Andrzej Marchel

Matrix metalloproteinase-9 (MMP-9) in human intractable epilepsy caused by focal cortical dysplasia

Focal cortical dysplasia (FCD) is a developmental brain disorder characterized by localized abnormalities of cortical layering and neuronal morphology. It is associated with pharmacologically intractable forms of epilepsy in both children and adults. The mechanisms that underlie FCD-associated seizures and lead to the progression of the disease are unclear. Matrix metalloproteinases (MMPs) are enzymes that are able to influence neuronal function through extracellular proteolysis in various normal and pathological conditions. The results of experiments that have used rodent models showed that extracellular MMP-9 can play an important role in epileptogenesis. However, no studies have shown that MMP-9 is involved in the pathogenesis of human epilepsy. The aim of the present study was to determine whether MMP-9 plays a role in intractable epilepsy. Using an unbiased antibody microarray approach, we found that up regulation of MMP-9 is prominent and consistent in FCD tissue derived from epilepsy surgery, regardless of the patients age. Additionally, an up regulation of MMP-1, -2, -8, -10, and -13 was found but was either less pronounced or limited only to adult cases. In the dysplastic cortex, immunohistochemistry revealed that the highest MMP-9 immuno reactivity occurred in the cytoplasm of abnormal neurons and balloon cells. The neuronal over expression of MMP-9 also occurred in sclerotic hippocampi that were excised together with the dysplastic cortex, but sclerotic hippocampi were free of dysplastic features. In both locations, MMP-9 was also found in reactive astrocytes, albeit to a lesser extent. At the subcellular level, increased MMP-9 immunoreactivity was prominently upregulated at synapses. Thus, although upregulation of the enzyme in FCD is not causally linked to the developmental malformation, it may be a result of ongoing abnormal synaptic plasticity. The present findings support the hypothesis of the pathogenic role of MMP-9 in human epilepsy and may stimulate discussions about whether MMPs could be novel therapeutic targets for intractable epilepsy.

Reanimation of the face after facial nerve palsy resulting from resection of a cerebellopontine angle tumour

Twenty-three patients with facial nerve paralysis following surgery for a cerebellopontine angle tumour had a facial-hypoglossal anastomosis and simultaneous anastomosis of the cervical ansa with the distal stump of the hypoglossal nerve. In 18 patients, simultaneously with the neural anastomoses, additional transpositions of the temporalis and masseter muscles were performed. At follow-up examination 3-87 months after reconstructive surgery, eight patients had House grade II, ten grade III and five grade IV outcome. The EMG evidence of reinnervation was observed 5-11 months after anastomosis. Combination of the facial-hypoglossal anastomosis with simultaneous myoplasty and with anastomosis of the distal hypoglossal nerve stump to the ansa cervicalis provides the advantage of immediate protection against ophthalmic complications, prevents hemiatrophy of the tongue and gives good functional results when reinnervation of the facial muscles takes place.

Management and neurological outcome of spontaneous spinal epidural hematoma.

This study assesses the etiology, clinical management, and outcome of patients with spontaneous spinal epidural hematoma (SSEH). SSEH is an uncommon neurosurgical emergency. We analyzed data from 10 patients (six women, four men) treated for SSEH (mean age, 63.5 years). Five patients had bleeding disorders due to anticoagulant therapy at the time of diagnosis. The initial clinical symptom in most patients was severe pain (n=8). Spinal injury was assessed using the American Spinal Injury Association (ASIA) scale, with six Grade A, one Grade C, and three Grade D patients. Lesions were in the cervicothoracic (n=4), thoracic (n=5), and thoracolumbar regions (n=1). Location was dorsal in seven patients and ventral in three. SSEH extension ranged from three to 15 spinal levels (mean, 6.9 levels). ASIA scale outcomes for the entire group were Grade A, n=2; Grade B, n=1; Grade C, n=1; Grade D, n=2; and Grade E, n=4. Outcomes for patients with no bleeding disorders (n=5) were Grade D, n=1; and Grade E, n=4. Outcomes for patients with bleeding disorders (n=5) were Grade A, n=2; Grade B, n=1; Grade C, n=1; and Grade D, n=1. After surgical treatment, patients improved by at least by one ASIA grade. The patients with mild neurological deficit who were treated conservatively also improved. Emergent spinal cord decompression is the only way to preserve spinal cord function in patients with severe deficit. Coagulation disorders were related to poor neurological status at admission and with poor neurological outcome. Conservative treatment was acceptable in patients with minimal neurological deficit.

Benign versus atypical meningiomas: Risk factors predicting recurrence

OBJECTIVE The aim of the study is to determine which clinic, radiologic, and surgical characteristics of benign and atypical meningioma are associated with tumor progression. METHODS 335 patients who underwent gross-total resection of intracranial benign and atypical meningiomas between 2000 and 2009 were followed during the period of at least 3 years. Clinical, radiological and surgical features possibly associated with progression-free survival and influencing tumor recurrence were assessed. RESULTS 291 lesions were benign (WHO Grade I) and 44 were atypical (WHO Grade II). In the median follow-up period of 82 months 34 meningiomas recurred. The 3-, 5- and 10-year progression-free survival (PFS) rates for benign and atypical tumors were 99.7 and 81.4%, 97.5 and 69.7%, 87.5 and 69.7%, respectively. In a Kaplan-Meier analysis subpial plane of surgical dissection (pial invasion) was associated with increased tumor progression both in benign (p=0.0084) and atypical cohort (p=0.0104), and bone involvement (p=0.0033) and peritumoral brain edema (p=0.0073) were associated with increased tumor progression only in atypical meningiomas. In a multivariate analysis pial invasion and WHO Grade II type were significantly associated with tumor recurrence. All recurrences in atypical meningioma group occurred within 4 years of the surgical resection. CONCLUSION Pial invasion is an important predictor of tumor recurrence in benign and atypical meningiomas. In atypical meningiomas bone involvement and large peritumoral brain edema are associated with increased tumor progression.

Surgical treatment of jugular foramen schwannomas.

OBJECTIVE We present our experience with surgery of jugular foramen schwannomas with special consideration of clinical presentation, surgical technique, complications, and outcomes. METHODS This retrospective study includes ten patients with jugular foramen schwannomas treated by the senior author between January 2007 and December 2012. Three patients had undergone partial tumour resection elsewhere. The initial symptom for which they sought medical help was hearing loss, dysphagia, hoarseness, and shoulder weakness. Preoperative glossopharyngeal and vagal nerve deficits were the most common signs. In our series, tumour extension was classified according to Kaye-Pellet grading system. In two cases the tumours were classified into type A and 8 patients presented with type D tumours. A retromastoid suboccipital craniotomy was performed for type A tumours and modifications of cranio-cervical approach were suitable for type D. RESULTS No death occurred in this series. Four patients deteriorated after surgery: in two patients preoperative cranial nerve deficits deteriorated after surgery while new cranial nerve palsy occurred in 2 other patients. In four patients, the cranial nerve dysfunction had improved at the last follow-up examination. In all other patients, the cranial nerve dysfunction remained the same. One patient experienced tumour recurrence over a follow-up period of 40 months. This patient underwent a successful second surgery without further evidence of tumour growth. CONCLUSIONS Jugular foramen schwannomas can be radically managed with the use of skull base surgery techniques. However, the surgical treatment of jugular foramen schwannomas carries a significant risk of the lower CN deficits.

Necrotic rhabdoid meningiomas with aggressive clinical behavior.

Rhabdoid meningioma (RM) is a rare, aggressive variant of meningioma classified as a WHO Grade III malignancy. RM exhibits a striking histological resemblance to other rhabdoid tumors and strong tendency towards local recurrences, CSF dissemination, and/or remote metastasis. The majority of reported cases are of secondary rhabdoid transformation in recurrent meningiomas. We present two unusual cases of rhabdoid meningiomas diagnosed as a primary intracranial lesion in adults that were associated with extensive necrosis and an aggressive clinical course. On histological examination, the majority of the tumor mass was composed of necrotic tissue with focal clusters of neoplastic cells, often localized around blood vessels. Most tumor cells exhibited typical rhabdoid morphology with large, vesicular, often eccentrically located nuclei with distinct nucleoli and abundant cytoplasm containing eosinophilic hyaline inclusions. Classical meningothelial features with focal whorl formation were scarce and seen only in one case; in the second case the tumor was entirely rhabdoid. The differential diagnosis with atypical teratoid/rhabdoid tumors (AT/RTs) and other neoplasms, particularly metastatic carcinoma, was considered. Immunohistochemical and electron microscopic study were critical for the accurate diagnosis of the rhabdoid subtype of meningiomas. Rhabdoid cells stained diffusely positive for vimentin and S-100 protein and showed focal but strong expression of epithelial membrane antigen and cytokeratins. The rhabdoid areas of the tumors exhibited high mitotic activity with a MIB-1 labeling index of 80 - 90%. The diagnosis of rhabdoid meningioma was supported by evidence of SNF5 (INI1) protein expression. Ultrastructural examination demonstrated the presence of interdigitating cell processes joined by numerous desmosomes and paranuclear whorls of intermediate filaments typical of the rhabdoid phenotype. Our two cases of rhabdoid meningiomas were associated with lethal outcome within a few months of initial diagnosis. Extensive necrosis in rhabdoid meningioma might be considered an additional predictor of aggressive clinical behavior.

Rapid growth of small, asymptomatic meningioma following radiosurgery

The authors present the case of a 62-year-old woman with rapid enlargement of a meningioma following radiosurgery (RS). Previous slow growth of the tumor over a 3-year period and the radiological signs of benign meningioma had been confirmed by successive MR scans. Histopathological examination performed after successful surgical removal revealed an atypical, infiltrating meningioma.

Epigenetics of Epileptogenesis-Evoked Upregulation of Matrix Metalloproteinase-9 in Hippocampus

Enhanced levels of Matrix Metalloproteinase-9 (MMP-9) have been implicated in the pathogenesis of epilepsy in humans and rodents. Lack of Mmp-9 impoverishes, whereas excess of Mmp-9 facilitates epileptogenesis. Epigenetic mechanisms driving the epileptogenesis-related upregulation of MMP-9 expression are virtually unknown. The aim of this study was to reveal these mechanisms. We analyzed hippocampi extracted from adult and pediatric patients with temporal lobe epilepsy as well as from partially and fully pentylenetetrazole kindled rats. We used a unique approach to the analysis of the kindling model results (inclusion in the analysis of rats being during kindling, and not only a group of fully kindled animals), which allowed us to separate the molecular effects exerted by the epileptogenesis from those related to epilepsy and epileptic activity. Consequently, it allowed for a disclosure of molecular mechanisms underlying causes, and not consequences, of epilepsy. Our data show that the epileptogenesis-evoked upregulation of Mmp-9 expression is regulated by removal from Mmp-9 gene proximal promoter of the two, interweaved potent silencing mechanisms–DNA methylation and Polycomb Repressive Complex 2 (PRC2)-related repression. Demethylation depends on a gradual dissociation of the DNA methyltransferases, Dnmt3a and Dnmt3b, and on progressive association of the DNA demethylation promoting protein Gadd45β to Mmp-9 proximal gene promoter in vivo. The PRC2-related mechanism relies on dissociation of the repressive transcription factor YY1 and the dissipation of the PRC2-evoked trimethylation on Lys27 of the histone H3 from the proximal Mmp-9 promoter chromatin in vivo. Moreover, we show that the DNA hydroxymethylation, a new epigenetic DNA modification, which is localized predominantly in the gene promoters and is particularly abundant in the brain, is not involved in a regulation of MMP-9 expression during the epileptogenesis in the rat hippocampus as well as in the hippocampi of pediatric and adult epileptic patients. Additionally, we have also found that despite of its transient nature, the histone modification H3S10ph is strongly and gradually accumulated during epileptogenesis in the cell nuclei and in the proximal Mmp-9 gene promoter in the hippocampus, which suggests that H3S10ph can be involved in DNA demethylation in mammals, and not only in Neurospora. The study identifies MMP-9 as the first protein coding gene which expression is regulated by DNA methylation in human epilepsy. We present a detailed epigenetic model of the epileptogenesis-evoked upregulation of MMP-9 expression in the hippocampus. To our knowledge, it is the most complex and most detailed mechanism of epigenetic regulation of gene expression ever revealed for a particular gene in epileptogenesis. Our results also suggest for the first time that dysregulation of DNA methylation found in epilepsy is a cause rather than a consequence of this condition.

Changes of size and shape of small, unruptured intracranial aneurysms in repeated computed tomography angiography studies.

Introduction Unruptured intracranial aneurysms (UIAs) are frequently detected in noninvasive imaging studies such as computed tomography angiography (CTA) or magnetic resonance angiography (MRA). If small, UIAs are observed in these modalities in order to detect growth or shape change, but there are many questions about proper protocol of the follow-up. Aim To assess changes of small (< 7 mm) UIAs dome size and shape in repeated CTA studies as predictors of growth and rupture. Material and methods One hundred and ten UIAs (10 posterior circulation) in 70 patients (55 women) were observed, with a cumulative observation time of 333.32 years. Aneurysms’ dome and neck perpendicular dimensions were measured in the first and the last CTA study at least twice with the developed application. Confidence intervals (CI) for measurements and dome shape parameters were calculated. For aneurysms ruptured during follow-up intermediate studies were analyzed. Patients’ clinical information was recorded. The aneurysm growth detection algorithm integrated CI and spatial resolution of the CT scanner. Results Twenty-three aneurysms increased in volume, 10 in height and 14 in dome width. Volume increased in 90% of cases of height and 93% of width increase. Posterior circulation aneurysms grew faster than anterior ones (p < 0.003), but calculated time to significant size increase (eT) did not differ between the groups due to higher CI in the posterior circulation. Analysis of eT with Kaplan-Meier curves showed that 75% of growing aneurysms could be detected in the first 3 years of observation. During the follow-up 3 aneurysms bled, and they grew faster than other growing aneurysms. Two of the bleeding aneurysms formed daughter sacs. Conclusions Dome volume assessment is superior to single dimension assessment in aneurysm growth detection. Confidence intervals assessment helps to avoid overestimation of growth. Seventy-five percent of growing aneurysms could be detected in the first 3 years of observation. Daughter sac formation and fast increase in size are strong predictors of aneurysm rupture.

Falcotentorial and velum interpositum meningiomas: Two distinct entities of the pineal region

OBJECTIVE Among pineal region lesions meningiomas are extremely rare and include falcotentorial and velum interpositum meningiomas. It is very difficult to discriminate between these two lesions and description of the clinical presentation and the surgical technique in approaching these tumors is limited. We respectively analyzed a series of patients harboring pineal region meningiomas with regard to clinical features, neuroimaging studies, and results of surgical treatment. METHODS Clinical data of 5 women and 1 man with pineal region meningiomas treated between January 1993 and December 2012 were retrospectively reviewed. All patients were assessed preoperatively with MRI and cerebral angiography. The only surgical approach we used was occipital transtentorial route. RESULTS There were four falcotentorial and two velum interpositum meningiomas. The main presenting symptom was headache, dizziness and gait disturbance. The angiogram revealed that these tumors were fed by tentorial artery, posterior choroidal arteries, and branches of the posterior cerebral artery and in four cases additional evidence of occlusion of the galenic venous system was seen. Two patients had total resection (Simpson Grade I and Grade II) and in four patients small remnants of tumor were left (Simpson Grade III). No death occurred in this series. The most common complication after surgery was homonymous hemianopsia which fully recovered in all patients in the follow-up. CONCLUSION The falcotentorial and velum interpositum meningiomas can be safely managed with the use of occipital transtentorial approach. Homonymous hemianopsia is the most common although always transient complication of surgery.