Pathological assessment of epilepsy surgery brain tissue.

Surgical resection represents a successful strategy to achieve seizure control in patients with drug resistant epilepsy. In the last years increasing importance has been recognized to pathological substrate for epilepsy classifications and for predicting seizure and neuropsychological outcome after surgery. The current histopathological classifications of epilepsy-associated abnormalities certainly represent an amazing effort to overcome the limits of the previous classifications and constitute a formidable tool in the management of patients after epilepsy surgery. However the correct application of the recent ILAE classification systems begins with a proper epilepsy surgery technique, able to provide "en bloc" and "spatially oriented" surgical specimens and continues with the use of an appropriate pathological workup and reproducible stains. This methodological approach permits to relate the surgical outcome to the specific pathological findings, the site of the lesion, and the surgical strategy. These data are essential to an adequate preoperative patient and family counselling. Furthermore in this paper, besides the workup and the classification systems, we evidence some aspects which may be challenging and sometime misleading in clinical practice. In conclusion, a pathology based approach to epilepsy surgery is essential and might improve the interpretation of the outcomes and the comprehension of the causes of failures.

Focal epilepsies associated with glioneuronal tumors: review article.

Glioneuronal tumors (GNTs) are an increasingly recognized cause of focal epilepsies, particularly in children and young adults. GNTs consist of a mixture of glial and neuronal elements and most commonly arise in the temporal lobe, particularly in the temporo-anterior-basal mesial site. They are often associated with cortical dysplasia or other neuronal migration abnormalities. Epilepsy associated with GNT is poorly controlled by antiepileptic drugs in many cases; but, it is extremely responsive to surgical treatment. However, the best management strategy of tumor-related focal epilepsies remains controversial and still remain one of the contemporary issues in epilepsy surgery. Temporo-mesial GNT are associated with a widespread epileptic network, defining, therefore, a distinct anatomo-clinico-pathological group with complex epileptogenic mechanisms. By using an epilepsy surgery oriented strategy GNT associated with focal epilepsies may have an excellent seizure outcome and, therefore, surgical treatment can be offered early to avoid both the consequences of uncontrolled seizures as well as the side effects of prolonged pharmacological therapy and the rare risk of tumor growth or malignant transformation.

MRI findings in low grade tumours associated with focal cortical dysplasia.

Magnetic resonance imaging (MRI) is mandatory to identify the epileptogenic zone in refractory temporal lobe epilepsy (TLE). The correct identification of lesions is essential to obtain good post-surgery seizure control. Low grade tumours (LGT) and focal cortical dysplasia (FCD) are common findings in symptomatic TLE, and frequently coexist. The aim of this study was to identify the MRI characteristics in the diagnosis of FCD associated with LGT. We analyzed 24 subjects with TLE who underwent tailored surgery. They all had LGTs. Two expert neuroradiologists analyzed the imaging data and compared them with histological results, hypothesizing the causes of diagnostic errors in the identification of FCD. We selected three exemplary cases to report the most important causes of errors. In the diagnosis of FCD we reported false positives and false negatives due to different causes. An incomplete MRI protocol, the large dimensions of the tumour, infiltration and related oedema were the most important factors limiting MRI accuracy. MRI can be limited by an incomplete protocol. In addition, the presence of an LGT may limit the neuroradiological diagnosis of FCD in the temporal lobe. Advanced MRI techniques could help reveal subtle lesions that eluded a previous imaging inspection.

Ex vivo study of dentate gyrus neurogenesis in human pharmacoresistant temporal lobe epilepsy.

AIMS: Neurogenesis in adult humans occurs in at least two areas of the brain, the subventricular zone of the telencephalon and the subgranular layer of the dentate gyrus in the hippocampal formation. We studied dentate gyrus subgranular layer neurogenesis in patients subjected to tailored antero-mesial temporal resection including amygdalohippocampectomy due to pharmacoresistant temporal lobe epilepsy (TLE) using the in vitro neurosphere assay. METHODS: Sixteen patients were enrolled in the study; mesial temporal sclerosis (MTS) was present in eight patients. Neurogenesis was investigated by ex vivo neurosphere expansion in the presence of mitogens (epidermal growth factor + basic fibroblast growth factor) and spontaneous differentiation after mitogen withdrawal. Growth factor synthesis was investigated by qRT-PCR in neurospheres. RESULTS: We demonstrate that in vitro proliferation of cells derived from dentate gyrus of TLE patients is dependent on disease duration. Moreover, the presence of MTS impairs proliferation. As long as in vitro proliferation occurs, neurogenesis is maintained, and cells expressing a mature neurone phenotype (TuJ1, MAP2, GAD) are spontaneously formed after mitogen withdrawal. Finally, formed neurospheres express mRNAs encoding for growth (vascular endothelial growth factor) as well as neurotrophic factors (brain-derived neurotrophic factor, ciliary neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor). CONCLUSION: We demonstrated that residual neurogenesis in the subgranular layer of the dentate gyrus in TLE is dependent on diseases duration and absent in MTS.

Role of dentate gyrus alterations in mesial temporal sclerosis.

Drug-resistant chronic temporal lobe epilepsy is the most common type of epilepsy that undergoes surgical treatment. To verify if dentate gyrus alterations may play a role in patients with mesial temporal sclerosis (MTS), 14 patients, submitted to epilepsy surgery, were selected. Only cases with MTS alone were included. Granule cell dispersion (GCD) was observed in 7 cases (50%). A statistically significant correlation between GCD and the mean number of seizures/month was evidenced. The percentage of patients who did not achieve seizure relief (i.e. they were not in Engel class 1A) was 57.14% in patients without GCD, whereas that percentage dropped to 14.29% in patients with GCD. The association between a more favorable postsurgical epileptogenic outcome and granule cell pathology in patients with MTS has been observed, thus suggesting that dentate gyrus alterations may play a role in drug-resistant TLE.

Quantitative assessment of cerebral autoregulation from transcranial Doppler pulsatility: a computer simulation study.

Transcranial Doppler (TCD) ultrasonography is largely used today to achieve non-invasive assessment of cerebral autoregulation and cerebrovascular reactivity in neurosurgical patients. Recent experimental and clinical studies suggest that not only the pattern of mean velocity, but also velocity pulse amplitude alterations during changes in cerebral perfusion pressure (CPP) contain information on autoregulation status. The aim of this work is to investigate the relationship between cerebral autoregulation and TCD pulsatility by means of a comprehensive mathematical model of intracranial dynamics and cerebrovascular regulation. Simulation results, performed using different values of the most important clinical parameters of the model (autoregulation strength, cerebrospinal fluid (CSF) outflow resistance and intracranial elastance coefficient) show that velocity pulse amplitude increases with a reduction in CPP in patients with intact autoregulation, whereas changes in velocity pulsatility are modest in patients with weak autoregulation. Finally, velocity pulse amplitude decreases during a CPP reduction in patients with impaired autoregulation. Moreover, the relationship between the velocity pulse amplitude changes and autoregulation strength is almost linear in a wide range of CPP values, and is scarcely affected by changes in CSF circulation and intracranial elasticity. Starting from these results, we suggest a new quantitative index to assess autoregulation strength, i.e. G(aut)% = (s-b)/a, where G(aut)% is autoregulation strength (100% means intact autoregulation, 0% means impaired autoregulation), a approximately -0.03; b approximately 1.5 and s is the slope of the relationship ' percentage changes of velocity pulse amplitude to arterial pressure pulse amplitude vs. CPP changes'.

Relationships among cerebral perfusion pressure, autoregulation, and transcranial Doppler waveform: a modeling study.

OBJECT: The aim of this study was to analyze how the main values extrapolated from the transcranial Doppler (TCD) waveform (systolic, mean, and diastolic velocity; velocity peak-to-peak amplitude; and pulsatility index [PI]) are affected by changes in intracranial pressure (ICP), systemic arterial pressure (SAP), autoregulation, and intracranial compliance. METHODS: The analysis was performed using a mathematical model of the intracranial dynamics. This model includes a passive middle cerebral artery, the biomechanics of large and small pial arteries subjected to autoregulatory mechanisms, a collapsing venous cerebrovascular bed, the cerebrospinal fluid circulation, and the ICP-volume relationship. The results indicate that there are approximately three distinct zones characterized by different relationships between cerebral perfusion pressure (CPP) and velocity parameters in patients with preserved autoregulation. In the central autoregulatory zone (CPP > 70 mm Hg) the mean velocity does not change with decreasing CPP, whereas the PI and velocity peak-to-peak amplitude increase moderately. In a second zone (CPP between 4045 and 70 mm Hg), in which vasodilation of small pial arteries becomes maximal, the mean velocity starts to decrease, whereas the PI and velocity amplitude continue to increase. In the third zone, in which autoregulation is completely exhausted (CPP < 40 mm Hg), arterioles behave passively, mean velocity and velocity amplitude decline abruptly, and the PI exhibits a disproportionate rise. Moreover, this rise is quite independent of whether CPP is reduced by increasing ICP or reducing mean SAP. In contrast, in patients with defective autoregulation, the mean velocity and velocity amplitude decrease linearly with decreasing CPP, but the PI still increases in a way similar to that observed in patients with preserved autoregulation. CONCLUSIONS: The information contained in the TCD waveform is affected by many factors, including ICP, SAP, autoregulation. and intracranial compliance. Model results indicate that only a comparative analysis of the concomitant changes in ultrasonographic quantities during multimodality monitoring may permit the assessment of several aspects of intracranial dynamics (cerebral blood flow changes, vascular pulsatility, ICP changes, intracranial compliance, CPP, and autoregulation).

A phase II study of interferon alpha and low-dose subcutaneous interleukin-2 in advanced renal cell carcinoma.

The activity of the drugs employed in the treatment of metastatic renal cell carcinoma, including biological response modifiers, is limited; one of the aims of clinical research in this area is to maintain the benefits of treatment whilst reducing its toxicity to a minimum level. We have evaluated toxicity and response of the combined administration of recombinant interferon alpha (IFN alpha) and low-dose subcutaneous (s.c.) recombinant interleukin-2 (IL-2) in patients with advanced renal cell carcinoma. A group of 20 previously untreated patients with advanced renal cell carcinoma were included in the study. Treatment consisted of 3 MU/m2 recombinant IFN alpha daily i.m. continuously, and 0.5 MU/m2 recombinant IL-2 twice a day s.c. on days 1-5 for the first week, followed by 1 MU/m2 twice a day for 5 days in the following weeks. For IL-2, a 1-week rest was allowed after 4 weeks of treatment. Response was assessed after 3 months of therapy. Three objective responses were seen, one complete and two partial. Eight patients had stable disease. The median time to progression was 6 months; the median survival for all patients was 14 months. Side-effects were low, limited to grades 1 and 2 in the majority of patients, and included fever, anemia, leukopenia, dyspnea, and abnormalities of liver and renal function tests. Any flu-like syndrome was judged moderate in most patients; however, one-third of the patients refused treatment mostly because of the flu-like syndrome. One of these was the patient experiencing a complete response, who virtually received IFN alpha alone. This regimen, similar to others employed in the treatment of advanced renal cell carcinoma, produced a 15% response rate (95% confidence interval, 0-31%) with 14 months median survival, moderate toxicity and low cost, and required no hospitalization. These data seem to indicate an effectiveness comparable to, and a toxicity lower than, that of regimens employing higher doses of IL-2.

Cavernous angiomas of the spinal district: surgical treatment of 11 patients.

Cavernous angiomas, also called cavernous malformations or cavernomas, are vascular hamartomas accounting for 3-16% of all angiomatous lesions of the spinal district. Although histologically identical, these vascular anomalies may exhibit different clinical behavior and radiological features, depending on their location, hinting at different managements and therapeutic approaches. The authors report 11 cases of symptomatic spinal cavernous angiomas diagnosed and surgically treated over the past 18 years. Age of patients ranged from 15-75 years; males outnumbered females. Three patients had vertebral cavernous malformations, secondarily invading the epidural space; two had pure epidural lesions; two patients had intradural extramedullary lesions, and four intramedullary lesions. Surgical removal was completely achieved in four patients with intramedullary lesions, in two with subdural extramedullary lesions, and in one with a pure epidural lesion. Subtotal excision of another one epidural and three vertebral cavernous angiomas was followed by radiotherapy. There was no morbidity related to surgery; the mean follow-up was 2 years. The outcome was excellent in two cases, good in six, and unchanged in the other three. The authors discuss the different modalities of treatment of these vascular lesions variously placed along the spine.

Impact of cerebral perfusion pressure and autoregulation on intracranial dynamics: a modeling study.

OBJECTIVE: The aim of this work was to study the impact of acute cerebral perfusion pressure (CPP) changes and autoregulation on cerebral hemodynamics, intracranial pressure (ICP), and estimation of the pressure-volume index (PVI) and the possible involvement of these factors in the development of secondary brain damage. METHODS: The study was performed by using a mathematical model of intracranial hemodynamics and cerebrospinal fluid (CSF) dynamics. The model includes the biomechanics of proximal and distal arterial intracranial vessels, cerebral veins, and CSF circulation, the intracranial pressure-volume relationship, and the action of autoregulation mechanisms on proximal and distal vessels. RESULTS: In the case of normal intracranial dynamics, lowering mean systemic arterial pressure (SAP) in the range of 100 to 60 mm Hg causes only a mild ICP increase (+1-2 mm Hg). In contrast, in the case of severe impairment of intracranial dynamics (reductions in CSF outflow and storage capacity), even a modest mean SAP decrease (from 100 to 90 mm Hg) may induce a transient abrupt ICP rise (+30-40 mm Hg), because of the presence of a vicious cycle among CPP, cerebral blood volume, and ICP. In the case of intact autoregulation, PVI shows a mild positive correlation with SAP in the central autoregulation range and a strongly negative correlation below the autoregulation lower limit. In the case of impaired autoregulation, PVI exhibits higher values than in the regulated case, with a mild negative correlation with SAP. CONCLUSION: The present study emphasizes the relevant role of CPP changes, elicited by acute arterial hypotension, in intracranial dynamics. To achieve intracranial stability, CPP should be maintained above 80 to 90 mm Hg. PVI is significantly affected by the active response of cerebral vessels. Hence, it may provide misleading information on craniospinal capacity if it is considered as an autonomous index: rather, it should always be considered together with information on CPP and the status of autoregulation.

Orbital cavernous angiomas: surgical experience on a series of 13 cases.

Cavernous angiomas of the orbit are benign vascular growths, commonly occurring in adults and usually causing a slowly progressive proptosis from their mass effect. These lesions have behavioural and radiological findings different from those of brain cavernous angiomas, probably due to their particular origin and structure. The authors present a surgical series of 13 patients with orbital cavernous angiomas. Complete excision of lesions, with histological diagnosis, was obtained in all the 13 cases. Results were good in 10 patients, while 2 remained clinically unchanged and another one showed acute visual deterioration after a period of postoperative clinical stabilization. The main clinical and radiological characteristics of orbital cavernous angiomas are analyzed, together with their surgical management.

Results of surgery in children with cerebral cavernous angiomas causing epilepsy.

Epilepsy is the most frequent presenting symptom of cerebral cavernous angiomas or cavernomas, and surgical removal of these vascular malformations is considered the treatment of choice in patients with intractable or long-standing seizures, or in those with poor compliance to medical therapy. In this paper the results of surgical treatment in 11 children with seizures from cerebral cavernomas are reported. Surgery for deep-seated cavernomas was aided in 3 cases by a stereotactic localization technique, that allowed a limited approach with minimal brain damage. Major morbidity and mortality were absent; follow-up ranged between 1 to 16 years. Improved seizure control was seen in all the patients: eight (72%) became seizure-free with the same preoperative therapy; one became seizure-free with a lower drug dosage, and two (18%) were seizure-free without medical therapy. The removal of cavernomas prevented the risk of haemorrhages or further deficits from growth and, above all, avoided spreading and autonomization of the epileptogenic area induced by the cavernoma.

Surgical management of cerebral cavernous angiomas causing epilepsy.

Epilepsy is the most frequent presenting symptom in patients with cerebral cavernous angiomas. Surgical removal of these vascular malformations causing epilepsy is usually recommended for patients with disabling, intractable seizures, while conservative management is indicated for neurologically intact patients with well controlled seizures. In this paper is reported a retrospective series of 36 patients suffering epilepsy from cerebral cavernous angiomas, and admitted at our Institution between 1975 and 1992. All patients were surgically treated; mortality and morbility were absent. The mean follow-up period was 5.9 years, since the 36 patients were alive and available for a control review in December, 1993. Seizure outcome of the patients resulted in a complete cure of the epileptic disorders in 9 (25%), improved seizure control with decreased medication in other 11 (30.5%), and epilepsy control with the same preoperative therapy in the remaining 16 (44.5%) patients. Furthermore, patients with preoperative neurological signs associated to epilepsy resulted improved. The authors conclude that surgery, where it is unlikely to cause neurological deficits, may allow a definitive cure of epilepsy in patients with cerebral cavernous angiomas, preventing the possible risks from hemorrhage and mass effect.

Surgical management of cavernous angiomas in children.

Cavernous angiomas are vascular malformations affecting any part of the central nervous system (CNS). The management of asymptomatic cavernous angiomas is still debated due to their poorly understood natural history, although more data are now available regarding results of surgical treatment in symptomatic cases. The authors report their surgical experience with 18 pediatric patients operated on for symptomatic CNS cavernous angiomas. The children ranged in age from 10 months to 17 years, without a relevant sex difference. Cavernous angiomas were intracranial in 17 cases: 15 being in the supratentorial compartments and two in the cerebellum. Clinical manifestations were as follows: seizures in 11 cases, focal neurologic deficits in five, and headache in one. The 18th case was observed in a girl showing paraparesis in the spinal subdural-extramedullary space at T8-T9 level. Excision of four deep cerebral lesions was performed after stereotactic localization through non-eloquent cortex. Pathologic confirmation of cavernous angiomas was obtained in all patients. Mortality from surgical procedures was absent in this series. The follow-up period ranged from 1 to 16 years. All 11 epileptic patients obtained seizure control; improvement or stabilization of neurologic symptoms was observed in the remaining seven patients.

Cerebral astrocytoma and cavernous angioma: a case report.

The authors report a case of cerebral astrocytoma associated with a cavernous angioma. The patient presented with seizures and progressive hemiparesis. Diagnostic studies suggested the presence of a cavernous malformation with signs of previous haemorrhage. Surgery disclosed a complex tumour, which on histological examination revealed to be an anaplastic astrocytoma associated with a cavernous angioma.

Surgical treatment of spinal cavernous angiomas.

Cavernous angiomas are vascular malformations that can occur in several compartments of the spine. Depending on their location, these lesions present particular clinico-diagnostic findings, and may require different modalities of treatment. The authors report a series of 10 patients with vertebral, epidural, subdural extra- and intramedullary cavernous angiomas. Clinical and radiological features, as well as surgical results of this series are presented. The different modalities of surgical treatment of cavernous angiomas variously placed along the spine are discussed.

[Surgical and radiologic treatment of cancer of the uterine body. Results of 12 years]. / Il trattamento radiochirurgico del cancro del corpo dell'utero. Risultati di 12 anni.

Findings were reviewed of 518 female patients with carcinoma of the body of the uterus treated and followed up during the 12 year period 1970-1982. For the patients treated with total hysterectomy and bilateral salpingo-oophorectomy followed by postoperative radiation therapy, the five-year overall survival was 88% for stage I histologic grade G1, as compared with 73% for stage I grade G2 + G3 and 48% for stages II + III. The survival rates were also analyzed in terms of myometrial infiltration. The rates of pelvic and paraaortic nodal metastases were analyzed; these observations suggested that routine postoperative radiotherapy should be considered.

Intracranial and orbital cavernous angiomas: a review of 74 surgical cases.

We present a surgical series of 74 patients (30 males and 44 females) with pathologically verified cavernous angiomas of the intracranial and orbital compartments. Patients were admitted between 1975 and 1991; six had a family history of cerebral cavernomas, and two had multiple (two) lesions. The 76 malformations were located as follows: 57 were in the cerebral hemispheres, four in the supratentorial ventricles, one was in the middle cranial fossa, two were in the brain stem, five in the cerebellum and seven in the orbits. Seizures and focal neurological deficits, and decrease of visual acuity with exophthalmus, were the main clinical signs observed in patients with intracranial and orbital cavernomas, respectively. Sixteen patients (21.6%) had a clinically significant haemorrhage attributable to the cavernous angioma. A number of these vascular malformations were misdiagnosed by computed tomography. In the last 10 years magnetic resonance imaging has been the most sensitive method for detecting these lesions. Seventy-four of the 76 diagnosed cavernomas were treated surgically: a complete excision was obtained in 68 patients; in two patients with multiple lesions only those causing symptoms were removed. Surgery for the 10 deep lesions was aided considerably by stereotactic localization. Two patients died in the immediate postoperative course. The overall outcome was good in 66 of the 72 remaining patients, resulting in improved seizure control or lessened neurological deficit.

Intracranial squamous cell carcinoma arising in an epidermoid cyst.

Intracranial epidermoid cysts are uncommon benign tumors of developmental origin; malignant transformation is extremely rare. We report a case of squamous cell carcinoma arising in a chiasmatic-parasellar epidermoid cyst. Malignant change had not been suspected until histological examination revealed it.