Subarachnoid hemorrhage and negative angiography: clinical course and long-term follow-up.

The aim of this study was to investigate the long-term natural history of nontraumatic angiogram-negative subarachnoid hemorrhage with typical pretruncal (P-SAH) and diffuse (D-SAH) pattern of hemorrhage. A retrospective review of 102 patients who experienced angiographically negative SAH at our institution was undertaken (11.6% of 882 spontaneous SAH). Follow-ups were obtained at 7.9 to 16 years. In the D-SAH group, 11 patients (13.9%) out of 79 had an aneurysm, and four (5.1%) had rebleeding episodes. In the P-SAH group, the second angiography was negative in all of the 23 cases, and no rebleeding episodes were recorded. The long-term follow-up confirms that P-SAH is a benign disease. A second angiography could not be necessary. D-SAH is probably due to an aneurysm that thrombose early after the bleeding. At short-term follow-up, the sack could frequently recanalize and rebleed, whereas a late follow-up shows that rebleeding is very rare.

Clinical and radiological outcome of craniocervical osteo-dural decompression for Chiari I-associated syringomyelia.

The aim of this study was to analyze the long-term clinical and radiological outcomes of craniocervical decompression for patients affected by Chiari I-related syringomyelia. We performed a retrospective analysis of a group of patients affected by Chiari I-associated syringomyelia treated by craniocervical decompression (CCD). Surgical and technical aspects and preoperative factors predicting outcome were discussed. A total of 36 patients were reviewed. There were 17 men and 19 women (female/male ratio 1.11), and the mean age was 40.4 (range 18-68). The most important preoperative symptoms were related to myelopathy (pain, weakness, atrophy, spasticity, sensory loss, and dysesthesias). Most syrinxes were in the cervico-thoracic region (61.1%), and the majority of patients had tonsillar descent between the foramen magnum and C1. All patients underwent a craniectomy less than 3 cm in diameter followed by a duroplasty with dura substitute. No arachnoid manipulation was necessary. Three patients (8.1%) experienced cerebrospinal fluid leaks that resolved without complications. At a mean follow up of 40 months (range 16-72) 80.5% of patients exhibited improvement over their preoperative neurological examination while 11.1% stabilized. The syrinx shrank in 80.5% of patients. Chi-square test showed that preoperative syrinx extension and degree of tonsillar descent did not correlate with clinical and neuroradiological postoperative evolution. Treating syringomyelia associated in Chiari I malformation with CCD leads to a large percentage of patients with satisfying results and no irreversible complications.

Pro-inflammatory cytokine genes influence the clinical features of frontotemporal lobar degeneration.

BACKGROUND/AIMS: Recent studies suggested a role for pro-inflammatory mediators in frontotemporal lobar degeneration (FTLD). The objective of this study was to evaluate the association of functionally active polymorphisms in pro-inflammatory cytokine genes with the occurrence and the clinical features of the disease. METHODS: Using a case-control study, we compared allelic and genotypic frequencies of several polymorphisms in the interleukin (IL)-1alpha, interleukin (IL)-1beta, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha genes between 110 FTLD patients and 119 healthy controls. RESULTS: No significant association between the examined polymorphisms and the disease was found. However, in comparison with remaining genotypes, patients carrying the T/T genotype of the IL-1beta gene showed a significantly lower age at onset of the disease. In addition, scores of the Frontal Assessment Battery were significantly modified by the IL-6 -174G>C polymorphism. CONCLUSION: Our findings support a role for pro-inflammatory cytokine genes in the pathogenesis of frontotemporal lobar degeneration.

Haplotype analysis confirms the association between the HCRTR2 gene and cluster headache.

BACKGROUND: Several studies suggested that genetic factors play a role in cluster headache (CH) susceptibility. We found a significant association between the 1246 G>A polymorphism of the hypocretin receptor-2 (HCRTR2) gene and the disease. This association was confirmed in a large study from Germany but was not replicated in a dataset of CH patients from Northern Europe. OBJECTIVE: The purpose of this study was to further evaluate the association between CH and the HCRTR2 gene using new polymorphisms, estimating the frequency of different gene haplotypes, searching for gene mutations, and evaluating the effects of the examined polymorphisms on hypocretin binding sites. METHODS: We genotyped 109 CH patients and 211 healthy controls for 5 new polymorphisms of the HCRTR2 gene and we inferred different gene haplotypes. Complete HCRTR2 sequencing was undertaken for 11 independent CH patients, 5 of whom had a positive family history. The effects of the 1246 G>A polymorphism on the hypocretin binding sites were evaluated using different computer-assisted analyses. RESULTS: Three new polymorphisms of the HCRTR2 gene resulted significantly associated with CH. The GTAAGG haplotype resulted more frequent in cases than in controls (OR: 3.68; 95% CI: 1.85-7.67). No point mutation of the HCRTR2 gene was found. Binding analyses showed that the 1246 G>A polymorphism (substitution of valine at position 308 by isoleucine) has no effect on the hypocretin binding sites but could influence the dimerization process of the receptor. CONCLUSION: Our data confirm previous studies suggesting that the HCRTR2 gene or a linked locus significantly modulates the risk for CH. In addition, we suggest that the V308I substitution of the HCRTR2 may interfere with the dimerization process of the receptor, thereby influencing its functional activity.

Vasospasm after SAH due to aneurysm rupture of the anterior circle of Willis: value of TCD monitoring.

OBJECTIVE: The aim of this study was to verify the presence of angiographic vasospasm in patients with transcranial Doppler (TCD) of high velocities after subarachnoid hemorrhage (SAH). METHODS: Seven hundred and eighty-six cases admitted within 48 hours after SAH due to the rupture of anterior circulation aneurysm, were prospectively studied with TCD. In cases of TCD velocities higher than 120 cm/s (TCD vasospasm), the patient underwent a control angiography. Hunt-Hess and Fisher's grade on admission CT and location of the aneurysm were related to occurrence of TCD vasospasm. The increase in TCD velocities within 24 hours was calculated and related to the presence of cerebral ischemia on discharge CT, considering three groups of patients: Group A with an increase in velocities higher than 60%, Group B with an increase in velocities between 30 and 60%, and Group C with an increase in velocities lower than 30%. RESULTS: TCD vasospasm was observed in 216 patients (27%). In 97% of patients with TCD vasospasm on middle cerebral artery (MCA) and in 71% with TCD vasospasm on anterior cerebral artery (ACA), control angiography confirmed the vasospasm, with a significant lower diagnostic TCD predictivity of ACA spasm (chi2=28.204, p=0.000). The overall positive predictive value of TCD was 89%. There was no significant correlation of TCD vasospasm with clinical status on admission and location of the aneurysm, but a significant correlation between occurrence of TCD vasospasm and Fisher's grade (chi2=15.470, p=0.002) and between the increase rate in TCD velocities and cerebral ischemia (chi2=56.564, p=0.000). CONCLUSION: Our study shows a good correlation between TCD and angiography to detect vasospasm on MCA, but the correlation is low for ACA. TCD alone cannot discriminate different hemodynamic pathways after SAH.

Lack of association between the apolipoprotein E gene and aneurysmal subarachnoid hemorrhage in an Italian population.

OBJECT: The results of genome-wide scan studies have suggested the presence of a genetic risk factor for aneurysmal subarachnoid hemorrhage (SAH) on chromosome 19 (at 19p13). The apolipoprotein E (APOE) gene is located in this chromosomal region and encodes a protein that exerts several neuroprotective and neurotrophic functions in the brain. The purpose of this study was to evaluate whether a particular allele or genotype of the APOE gene would modify the occurrence or the clinical features of SAH. METHODS: Genomic DNA was extracted from 146 patients with aneurysmal SAH and 222 age- and sex-matched healthy controls and genotyped for the triallelic polymorphism of the APOE gene (epsilon2, epsilon3, and epsilon4). Allele and genotype frequencies were compared between patients and controls. The clinical characteristics of the disease were compared according to the different APOE genotypes. Allele and genotype frequencies of the APOE gene polymorphism were nearly identical in cases and controls. Patients carrying the APOE epsilon4 allele had a significantly higher Hunt and Hess grade on admission (p = 0.0014). There was no significant relationship between any of the other clinical characteristics and the APOE genotype. CONCLUSIONS: The authors' data do not support the hypothesis that genetic variations within the APOE gene are associated with aneurysmal SAH. However, the APOE gene influences the disease phenotype and may be regarded as a disease modifier gene.

HLA-DRB1 genotyping in Italian migraine patients.

We examined the distribution of HLA-DRB1 alleles in a cohort 255 Italian migraine patients and in a control group of 325 healthy subjects. 214 patients fulfilled the ICHD-II criteria for migraine without aura and 41 patients the criteria for migraine with aura. The frequency of DRB1*16 allele was found to be significantly increased in migraine without aura patients (p=0.02; OR 1.97, 95% CI: 1.10-3.54) than in healthy controls. The frequencies of HLA-DRB1 alleles were not significantly different between migraine with aura patients and controls. We did not detect any effect of DRB1 alleles on age at onset, duration of the disease, frequency and duration of migraine attacks. Our data suggest the presence of a genetic susceptibility factor for migraine without aura within the HLA region.

Apolipoprotein E gene polymorphisms in patients with migraine.

To investigate the role of apolipoprotein E (APOE) polymorphisms in migraine, we analyzed the APOE genotypes of 241 migraine patients and 587 controls. The results of a Chi-square analysis indicated that APOE alleles were similarly distributed (chi(2)=2.89, P=0.24) between cases and controls. However, we found a significant (P<0.001) increase of the varepsilon2-varepsilon4 genotype in the group of migraine patients. Patients were divided into three subgroups: migraine with aura; migraine without aura; and mixed headaches (migraine associated with tension-type headache). Subgroup analysis showed that the varepsilon2-varepsilon4 genotype was significantly increased only in patients with mixed headaches. The stratification of patients by APOE status did not reveal significant associations with the clinical features of the disease. In conclusion, we observed no significant association between APOE polymorphisms and migraine. The association between the APOE varepsilon2-varepsilon4 genotype and the tension-type headache deserves further evaluation.

Absence of linkage between the interleukin-6 gene (-174 G/C) polymorphism and migraine.

To assess the role of interleukin-6 (IL-6) in migraine, we analyzed the -174 G/C IL-6 gene polymorphism in 268 patients with migraine and 305 controls. No significant difference in the distribution of IL-6 genotypes (chi(2)=0.601, P=0.74) and allelic frequencies (chi(2)=0.024, P=0.876) was found. When patients were subdivided into subgroups (migraine with aura, migraine without aura and mixed headaches), IL-6 alleles were similarly distributed. Comparison of the clinical features of the disease with the -174 G/C IL-6 genotypes showed no significant difference. In conclusion, we found no significant association between the -174 G/C IL-6 polymorphism and the occurrence or the clinical features of migraine.

A comparison of familial and sporadic migraine in a headache clinic population.

We compared the clinical, psychological and pharmacological characteristics of patients with familial migraine and patients with sporadic migraine. Five hundred and thirty consecutive new patients attending our Headache Center over a two-year period were involved in the study. The patients were divided into two groups: A. Familial migraine (famM)--at least one first-degree relative affected; B. Sporadic migraine (spoM)--no first-degree relative affected. Four hundred and twenty-four patients (80%) fulfilled the criteria for famM and 106 (20%) for spoM. The patients with famM showed a significantly (p<0.01) earlier age at onset of the disease. No significant difference in all the remaining features examined was found. Our data suggest that famM and spoM represent a single disease entity.

Interleukin-1 cluster gene polymorphisms and aneurysmal subarachnoid hemorrhage.

BACKGROUND: Emerging data indicate that proinflammatory cytokines may be involved in the pathogenesis of intracranial aneurysms. Interleukin (IL)-1 is a proinflammatory cytokine that plays a pivotal role in both acute and chronic central nervous system injuries. OBJECTIVE: To investigate whether select polymorphisms in the IL-1alpha, IL-1beta, and IL-1 receptor antagonist genes are associated with both susceptibility to and clinical characteristics of subarachnoid hemorrhage due to intracranial aneurysm rupture. METHODS: Allelic and genotypic frequencies of the IL-1alpha (-889), IL-1beta (-511), and IL-1 receptor antagonist (VNTR) genes were determined in 215 patients and 155 healthy controls. Patient files were reviewed for the clinical characteristics at hospital admission and at 6-month follow-up. RESULTS: No association between aneurysmal subarachnoid hemorrhage susceptibility and the examined cytokine gene polymorphisms was found. Haplotype analysis did not show any significant difference between cases and controls. However, aneurysmal subarachnoid hemorrhage patients carrying the T/T genotype of the IL-1beta gene showed a significant (P = .034) increase in the Hunt and Hess scores at hospital admission and a significant (P = .026) reduction in 6-month Glasgow Outcome Scale scores. The remaining polymorphisms showed no effect on the clinical features examined. CONCLUSION: Our results do not support the hypothesis that genetic variation in select polymorphisms of the IL-1 cluster genes is associated with aneurysmal subarachnoid cerebral hemorrhage. However, the IL-1beta gene may modify disease severity and may be regarded as disease severity gene.

Voxel-based morphometry reveals gray matter abnormalities in migraine.

BACKGROUND: Migraine is generally considered a functional brain disorder lacking structural abnormalities. Recent magnetic resonance imaging (MRI) studies, however, suggested that migraine may be associated with subtle brain lesions. OBJECTIVE: We evaluated the presence of global or focal gray or white matter alterations in migraine patients using voxel-based morphometry (VBM), a fully automated method of analyzing changes in brain structure. VBM data also were used to evaluate possible differences between episodic and chronic migraine. METHODS: Twenty-seven migraine right-handed patients and 27 healthy controls were selected for the study. Sixteen patients fulfilled the International Headache Society criteria for episodic migraine and 11 for chronic migraine. MRI scans were analyzed with MATLAB 6.5 and SPM2 software, using VBM method. RESULTS: In comparison with controls, migraineurs presented a significant focal gray matter reduction in the Right Superior Temporal Gyrus, Right Inferior Frontal Gyrus, and Left Precentral Gyrus. Chronic migraine patients, compared to episodic, showed a focal gray matter decrease in the bilateral Anterior Cingulate Cortex, Left Amygdala, Left Parietal Operculum, Left Middle and Inferior Frontal Gyrus, Right Inferior Frontal Gyrus, and bilateral Insula. Considering all the migraine patients, a significant correlation between gray matter reduction in anterior cingulate cortex and frequency of migraine attacks was found. CONCLUSIONS: Our study shows that migraine is associated with a significant gray matter reduction in several of the cortical areas involved in pain circuitry. In addition, we found a significant correlation between frequency of migraine attacks and signal alteration in the Anterior Cingulate Cortex. Our data provide new insight into migraine pathophysiology and support the concept that migraine may be a progressive disorder.

Association between the G1246A polymorphism of the hypocretin receptor 2 gene and cluster headache: a meta-analysis.

The objective of this study was to investigate the association between polymorphisms of the hypocretin receptor 2 gene (HCRTR2) and the risk of cluster headache (CH). The study is a meta-analysis of published case-control studies investigating the association between polymorphisms of the HCRTR2 gene and CH. Pooled odds ratios (OR) were estimated using both random (RE) and fixed effects (FE) models. Three studies, performed in five different European countries, with 593 cases and 599 controls, were included in the study. Allele G of the G1246A HCRTR2 polymorphism was significantly associated with CH (FE OR 1.58, CI 95% 1.27-1.95; RE OR 1.55 (1.14-2.12)). Carriers of the GG genotype showed a higher disease risk compared to the remaining genotypes (FE OR 1.75, CI 95% 1.37-2.25; RE OR 1.69, CI 95% 1.11-2.58). Our data confirm that the G1246A polymorphism of the HCRTR2 gene may modulate the genetic risk for CH.

Tumor necrosis factor-alpha gene and cerebral aneurysms.

OBJECTIVE: The pathogenesis of intracranial aneurysms is still uncertain. In addition to atherosclerosis, immunological factors may play a role in the disease. Recent studies have suggested that tumor necrosis factor-alpha (TNF-alpha), one of the main proinflammatory cytokines, may play a key role in the formation and rupture of cerebral aneurysms. The purpose of this study is to evaluate the association of a functionally active polymorphism (-308 G

Endocrine function is altered in chronic migraine patients with medication-overuse.

OBJECTIVE: To evaluate the effects of analgesic overuse on endocrine function in patients with chronic migraine and medication-overuse headache (CM-MOH). BACKGROUND: Chronic migraine is frequently associated with an overuse of symptomatic medications. Drugs currently used in acute migraine attacks are associated with several endocrine effects. At present, the endocrine effects of medication overuse in chronic migraine patients are unknown. METHODS: Eighteen patients with CM-MOH, diagnosed according to the ICHD-II criteria, and 18 healthy controls received an intravenous administration of GHRH, hCRH, and TRH. Plasma concentrations of GH, TSH, ACTH, and cortisol were measured for a 90-minute period after administration of the specific releasing hormones. RESULTS: Hormonal basal concentrations were similar in both groups. GH response to GHRH was significantly reduced in patients with CM-MOH in comparison with controls. TRH induced a reduction of TSH concentrations only at the end of the test. After hCRH administration, ACTH and cortisol concentrations were significantly higher in cases than in controls. A significant correlation between duration of the disease and altered hormonal response was found. CONCLUSIONS: Our study shows that both corticotropic and somatotropic functions are significantly impaired in CM-MOH patients and suggests a role for hormones in the development of chronic migraine.

Anger and emotional distress in patients with migraine and tension-type headache.

The objective was to evaluate the prevalence and the characteristics of anger and emotional distress in migraine and tension- type headache patients. Two hundred and one headache patients attending the Headache Center of the University of Turin were selected for the study and divided into 5 groups: (1) migraine, (2) episodic tension-type headache, (3) chronic tension-type headache, (4) migraine associated with episodic tension-type headache and (5) migraine associated with chronic tension-type headache. A group of 45 healthy subjects served as controls. All the subjects completed the State-Trait Anger Expression Inventory, the Beck's Depression Inventory and the Cognitive Behavioral Assessment. Anger control was significantly lower in all headache patients (p<0.05) except in migraineurs. Patients with migraine and tension-type headache showed a significantly higher level of angry temperament and angry reaction (p<0.05). In addition, chronic tension-type headache and migraine associated with tension-type headache patients reported a higher level of anxiety (p<0.05), depression (p<0.001), phobias (p<0.001) and obsessive-compulsive symptoms (p<0.01), emotional liability (p<0.001) and psychophysiological disorders (p<0.001). Our study shows that chronic tension-type headache and migraine associated with tension-type headache patients present a significant impairment of anger control and suggests a connection between anger and the duration of headache experience.

Prevalence of HFE (hemochromatosis) gene mutations in patients with cluster headache.

OBJECTIVE: To evaluate whether polymorphisms of the HFE gene would modify the occurrence and the clinical features of cluster headache (CH). BACKGROUND: Recent studies suggested that iron metabolism may be involved in the pathophysiology of primary headaches. The HFE gene encodes for a protein that modulates iron absorption. Mutations in this gene are responsible for toxic iron overload in several body organs. METHODS: Genomic DNA was extracted from 109 CH patients and 211 age and sex-matched healthy controls and genotyped for the C282Y and H63D mutations of the HFE gene. Allele and genotype frequencies of the HFE gene were compared between cases and controls. The clinical characteristics of the disease were compared according to the different HFE gene genotypes. RESULTS: No C282Y mutation was found in both cases and controls. The prevalence of the H63D mutation was nearly identical in cases and controls. The four patients carrying the HFE D63D genotype showed a significantly (P < .001) later age at onset of the disease in comparison with both H63H and H63D patients. The remaining clinical characteristics of the disease did not significantly differ in the presence or absence of the H63D mutation. CONCLUSION: Our data do not support the hypothesis that genetic variations within the HFE gene are associated with CH. However, the HFE gene may influence the disease phenotype and may be regarded as a disease modifier gene.

Association between migraine and HLA-DRB1 gene polymorphisms.

We examined the distribution of HLA-DRB1 alleles in a cohort of 255 Italian migraine patients and in a control group of 325 healthy subjects. The frequency of DRB1*12 allele was found to be significantly reduced (p=0.02) in patients with migraine while the DRB1*16 allele was significantly increased (p=0.04) in comparison with controls. When the patients were divided into disease subgroups (migraine with and without aura), HLA-DRB1**16 allele was significantly increased (p<0.05) only in migraine without aura patients. We conclude that, in Italian patients, migraine is associated with different alleles of the HLA-DRB1 locus. Our data suggest the presence of a genetic susceptibility factor for migraine within the HLA region.

A polymorphism in the interleukin-1alpha gene influences the clinical features of migraine.

OBJECTIVE: To evaluate whether a particular genotype of the interleukin-1alpha (IL1A) gene affects the clinical features of migraine. BACKGROUND: Proinflammatory mediators have been reported to play a role in the pathophysiology of migraine. Recent studies suggest that polymorphisms in the interleukin-1 genes influence the age at onset and subsequent course of several chronic inflammatory diseases. METHODS: In a group of 269 patients with migraine, we tested the association of the -889 C/T biallelic polymorphism of the IL1A gene with several clinical features of the disease. RESULTS: Patients with migraine carrying the T/T genotype show an age at onset of the disease that is significantly (P <.01) lower than IL1A C/C or C/T carriers. In addition, the same genotype was significantly (P <.05) more frequent in patients with migraine with aura than in patients with migraine without aura. CONCLUSIONS: The results of our study suggest a role for the IL1A gene in modifying the clinical features of migraine.