, this deficit disappeared. Two patients died within 6 months after the operative treatment, due to complications related to the underlying illness. One patient was left with a subtotal paraplegia.

Subcutaneous ventricular catheter reservoir and ventriculoperitoneal drain-related infections in preterm infants and young children.

OBJECTIVE: In the period January 1990 to September 1997, 70 patients, aged under 6 years were treated for hydrocephalus with a subcutaneous ventricular catheter reservoir and/or a ventriculoperitoneal drain at the University Hospital of Maastricht. METHODS: By means of a retrospective chart analysis, the number of shunt infections and related risk factors were analyzed. RESULTS: Twenty-one patients (30%) developed one or more infections, with an infection rate of 15.2% per surgical event. For an implanted reservoir or drain, the infection rates were 15.9 and 16.4%, respectively. The study group consisted of 39 (55.7%) preterm infants (< 37 weeks) and 31 (44.3%) full-term infants (> or = 37 weeks), with infection rates of 33.3 and 25.8%, respectively. At the first surgical intervention 28 patients (40%) had a postmenstrual age less than 37 weeks, with an infection rate of 46.4%. At the time of surgery, 69.7% of the patients were aged less than 6 months, with an infection rate of 19.6%. The most frequent causative microorganism of the shunt infections was Staphylococcus epidermidis (42.1%). CONCLUSIONS: Prematurity is an important risk factor for ventricular catheter reservoir and ventriculoperitoneal drain-related infections, especially for patients with a postmenstrual age of less than 37 weeks at their initial shunt placement and extreme low birth weight infants have a high risk for infection. In our opinion the use of adequate antibiotic prophylaxis and optimal infection control measures are necessary to keep the rate of infection as low as possible.

Intramedullary spinal teratoma presenting with urinary retention: case report and review of the literature.

OBJECTIVE AND IMPORTANCE: Intramedullary tumors affect a small but significant segment of patients with spinal cord tumors. Intramedullary teratomas are rare entities that are usually located in the sacrococcygeal region. Although some reports claim that diagnostic studies can exactly predict the nature of intramedullary tumors, this case report demonstrates the lack of preoperative diagnostic specificity. Therefore, the aim of surgery should be radical extirpation whenever possible. CLINICAL PRESENTATION: A case report of a thoracolumbar intramedullary teratoma is presented. This young male patient displayed urinary retention and motor deficits. Computed tomographic and magnetic resonance imaging examination revealed an intramedullary tumor; however, the exact nature of the tumor could not be determined preoperatively. The literature concerning these tumors is extensively reviewed. INTERVENTION: During surgery, a multicystic tumor was found at the base of the filum terminale, which was resected as far as possible. CONCLUSION: It is concluded that surgery should be the first choice for treatment. More aggressive teratomas are found in intramedullary locations, especially in children, emphasizing the importance of radical tumor resection. The use of adjuvant chemo- or radiotherapy should be explicitly substantiated for the nonbenign teratoma group.

Spinal cord compression caused by unusual location and extension of ossified ligamenta flava in a Caucasian male. A case report and literature review.

STUDY DESIGN: A case report of a spinal cord compression caused by ossification of the ligamenta flava is presented together with a review of the literature. OBJECTIVE: To present the diagnosis of ossification of the ligamenta flava in a Caucasian man with a proximal thoracic myelopathy. SUMMARY OF BACKGROUND DATA: This case shows that the upper parts of the thoracic spine can be involved in ossification of the ligamenta flava, which never before has been reported in Caucasian individuals. Furthermore, it is advised that computed tomography scanning and magnetic resonance imaging be combined to provide an accurate diagnosis and proper preoperative evaluation of the bony changes, spinal cord, and compression of the spinal cord. METHODS: A patient with a thoracic spinal cord compression caused by ossification of the ligamenta flava was treated surgically and made a good clinical recovery. Imaging studies, surgical findings, and results of histopathologic investigations were analyzed to substantiate the diagnosis. RESULTS: The results of the surgical findings seemed to be in contrast with those of the imaging studies. This contrast was occasioned by the uncommon perioperative finding of a fusion of the completely ossified upper and lower parts of the involved adjacent ligamenta flava. Ossification of the ligamenta flava was diagnosed by histopathologic examination, which revealed endochondral ossification and lamellar bone formation without fragments of ligamenta flava. CONCLUSION: Although rarely reported in whites, ossification of the ligamenta flava should be considered in all patients presenting with a spinal cord compression, even at high thoracic levels. The prognosis after decompressive surgery can be good, especially if intramedullary hyperintensities are absent on preoperatively performed T2-weighted magnetic resonance images.

Neurogenic claudication, a delayed complication of a retained bullet.

STUDY DESIGN: A case report is presented of a 31-year-old man who visited the authors' neurosurgical department in 1993, complaining of neurogenic claudication. History revealed a gunshot incident 11 years ago, with a bullet left in situ. OBJECTIVES: To determine whether to operate on patients who have a bullet in situ near the spinal cord without initial neurologic deficits. SUMMARY OF BACKGROUND DATA: In the literature, only four publications report an epidural chronic inflammatory mass as a reaction to a retained bullet, thereby causing delayed neurologic symptoms. Previous to this report, only one case is described of a patient with a bullet lodged in the paravertebral musculature. METHODS: Clinically, the patient had pain radiating from his lower back to both his thighs, provoked by walking, standing, and the Valsalva maneuver. Comparison of radiographs made in 1990 and in 1993 showed the lead bullet still completely intact in 1990, whereas in 1993, a partial disintegration and displacement of the bullet, causing a chronic inflammatory reaction (extraspinal and intraspinal), as well as cyst formation, was seen. Particularly notable was the radiographic feature of a sort of "fallen leaf sign" at the level of L5-S1. RESULTS: The preoperative complaints were still absent 1 year after surgery. CONCLUSIONS: It is argued that with regard to a retained bullet in the vicinity of the spinal canal, the presence or absence of neurologic symptoms should be the guide for further diagnostic procedures. Only if a neurologic deficit develops, which is possible after many years, should surgical intervention be considered, depending on the severity and type of the deficit, as presented in this case report.

Assessment of cognitive performance after progesterone administration in healthy male volunteers.

Administration of progesterone produces sleep EEG patterns that resemble those of agonistic modulators at the GABAA receptor. Previous studies evaluating the effects of an oral progesterone administration on attention performance in females pointed to putative sedative effects of progesterone at high dosages. However, no data are available whether progesterone dosages that influence sleep produce sedative hangover effects on the following morning. Therefore, we assessed the effects of a single oral dose of 300 mg micronized progesterone administered in the evening on cognitive performance parameters in male healthy volunteers on the following morning using a placebo-controlled double-blind crossover design. There was a great variability in bioavailability following progesterone intake. The administration of progesterone produced no consistent effects on attention performance. Thus, dosages of progesterone that are sufficient to modulate sleep are not likely to exert sedative hangover effects.

Use of neonatal intensive care unit as a safe place for neonatal surgery.

AIM: To evaluate the advantages, disadvantages, and short term morbidity and mortality of major surgical interventions performed in the neonatal intensive care unit. METHODS: A retrospective case review of 45 neonates was performed from April 1991 to September 1995. The characteristics of the patients were: gestational age 29 (SD 4) weeks (range 24 to 41 weeks); birth-weight 1305 (870) g (range 540 to 4040 g); presurgical weight 1430 (895) g (range 550 to 4370 g); postconceptional age at surgery 31 (4) weeks (26 to 47 weeks). The indications for surgery were: ligation of patent ductus arteriosus (n = 16); insertion of a subcutaneous ventricular catheter reservoir for hydrocephalus (n = 14); repair of congenital diaphragmatic hernia (n = 2); open lung biopsy (n = 1); and laparotomies (because of necrotising enterocolitis, anorectal malformations, and intestinal obstructions) (n = 12). The management of these neonates at laparotomy was: bowel resection with stomas (n = 8) and stomas (n = 4). No specially designed area was used to perform surgery. RESULTS: Local or systemic infection associated with surgery was not seen and no perioperative mortality was related to the surgical procedure. CONCLUSIONS: The neonatal intensive care unit is suitable for major surgery during the neonatal period and no special area is needed to perform complication free surgery.

Effectiveness of antiepileptic prophylaxis used with supratentorial craniotomies: a meta-analysis.

Thirty publications on the effectiveness of prophylactic antiepileptic drugs (AEDs) with supratentorial craniotomies were reviewed (1980-1995). After a first selection, six controlled studies remained (11 publications). These six were evaluated according to previously defined methodological criteria. The criteria were divided into three main categories: (1) internal validity, (2) proper and relevant outcome-measures and (3) analysis. In this way a maximum of 145 points could be obtained for each study. Three studies were considered to be of satisfactory methodological quality (> or = 55% or 145 points) and the odds ratios were calculated as a measure of association between treatment and occurrence of convulsions. The odds ratios of these three studies were statistically pooled using the Mantel-Haenszel Estimator. From this test it appeared that prophylactically used AEDs showed a tendency to prevent postoperative convulsions, but this effect was certainly not statistically significant (P = 0.1 one-tailed). Points of attention concerning possible future investigations are stressed.

Deformation of the cervicomedullary junction and spinal cord in a surgically treated adult Chiari I hindbrain hernia associated with syringomyelia: a magnetic resonance microscopic and neuropathological study. Case report.

The lower brainstem and cervical spinal cord from an ordinarily treated case of Chiari Type I hindbrain hernia associated with syringomyelia was examined using high-resolution magnetic resonance microscopy and standard neuropathological techniques. Magnetic resonance microscopy allows total screening and visualizes the disturbed internal and external microanatomy in the three orthogonal planes with the resolution of low-power optical microscopy. An additional advantage is the in situ visualization of the shunts. Afterwards the intact specimen is still available for microscopic examination. Part of the deformation of the medulla is caused by chronic tonsillar compression and molding inside the foramen magnum. Other anomalies, such as atrophy caused by demyelination, elongation, and unusual disturbances at the level of the trigeminal and solitary nuclear complexes contribute to the deformation. At the level of the syrinx-free upper part of the cervical cord, anomalies of the dorsal root and the dorsal horn are demonstrated.

Pleomorphic xanthoastrocytoma in the spinal cord. Case report.

The authors present the clinical, radiological, and pathological features of a patient with a recurrent pleomorphic xanthoastrocytoma located in the spinal cord. This is the first report of a pleomorphic xanthoastrocytoma at this location; until now, only cerebral supratentorial pleomorphic xanthoastrocytomas have been described. The treatment of this case is discussed.

Co-expression of glial fibrillary acidic protein- and vimentin-type intermediate filaments in human astrocytomas.

The expression of intermediate filament (IF) proteins was studied in 71 cases of malignant human astrocytoma and in 17 cases of reactive gliosis, using immunocytochemical techniques with polyclonal and monoclonal antibodies to glial fibrillary acidic protein (GFAP) and vimentin. In all cases of astrocytoma, varying in degree of malignancy from grade I to grade IV, co-expression of GFAP and vimentin was found. No change in vimentin- or GFAP-IF expression with increasing anaplasia was seen. In addition astrocytic cells in reactive gliosis showed simultaneous expression of GFAP and vimentin. The intracellular distribution of these IF proteins differed. Vimentin was found to be located in a more juxta-nuclear position, whereas GFAP immunoreactivity showed a more intense staining of the cellular processes. Astrocytes in reactive gliosis behaved more or less like neoplastic cells. However, thin cell processes of reactive astrocytes in the cortex and superficial white matter only contained GFAP immunoreactivity. Simultaneous expression of GFAP and vimentin and their proportion in malignant and reactive glial cells are discussed in the light of earlier reports on the IF content of glial cells during development and maturation, in which vimentin precedes GFAP-expression. The existence of two separate (functional) IF systems in astroglia is suggested.

Primitive neuroectodermal tumors including the medulloblastoma: glial differentiation signaled by immunoreactivity for GFAP is restricted to the pure desmoplastic medulloblastoma ("arachnoidal sarcoma of the cerebellum").

Immunoreactivity of tumor cells for glial fibrillary acidic protein (GFAP) is usually regarded as sign of astrocytic histogenesis and/or differentiation. The present study aimed at a systematic evaluation of the significance of GFAP-containing cells in primitive neuroectodermal tumors (PNETs) with special reference to the controversial entity of desmoplastic medulloblastoma (so-called "circumscribed arachnoidal sarcoma of the cerebellum"). Fifty-three PNETs, including 17 pure desmoplastic medulloblastomas were investigated, using GFAP antisera and the peroxidase-antiperoxidase (PAP) technique. Seventy percent of the pure desmoplastic medulloblastomas showed GFAP immunoreactive cells, in 47% indistinguishable from adjacent nonreacting tumor cells. Most immunoreacting cells were found in the reticulin free islands, showing in 6 cases a gradual transition of immunoreacting cells from tumor cells to larger cells shaped like astrocytes. The classical medulloblastomas showed only larger immunoreacting cells which were interpreted as reactive astrocytes. Therefore, the so-called circumscribed arachnoidal cerebellar sarcoma or pure desmoplastic medulloblastoma merits a separate place in the group of PNETs as a tumor with frequent signs of astroglial differentiation; this interpretation appears to be clinically correlated by a difference in age incidence and prognosis of that special tumor-type in comparison with classical medulloblastoma.

Glial fibrillary acidic protein (GFAP) in oligodendroglial tumors: gliofibrillary oligodendroglioma and transitional oligoastrocytoma as subtypes of oligodendroglioma.

Immuno-reactivity to glial fibrillary acidic protein (GFAP) is mainly regarded as a sign of astroglial histogenesis and/or differentiation. The presence of astrocytes in oligodendrogliomas is a well known phenomenon; in addition, GFAP-positive neoplastic oligodendrocytes have also been described but have not yet been studied systematically. Using an anti-GFAP serum in the peroxidase-antiperoxidase antiperoxidase (PAP) technique, 50 oligodendrogliomas and 16 mixed oligodendrocytomas were investigated; they had been diagnosed by routine histological stains. In half of all oligodendrogliomas, and only in a few (12%) of the mixed oligoastrocytomas, GFAP-positive oligodendrocytes were found in some areas of the classical honey-comb texture with a prominent vascular stroma. The term 'gliofibrillary oligodendrocyte' (gfoc) is proposed for these immuno-reactive cells. The existence of a tumour cell combining morphological characteristics of oligodendroglia with GFAP production in its cytoplasm may be considered analogous to transient GFAP expression by myelin-forming glia during normal development (Choi and Kim 1984), thus suggesting the return to a foetal behaviour by some neoplastic oligodendrocytes. Three tumours of the present series consisted largely of gfocs and, therefore, may be termed gliofibrillary oligodendrogliomas. In about 32% of all oligodendrogliomas, but only once in the mixed tumour group, a gradual morphological transition from gfocs to gemistocytic astrocytes was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Production of glial fibrillary acidic protein (GFAP) by neoplastic cells: adaptation to the microenvironment.

In 80 specimens of human glioma the production of glial fibrillary acidic protein (GFAP) by tumour cells invading meninges or connective tissue was studied immuno-cytochemically by the PAP technique. In 38 of 55 cases of astrocytoma, glioblastoma, gliosarcoma, and oligoastrocytoma, GFAP immunoreactivity was greater in the invading cells as compared with the main part of the neoplasm. Fifty-eight percent of the astroglial tumours invading the leptomeninges, all astroglial tumours invading connective tissue and all gliosarcomas showed enhanced GFAP immuno-reactivity of tumour cells getting in contact with collagenous tissue, whereas meningeal infiltrates of 25 non-astroglial tumours (oligodendroglioma, ependymoma, medulloblastoma) remained GFAP-negative like the main part of the respective tumours. In the majority of astroglial tumours an increase of GFAP immunoreactivity was found also in perivascular cells of the main part of the tumour. It is concluded that glioma cells are capable of adapting their cytoskeleton to their micro-environment. Contact with dense collagenous tissue appears as an important factor able to induce an increased production of GFAP by adjacent glial cells.