Heike Israel

Clinical and psychopathological definition of the interictal dysphoric disorder of epilepsy.

Purpose: Different authors suggested the occurrence of a pleomorphic affective syndrome in patients with epilepsy named interictal dysphoric disorder (IDD). We sought to investigate whether IDD occurs only in patients with epilepsy and to validate IDD features against DSM‐IV criteria.

Increased serotonin transporter availability in the brainstem of migraineurs

For decades, serotonin has been speculated to play a major role in migraine pathophysiology. The central serotonergic system is located in the raphe nuclei and the adjacent reticular formation in the brainstem. Recently, radioligands targeting the brain serotonin transport protein (SERT) have been developed. We used the highly specific SERT-radioligand 123I-ADAM [2-((2-((dimethylamino) methyl)phenyl)thio)-5-iodophenylamine] to test the hypothesis of the mesopontine serotonergic system being involved in the pathophysiology of migraine. Nineteen migraine patients and 10 healthy, age- and sex-matched controls were enrolled. The neuroimaging study was performed interictally during the pain-free interval. Single Photon Emission Computed Tomography (SPECT)-images were coregistered with MRI-scans. Region of interest (ROI)-analysis revealed a highly significant increase of 123I-ADAM uptake in the mesopontine brainstem of migraineurs (p < 0.001). In contrast, 123IADAM uptake in the thalamus did not differ significantly between migraineurs and controls. Our study demonstrates for the first time a significant increase of brainstem SERT-availability in migraineurs, suggesting a dysregulation of the brainstem serotonergic system. It remains to be elucidated whether the altered SERT-availability is causally related to migraine pathophysiology or whether it reflects secondary pathophysiological mechanisms.

Efficacy of lisinopril in migraine prophylaxis – an open label study

The ACE‐inhibitor lisinopril has previously been shown to be effective in migraine prophylaxis at a daily dose of 20 mg. To test the effect of a low dose of lisinopril (5 mg daily) in migraine prevention, we performed an open label study in 21 migraineurs. The primary outcome measure was frequency of migraine attacks. Secondary efficacy measures were migraine hours, intake of acute migraine drugs, pain intensity and responder rate. Compared with baseline conditions, the attack frequency of migraine attacks was significantly reduced (P < 0.0005). The number of acute migraine drugs dropped significantly (P = 0.002). Three patients dropped out because of intolerable cough. Our study suggests that even low doses of lisinopril may be effective in migraine treatment. However, its use may be limited by intolerable side‐effects.

The use of gabapentin in chronic cluster headache patients refractory to first‐line therapy

Chronic cluster headache (CCH) is a rare but challenging condition. About 20% of CCH patients get refractory to treatment. Gabapentin has recently been reported to be efficacious in the treatment of CCH. To test the potential of gabapentin as second‐line drug, we prospectively studied the efficacy of gabapentin as add‐on drug in eight patients suffering from CCH refractory to first‐line treatment. Six of eight CCH patients responded to treatment. After the end of the study phase, the patients’ clinical course was further followed up until January 2006. The longest period of being continuously pain‐free under gabapentin treatment was 18 months. In some individuals, increasing doses were needed with time. We conclude that gabapentin may be offered as treatment trial in patients refractory to first‐line treatment. However, patients may fail to respond to treatment and drug tolerance may occur with time.

Levetiracetam in patients with central neuropathic post-stroke pain: A randomized, double-blind, placebo-controlled trial

Central post‐stroke pain (CPSP) is a severe chronic neuropathic pain condition defined as a spontaneous pain or allodynia corresponding to a vascular lesion. It usually evolves weeks after stroke, and can distinctively impair the quality of life. Treatment is complex and mostly unsatisfactory. We hypothesized that the anti‐epileptic drug levetiracetam (LEV) improves CPSP compared with placebo. The purpose of this study was to examine the efficacy and tolerability of LEV in patients with CPSP.

The use of radiolabelled human serum albumin and SPECT/MRI co-registration to study inflammation in the cavernous sinus of cluster headache patients.

A sterile inflammation in the cavernous sinus was hypothesized to underlie cluster headache (CH). Neurogenic inflammation is accompanied by the extravasation of plasma proteins in the surrounding tissue. We tested the hypothesis of an inflammatory process in the cavernous sinus in CH patients using 99mTc-human serum albumin (HSA) and single photon emission computed tomography (SPECT). Six patients with episodic CH were enrolled. After baseline imaging, CH attacks were induced by IV injection of nitroglycerin. The patients remained untreated for 20 min. A second SPECT was performed after successful treatment. Region of interest (ROI) analysis was performed on the basis of coregistered MRI/SPECT data. There was no statistical difference between the 99mTc-HSA uptake in the ipsilateral cavernous sinus before and after induction of an acute CH attack. There was no evidence for 99mTc-HSA extravasation in the cavernous sinus during the active episode as compared with the remission phase. Our results do not support the hypothesis of an inflammation in the cavernous sinus.

Corticosteroids alter CGRP and melatonin release in cluster headache episodes.

Background Calcitonin gene-related peptide (CGRP) is a marker of trigeminal activation in acute cluster headache (CH). Melatonin production is altered in CH patients and may reflect hypothalamic dysfunction. We assessed the effects of short-term CH prevention with corticosteroids on CGRP and melatonin release in a prospective observational cohort study hypothesizing that corticosteroids influence the interictal activity of both systems indicated by the change of these biomarkers. Methods Episodic CH subjects (n = 9) in the bout and controls with multiple sclerosis (n = 6) received 1000 mg/d methylprednisolone (MPD) i.v. for three days followed by oral tapering with prednisone. We determined CGRP plasma levels in external jugular vein blood outside an attack and 6-sulfatoxymelatonin (aMT6s) – the stable metabolite of melatonin – in 12-hour day- and nighttime urine collection prior to and several times after MPD therapy and again when CH subjects were outside the bout in complete remission. CH patients recorded the frequency of attacks. Results In parallel to the reduction of headache frequency, administration of corticosteroids resulted in significantly decreased CGRP plasma levels and increased nocturnal aMT6s urine excretion in CH subjects. No significant changes were observed in controls. Conclusion Corticosteroids alter CGRP plasma and aMT6s urine levels in a cluster bout. These changes may indicate an effect of corticosteroids on trigeminal activation and hypothalamic dysfunction.

The pharmacological profile and clinical prospects of the oral 5-HT1F receptor agonist lasmiditan in the acute treatment of migraine

More than 20 years have passed without the launch of a new substance class for acute migraine therapy. Triptans were the latest class of substances which successfully passed all developmental stages with a significant antimigraine efficacy and a sufficient safety profile. New drugs with a better adverse event profile and at least similar efficacy are needed for migraine subjects who cannot tolerate triptans for attack treatment. Lasmiditan is a novel highly specific 5-HT1F receptor agonist currently in clinical trials for acute migraine therapy and devoid of vasoconstriction in coronary arteries as determined in a surrogate assay. In both phase II randomized, placebo-controlled trials in acute migraine the primary endpoint was met. For the intravenous formulation a clear dose-dependent effect on headaches could be determined. Lasmiditan tablets in doses of 50–400 mg show significant headache relief after 2 hours compared with placebo and improved accompanying symptoms. This substance is chemically clearly different from other antimigraine drugs, which is also reflected by its dose-dependent adverse event profile chiefly including dizziness, vertigo, paresthesia and fatigue. Adverse events are usually linked to the central nervous system. Future phase III clinical trials with an active triptan comparator or in a preferential trial design will allow a better comparison of lasmiditan and triptans. They will also determine whether lasmiditan will become available to the migraine patient.

No Microstructural White Matter Alterations in Chronic and Episodic Migraineurs: A Case-Control Diffusion Tensor Magnetic Resonance Imaging Study

In patients with episodic migraine (EM), diffusion tensor imaging (DTI) revealed microstructural white matter alterations in various brain regions related to pain processing. Some of these changes were correlated with migraine duration and attack frequency, suggesting that migraine is a progressive disease with proceeding structural alterations of the brain. This study aimed to identify possible microstructural white matter alterations in patients with chronic migraine (CM) using DTI. We hypothesized that alterations in DTI are more pronounced in patients with CM compared with EM.

Health-related quality of life measures and psychiatric comorbidity in patients with migraine

Background and purpose:  The identification of factors associated to health‐related quality of life (HRQoL) measures in patients with migraine has major implications in terms of prognosis and treatment. This study aimed at investigating associations between HRQoL and comorbid mood and anxiety disorders.