Surgical resection can be successful in a large fraction of patients with drug-resistant epilepsy associated with multiple cerebral cavernous malformations.

BACKGROUND: Multiple cerebral cavernous malformations (mCCMs) are known as potentially epileptogenic lesions. Treatment might be multimodal. Management of patients with mCCMs and epilepsy is challenging. OBJECTIVE: To evaluate (1) algorhythmic therapeutic sequences in patients with epilepsy associated to mCCMs, (2) whether there are predictive parameters to anticipate the development of drug-resistant epilepsy, and (3) seizure after epilepsy surgery compared to conservatively-treated drug-resistant patients. METHODS: All inpatients and outpatients with epilepsy associated to mCCMs from 1990 to 2010 and follow-up >12 months available were retrospectively analyzed. RESULTS: Twenty-three patients matched inclusion criteria. Epilepsy became drug-resistant in 18/23 (78%) patients. No predictors were found for development of drug-resistant epilepsy. Median follow-up for both groups was 7.8 years. Nine patients did not qualify for surgical therapy and were treated conservatively. One patient of this cohort (11%) was seizure-free (International League Against Epilepsy [ILAE] class 1). Surgical treatment was performed in 9 patients; 7/9 (78%) of these patients were seizure-free (ILAE class 1) after epilepsy surgery for at least 12 months compared with 1/9 patients in the non-operated group. In 7/9 cases (78%) the largest CCM was resected. In 8/9 (89%) not all CCMs were resected. CONCLUSION: After initial diagnosis of epilepsy associated to mCCMs, a primary conservative approach is reasonable. Surgical treatment can be successful in a large fraction of cases with drug-resistant epilepsy where an epileptogenic lesion is identified. Cases where surgery is not undertaken are likely to remain intractable.

Focal cortical dysplasia type IIIc associates with multiple cerebral cavernomas.

The distinction of isolated malformations and combined lesions constitutes a major novelty in the 2011 consensus classification of the International League against Epilepsy (ILAE) for focal cortical dysplasias (FCD). Cortical lamination abnormalities together with vascular lesions are subsumed as FCD IIIc. Little is known regarding frequency and etiology of this entity. Here, we systematically evaluated biopsy specimens from 72 drug-refractory epilepsy patients with cerebral cavernous malformations (CCM) regarding presence of associated FCD. Due to a non-perpendicular orientation of the cortical structures or absence of sufficient cortical tissue adjacent to the vascular lesion 25 samples were not classifiable. In the remaining 47 cases FCD IIIc was rare (4.3%), but significantly increased in patients with multiple CCM (28.6%; p<0.05 vs. single CCM). Association of FCD IIIc with multiple CCM may argue against FCD IIIc as an acquired lesion.

Trends in presurgical evaluation and surgical treatment of epilepsy at one centre from 1988-2009.

BACKGROUND: Presurgical epilepsy diagnostics and surgical treatment have become standard procedures of neurology. Here, we report on presurgical patients grouped according to their underlying pathology by giving results of presurgical evaluation, surgical therapy and long-term follow-up between 1989-2009 and describe trends over this period. PATIENTS AND METHODS: Data of prospectively documented presurgical patients were retrospectively analysed. Trends were evaluated by a year-by-year analysis. RESULTS: 2684 presurgical patients underwent presurgical work-up, 1721 of whom (64.1%) went on to resective surgery. The largest presurgical/surgical group was mediotemporal lobe epilepsy with hippocampal sclerosis (29.5%/35.4%). Of all operated patients, 1160 (67.4%) had a follow-up of ≥ 2 years. A total of 586 were continuously seizure-free without auras (50.5%; benign tumours: 61.0%; focal cortical dysplasia: 57.6%; mediotemporal lobe epilepsy with hippocampal sclerosis: 49.4%; non-lesional: 27.6%). Based on the number of the presurgically studied patients, we calculated as a novel measure of the effect of a presurgical/surgical programme an 'intention-to treat seizure-freedom' rate of 32.4%. Over time, the number of patients undergoing evaluation, but also of those not suitable or agreeable for invasive measures increased. Annual numbers of resective procedures remained stable. Average epilepsy duration of patients admitted for presurgical assessment increased. The proportion of patients with benign tumours declined. Intracranial studies and MRI-histopathology discrepancies decreased. Seizure-freedom rates remained constant. CONCLUSIONS: Epilepsy surgery is highly effective, especially in patients with clearly defined focal pathologies. At this specialised centre, there is a trend towards growing numbers of difficult patients and increasing epilepsy duration prior to referral for presurgical assessment.

Albumin storage in neoplastic astroglial elements of gangliogliomas.

PURPOSE: Low-grade neuroepithelial tumors are frequent neuropathological findings in patients with pharmacoresistant epilepsies. Little is known regarding epileptogenic mechanisms in this group of neoplasms with gangliogliomas (GG) as the most common entity. Presence of hemosiderin deposits in GG points to impairment of the blood-brain barrier (BBB). Therefore, we hypothesized a potential role of BBB dysfunction and astrocytic albumin uptake as potential epileptogenic factor in GG. METHODS: Prussian blue staining and fluorescent double-immunohistochemistry with antibodies against albumin, GFAP, CD34 and GLUT-1 were used to analyze hemosiderin deposits and astroglial albumin accumulation in tumor and adjacent pre-existing brain tissue of GG (n=10) and several control groups, i.e. dysembryoplastic neuroepithelial tumors (DNT; n=5), focal cortical dysplasia with balloon cells (FCD IIb; n=10), astrocytomas WHO grade II (n=5) and clear renal cell carcinoma brain metastases (RCCM, n=6). RESULTS: Our results revealed strong hemosiderin deposits in GG. Intriguingly, we noted substantial albumin uptake exclusively in neoplastic glial cell components of GG and DNT, whereas no significant albumin was present in perilesional reactive astrocytes. Strikingly, we did not observe substantial albumin uptake in further controls. CONCLUSION: Glial albumin uptake was restricted to long-term epilepsy associated, vasculature-containing tumors. Intratumoural BBB dysfunction in concert with subsequent accumulation of albumin by neoplastic glial cell elements represent a new putatively epileptogenic mechanism for long-term epilepsy-associated tumors.

Cliniconeuropathologic correlations show astroglial albumin storage as a common factor in epileptogenic vascular lesions.

PURPOSE: Intracerebral vascular malformations including cavernous angiomas (CAs) and arteriovenous malformations (AVMs) are an important cause of chronic pharmacoresistant epilepsies. Little is known about the pathogenetic basis of epilepsy in patients with vascular malformations. Intracerebral deposits of iron-containing blood products have been generally regarded as responsible for the strong epileptogenic potential of CAs. Here, we have analyzed whether blood-brain barrier (BBB) dysfunction and subsequent astrocytic albumin uptake, recently described as critical trigger of focal epilepsy, represent pathogenetic factors in vascular lesion-associated epileptogenesis. METHODS: We examined the correlation between hemosiderin deposits, albumin accumulation, and several clinical characteristics in a series of 80 drug-refractory epilepsy patients with CAs or AVMs who underwent surgical resection. Analysis of clinical parameters included gender, age of seizure onset, epilepsy frequency, duration of epilepsy before surgery, and postoperative seizure outcome classification according to Engel class scale. Hemosiderin deposits in the adjacent brain tissue of the vascular lesion were semiquantitatively analyzed. Fluorescent double-immunohistochemistry using GFAP/albumin costaining was performed to study albumin extravasation. KEY FINDINGS: Our results suggest that a shorter duration of preoperative epilepsy is correlated with significantly better postsurgical outcome (p < 0.05), whereas no additional clinical or neuropathologic parameter correlated significantly with the postsurgical seizure situation. Intriguingly, we observed strong albumin immunoreactivity within the vascular lesion and in perilesional astrocytes (57.65 ± 4.05%), but not in different control groups. SIGNIFICANCE: Our present data on albumin uptake in brain tissue adjacent to AVMs and CAs suggests BBB dysfunction and accumulation of albumin within astrocytes as a new pathologic feature potentially associated with the epileptogenic mechanism for vascular lesions and provides novel therapy perspectives for antiepileptogenesis in affected patients.

Promoter variants determine γ-aminobutyric acid homeostasis-related gene transcription in human epileptic hippocampi.

The functional consequences of single nucleotide polymorphisms associated with episodic brain disorders such as epilepsy and depression are unclear. Allelic associations with generalized epilepsies have been reported for single nucleotide polymorphisms rs1883415 (ALDH5A1; succinic semialdehyde dehydrogenase) and rs4906902 (GABRB3; GABAA ß3), both of which are present in the 5' regulatory region of genes involved in γ-aminobutyric acid (GABA) homeostasis. To address their allelic association with episodic brain disorders and allele-specific impact on the transcriptional regulation of these genes in human brain tissue, DNA and messenger RNA (mRNA) isolated from hippocampi were obtained at epilepsy surgery of 146 pharmacoresistant mesial temporal lobe epilepsy (mTLE) patients and from 651 healthy controls. We found that the C allele of rs1883415 is accumulated to a greater extentin mTLE versus controls. By real-time quantitative reverse transcription-polymerase chain reaction analyses, individuals homozygous for the C allele showed higher ALDH5A1 mRNA expression. The rs4906902 G allele of the GABRB3 gene was overrepresented in mTLE patients with depression; individuals homozygous for the G allele showed reduced GABRB3 mRNA expression. Bioinformatic analyses suggest that rs1883415 and rs4906902 alter the DNA binding affinity of the transcription factors Egr-3 in ALDH5A1 and MEF-2 in GABRB3 promoters, respectively. Using in vitro luciferase transfection assays, we observed that, in both cases, the transcription factors regulate gene expression depending on the allelic variant in the same direction as in the human hippocampi. Our data suggest that distinct promoter variants may sensitize individuals for differential, potentially stimulus-induced alterations of GABA homeostasis-relevant gene expression. This might contribute to the episodic onset of symptoms and point to new targets for pharmacotherapies.