Headache in patients with pituitary adenoma: clinical and paraclinical findings.

AIM: The aim of this article is to generate hypotheses for the mechanism of pituitary adenoma headache. PATIENTS AND METHODS: Fifty-eight patients with pituitary adenoma were prospectively analysed for prevalence and manifestation of tumour headache. Intrapersonal and neoplasm-associated risk factors were assessed. RESULTS: Twenty-four patients (41%) had tumour-attributed headache, seven had migraine-like, 11 tension-type headache-like headache, and three both. Cluster headache-like headache was found once, and two headaches remained unclassified. Tumour-attributed headache was associated with a positive history of headache (p = 0.03; OR 3.4), nicotine abuse (p < 0.01; OR 4.7), intake of acute headache medication (p = 0.04; OR 3.3), and a higher tumour proliferation indicated by a Ki67-labelling index (LI) >3% (p = 0.02; OR 11.0). For patients with migraine-like tumour-attributed headache, risk factors were younger age (p = 0.02), nicotine abuse (p < 0.01; OR 10.9), acute headache treatment (p < 0.01; OR 9.0), and Ki67-LI >3% (p = 0.03; OR 14.1). For tension-type headache-like headache, the main risk factor was a positive history of tension-type headache (p = 0.045; OR 5.6). CONCLUSION: Headache predisposition and local tumour effects might be important for the pathophysiology of pituitary adenoma headache and tumour headache in general.

Glioblastoma-dependent differentiation and angiogenic potential of human mesenchymal stem cells in vitro.

Tumor angiogenesis is of central importance in the malignancy of glioblastoma multiforme (GBM). As previously shown, human mesenchymal stem cells (hMSC) migrate towards GBM and are incorporated into tumor microvessels. However, phenotype and function of recruited hMSC remain unclear. We evaluated the differentiation and angiogenic potential of hMSC after stimulation with glioblastoma-conditioned medium in vitro. Immunostaining with endothelial, smooth muscle cell and pericyte markers was used to analyze hMSC differentiation in different concentrations of tumor-conditioned medium (CM), and the angiogenic potential was evaluated by matrigel-based tube-formation assay (TFA). Immunofluorescence staining revealed that tumor-conditioned hMSC (CM-hMSC) expressed CD 151, VE-cadherin, desmin, α-smooth muscle actin, nestin, and nerval/glial antigen 2 (NG2) in a CM concentration-dependent manner, whereas no expression of von-Willebrand factor (vWF) and smooth myosin could be detected. These findings are indicative of GBM-dependent differentiation of hMSC into pericyte-like cells, rather than endothelial or smooth muscle cells. Furthermore, TFA of hMSC and CM-hMSC revealed CM-dependent formation of capillary-like networks, which differed substantially from those formed by human endothelial cells (HUVEC), also implying pericyte-like tube formation. These results are indicative of GBM-derived differentiation of hMSC into pericyte-like mural cells, which might contribute to the neovascularization and stabilization of tumor vessels.

Headache in juvenile myoclonic epilepsy.

The objective of this study was to assess the prevalence of and risk factors for primary headaches in juvenile myoclonic epilepsy (JME). Headache was classified in 75 patients with JME using a questionnaire, and its prevalence was correlated with the literature on the general population and clinical data. Headache was present in 47 patients. Thirty-one had migraine [20 migraine without aura (MO), 11 migraine with aura (MA)]. Fourteen patients with migraine had tension-type headache (TTH) in addition. Sixteen had only TTH. Comparison with the general population revealed a significantly higher prevalence of migraine (RR 4.4), MO (3.6), MA (7.3) and TTH (3.4) in JME. Risk factors for migraine and MO were female gender and for MA family history of migraine in first-degree relatives. Migraine and MA were associated with fairly controlled generalized tonic clonic seizures, MO with absences. Together with its strong genetic background, JME appears to be an attractive homogenous subtype of epilepsy for genetic research on migraine.

Botulinum toxin type-A therapy in cluster headache: an open study.

The objective of this open single-centre study was to evaluate the efficacy and tolerability of botulinum toxin type-A (BTX-A) as add-on in the prophylactic treatment of cluster headache (CH). Twelve male patients with episodic (n=3) or chronic (n=9) CH, unresponsive to common prophylactic medications, were treated with a cumulative dose of 50 International Units (IU) BTX-A according to a standardised injection scheme into the ipsilateral pericranial muscles. One patient with chronic CH experienced a total cessation of attacks and in 2 patients attack intensity and frequency improved. In another patient with chronic CH typical attacks were not influenced, but an ipsilateral continuous occipital headache significantly improved. Patients with episodic CH did not benefit from BTX-A treatment. Tolerability was excellent. These findings provide evidence that BTX-A may be beneficial as an add-on prophylactic therapy for a limited number of patients with chronic CH.

Detection of bone marrow-derived cells expressing a neural phenotype in the human brain.

Animal studies suggest that adult bone marrow cells have the potential to migrate into the brain and generate new neural cells. Because data on this physiologic repair mechanism in humans are lacking, we investigated bone marrow engraftment into the brain of bone marrow recipients after sex-mismatched transplantation. Brain sections of seven allogeneic female bone marrow recipients were examined. The Y-chromosome, which served as a natural marker of donor bone marrow-derived cells after male-to-female transplantation, was identified by in situ hybridization. The neural phenotype of Y-chromosome-positive cells was determined using neural nuclear protein (NeuN) immunohistochemistry. Y-chromosome-positive cells expressing NeuN were found within the first 3 months after transplantation in both the cerebrum and the cerebellum at a frequency of 0.003% to 0.013% of all neurons. These cells were observed only in patients with cerebral lymphocytic infiltration and graft-versus-host disease. Our data suggest that adult bone marrow cells are capable of generating cells that express the neural marker NeuN early after transplantation. Cells with this specific phenotype may contribute to tissue repair in brain regions remote from neurogenic zones.

Evaluation of the efficacy of intravenous acetaminophen in the treatment of acute migraine attacks: a double-blind, placebo-controlled parallel group multicenter study.

The efficacy of intravenous acetaminophen (1000mg) in the treatment of acute migraine attacks as an alternative to parenteral application of lysine acetylsalicylate or triptans was investigated, using a multi-center, randomized, double-blind, placebo controlled study design. Migraine diagnosis was made according to the International Headache Society Classification. Sixty patients were included in three headache outpatient centers (Neurology Departments of the Universities of Regensburg, Münster and München). In the acute migraine attack patients were treated intravenously with either 1000mg paracetamol (acetaminophen) or placebo. The primary end point was pain-free after 2h. Secondary efficacy criteria were pain-free after 24h or pain relief after 2hours and after 24hours. With regard to the efficacy criteria, 37% of patients reported pain relief or painfree after two hours, 12 patients after treatment with acetaminophen and 10 patients after treatment with placebo. Out of these, 3 patients in the acetaminophen and 4 patients in the placebo group were painfree. After 24hours 86% of the patients reported pain relief: 24 treated with acetaminophen and 27 treated with placebo. The results indicate, that 1000mg intravenous acetaminophen is not superior to placebo in treating severe acute migraine attacks.

Calcineurin inhibitor-induced headache: clinical characteristics and possible mechanisms.

OBJECTIVE: To classify the headache syndromes under treatment with calcineurin inhibitors and to investigate whether the latter influence the nitric oxide production of human brain microvascular cells (HBMEC). BACKGROUND: Single cases of cyclosporine-induced headaches have been reported. Since calcineurin inhibitors are known to influence the renal metabolism of NO, a key molecule in tension-type headache and migraine, we were interested whether calcineurin inhibitors might change NO metabolism in HBMEC as well. DESIGN AND METHODS: Headache symptoms of 74 patients receiving cyclosporine and/or tacrolimus for organ transplantation were retrospectively assessed. Furthermore, the effect of cyclosporine and tacrolimus on nitric oxide production in human brain microvascular endothelial cells was investigated after incubation. RESULTS: Only 18 of the 74 patients reported no headache 1-36 months after liver, lung, or bone-marrow transplantation, 28 reported a new headache, and 17 an increase in the frequency or intensity of a pre-existing headache. The headache was generally classified as migraine without aura (IHS 1.1) or migraine-like headache (IHS 1.6). Furthermore, we found significantly increased NO production after co-incubation of calcineurin inhibitors with human brain microvascular endothelial cells. CONCLUSION: The pathophysiological mechanism of these headaches may be connected with an endothelial dysfunction in terms of increased production of NO.

Cerebral endothelial expression of adhesion molecules in mice with chronic graft-versus-host disease.

BACKGROUND AND PURPOSE: Graft-versus-host disease (GvHD) is a major complication after allogeneic bone marrow transplantation (BMT). The theory that the central nervous system (in addition to the peripheral nervous system) participates in GvHD has been supported by detection of cerebral lymphomononuclear infiltrates in experimental GvHD and the observation of cerebral angiitis-like disease in patients with chronic GvHD. METHODS: In a murine BMT model, we investigated the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on cerebral endothelium after allogeneic and syngeneic transplantation. Through the use of ICAM-1-knockout mice, the effect of ICAM-1 deficiency on cellular infiltration was evaluated. As an indicator of enhanced apoptotic cell death, we examined the cerebral expression of Fas antigen (Fas), the occurrence of the poly-ADP ribose polymerase p85 fragment, and the distribution of TUNEL positive-stained cells. RESULTS: In close correlation with earlier findings of cerebral infiltration in the same animals, we found cerebral endothelial upregulation of ICAM-1 and especially of VCAM-1 in allogeneic recipients compared with syngeneic animals without GvHD and unmanipulated controls. In ICAM-1-knockout mice, leukocytic infiltration did not differ from that in wild-type animals. Neither cerebral histopathologic changes nor an apoptotic effect of cellular infiltrates on brain parenchyma could be detected. CONCLUSIONS: In this model of experimental GvHD, VCAM-1 may play a critical role in leukocyte recruitment into the central nervous system of animals with chronic GvHD.

Expression of neuronal markers in differentiated marrow stromal cells and CD133+ stem-like cells.

Bone marrow stromal cells, which normally give rise to bone, cartilage, adipose tissue, and hematopoiesis-supporting cells, have been shown to differentiate in vitro and in vivo into neural-like cells. In this study, we examined the expression of neuronal and glial markers in human marrow stromal cells under culture conditions appropriate for neural stem cells, and compared the unsorted cell population to bone marrow CD133+ stem-like cells using immunofluorescence, Western blot, and functional patch-clamp analysis. Overall, the expression of the early neuronal marker beta3-tubulin was most pronounced in the presence of DMEM/F12 and neurotrophin 3 (NT3) or brain-derived neurotrophic factor (BDNF), when marrow stromal cells were cultured onto fibronectin. Electrophysiological examination, however, could not show fast sodium currents or functional neurotransmitter receptors in differentiated marrow stromal cells. CD133+ mesenchymal stem-like cells, but not CD34+/CD133- cells, generally showed a higher expression of neuronal markers than did unsorted marrow stromal cells, and differentiated CD133+ cells more resembled neuron-like cells.