Diagnosis, pathophysiology and management of chronic migraine: a proposal of the Belgian Headache Society.

Chronic migraine (CM) is a disabling neurological condition affecting 0.5-2 % of the population. In the current third edition of the International Classification of Headache Disorders, medication overuse is no longer an exclusion criterion and CM is diagnosed in patients suffering from at least 15 headache days per month of which at least eight are related to migraine. CM is difficult to treat, and preventive treatment options are limited. We provide a pathogenetic model for CM, integrating the latest findings from neurophysiological and neuroimaging studies. On behalf of the Belgian Headache Society, we present a management algorithm for CM based on the international literature and adapted to the Belgian situation. Pharmacological treatment options are discussed, and recent data on transcranial and invasive neuromodulation studies in CM are reviewed. An integrated multimodal treatment programme may be beneficial to refractory patients, but at present, this approach is only supported by a limited number of observational studies and quite variable between centres.

Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial.

OBJECTIVE: To assess efficacy and safety of trigeminal neurostimulation with a supraorbital transcutaneous stimulator (Cefaly, STX-Med., Herstal, Belgium) in migraine prevention. METHODS: This was a double-blinded, randomized, sham-controlled trial conducted at 5 Belgian tertiary headache clinics. After a 1-month run-in, patients with at least 2 migraine attacks/month were randomized 1:1 to verum or sham stimulation, and applied the stimulator daily for 20 minutes during 3 months. Primary outcome measures were change in monthly migraine days and 50% responder rate. RESULTS: Sixty-seven patients were randomized and included in the intention-to-treat analysis. Between run-in and third month of treatment, the mean number of migraine days decreased significantly in the verum (6.94 vs 4.88; p = 0.023), but not in the sham group (6.54 vs 6.22; p = 0.608). The 50% responder rate was significantly greater (p = 0.023) in the verum (38.1%) than in the sham group (12.1%). Monthly migraine attacks (p = 0.044), monthly headache days (p = 0.041), and monthly acute antimigraine drug intake (p = 0.007) were also significantly reduced in the verum but not in the sham group. There were no adverse events in either group. CONCLUSIONS: Supraorbital transcutaneous stimulation with the device used in this trial is effective and safe as a preventive therapy for migraine. The therapeutic gain (26%) is within the range of those reported for other preventive drug and nondrug antimigraine treatments. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that treatment with a supraorbital transcutaneous stimulator is effective and safe as a preventive therapy for migraine.

Orbitofrontal cortex involvement in chronic analgesic-overuse headache evolving from episodic migraine.

The way in which medication overuse transforms episodic migraine into chronic daily headache is unknown. To search for candidate brain areas involved in this process, we measured glucose metabolism with 18-FDG PET in 16 chronic migraineurs with analgesic overuse before and 3 weeks after medication withdrawal and compared the data with those of a control population (n = 68). Before withdrawal, the bilateral thalamus, orbitofrontal cortex (OFC), anterior cingulate gyrus, insula/ventral striatum and right inferior parietal lobule were hypometabolic, while the cerebellar vermis was hypermetabolic. All dysmetabolic areas recovered to almost normal glucose uptake after withdrawal of analgesics, except the OFC where a further metabolic decrease was found. A subanalysis showed that most of the orbitofrontal hypometabolism was due to eight patients overusing combination analgesics and/or an ergotamine-caffeine preparation. Medication overuse headache is thus associated with reversible metabolic changes in pain processing structures like other chronic pain disorders, but also with persistent orbitofrontal hypofunction. The latter is known to occur in drug dependence and could predispose subgroups of migraineurs to recurrent analgesic overuse.

Suboccipital injection with a mixture of rapid- and long-acting steroids in cluster headache: a double-blind placebo-controlled study.

Oral steroids can interrupt bouts of cluster headache (CH) attacks, but recurrence is frequent and may lead to steroid-dependency. Suboccipital steroid injection may be an effective 'single shot' alternative, but no placebo-controlled trial is available. The aim of our study was to assess in a double-blind placebo-controlled trial the preventative effect on CH attacks of an ipsilateral steroid injection in the region of the greater occipital nerve. Sixteen episodic (ECH) and seven chronic (CCH) CH outpatients were included. ECH patients were in a new bout since no more than 1 week. After a one-week run-in period, patients were allocated by randomization to the placebo or verum arms and received on the side of attacks a suboccipital injection of a mixture of long- and rapid-acting betamethasone (n=13; Verum-group) or physiological saline (n=10; Plac-group). Acute treatment was allowed at any time, additional preventative therapy if attacks persisted after 1 week. Three investigators performed the injections, while four others, blinded to group allocation, followed the patients. Follow-up visits were after 1 and 4 weeks, whereafter patients were followed routinely. Eleven Verum-group patients (3 CCH) (85%) became attack-free in the first week after the injection compared to none in the Plac-group (P=0.0001). Among them eight remained attack-free for 4 weeks (P=0.0026). Remission lasted between 4 and 26 months in five patients. A single suboccipital steroid injection completely suppresses attacks in more than 80% of CH patients. This effect is maintained for at least 4 weeks in the majority of them.

Somatosensory evoked high-frequency oscillations reflecting thalamo-cortical activity are decreased in migraine patients between attacks.

A deficit of habituation in cortical information processing, including somatosensory evoked potentials (SSEPs), is the most consistent neurophysiological abnormality in migraine patients between attacks. To explore further the mechanisms underlying this interictal neural dysfunction, we have studied the high-frequency oscillations (HFOs) embedded in SSEPs because they are thought to reflect spike activity in thalamo-cortical cholinergic fibres (early HFOs) and in cortical inhibitory GABAergic interneurons (late HFOs). Untreated migraine patients with (MA) and without (MO) aura were recorded during (n = 13: nine MO, four MA) and between attacks (n = 29: 14 MO, 15 MA) and compared with healthy volunteers. SSEPs were filtered off-line (digital band-pass between 450 and 750 Hz) to extract the two HFO bursts from the broad-band contralateral N20 somatosensory cortical response obtained by median nerve stimulation. In both migraine groups, amplitudes and latencies of conventional broad-band SSEPs recorded interictally from cervical and parietal active electrodes were not significantly different from those found in healthy volunteers. In contrast, maximum peak-to-peak amplitude and area under the rectified curve of the early HFO burst were significantly smaller in both MA and MO patients than in healthy volunteers. There was no significant difference in the later HFO burst between migraineurs and healthy volunteers. During attacks, all electrophysiological measurements in migraineurs were similar to those found in healthy volunteers. Thalamo-cortical activation, as reflected by the early SSEP HFO burst, may thus be reduced in migraine interictally, but normalizes during an attack, whereas intracortical inhibition, as indexed by the late HFO burst, is normal at any time. This supports the hypothesis that the habituation deficit in migraineurs is due to a reduced pre-activation level of sensory cortices and not to increased cortical excitability or reduced intracortical inhibition.

Transcranial magnetic stimulation in migraine: a review of facts and controversies.

There is compelling evidence that cortical excitability is modified in migraine patients between attacks. Transcranial magnetic stimulation (TMS) is a non-invasive tool to investigate this abnormality. Repetitive transcranial magnetic stimulation (rTMS) activates the underlying cortex at high, but inhibits it at low stimulation frequencies. This is a review of published results obtained in migraineurs with TMS and rTMS over motor or visual cortices. Prevalence and/or threshold data of phosphenes induced by single pulse TMS of the visual cortex are contradictory, some favouring increased, others decreased interictal excitability. The discrepancies may be due to differences in methodology and poor reliability of phosphene reporting. In a recent rTMS study of the occipital cortex we have found evidence in favour of an interictal decrease of the preactivation excitability level by using amplitude of visual evoked potentials and its habituation during sustained stimulation as indices of cortical excitability. The hypothesis of increased cortical excitability, taken in its strict physiological sense of a decreased response threshold and/or an increased response to a single suprathreshold stimulus, may thus not be any longer tenable. The long lasting effects of rTMS allow in future studies to assess metabolic changes of the cortex and subcortical structures with functional imaging methods and to explore novel therapeutic strategies for migraine.

Effects of repetitive transcranial magnetic stimulation on visual evoked potentials: new insights in healthy subjects.

In a previous comparative study with migraineurs, we found in 24 normal subjects that the amplitude of the pattern-reversal visual evoked potential (PR-VEP) in the first block of 100 responses and its habituation over 6 sequential blocks were significantly decreased after 1 Hz repetitive transcranial magnetic stimulation (rTMS), while 10 Hz rTMS had no significant effect. We report here our results on the reproducibility of the rTMS effect studied in ten of these subjects by repeating the recordings for each frequency three times on different days. We have also reanalysed the data obtained in 24 normal subjects, looking separately at the results in those stimulated at an intensity equal to phosphene threshold (group 1; n=14) and those stimulated at 110% of motor threshold because of unelicitable phosphenes (group 2; n=10). We finally determined the precise duration of the rTMS effect. Despite some interindividual variability, the effects of both rTMS frequencies on first block amplitude, habituation between first and sixth block and habituation slope over the six blocks were highly reproducible. The only difference between the two groups of subjects was the effect of 1 Hz rTMS on the second measured PR-VEP component. Whereas first block amplitude of the first P1-N1 component and habituation were decreased in both groups, such a decrease was found for the second P1-N2 component only in group 1 stimulated at phosphene threshold. The dishabituation of the N1-P1 component after 1 Hz rTMS was maximal at 15 min, but lasted up to 33 min, while that of P1-N2 disappeared after 3 min. There was a non-significant trend ( p=0.06) for a reduction of first block amplitude after 10 Hz rTMS in the total group of subjects, but no effect on habituation. The inhibitory effect of 1 Hz rTMS, which reduces in healthy controls both first block PR-VEP amplitude and habituation, probably by decreasing the preactivation excitability level of the underlying visual cortex, is thus reproducible and long lasting. Long trains of 10 Hz rTMS tend to attenuate reproducibly the cortical preactivation level in normal subjects, but they do not affect habituation at all, which contrasts with their effect in migraineurs, in whom, as previously reported, they significantly correct the habituation deficit. The absence of an effect of 1 Hz rTMS on PR-VEP P1-N2 in subjects stimulated at 110% of motor threshold may be explained by the deeper anatomical location of the cortical generators of this component and the lower stimulation intensity used. Taken together our results confirm that the effect of rTMS on the underlying cortex depends on several variables such as frequency, intensity and level of cortical preactivation.

Intravascular malignant lymphomatosis: report of 2 neurological cases.

We report two cases of intravascular malignant lymphomatosis (IML) with a clinical expression limited to the central nervous system. The first patient presented with signs of cerebral, cerebellar and spinal cord involvement. The second had an isolated involvement of the spinal cord. In both cases the diagnosis was made at post-mortem examination; pre-mortem examination of biopsy tissue from peripheral nerve and muscle in the first case, spleen and liver in the second were unhelpful for the diagnosis of lymphoma. We review the published literature on IML, its ante-mortem diagnosis and treatment.