Modifiable vascular risk factors in patients with cerebral and spinal cavernous malformations: a complete 10-year follow-up study.

BACKGROUND AND PURPOSE: The aim was to investigate the effect of modifiable vascular risk factors on the risk of first and recurrent bleeding for patients with a cavernous malformation (CM) of the central nervous system (CNS) over a 10-year period. METHODS: A retrospective review of our CM institutional database was performed spanning from 2003 to 2021. The inclusion criteria were non-missing serial magnetic resonance imaging studies and clinical baseline metrics such as vascular risk factors. The exclusion criteria were patients who underwent surgical CM removal and patients with less than a decade of follow-up. Kaplan-Meier and Cox regression analyses were performed to determine the cumulative risk (10 years) of hemorrhage. RESULTS: Eighty-nine patients with a CM of the CNS were included. Our results showed a non-significant increased risk of hemorrhage during 10 years of follow-up in patients using nicotine (hazard ratio 2.11, 95% confidence interval 0.86-5.21) and in patients with diabetes (hazard ratio 3.25, 95% confidence interval 0.71-14.81). For the presence of modifiable vascular risk factors at study baseline different cumulative 10-year risks of bleeding were observed: arterial hypertension 42.9% (18.8%-70.4%); diabetes 66.7% (12.5%-98.2%); hyperlipidemia 30% (8.1%-64.6%); active nicotine abuse 50% (24.1%-76%); and obesity 22.2% (4%-59.8%). Overall cumulative (10-year) hemorrhage risk was 30.3% (21.3%-41.1%). CONCLUSIONS: The probability of hemorrhage in untreated CNS CM patients increases progressively within a decade of follow-up. None of the modifiable vascular risk factors showed strong indication for an influence on hemorrhage risk, but our findings may suggest a more aggressive course in patients with active nicotine abuse or suffering from diabetes.

Outcome after conservative or surgical treatment for new-onset epilepsy in children with cerebral cavernous malformation.

OBJECTIVE: This study aimed to investigate and compare the outcome of conservatively or surgically treated children with cerebral cavernous malformation (CCM) and new-onset CCM-related epilepsy (CRE) during a 5-year period. METHODS: In this observational monocentric cohort study, data were collected ambispectivley. Our database was screened for CCM patients treated between 2003 and 2020. Patients ≤18 years of age with complete magnetic resonance imaging dataset, clinical baseline characteristics, and diagnosis of new-onset CRE were included. Definite seizure control was classified as International League Against Epilepsy class <2. Functional outcome was assessed using the modified Rankin Scale score. CRE patients were separated into two groups according to their treatment modality. Seizure control, intake of antiseizure medication, and functional outcomes were assessed. Systematic literature research was performed to identify other cases of new-onset CRE in children and to compare the collected data with published data. RESULTS: Thirty-nine pediatric CRE patients were analyzed. A total of 18 (46.1%) patients were conservatively treated, while 21 (53.8%) underwent surgical CCM removal. While the functional outcome was similar in both groups at the last follow-up, definite seizure control was better in the surgical group (77.8%) than in the conservative group (25.0%) both after 5-years of follow-up (p = 0.038), and at last follow-up with 85.7% versus 50% respectively (p = 0.035). We found substantially higher rates of discontinuation of antiseizure medication at the last available follow-up in patients undergoing surgical resection (p = 0.009). The systematic literature review identified 4 studies with a total of 30 additional children with early onset CRE. CONCLUSION: Surgical treatment of pediatric patients with new-onset CRE had higher rates of complete seizure control and early discontinuation of antiseizure medication than conservative treatment. Neurological outcomes of patients managed surgically or conservatively were comparable. These results encourage early surgical management of children with CRE even in the absence of pharmacoresistant epilepsy, but randomized control trials are urgently needed for further decision-making.

Serum cholesterol levels do not influence outcome or recovery in acute ischemic stroke.

OBJECTIVE: To examine the influence of admission serum cholesterol levels (SCL) on severity of initial neurological deficit, neurological outcome at month 3 and neurological recovery in patients with acute first-ever ischemic stroke. METHODS: Prospectively collected data from 889 consecutive patients with first-ever acute ischemic stroke were retrospectively analysed. Patients who suffered a recurrent ischemic stroke (n=22) or died (n=30) during the follow-up period were excluded from this study. Age, gender, arterial hypertension, diabetes mellitus, smoking, stroke etiology, SCL and severity of neurological deficit, using the National Institute of Health Stroke Scale (NIHSS), at presentation (NIHSS0) and after 3 months (NIHSS1), were assessed. Neurological recovery was defined as difference in NIHSS score (Delta(NIHSS)), according to Delta(NIHSS)=NIHSS0 - NIHSS1. RESULTS: Data from 837 patients (66% men, age: 62 +/- 14 years) were analysed. NIHSS1 was 2.3 +/- 1.8 and Delta(NIHSS) was 3.4 +/- 3. Clinically insignificant correlations between SCL and NIHSS0 (r=-0.13, p=0.0002), NIHSS1 (r=-0.09, p=0.001) and Delta(NIHSS) (r=-0.1, p=0.03) were evident. Multivariate binary logistic regression analysis revealed smoking (p=0.008), stroke etiology (p=0.023) and NIHSS0 (p<0.001) but not age, gender, arterial hypertension, diabetes mellitus or SCL as predictors for Delta(NIHSS). CONCLUSION: Our data suggest that SCL in patients with acute ischemic stroke are not associated with neurological deficit on admission, outcome or neurological recovery.

Going high with preexisting neurological conditions.

This review presents the potential impact of high altitude exposure on preexisting neurological conditions in patients usually living at low altitude. The neurological conditions include permanent and transient ischemia of the brain, occlusive cerebral artery disease, cerebral venous thrombosis, intracranial hemorrhage and vascular malformations, multiple sclerosis, intracranial space-occupying lesions, dementia, extrapyramidal disorders, migraine and other headaches, and epileptic seizures. New developments in diagnostic work-up and treatment of preexisting neurological conditions are also mentioned where applicable. For each neurological disorder, the authors developed absolute and relative contraindications for a trip to high altitude. These recommendations are not based on the results of controlled randomized trials, but mainly on case reports, pathophysiological considerations, and extrapolations from the low altitude situation.

Good outcomes in ischemic stroke patients treated with intravenous thrombolysis despite regressing neurological symptoms.

BACKGROUND AND PURPOSE: We evaluated the clinical course of 19 acute stroke patients with rapid early improvement of neurological deficit within the 3-hour window, treated with intravenous thrombolytics. RESULTS: No patient demonstrated a neurological deterioration during hospitalization. National Institutes of Health Stroke Scale (NIHSS) scores at therapy decision and discharge were 5 (4 to 6) and 0.5 (0 to 1.5), respectively. At 3-month follow-up, 1 patient had died; in remaining patients, NIHSS was 0 (0 to 1) and modified Rankin Scale 0.5 (0 to 1; < or =1 in 15 patients). CONCLUSIONS: Withholding of intravenous thrombolysis because of spontaneous early regression of neurological symptoms may not be justified.

Biological activity of adult cavernous malformations: a study of 56 patients.

OBJECT: Cerebral cavernous malformations (CCMs) have previously been considered as congenital and biologically static malformations. On the other hand, the potential for growth and de novo generation of CCMs have also been reported. It is therefore important to study the proliferative and neoangiogenetic capacity of these lesions. METHODS: The authors studied the surgical specimens of 56 CCMs (23 deep and 33 superficial) obtained from adult patients. The proliferative activity of the endothelium and the neoangiogenetic capacity of these lesions were considered through immunohistochemical anaylsis of proliferating cell nuclear antigen (PCNA), MIB-1, Flk-1, vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1alpha, and endoglin antibodies. Positive immunostaining of endothelial cells occurred in 86% of patients for PCNA and in 38% of the cases for MIB 1. The expression of Flk-1 was observed in the endothelium of 71% of the cases, for VEGF in 41%, for HIF-1 alpha in 48.1%, and for endoglin in 63.6% of the cases. The correlation of immunohistochemical and clinical data indicated that VEGF was expressed in significantly less deep-seated lesions when compared with superficial CCMs. Neither the expression of the proliferative markers nor the expression of the angiogenetic antibodies correlated with patient age at surgery, sex, or the number of recent prior hemorrhagic episodes in the patients. CONCLUSIONS: The CCMs from adult patients are active lesions exhibiting endothelial proliferation and neoangiogenesis. According to the data in this study, neoangiogenesis is more prominent in superficial CCMs than in deep-seated CCMs and is not associated with recent prior hemorrhages.

Did Fyodor Mikhailovich Dostoevsky suffer from mesial temporal lobe epilepsy?

Many scientific authors--among them famous names such as Henri Gastaut or Sigmund Freud--dealt with the question from what kind of epilepsy Fyodor Mikhailovitch Dostoevsky (1821-1881) might had suffered. Because of the tight interplay between Dostoevsky's literary work and his own disease we throw light on the author's epilepsy against the background of his epileptic fictional characters. Moreover, we attempt to classify Dostoevsky's epilepsy on the basis of his bibliography, language, and literary work.

Does asymmetric basal ganglia or thalamic activation aid in seizure foci lateralization on ictal SPECT studies?

UNLABELLED: Basal ganglia or thalamic activation has been reported in ictal SPECT studies of patients with intractable epilepsy. We hypothesized that lateralization of activation of these subcortical structures may aid in the lateralization of seizure foci in patients in whom the cortical focus is subtle or equivocal. METHODS: This was a retrospective analysis of 72 ictal (99m)Tc-ethylcysteinate dimer SPECT studies in 43 patients with intractable epilepsy in whom seizure laterality could be eventually determined. All patients underwent video-electroencephalography (EEG) monitoring, MRI, and one or more ictal SPECT scans as well as an interictal SPECT scan. Intracranial electrode EEG monitoring and surgery were performed as clinically indicated. Ictal and interictal studies were coregistered with patients' MRI scans using automated software, and ictal minus interictal subtraction images were obtained. The presence of asymmetric basal ganglia or thalamic activation was determined by 2 experienced observers who were unaware of clinical information. The final seizure focus was determined by surgical cure in 37 patients. In patients in whom surgery was not indicated or initial surgery was performed at another institution (n = 6), a consistent focus detected by intracranial electrode monitoring or repeated stereotypical seizures all originating from the same site on video-surface EEG monitoring was considered to indicate the final seizure focus. RESULTS: Thirty-five patients had neocortical seizures and 8 had mesial temporal lobe seizures. Asymmetric basal ganglia activation was seen in 22 (30.6%) studies. This activation was ipsilateral to the final determined seizure focus in 17 of 22 of these studies (77.3%) and contralateral in 5 of 22 (21.7%). Asymmetric thalamic activation was seen in 15 studies (20.8%), of which 12 of 15 (80%) were ipsilateral to the final seizure focus, whereas 3 of 15 (20%) were contralateral. In 3 of 5 studies with contralateral basal ganglia activation and 1 of 3 studies with contralateral thalamic activation, the SPECT study as a whole was found to be falsely localizing. In another 2 cases of contralateral subcortical activation, the SPECT study as a whole was considered nonlocalizing. Worse outcome was not observed in patients with false ictal SPECT subcortical lateralization; however, the presence of asymmetric subcortical uptake, regardless of relationship to seizure focus, was associated with decreased incidence of seizures at 1 y after surgery. CONCLUSION: Although asymmetric basal ganglia or thalamic activation is common, it is rarely the sole indicator of seizure localization. However, it may be a useful confirmatory sign in subtle cases of cortical localization. In cases of false ictal SPECT subcortical lateralization, the basal ganglia appear to follow cortical activation pattern. Furthermore, there appears to be a correlation between lateralizing uptake in subcortical structures on ictal SPECT and postsurgical outcome in intractable epilepsy patients.

Epilepsy with severe abdominal pain.

We describe a patient who experienced recurrent episodes of abdominal pain as a prominent feature of his seizure disorder. Treatment with carbamazepine could not prevent these painful sensations, but a selective amygdalohippocampectomy completely controlled the episodic pain and the seizures associated with loss or alteration of consciousness. During the presurgical evaluation, the episodes of abdominal pain correlated with amygdalar seizure discharges.

Mutational analysis of 206 families with cavernous malformations.

OBJECT: A gene contributing to the autosomal-dominant cerebral cavernous malformation (CCM) phenotype, KRIT1 (an acronym for Krev Interaction Trapped 1), has been identified through linkage analysis and mutation screening. The authors collected blood samples from 68 patients with familial CCM and 138 patients with apparently sporadic CCM as well as from their families, in an effort to characterize the prevalence and spectrum of disease-causing sequence variants in the KRIT1 gene. METHODS: The authors used single-strand conformational polymorphism analysis to identify genomic variants in KRIT1, which were sequenced to determine the specific mutation. Among 43 Hispanic-American kindreds who immigrated to the southwestern US from northern Mexico, 31 share an identical founder mutation. This Q455X mutation is found in 18 (86%) of 21 persons with a positive family history and in 13 (59%) of 22 persons with apparently sporadic CCM. This mutation was not found among 13 persons with CCM who were recruited from Mexico. These findings establish the key role of a recent founder mutation in Hispanic persons with CCM who live in the US. Although nearly all Hispanic families in the US in which there are multiple CCM cases linked to the CCM1 locus, only 13 of 25 non-Hispanic CCM-carrying families have displayed evidence of linkage to the CCM1 locus. Among these 13 families, the authors identified eight independent mutations in nine kindreds. They identified four additional mutations among 22 familial CCM kindreds with no linkage information, bringing the total number of independent mutations to 12. Inherited KRIT1 mutations were not detected among 103 non-Hispanic persons in whom a family history of CCM was rigorously excluded. CONCLUSIONS: All mutations were nonsense mutations, frame-shift mutations predicting premature termination, or splice-site mutations located throughout the KRIT1 gene, suggesting that these are genetic loss-of-function mutations. These genetic findings, in conjunction with the clinical phenotype, are consistent with a two-hit model for the occurrence of CCM.

Linkage to the CCM2 locus and genetic heterogeneity in familial cerebral cavernous malformation.

BACKGROUND: Cerebral cavernous malformation (CCM) is a form of intracranial vascular disease that may arise sporadically or be dominantly inherited. Linkage studies have revealed genetic heterogeneity among the dominantly inherited forms suggesting the existence of at least three loci called CCM1, CCM2 and CCM3. METHODS: In the present study, we screened five families with dominantly inherited CCM for CCM1 gene mutations with denaturing high performance liquid chromatography (DHPLC). Then, we performed linkage analysis and haplotyping on these five families using highly polymorphic markers at the candidate CCM loci. RESULTS: None of the five families tested with DHPLC were found to have mutations in the CCM1 gene. Based on haplotyping, we identified three families segregating alleles for CCM2, while two families segregated alleles for CCM3. Using linkage analysis, we could confirm that one family (IFCAS-1) had a positive Lod score of 2.03 (p<0.0001) at the CCM2 locus using marker D7S678. CONCLUSIONS: The present study is the first one to replicate linkage at the CCM2 locus and provides a fifth family identified as such. It also supports the concept of genetic heterogeneity in CCM, identifying four other families that showed no mutations in the CCM1 gene.

De novo cerebellar medulloblastoma in a 26-year recurrence-free case of temporal glioblastoma multiforme. Case report.

The authors describe a patient who survived 26 years after resection of a right temporal glioblastoma multiforme (GBM) without signs of tumor recurrence. Preoperative emergency angiography demonstrated a hypovascular mass localized in the right temporal lobe with right-to-left shift of the vascular structures. At surgery, the tumor had cystic and solid components localized in the lateral occipitotemporal gyrus, reaching the posterolateral wall of the inferior horn of the right lateral ventricle and extending to the trigone and posterior horn. The initial pathological diagnosis of a GBM was reviewed and confirmed throughout the follow-up period. Twenty-six years after surgery and subsequent radiosurgery, the patient underwent resection of a medulloblastoma localized in the right cerebellum as well as stereotactic biopsy sampling of tissue at the original GBM site. Neither radiological nor histological evidence of recurrence of the GBM could be documented. The intraoperative, histological, and radiological findings are described.

The value of interictal brain SPECT in epilepsy patients without mesial-temporal sclerosis.

PURPOSE: Most of the literature concerning interictal SPECT brain scanning in patients with seizures has involved the evaluation of those with temporal lobe epilepsy. The authors' aim was to determine the utility of interictal SPECT in patients with neocortical epilepsy. MATERIALS AND METHODS: Eighty-four patients with neocortical epilepsy were evaluated with 95 interictal SPECT scans and magnetic resonance imaging (MRI). RESULTS: Fifty-four percent of studies with normal MRI findings had SPECT images without regions of hypoperfusion. Sixty-one percent of patients with abnormal MRI results had matching defects visible on SPECT images. Fourteen scans (only 24%) had focal hypoperfusion by SPECT and no obvious matching MRI finding. CONCLUSIONS: Interictal SPECT, without a comparison ictal study, is of potentially limited value in localizing neocortical seizure foci. SPECT findings usually match MRI findings. Interictal SPECT, however, may still be of value in confirming abnormalities detected by ictal examination.

The architecture of the chess player's brain.

The game of chess can be seen as a typical example for an expertise task requiring domain-specific training and experience. Despite intensive behavioural studies the neural underpinnings of chess performance and expertise are not entirely understood. A few functional neuroimaging studies have shown that expert chess players recruit different psychological functions and activate different brain areas while they are engaged in chess-related activities. Based on this functional literature, we predicted to find morphological differences in a network comprised by parietal and frontal areas and especially the occipito-temporal junction (OTJ), fusiform gyrus, and caudate nucleus. Twenty expert chess players and 20 control subjects were investigated using voxel-based and surface-based morphometry as well as diffusion tensor imaging. Grey matter volume and cortical thickness were reduced in chess players compared with those of control men in the OTJ and precunei. The volumes of both caudate nuclei were not different between groups, but correlated inversely with the years of chess playing experience. Mean diffusivity was increased in chess players compared with that of controls in the left superior longitudinal fasciculus and the Elo score (a chess tournament ranking) was inversely related to mean diffusivity within the right superior longitudinal fasciculus. To the best of our knowledge we showed for the first time that there are specific differences in grey and white matter morphology between chess players and control subjects in brain regions associated with cognitive functions important for playing chess. Whether these anatomical alterations are the cause or consequence of the intensive and long-term chess training and practice remains to be shown in future studies.

Effective surgical treatment of cerebral cavernous malformations: a multicenter study of 79 pediatric patients.

OBJECT: Cerebral cavernous malformations (CCMs) are common vascular lesions in the brain, affecting approximately 0.5% of the population and representing 10%-20% of all cerebral vascular lesions. One-quarter of all CCMs affect pediatric patients, and CCMs are reported as one of the main causes of brain hemorrhage in this age group. Symptoms include epileptic seizures, headache, and focal neurological deficits. Patients with symptomatic CCMs can be treated either conservatively or with resection if lesions cause medically refractory epilepsy or other persistent symptoms. METHODS: The authors retrospectively analyzed 79 pediatric patients (41 boys and 38 girls) from 3 different centers, who were surgically treated for their symptomatic CCMs between 1974 and 2004. The mean age of the children at first manifestation was 9.7 years, and the mean age at operation was 11.3 years. The main goal was to compare the clinical outcomes with respect to the location of the lesion of children who preoperatively suffered from epileptic seizures. RESULTS: Of these patients, 77.3% were seizure free (Engel Class I) after the resection of the CCM. Significant differences in the outcome between children who harbored CCMs at different locations were not found. CONCLUSIONS: Resection seems to be the favorable treatment of symptomatic CCMs not only in adults but also in children.

Gustav Flaubert's "nervous disease": an autobiographic and epileptological approach.

More than 20 years ago, complex partial epilepsy of occipital-temporal origin was suggested as having been the "nervous disease" of Gustave Flaubert, one of the most famous French novelists. The aim of the present work, therefore, was to reevaluate the diagnosis of Flaubert's "nervous disease" in the light of reemerged biographic information and letters, as well as the numerous scientific advances in epilepsy and its psychopathology in recent years. If the semiology of the reported attacks is considered, epilepsy ranks among the most probable diagnoses. In our opinion, psychopathological considerations suggest primary involvement of mesial temporal lobe structures with typical findings of ictal and interictal mood behavior.

Seizure outcome after resection of supratentorial cavernous malformations: a study of 168 patients.

PURPOSE: The optimal management of cerebral cavernous malformations (CCMs) with epileptic seizures is still a matter of debate. The aim of our study was to examine seizure outcome in the largest published series of surgically treated patients with epilepsy due to a supratentorial CCM, and to define predictors for good surgical outcome. METHODS: We retrospectively studied 168 consecutive patients with a single supratentorial CCM and symptomatic epilepsy in a multicenter study. Pre- and postoperative clinical examinations, age at epilepsy onset, age at operation, type of symptoms due to the CCM (seizures, headache, hemorrhage, focal deficits), type and frequency of epileptic seizures, and the localization and size of the CCM were assessed. Seizure outcome was determined in the first, second, and third postoperative years. RESULTS: The CCM was completely resected in all patients. More than two thirds of the patients were classified as seizure free in the first 3 postoperative years. Predictors for good seizure outcome were age older than 30 years at the time of surgery, mesiotemporal CCM localization, CCM size <1.5 cm, and the absence of secondarily generalized seizures. No mortality occurred in our series, but only mild postoperative neurologic deficits in 12 (7%) patients. CONCLUSIONS: Considering the natural history of CCMs, the favorable neurologic and seizure outcome, surgical resection of CCMs should be considered in all patients with supratentorial CCMs and concomitant epilepsy, irrespective of the presence or absence of predictors for a favorable seizure outcome.

Lipoma on the corpus callosum in a patient with schizophrenia-like episode: is there a causal relationship?

Disturbed interhemispheric communication has been proposed as responsible for schizophrenia. We present a case of a schizophrenia-like episode with no neurologic or other psychiatric symptoms. However, magnetic resonance imaging revealed a lipoma on the splenium of the corpus callosum. Neuropsychologic examination revealed normal interhemispheric transfer, but a slight dysfunction associated with right-hemispheric anterior regions. Rather than supporting the hypothesis of a causal relationship between callosal abnormality and schizophrenia-like symptoms, our findings argue against a direct causal relationship between lesion site and psychotic episode. We conclude that cerebral abnormality per se may represent a risk factor for neuropsychiatric symptoms.

Biological activity of paediatric cerebral cavernomas: an immunohistochemical study of 28 patients.

OBJECTIVE: According to the hypothesis that paediatric cerebral cavernomas may have different biological activity compared to adult cavernomas, immunohistochemical analysis was used to elucidate the biological nature of paediatric cavernomas. PATIENTS AND METHODS: We examined the histological features and the proliferative and angiogenic capacity of the tissue specimens acquired from 28 paediatric patients. Normal paediatric brain tissues obtained from paediatric autopsy cases were used as a control group. The proliferative activity of the endothelium and the neoangiogenetic capacity were investigated by immunohistochemistry for proliferating cell nuclear antigen (PCNA), Ki-67 epitope (MIB-1), Flk-1 receptor, vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1 alpha, and endoglin antibody, respectively. Afterwards, the results of the paediatric lesions were analysed and compared with the correspondent values of previously reported immunohistochemical analysis in adult cavernomas. RESULTS: Positive immunostaining of VEGF was detected significantly less in paediatric cavernomas compared to adult cases (p<0.05). In contrast, endoglin, a protein that is upregulated during an increased vascular shear stress, was expressed more often in paediatric cavernomas (p<0.05). Neither the expression of the PCNA nor the expression of the HIF-1alpha was found significantly different between paediatric and adult cavernomas. However, the positive immunoreaction for MIB-1 occurred more often in the paediatric cases (p<0.05). CONCLUSIONS: The immunohistochemical study indicates that paediatric cavernomas are dynamic lesions. The VEGF/Flk-1 associated neoangiogenesis may play a minor role for the biology of paediatric cavernomas, while endoglin seems to act more prominently than previously thought, particularly for the biology of paediatric cavernomas.