Predictive factors for neurocognitive function and Quality of Life after surgical treatment for Cushing's disease and acromegaly.

BACKGROUND: Cushing's disease (CD) and acromegaly (AC) are associated with impairment in quality of life (QoL) and neurocognition that can persist after successful treatment. AIM: To investigate the influence of current disease status (remission vs no remission) on neurocognitive function and QoL in treated CD and AC patients and to determine predictive factors (e.g. demographic, clinical, neurosurgical, endocrinological) for post-operative neurocognition and QoL. SUBJECTS AND METHODS: Twenty-four CD and 37 AC patients underwent neuropsychological testing 1 to 10 yr following surgical therapy. Additionally, QoL was assessed. An overnight 2-mg dexamethasone suppression test in CD and IGF-I and GH levels in AC patients were assessed to determine current disease status. The results were compared with 28 sex-, education- and age-matched healthy controls (HC). RESULTS: Impaired QoL was more pronounced than neurocognitive decrease in both pathologies compared to HC. This finding was independent of the current status of disease. In AC, persistent comorbidities were associated with impaired QoL (p<0.05). Older age at operation in AC patients was a significant predictor for adverse effects on psychomotor speed and attentional functions (p<0.05). In CD persistent hypocortisolism, not hypercortisolism, had adverse effects on neurocognition (p<0.01). CONCLUSIONS: The current status of disease plays a subordinate role in postoperative outcome concerning QoL and neurocognition in either pathology. A possible explanation might be the considerably improved endocrinopathy after treatment compared to untreated patients, even if no cure is achieved. The lasting impairments might be explained by irreversible changes that have occurred during the active phase of the disease.

[Neonatal intracerebral bleeding as initial symptom of gliomatosis cerebri WHO III--neurological outcome after partial hemispherectomy]. / Eine neonatale intrazerebrale Blutung als Initialsymptom einer Gliomatosis cerebri WHO III--neurologisches Outcome nach partieller Hemisphärektomie.

INTRODUCTION: Anaplastic astrocytomas presenting as gliomatosis cerebri in neonates are extremely rare. Tumours in newborns are mostly of neuroectodermal origin. CASE REPORT: We report about a female newborn at term [birth weight 3 600 g (P 90), head circumference 35 cm (P 95) APGAR 9/10/10] with an intracerebral partially clotted bleeding in the left parieto-occipital region. The bleeding was expansive leading to axial and lateral cerebral herniation. The intracerebral bleeding in the left occipital region was surgically removed. Macroscopically no solid tumour was seen, but small fragments of an anaplastic astrocytic tumour (WHO grade III) were diagnosed histologically. After surgery, no remaining tumour was visible in the MRI. 6 weeks later, a recurrent tumour (4×4 cm) was found in the area of the initial bleeding. Further treatment was initially refused by the parents. The child was readmitted to our hospital at the age of 11 months in good clinical condition and presented with left-sided hemiparesis, right-sided hemianopsia and intermittent strabismus convergens alternans. Because of the good clinical condition further therapeutic treatment was initiated. Due to the final extension of the tumour into the temporal, parietal and occipital lobes, a gliomatosis cerebri WHO III was diagnosed. An extended partial hemispherectomy was done. After neurosurgery, no further neurological failures occurred. In the follow-up examination, MRI showed no relapse of the tumour. Chemotherapy according to the HIT SKK protocol was initiated. A relapse did not occur over a follow-up of 2 years. CONCLUSION: This is a rare case report of a congenital gliomatosis cerebri WHO grade III, treated with partial hemispherectomy, leading to a good clinical and neurological long-term outcome.

Parental perception of treatment and medical care in children with craniosynostosis.

Surgery for craniosynostosis implies a relevant strain on the child and the parents. The development of the child's self-perception and self-confidence is mainly influenced by parental attitudes. The outcomes of 46 patients were analysed, taking into consideration parental perceptions. Parents were asked to indicate their satisfaction with the medical care and treatment provided using a questionnaire. Aesthetics were evaluated by the parents and doctors using a score (1=perfect, 5=deficient). Major surgical complications (2.2%) were reported only in the case of complex synostosis. Reoperation was necessary in 2.9% of isolated cases and 45.5% of complex cases. In general, parents were satisfied with the medical (1.3) and nursing (1.6) inpatient care. Aesthetic assessments differed between parents and surgeons, although not significantly (P=0.27). The surgeons perceived the results to be better than the parents, especially for complex synostosis (1.3 vs. 2.7). Alopecia and persistent asymmetry led to a worse perception of aesthetics. Persistent bone defects did not influence parental satisfaction. All participating parents would opt for surgery again. Surgery led to satisfactory results with a low risk of severe complications. Nevertheless, the outcomes and limits of the surgical procedure must be communicated effectively to parents, especially in complex cases, to avoid a mismatch in expectations. It would be desirable to implement structured interviews with parents during regular treatment management.

[Effects of methamphetamine and enriched experience on behavioral recovery after brain damage (author's transl)]. / Effets de la méthamphétamine et d'un environnement complexe sur la récupération comportementale aprés atteinte cérébrale

Two factorial experiments (brain status x environment x drug) were designed to measure the effects of methamphetamine and enriched experience on recovery after bilateral cortical lesions. Fisher male rats were operated or sham operated when 30 days old and thereafter raised in either an enriched (EC) or impoverished (IC) condition while daily injected with either methampheteamine (2 mg/kg) or saline. In EC, 12 rats lived together in a large cage with stimulus objects that were changed daily. In IC, a rat was kept alone in a small cage. The animals' performance was measured on a standard series of problems in a Hebb-Williams maze. The animals' scores were impaired by removal of tissue from the occipital cortex. Enriched experience, on the contrary, helped significantly in overcoming, at least partially, the effects of brain damage on problem-solving behavior regardless of whether this experience was given, for 2 h per day over a 60-day period (Expt. 1), or for 2 h per day over only a 30-day period (EXPT. 2). No drug effect was found in any of these experiments.

Susceptibility to pentylenetetrazol-induced and audiogenic seizures in rats given aspirative lesions of the fimbria-fornix pathways followed by intrahippocampal grafts: a time-course approach.

Long-Evans female rats sustained aspirative lesions of the fimbria-fornix pathways and part of the overlying structures (Lesion). Eight or 9 days later, one third of these lesioned rats received intrahippocampal septal cell suspension grafts (Sept-G) and another third received grafts of hippocampal origin (Hipp-G). Sham-operated rats (Sham) served as controls. For each surgical treatment, 3 subgroups were assigned to one of 3 experiments which differed by the delay separating grafting from testing. Three months (EXP1), seven months (EXP2) and twelve months (EXP3) after grafting, rats were tested for reactivity to pentylenetetrazol (PTZ, 30 mg/kg, i.p.) and to sound (10-20 kHz peaks, 120 dB, 90 s), two models of generalized convulsive seizures. Three months after grafting, lesion-only rats showed increased reactivity to PTZ as compared to Sham rats; both types of grafts (Sept-G, Hipp-G) attenuated this lesion-induced effect. Whether 7 or 12 months after grafting, no significant between-group differences were observed anymore. Three months after grafting, reactivity to sound tended to increase in lesion-only rats and was significantly increased in both groups with grafts (Sept-G, Hipp-G) as compared to the Sham group. Seven months after grafting, only Hipp-G rats showed increased reactivity to sound compared to Sham or lesion-only rats. No significant between-group difference was observed at 12 months post-grafting. At all 3 delays, histological analyses revealed well integrated grafts, but only septal grafts provided the denervated hippocampus with an AChE-positive fiber ingrowth. Reactivity to PTZ or to sound was correlated neither with the size of the graft, nor with the acetylcholinesterase (AChE)-positive graft-derived reinnervation of the dorsal hippocampus. The present results suggest that hippocampal denervation may result in a temporary increase in reactivity to PTZ and susceptibility to sound, the former being transitorily attenuated and the latter being transitorily increased by both kinds of grafts. Our data confirm earlier reports showing that grafts may influence sensitivity to convulsive seizure-inducing treatments. In addition, these data indicate that this influence is not necessarily lasting and that the kind and duration of this influence is dependent upon the model of convulsive seizures used.

Factors influencing structure and function of intracerebral grafts in the mammalian brain: a review.

After twenty years of intensive research, the possibility to induce recovery from various disorders in brain damaged mammals by means of intracerebral grafts of fetal CNS tissue is well documented and largely accepted by the scientific community. However, there are several reports on animal research suggesting that intracerebral grafts may fail to induce the expected recovery after brain injury or even that they may cause deficits which are actually more pronounced than those induced by the lesions alone. In addition, attempts to produce functional benefits with catecholamine-releasing tissue grafts in the brain of Parkinsonian patients have given limited and variable results; graft-induced deleterious effects have also been occasionally reported in a few clinical cases. One way to progress towards a better understanding of such disappointing, although informative, discrepancies between successful and less successful experimental studies and clinical trials would be to consider that there are several factors which may influence, in one direction or the other, the survival, development, integration and functional expression of intracerebral fetal CNS grafts. The present review considers the following factors: (i) some of the technical factors such as the constraints of transplantation surgery, the origin of donor tissue, the implantation site, the age of both the donor and the recipient, and tissue manipulations prior to grafting (i.e., cryopreservation, culture, genetic modification); (ii) exogenous and endogenous neurotrophic factors, the latter being distinguished by whether they may be host- or graft-derived; (iii) immunological factors (from the particular immunological status of the brain to some effects of immunosuppression in the case of xenografting)', (iv) pharmacological factors, with a particular focus on experimental data suggesting that administration of drugs may or might contribute to elicit, enhance or block some functional effects of grafts. It is concluded that all these factors may become simultaneously operative and interacting, thereby presiding over the functional outcome of intracerebral grafting in both experimental research and clinical trials.

Unilateral infusion of GABA and saline into the nucleus basalis of rats: 1. Effects on motor function and brain morphology.

Motor behavior was investigated in rats following acute and chronic gamma-aminobutyric acid (GABA) microinfusions into the nucleus basalis. For acute treatment, the rats received GABA (100 micrograms in 1 microliter), then saline, or these solutions in the reverse order, into the nucleus basalis contralateral to their preferred turning direction in a radial maze. For chronic treatment, half the rats received saline (1 microliter/h for 4 days), and than GABA (100 micrograms/microliters/h) for the same period of time ('saline-first' group). In the other half, this sequence was reversed ('GABA-first' group). Acute microinjections of GABA decreased turning towards the non-injected side; chronic treatment enhanced this effect by reversing the preferred turning direction. Return to initial turning direction was observed after acute GABA-injection in both experimental groups, but only in the 'saline-first' group after chronic treatment. The 'GABA-first' group showed gliosis in and around the nucleus basalis area and a reduction of cortical acetyl-cholinesterase-positivity which were significantly greater than in the 'saline-first' group. This, chronic saline pretreatment is associated with diminished neurotoxicity of chronic GABA infusion and with a reversibility of the drug-induced behavioral effects.

Effects of septal and/or raphe cell suspension grafts on hippocampal choline acetyltransferase activity, high affinity synaptosomal uptake of choline and serotonin, and behavior in rats with extensive septohippocampal lesions.

At 31 days of age, Long-Evans female rats sustained aspirative lesions of the septohippocampal pathways and, 14 days later, received intrahippocampal suspension grafts prepared from the region including the medial septum and the diagonal band of Broca (Group S, n = 11), from the region including the mesencephalic raphe (Group R, n = 11) or from both regions together (Group S+R, n = 11). Sham-operated (Group Sham, n = 9) and lesion-only (Group Les, n = 11) rats served as non-grafted controls. Seven Sham, 7 Les and 8 rats from each transplant group were tested for home cage activity (6 months after grafting) and radial maze performance (between 7.5 and 8.5 months post-grafting). One month after completion of behavioral testing, the dorsal hippocampi of these rats were prepared for measuring choline acetyltransferase (ChAT) activity and high affinity synaptosomal uptake of both [3H]choline and [3H]serotonin. The remaining rats were used for histological verifications on brain sections stained for acetylcholinesterase (AChE). The lesions increased locomotor activity, impaired radial maze learning and, in the dorsal hippocampus, reduced AChE positive staining, decreased ChAT activity (-73%) as well as high affinity uptake of both choline (-81%) and serotonin (-82%). Neither type of transplant produced any significant behavioral recovery. However, septal transplants increased hippocampal AChE positivity, restored ChAT activity and enhanced choline uptake to 116% and 70% of the values found in sham-operated rats, respectively; they had no significant effect on uptake of serotonin. Transplants from the raphe region had weak effects on hippocampal AChE positivity, increased both the ChAT activity and the choline uptake to 70% ad 38% of the sham-operated rats, respectively, and produced an (over)compensation of the serotonin uptake which reached 324% of the values found in sham-operated rats. The co-transplantation of both regions resulted in restoration of ChAT activity (113% of sham-operated rats values), choline uptake (83% of sham-operated rats) and serotonin uptake (129% of sham-operated rats). Our neurochemical data show that after extensive denervation of the hippocampus, intrahippocampal grafts of fetal neurons may foster a neurotransmitter-specific recovery which depends upon the anatomical origin of the grafted cells: a graft rich in serotonergic neurons overcompensates the serotonergic deficit, a graft rich in cholinergic neurons attenuates the cholinergic deficit, whereas a mixture of both types of grafts produces recovery from both types of deficits. Thereby, both the feasibility and the interest of the co-grafting technique are confirmed.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of grafts containing cholinergic and/or serotonergic neurons on cholinergic, serotonergic and noradrenergic markers in the denervated rat hippocampus.

Long-Evans female rats sustained aspirative lesions of the septohippocampal pathways and, 2 weeks later, received intrahippocampal suspension grafts prepared from the regions including either the medial septum and the diagonal band of Broca (group S), or the mesencephalic raphe (group R), or from both these regions together (group S + R). Sham-operated (group SHAM) and lesion-only (group LES) rats were used as controls. Six months after grafting, high affinity synaptosomal uptake of choline (HACU) and serotonin (HASU), choline acetyltransferase (ChAT) activity and, using HPLC, the content of serotonin ([5-HT]), 5-hydroxyindolacetic acid ([5-HIAA]) and noradrenaline ([NA]) were determined in three rostro-caudal segments of the hippocampus (designated hereafter as the dorsal, the 'middle' and the ventral segments). In all three segments of the dorsal hippocampus, septohippocampal lesions decreased HACU, ChAT activity, HASU and [5-HT]; [5-HIAA] was decreased only in the middle and ventral hippocampal segments. The lesions also resulted in an above normal increase of [NA]. Septal grafts increased HACU and ChAT in the three hippocampal regions, had no effect on serotonergic markers and attenuated the lesion-induced increase of [NA] in only the dorsal and middle hippocampal segments. Raphe grafts increased HASU, [5-HT] and [5-HIAA] in the dorsal and middle hippocampal segments, had no effects on cholinergic markers and did not affect the lesion-induced increase of [NA]. Co-grafts increased HACU, ChAT activity, HASU, [5-HT] and [5-HIAA], and attenuated the lesion-induced increase in [NA]. These data demonstrate that grafts of fetal neurons placed into the denervated hippocampus may induce a neurochemical recovery which depends upon the anatomical origin of the grafted cells. They also show that co-grafting allows to combine the neurochemical properties of two fetal brain regions grafted separately. Furthermore, our findings suggest that graft-derived cholinergic reinnervation of the hippocampus prevents the lesion-induced increase of noradrenaline concentration which is likely to result from sympathetic sprouting. Thus, our data confirm the results of a previous experiment carried out at a post-grafting delay of 10-11 months, and show that the graft-induced effects reported previously are already massively present by 6 months after surgery.

Graft-induced learning impairment despite graft-enhanced cholinergic functions in the hippocampus of rats with septohippocampal lesions.

Effects of aspirative fimbria-fornix lesions and intrahippocampal grafts of fetal septal-diagonal band or hippocampal tissue were examined, in Long Evans female rats, on spontaneous alternation, radial maze learning, hippocampal acetylcholine concentrations and [3H]choline accumulation by hippocampal slices. Septohippocampal damage decreased all of these variables. Septal-diagonal band grafts increased hippocampal acetylcholine levels as well as [3H]choline accumulation of tissue (when incubated for 45 min), but they had no effect on alternation rates and further impaired radial maze performances. No such behavioral and neurochemical effects were observed in rats with hippocampal grafts. Our data suggest that factors other than graft-induced improvement of cholinergic functions in the denervated hippocampus may be involved in the expression of behavioral effects by intrahippocampal acetylcholine-rich grafts.

Graft-derived cholinergic reinnervation of the hippocampus prevents a lasting increase of hippocampal noradrenaline concentration induced by septohippocampal damage in rats.

Long-Evans female rats sustained aspirative lesions of the septohippocampal pathways and, 2 weeks later, received into the dorsal hippocampus grafts prepared from the septal area (rich in cholinergic neurons; Group Sep) or from the mesencephalic raphe (poor in cholinergic neurons; Group Rap) of rat fetuses. Lesion-only (Group Les) and virtually intact (Group Sham) rats served as controls. Between 9.5 and 10.5 months after grafting surgery, we found the lesions to decrease choline acetyltransferase activity (ChAT), high affinity synaptosomal uptake of [3H]choline (HACU) and serotonin concentration ([5-HT]), as well as to increase the noradrenaline concentration ([NA]) in the dorsal hippocampus. Raphe grafts increased [5-HT] to 456% of normal, but had only weak or no effects on the other lesion-induced modifications in brain neurochemistry. Septal grafts dramatically increased ChAT activity and HACU, enhanced [5-HT], and reduced [NA] to near-normal levels. We also found a significant negative correlation between HACU and [NA] in rats with lesions, whether grafted or not. These data show that grafts providing the denervated hippocampus with a new cholinergic innervation might be able to exert inhibitory effects on the lesion-induced increase of [NA]. Since such an increase is indicative of sympathetic sprouting, the finding of reduced [NA] in rats with graft-derived cholinergic reinnervation of the hippocampus is in line with the hypothesis that hippocampal cholinergic denervation plays a crucial role in the induction of sympathetic sprouting. However, our data do not allow to distinguish whether grafts rich in cholinergic neurons inhibited the sympathetic sprouting itself, or rather reduced the NA content of sprouted fibers.

Ethanol intoxication fails to affect sprouting induced by entorhinal cortex lesions.

After unilateral entorhinal cortex lesions, acute ethanol exposure (mean daily intake = 16.3 +/- 0.3 g/kg for 15 days) of juvenile rats failed to alter lesion-induced axonal sprouting in the dentate gyrus. The distribution of acetylcholinesterase in the dentate gyrus was identified histochemically as an indicator of axonal sprouting. Comparisons between operated and intact sides were based on qualitative observations and quantitative morphometry techniques using a computerized image analyser to evaluate the widths of the bands of the molecular layer. Whether ethanol-exposed or not, rats with unilateral entorhinal cortex lesions exhibited substantial qualitative and quantitative evidence of axonal sprouting. These results indicate that a 15-day post-operative ethanol exposure had no effect on axonal sprouting in juvenile rats and thus qualify previous findings about ethanol-mediated effects on axonal sprouting.

[A topodiagnostically characteristic visual field defect]. / Ein topodiagnostisch wegweisender Gesichtsfeldausfall.

A 69-year-old female patient presented with unilateral optic nerve atrophy and visual loss. The visual field examination showed not only a subtotal visual field loss in the affected eye but also a visual field defect in the other eye which was classified as an anterior junction syndrome. Cranial MRI revealed a tuberculum sellae meningioma which was treated surgically.

Surgical technique and validation of outcome assessment in sagittal synostosis.

BACKGROUND: Aim of the study was to evaluate the outcome of children operated for sagittal synostosis, with special attention paid to the postoperative aesthetic result, as seen from the parents' and the treating medical doctors' perspective, and to assess the time point for operative correction. METHODS: A retrospective chart review of 87 patients operated over 15 years was performed. Data included age at the time of operation, perioperative complications, duration of hospital stay, intraoperative blood loss, transfusion volume, neurological outcome, and postoperative skull growth. Aesthetic outcome was assessed at 6, 12 and 18 months after surgery separately by the treating medical team and the children's parents. RESULTS: Sagittal synostosis was diagnosed in 98.9% of cases in the first six months of life. We performed the same operative technique in all children with bilateral total removal of parietal bones. The median age at operation was 5 months. There was no correlation between age at the time of operation and blood loss (p<0.602). 5.7% of the children presented with significant postoperative skull asymmetries. All of these children had undergone operation in the first four months of life (p<0.01). The evaluation of the postoperative aesthetic outcome as seen by parents and doctors was highly convergent, with 79.3% of children in the excellent or good outcome group CONCLUSIONS: Our results suggest that the feasible time period for the method used by us is around the 5th - 6th month of life, with satisfying results. With regard to the aesthetic outcome assessment we recommend our approach using validation by parents as a valuable new principle.