Pituitary-adrenal dynamics after ACTH-secreting pituitary tumor resection in patients receiving no steroids post-operatively.

It has recently been suggested that the classical routine of glucocorticoid administration before and after transsphenoidal surgery (TSS) in Cushing's disease (CD) patients may not be necessary, since it is likely that peritumoral normal corticotrophs are not completely suppressed during this period. We compared the dynamics of ACTH and cortisol from a group of CD patients (cured and not cured), receiving no steroids post-operatively, with a control group of acromegalic patients who presented normal hypothalamic-pituitary-adrenal (HPA) axis. Blood samples for ACTH and cortisol determination were obtained immediately before, at the end of surgery and at 4, 8, 12, 16, 24, 48 and 72 h after surgery, in 8 cured CD patients (Group I), 9 not cured CD patients (Group II) and in 7 subjects with acromegaly (Group III) who presented normal HPA axis (control group). The mean ACTH level in Group I was significantly lower than in Group III from 4 to 12 h and lower than in Group II from 8 to 12 h post-operatively. The mean cortisol level in Group I was lower than in Groups II and III from 8 to 72 h after surgery. No difference in mean cortisol level was observed among Groups II and III during the evaluated period. The lowest cortisol value in Group II was 193 nmol/l (at 24 h after surgery) and in Group I patients, after 20 h post-operatively, the highest cortisol level was 165 nmol/l. Although all cured CD patients (Group I) presented serum cortisol level lower than 55 nmol/l until 72 h after surgery, none had significant complications related to adrenal insufficiency. Ours findings are in agreement with recent observations that there is probably no need for glucocorticoid administration until clinical and/or laboratorial data are suggestive of adrenal insufficiency. However, we have also shown that a subphysiological HPA axis response could be observed in cured CD patients after TSS, and a definitive conclusion about glucocorticoid management during and after this procedure could not be made on the ground of the few cases studied in the literature.

Glucocorticoid receptor gene polymorphisms in ACTH-secreting pituitary tumours.

OBJECTIVE: The inhibitory action of glucocorticoids on the hypothalamic-pituitary axis is disrupted in ACTH-secreting pituitary tumours. The molecular events leading to the development of these tumours and their relative resistance to glucocorticoids are unknown. We investigated the presence of mutations and polymorphisms of the glucocorticoid receptor (GR) gene in corticotropinoma and their possible relationship with the tissue-specific resistance to glucocorticoids. DESIGN AND METHODS: DNA or RNA was extracted from 18 corticotropinomas and the GR gene was amplified by the polymerase chain reaction (PCR) or reverse transcriptase-PCR followed by automated direct sequencing. RESULTS: We did not identify any mutation in the coding region and the exon-intron boundary regions of the GR gene. The polymorphism AAT > AGT at codon 363 (N363S) was found in 17% and the polymorphism AAT > AAC at codon 766 (N766N) in 11% of tumours, both in heterozygous state. The polymorphisms at codons 22 and 23, at introns 3 and 4, and at codon 618, previously described in normal population, were not observed. CONCLUSIONS: Our results show that GR gene mutations are rare and unlikely to contribute to the glucocorticoid resistance observed in corticotropinomas. Polymorphisms in the GR gene might confer a selective advantage to tumorigenesis in corticotropinoma. However, there was no relationship between GR gene polymorphism and clinical presentation, tumour size or surgery outcome, suggesting that tumour growth may not be directly related to alterations of the GR gene structure.

Glycosaminoglycan levels and proteoglycan expression are altered in the hippocampus of patients with mesial temporal lobe epilepsy.

Extracellular matrix proteoglycans (PGs) and glycosaminoglycans (GAGs) play a crucial role in cell differentiation and synaptogenesis by modulating neurite outgrowth. The chondroitin sulfate (CS)-rich PG, the receptor protein tyrosine phosphatase zeta/beta (RPTP zeta/beta), has been related to neural morphogenesis and axon guidance. Hippocampal sclerosis is the most frequent pathologic finding in patients with intractable mesial temporal lobe epilepsy (MTLE), which is associated with neuron loss, reactive gliosis, and mossy fiber sprouting. In the present study, we investigated the concentration of CS, heparan sulfate (HS) and hyaluronic acid (HA) in the hippocampus and temporal neocortex as well as RPTP zeta/beta expression in the hippocampus of patients with MTLE. Compared to autopsy control tissue, epileptic hippocampi showed a significantly increased concentration of CS (224%; p=0.0109) and HA (146%; p=0.039). HS was instead similar to control values. No differences were found in the concentration of CS, HS, or HA in the temporal neocortex of epileptic patients when compared to control values. In contrast, RPTP zeta/beta immunoreactivity was induced in astrocytes of the inner molecular layer of the dentate gyrus of the sclerotic hippocampus. Because matrix compounds have been associated with tissue injury and repair, the present findings suggest that changes in PGs and GAGs might be related to damage-induced gliosis and neuronal reorganization in the hippocampus of MTLE patients.

Extracellular matrix components are altered in the hippocampus, cortex, and cerebrospinal fluid of patients with mesial temporal lobe epilepsy.

PURPOSE: This work studied the profile of glycosaminoglycans (GAGs) in the hippocampus, cortex, and cerebrospinal fluid of patients with temporal lobe epilepsy (TLE). METHODS: The GAGs were analyzed by agarose gel electrophoresis, enzymatic degradation, and enzyme-linked immunosorbent assay (ELISA). RESULTS: The hippocampus of TLE patients showed increased levels of chondroitin sulfate and hyaluronic acid against normal levels of these GAGs in the neocortex and cerebrospinal fluid (CSF). CONCLUSIONS: These results suggest that these matrix components could be involved in the pathophysiology of TLE.

Seizure's outcome after cortical resections including the face and tongue rolandic areas in patients with refractory epilepsy and normal MRI submitted to subdural grids' implantation.

PURPOSE: To study the seizure's outcome in patients with refractory epilepsy and normal MRI submitted to resections including the rolandic cortex. METHODS: Four adult patients were studied. All patients had motor or somatosensory simple partial seizures and normal MRI and were submitted to subdural grids' implantation with extensive coverage of the cortical convexity (1 in the non-dominant and 3 in the dominant hemisphere). RESULTS: ECoG was able to define focal areas of seizures' onset in every patient. All patients were submitted to resection of the face and tongue motor and sensitive cortex; two patients had resections including the perirolandic cortex and 2 had additional cortical removals. Three patients are seizures' free and one had a greater then 90% reduction in seizure frequency. CONCLUSION: Resections including the face and tongue rolandic cortex can be safely performed even within the dominant hemisphere.

Results of surgery in patients with refractory extratemporal epilepsy with normal or nonlocalizing magnetic resonance findings investigated with subdural grids.

PURPOSE: To study the efficacy of extensive coverage of the brain surface with subdural grids in defining extratemporal cortical areas amenable for resection in patients with refractory extratemporal epilepy (R-ExTE) and normal or nonlocalizing magnetic resonance imaging (MRI) scans. METHODS: Sixteen patients with R-ExTE were studied. Eleven patients had simple partial, eight had complex partial, and three had supplementary motor area seizures. Seizure frequency ranged from three per month to daily episodes. Interictal EEG showed large focal spiking areas in 11 patients, secondary bilateral synchrony in four, and was normal in one patient. Surface ictal recordings were nonlocalizing in six patients, and in 10, they disclosed large ictal focal spiking areas. MRI was normal in 10 patients, and in six patients, focal nonlocalizing potentially epileptogenic lesions were found. All patients were given an extensive coverage of the cortical convexity with subdural electrodes through large unilateral (n = 13) or bilateral (n = 3) craniotomies. Bipolar cortical stimulation was carried out through the implanted electrodes. RESULTS: Interictal invasive recording findings showed widespread spiking areas in 13 patients and secondary bilateral synchrony in three. Ictal invasive recordings showed focal seizure onset in all patients. There were six frontal, two parietal, one temporooccipital, four rolandic, and three posterior quadrant resections. Thirteen patients had been rendered seizure free after surgery, and three had > or =90% of seizure-frequency reduction. Pathologic findings included gliosis (n = 10), cortical dysplasia (n = 5), or no abnormalities (n = 1). Six patients had transient postoperative neurologic morbidity. CONCLUSIONS: Extensive subdural electrodes coverage seems to be an effective way to investigate patients with R-ExTE and normal or nonlocalizing MRI findings.

Adrenocorticotropin levels do not change during early recovery of transsphenoidal surgery for ACTH-secreting pituitary tumors.

In patients with ACTH-secreting pituitary tumor the peri-tumoral normal corticotrophs were supposed to be suppressed by cronic hypercortisolemia since frequently they develop transient secondary adrenal insufficiency after pituitary tumor resection and during early postoperative days. We evaluated the ACTH dynamics during transsphenoidal surgery in 16 patients with ACTH-secreting pituitary tumors (6 cured by surgery, 8 not cured Cushing's disease patients and 1 cured by surgery and 1 not cured Nelson's syndrome patients) and tested the hypothesis that in these patients, ACTH secretion from the peri-tumoral normal corticotrophs is inhibited and hence removal of the entire tumor should result in subtle postoperative reduction in plasma ACTH. Blood samples for ACTH determination were obtained from 14 Cushing's disease patients immediately before pituitary gland manipulation and 10, 30, 60, 90, 120, 150 and 300 min after pituitary tumor resection and on postoperative day one. In Nelson's syndrome patients the blood sample was obtained only after tumor removal. All patients received intravenous hydrocortisone during surgery and on the first postoperative day. Patients were considered cured by surgery if they presented adrenal insufficiency after hydrocortisone withdrawal. Mechanical pituitary manipulation induced increase in ACTH level. In all 14 Cushing's disease patients (cured and not cured), mean plasma ACTH levels were significantly greater 10 min after pituitary tumor resection (54.4+/-12.8 pmol/l) than in the premanipulation period (ACTH=26.3+/-5.3 pmol/l) (p=0.005). In Cushing's disease patients, the ACTH levels did not change significantly until 300 min after pituitary tumor resection either in those 6 patients cured by surgery (at 10 min after pituitary tumor resection ACTH was 54.4+/-12.8 pmol/l for all 14 Cushing's disease patients and at 300 min after tumor removal ACTH was 39.0+/-12.6 pmol/l for cured and 41.3+/-15.7 pmol/l for not cured Cushing's disease patients). The ACTH level also persisted high until 300 min after complete pituitary tumor resection in one cured patient with Nelson's syndrome. ACTH level does not change in the early recovery period after ACTH-secreting pituitary tumor, even in those cured patients, and probably peri-tumoral normal corticotrophs are not completely suppressed by cronic hypercortisolemia (and acute glucocorticoid administration) when these patients are under intense stress, like transsphenoidal surgery. Mechanical pituitary manipulation may induce ACTH release in patients with ACTH-secreting pituitary tumors but probably does not interfere in the maintenance of high ACTH-levels during the early postoperative period, since ACTH half-life is only 8-15 min. In patients with ACTH-secreting pituitary tumors, the behavior of the human hypothalamic-pituitary-adrenal system during transsphenoidal surgery does not conform to the specifications of a negative feedback mechanism.

Results of surgery in patients with bilateral independent temporal lobe spiking (BITLS) with normal MRI or bilateral mesial temporal sclerosis (MTS) investigated with bilateral subdural grids.

PURPOSE: The introduction of new technologies in the clinical practice have greatly decreased the number of patients submitted to invasive recordings. On the other hand, some patients with refractory temporal lobe epilepsy have normal MR scans or bilateral potentially epileptogenic lesions. This paper reports the results of invasive neurophysiology and surgical outcome in such patients. METHOD: Sixteen patients were studied. Eleven had normal MRI (Group I) and five had bilateral mesial temporal sclerosis (Group II). All patients had BITLS and non-localizatory seizures on video-EEG monitoring. All patients were implanted bilaterally with 32-contacts subdural grids. They were submitted to a cortico-amygdalo-total hippocampectomy at the side defined by chronic electrocorticography (ECoG). RESULTS: In Group I, seizures came from a single side in nine patients. In nine patients, seizures started at one side, spread to the ipsolateral contacts and contralaterally afterwards. On the other hand, in two Group I patients seizures started in one mesial region and spread to the contralateral parahippocampus and neocortex before spreading to ipsolateral contacts. All patients in Group II had seizures starting unilaterally with focal EcoG onset in the mesial regions. Eight Group I patients are seizure-free and three are in Engel's class II. Eighty percent of Group II patients are seizure-free after surgery and one patient is in Engel's class II. CONCLUSION: Good surgical results can be obtained in patients with BITLS. Patients with normal MRI seem to have a worse prognosis when compared to patients with unilateral or even bilateral MTS. Extensive subdural coverage is essential in patients with normal MRI.

Paradigms for subdural grids' implantation in patients with refractory epilepsy.

RATIONALE: The need for invasive monitoring in patients with refractory epilepsy has been greatly reduced by the introduction of new technologies such as PET, SPECT and MRI in the clinical practice. On the other hand, 10 to 30% of the patients with refractory epilepsy have non-localizatory non-invasive preoperative work-up results. This paper reports on the paradigms for subdural electrodes implantation in patients with different refractory epileptic syndromes. METHODS: Twenty-nine adult refractory epileptic patients were studied. Patients were divided into five different epileptic syndromes that represented the majority of the patients who needed invasive recordings: bitemporal (Group I; n=16 ), bi-frontal-mesial (Group II, n=5), hemispheric (Group III; n=2), anterior quadrant (Group IV; n=3) and posterior quadrant (Group V; n=3). All of them were submitted to extensive subdural electrodes' implantation (from 64 to 160 contacts) covering all the cortical surface potentially involved in epileptogenesis under general anesthesia. RESULTS: All patients tolerated well the procedure. There was no sign or symptom of intracranial hypertension except for headache in 22 patients. In all except one Group II patient, prolonged electrocorticographic monitoring using the described subdural cortical coverage patterns was able to define a focal area amenable for resection. In all Groups II-V patients cortical stimulation was able to adequately map the rolandic and speach areas as necessary. CONCLUSION: Despite recent technological advances invasive neurophysiological studies are still necessary in some patients with refractory epilepsy. The standardization of the paradigms for subdural implantation coupled to the study of homogeneous patients' populations as defined by MRI will certainly lead to a better understanding of the pathophysiology involved in such cases and an improved surgical outcome.

[Quality of life of patients after epilepsy surgery]. / Qualidade de vida de pacientes submetidos a cirurgia de epilepsia.

Drug resistant epilepsy impairs patients' quality of life making social interaction more difficult. Surgical treatment is an option for seizure control in medically refractory patients. We evaluated pre-operative and post-operative quality of life using a standardized questionnaire based on the QOLIE-10. The questionnaire included ten questions dealing with psychosocial and drug's side effects and was applied before surgery and eight months post-operatively. The studied sample comprised twelve consecutive adult patients with epilepsy treated surgically who were seizure free. Differences were found between the pre-operative and post-operative periods in 70% of the questions, with a better post-operative profile. Successful epilepsy surgery has a great impact in the quality of life of these patients.

[Subclinical apoplexy in pituitary tumors]. / Apoplexia subclínica em tumores pituitários.

Acute pituitary apoplexy is a rare event, even in patients with pituitary macroadenomas. On the other hand, the presence of necrotic/hemorrhagic areas, especially in macroadenomas, seems to be more common than earlier reported in the CT period. After the introduction of MR in the presurgical workup of these patients, these apopleptic areas have been more easily diagnosed preoperatively. Forty consecutive patients with pituitary macroadenomas were studied with high-resolution 1.5 T T1 coronal, sagittal and axial slices over the sellar region. Special attention was paid in the detection of necrotic, cystic and hemorrhagic areas within these tumors. Ten patients had hemorrhagic/necrotic areas within their tumors, without any sign or symptom of acute apoplexy. These areas varied from small (2 mm) to very large (30 mm) ones. Seven patients had non-secreting tumors, 2 GH and 1 prolactin secreting tumors, which is the same profile of secretory pattern for the whole series (40 patients). The clinical picture included (other than that caused by endocrine secretion) slowly progressive (but not acute) visual loss (n = 8) and headache (n = 3). After surgical decompression of the surrounding structures and visual apparatus, which was facilitated by the presence of the necrotic areas, there was visual improvement in 6 patients and headache resolution in 2. The presence of asymptomatic apopletic areas in these macroadenomas and their absence in microadenomas as can be seen in the literature suggest that they are related more to the size of the tumor than to its endocrine secretion pattern. This is in agreement with a vascular insufficiency hypothesis in the pathogenesis of these lesions.

Secondary bilateral synchrony due to fronto-mesial lesions. An invasive recording study.

Frontal lobe epilepsies may present difficulties in focus localization in the pre-operative work-up for epilepsy surgery. This is specially true in patients with normal MRIs. We report on a 16 years-old girl that started with seizures by the age of 8 years. They were brief nocturnal episodes with automatisms such as bicycling and boxing. Seizure frequency ranged from 4-10 per night. Scalp EEG showed few right frontal convexity spiking and intense secondary bilateral synchrony (SBS). High resolution MRI directed to the frontal lobes was normal. Ictal SPECT suggested a right fronto-lateral focus. Ictal video-EEG showed no focal onset. She was submitted to invasive recordings after subdural plates implantation. Electrodes covered all the frontal convexity and mesial surface bilaterally. Ictal recordings disclosed stereotyped seizures starting from the right mesial frontal. Using a high-resolution tool to measure intra and interhemispheric latencies, the timing and direction of seizure spread from the right fronto-mesial region were studied. Motor strip mapping was performed by means of electrical stimulation. She was submitted to a right frontal lobe resection, 1.5 cm ahead of the motor strip and has been seizure free since surgery (8 months). Pathological examination found a 4 mm area of cortical dysplasia. Invasive studies are needed to allow adequate localization in patients with non-localizatory non-invasive work-up and may lead to excellent results in relation to seizures after surgery.

[Identical twins discordant for Cushing's disease: case report[]. / Gêmeas idênticas discordantes para a doença de Cushing. Relato de caso.

Cushing's disease is rare in children and its occurrence in identical twins is extremely rare. This paper reports on identical twins discordant for Cushing's disease. One of them first presented with a cushingoid phenotype by the age of 10. Her evaluation showed an increased urinary free-cortisol and serum ACTH. Her pattern in the dexametazone suppression tests was compatible with Cushing's disease. MRI disclosed a pituitary macroadenoma which was removed by the transesphenoidal approach. Immunohistochemical studies of the tumor showed the presence of ACTH-producing cells. The patient went into clinical and laboratorial remission after surgery. She re-started to grow after the disappearance of the Cushing's phenotype but she is still shorter than her healthy sister. The latter remains disease-free 4 years after her sister's diagnosis. This represents the third such case reported in the literature. Our findings suggest that acquired factors may be responsible for the genesis of Cushing's disease.

[Pituitary apoplexy followed by endocrine remission. Report of two cases]. / Apoplexia pituitária seguida de remissão endócrina. Relato de dois casos.

Pituitary apoplexy is rare and endocrine remission in patients with apopletic secreting pituitary adenomas is even rarer. This study reports on two patients with pituitary macroadenomas (one with Cushing's disease and the other with acromegaly) in whom endocrine remission occurred after apoplexy. The first patient had Cushing's disease and had an ictus of headache and vomiting after which she started a progressive remission of hypercortisolism. A post-apoplexy MRI disclosed persistence of a sellar and supra-sellar mass. She was submitted to transesphenoidal surgery. An hypertensive hemorrhagic cyst was found with no tumor. The second patient had acromegaly. While performing a LHRH-stimulation test he had an ictus of headache, vomiting, no visual loss and appearance of diabetes insipidus. A CT scan disclosed an intrasellar hematoma. Despite the size of the tumor and since there was no visual impairment, this patient was followed up without surgery. Imaging follow-up showed a progressive shrinkage and disappearance of the mass, which was corroborated by endocrine remission. A high rate of recurrence is reported in such patients in the literature. Both patients are being currently followed-up on a long-term basis.

Cavernous sinus invasion by pituitary macroadenomas. Neuroradiological, clinical and surgical correlation.

The classical imaging gold-standard for this diagnosis is the presence of tumor lateral to the carotid artery. Seventeen patients with pituitary macroadenomas with intraoperative confirmation of cavernous sinus invasion were studied with MRI. Only 8 patients had tumor lateral to the carotid artery; 13 had tumor within the carotid syphon and all lacked the ring enhancement of the medial wall of the cavernous sinus. In 10 patients, widening of the posterior double leaflets of the cavernous sinus could be. All patients were operated by the transesphenoidal route. Only one patient was cured by surgery alone. Only 3 patients disclosing the above mentioned MRI features were identified in a series of 250 patients and did not have cavernous sinus invasion. The present criteria proved to be useful in the pre-operative diagnosis of cavernous sinus invasion and patients' counselling. Pre-operative diagnosis of cavernous sinus invasion of pituitary tumors has a great impact in the management of such patients.

Insular epilepsy. Similarities to temporal lobe epilepsy. Case report.

Insular epilepsy has been rarely reported and its clinical and electrographic features are poorly understood. The electrographic study of the insula is difficult since it is hidden from the brain surface by the frontal and temporal lobe. A 48 years-old woman started having simple partial autonomic and complex partial seizures with automatisms and ictal left arm paresis 8 years prior to admission. Seizure's frequency was 1 per week. Pre-operative EEG showed a right temporal lobe focus. Neuropsychological testing disclosed right fronto-temporal dysfunction. MRI showed a right anterior insular cavernous angioma. Intraoperative ECoG obtained after splitting of the sylvian fissure showed independent spiking from the insula and temporal lobe and insular spikes that spread to the temporal lobe. The cavernous angioma and the surrounding gliotic tissue were removed and the temporal lobe was left in place. Post-resection ECoG still disclosed independent temporal and insular spiking with a lower frequency. The patient has been seizure-free since surgery. Insular epilepsy may share many clinical and electroencephalographic features with temporal lobe epilepsy.

Somatotrophic and corticotrophic function outcome after transesphenoidal surgery in patients with sellar tumors and pre-operative endocrine deficits.

Sixteen patients with sellar tumors that were treated surgically and who had pre-operative somatotrophic and corticotrophic function deficits were submitted to pre- and early post-operative insulin tolerance tests (ITTs). Seven patients had non-functioning adenomas, 5 had prolactinomas, 3 had craniopharyngioma and 1 had cordoma of the clivus. All patients had macro-tumors and none received radiotherapy within the studied period. Seven patients had GH, 4 had cortisol and 5 had both GH/cortisol function pre-operative deficit. Five patients with isolated GH, 4 with isolated cortisol and 3 with both GH/cortisol deficiencies showed a postoperative functional recovery. New cortisol secretion deficits were observed in 2 patients postoperatively and both required long-term steroid replacement. These data suggest that preoperative endocrine deficits may be reversible after surgical decompression of the sellar region and that new endocrine deficits are rarely seen after surgery. All such patients should be tested postoperatively from an endocrinological point of view to reevaluate the need for replacement therapies.

Unilateral mesial temporal atrophy after a systemic insult as a possible etiology of refractory temporal lobe epilepsy. Case report.

Mesial temporal sclerosis is the main pathological substrate present in refractory temporal lobe epilepsy and its presence is often related to the occurrence of febrile seizures in infancy. There is an on-going discussion on the nature of mesial temporal sclerosis as it related to epilepsy: cause or consequence. A previously normal child developed hyperosmolar coma after abdominal surgery at the age of 6. Three months afterwards he developed simple and complex partial seizures with an increasing frequency and refractory to multiple mono- and polytherapic drug regimens. He was evaluated for surgery at the age of 13. Ictal and interictal recordings showed left temporal lobe abnormalities. Early CT scanning suggested left temporal atrophy. MRI showed mesial temporal sclerosis. Neuropsychological testing showed verbal memory deficits and he passed a left carotid artery amytal injection. He was submitted to a cortico-amygdalo-hippocampectomy and has been seizure-free since then. The clinical data obtained from this patient suggest that at least in this case mesial temporal sclerosis would be related to the cause of epilepsy and not resultant from repeated seizure activity.

Monoamines and their metabolites in cerebrospinal fluid and temporal cortex of epileptic patients.

The involvement of monoamines in the initiation or maintenance of epileptic phenomena has been extensively studied in cerebral tissues and in cerebrospinal fluid. The present work was undertaken to study monoamines and their metabolites in human spiking and non-spiking temporal cortex excised from patients with complex partial seizures unresponsive to available anticonvulsants. The same substances were also analyzed by HPLC-ED in cerebrospinal fluid obtained 24 h before the surgical procedure and compared with those from patients with chronic headache and normal neurological evaluation. The results show increased 5-HT, 5-HIAA and HVA levels in spiking compared with non-spiking cortex. Cerebrospinal fluid levels of 5-HIAA and HVA are concomitantly increased in epileptic compared with headache patients.