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.

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.

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.

Correlations among intracranial pulsatility, intracranial hemodynamics, and transcranial Doppler wave form: literature review and hypothesis for future studies.

In the present work, the major correlations among cerebrospinal fluid (CSF) pulsatility, cerebral hemodynamic changes, the action of mechanisms regulating cerebral blood flow and cerebral blood volume, and the main aspects of the intracranial basal artery transcranial Doppler wave form are critically examined. CSF pulsatility is a consequence of rigidity of the craniospinal compartment and the pulsating changes in cerebral blood volume. At low and medium intracranial pressures (ICPs), changes in CSF pulsatility are mainly the result of changes in craniospinal elastance. During severe intracranial hypertension, however, CSF pulse pressure reflects an abrupt increase in cerebrovascular (i.e., cerebral vessel) compliance. The mechanisms controlling cerebral blood flow and cerebral blood volume affect CSF pulsatility through both an alteration in craniospinal blood volume and a change in vascular wall pulsatility. Examination of the main parameters of the Doppler velocity pattern (maximal systolic blood velocity, diastolic blood velocity, and peak to peak pulsatility index) in cerebral basal arteries reveals a significant alteration in the velocity wave form during severe ICP increase (above 60 mm Hg). During moderate ICP increase, when cerebral regulatory mechanisms are effective, the Doppler velocity pattern is not significantly affected by ICP changes.

Long-term results of surgically treated congenital intradural spinal arachnoid cysts.

The authors report long-term results in 17 patients with surgically treated congenital intradural spinal arachnoid cysts. Comparison between the immediate and long-term results demonstrates that surgical removal of the cyst allowed a significant neurological improvement in all cases, but clinical worsening of various degrees was observed later. The authors attempt to explain the results in terms of mechanical and vascular factors.

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).

Cervical spine changes following laminectomy. Clinico-radiological study.

The authors performed follow-up examinations on 84 patients who had undergone cervical laminectomy in order to relieve the pressure caused by tumors, malformations, leptomeningeal cysts and spondylarthrosis. In an attempt to quantify the post-laminectomy cervical spine changes on plain X-ray films, the authors used an original radiological grading. A clinical evaluation was made and graded either as improved, unchanged and worsened. The authors found significant clinico-radiological correlations and concluded that a neuromuscular imbalance may determine the most severe post-laminectomy cervical spine changes.

The control mechanism involved in post-subarachnoid hemorrhage vasospasm.

In the present work the main relationships among cerebral blood volume (CBV), cerebrospinal fluid (CSF) dynamics, cerebral blood flow (CBF) and cerebrovascular reactivity following subarachnoid hemorrhage are critically examined and discussed. It is hypothesized that, following the rupture of an aneurysm, antagonistic mechanism which regulate CBF (through a vasodilatation of the arteriolar vessels) and CBV (through a constriction of basal intracranial arteries) are activated, due to the initial increase in intracranial pressure (ICP) the time pattern of ICP and cerebral hemodynamics in the following days can be largely different depending on the state of CSF dynamics. When the CSF outflow is not altered by blood in the subarachnoid space ICP suddenly returns to the basal value, and a normal cerebral hemodynamics is rapidly restored. By contrast, in conditions in which the normal CSF dynamics is impaired, the opposite action of mechanisms regulating CBF and CBV may lead to instability of the cerebrovascular bed, with the result of a maximal dilatation of pial vessels and a strong constriction of basal arteries (spasm). In our opinion the phenomenon of vasospasm can be better understood if the reactivity of basal intracranial arteries is analyzed as a part of the complex physiological system of cerebrovascular regulation.

The surgical treatment of congenital hydrocephalus.

The Authors discuss the incidence, the etiology, the pathology and the pathophysiology of congenital hydrocephalus. Furthermore, the problems of intrauterine surgical procedures are in particular discussed. On the light of the experimental and clinical results the Authors believe that the shunting fetal procedures should be considered anything but experimental and, therefore, subject to rigorous limitations. The results of the postnatal surgical procedures in congenital hydrocephalus are also discussed. Owing to the fact that early treatment of hydrocephalus in newborns seems to obtain the most satisfactory results, particular regard is reserved to that diagnostic techniques which could allow to recognize the right and early moment for surgical intervention, such as transfontanelle Doppler ultrasound examination.

Extracranial internal carotid artery occlusion associated with ipsilateral cerebral glioblastoma.

A case of left extracranial internal carotid artery occlusion, associated with ipsilateral parietal glioblastoma, is reported. The clinical and radiological aspects are discussed. The Authors stress the usefulness of a complete investigation in patients with symptoms of cerebrovascular insufficiency.

Sacral agenesis: usefulness of CT study.

The authors report on a case of sacral agenesis evaluated by Computed Tomography (CT) of the spine. Sacral agenesis is an exceedingly rare, nongenetic, developmental anomaly which consists in an absence of the entire sacrococcygeal complex. Although maternal diabetes appears to be the most important etiologic factor, the significant teratogenetic effects related to maternal diabetes are not yet completely understood. Only few cases have been reported in neurological and neurosurgical literature because most authors believe that the neurological deficits associated with sacral agenesis are static and, therefore, myelography and surgical approach are useless. However, sacral agenesis can be surgically treated when dural sac stenosis is evident in presence of progressive neurological deficits. The usefulness of CT in depicting nervous anomalies which may favorably respond to surgical treatment is emphasized, in particular when compared with contrast myelography. CT scan seems able to replace contrast myelography in delineating the intraspinal nervous anomalies, thus avoiding the myelographic risks.

Long-term evaluation of cervical spine disorders following laminectomy.

The Authors report the results obtained by long-term clinical and radiological evaluation of patients who had undergone cervical multiple bilateral laminectomy to relieve the compression exerted on the cord by different diseases (spondylarthrosis, syringohydromyelia, intramedullary and extramedullary tumours, leptomeningeal cysts and extradural tumours). 98 patients were reviewed, the follow-up ranging from 8 to 24 years (mean 14 years). The results demonstrate that the most severe post-laminectomy changes are recorded in patients with intramedullary lesions and when middle-low cervical spine levels (C4-C7) are affected. The significance of spinal deformities such as kyphosis, spondylolisthesis and swan-neck is also discussed.

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.

The control mechanisms activated by experimental intracranial hemodynamics changes.

The Authors describe an experimental model (rat) performed in order to evaluate the cerebrovascular changes which occur following the venous outflow impedance increase. This increase was obtained by bilateral occlusion of the external jugular veins at the neck. The rat was chosen because its intracranial and extracranial circulation is very similar to the human one, thus allowing the recording of blood flow velocity changes in the common carotid artery by means of a noninvasive technique such as Doppler ultrasound. Ligature of both the external jugular veins, performed on 35 rats, produced a decrease of common carotid artery blood flow velocity in 2/3 of the animals. The remaining 1/3 presented increased common carotid velocity. These changes were recorded within 15 minutes after ligation of the veins. On the contrary, the epidural pressure, measured in 6 cases, showed a constant increase. The results demonstrate that the different patterns of CBF and EDP do not permit univocal interpretation of the cerebrovascular reactivity control mechanisms, that is, myogenic, metabolic or neurogenic.

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.

Experimental cerebral "no-reflow phenomenon".

The authors describe an experimental model of transient (15 min). unilateral, cerebral ischemia followed by 60 min of reperfusion in anesthetized rats. Zones of non perfusion are recorded and referred to as the "no-reflow phenomenon". The authors believe that vascular changes which interfere with postischemic reperfusion are due to ischemia-induced swelling of perivascular glia. The effects of the intracarotid injection of dexamethasone, furosemide and escina are evaluated in the attempt to show the importance of brain edema in ischemic cerebral damage.

Epidural pressure measurement in the rat.

An original device for the epidural pressure measurement in the rat is presented. The reliability of epidural pressure as an index of intracranial pressure is discussed and several possible causes of error are examined. The device has been tested under conditions both of transient and prolonged cerebral blood volume increase, obtained by venous outflow obstruction.

Further experiences on experimental cerebral "no-reflow phenomenon".

The authors evaluate the effectiveness of combination groups of antiedema pharmacological agents on experimental transient bilateral cerebral ischemia. The results show that dexamethasone and furosemide appear to be the most useful combination group. However, the improvement of post-ischemic vascular re-perfusion is not different when these antiedema agents are employed simultaneously or when they are administrated alone. The experimental model allows the authors to evaluate various modalities of the injection of the dye and drugs. Better filling of the cerebral hemisphere in which the antiedema agents were injected through the common carotid artery is always recorded. Therefore, the authors conclude that the best way to obtain homogeneous post-ischemic vascular re-perfusion is to inject half of drugs through the left common carotid artery and half through the right common carotid artery.

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.