Vincenzo Tullo

Vagus nerve stimulation in drug-resistant daily chronic migraine with depression: preliminary data

Drug refractory chronic daily headache (CDH) is a highly disabling condition. CDH is usually regarded as the negative evolution of chronic migraine (CM) and is characterized by high prevalence of psychiatric disorders, especially mood disorders. Vagal nerve stimulation (VNS) is an established treatment option for selected patients with medically refractory epilepsy and depression. Neurobiological similarities suggest that VNS could be useful in the treatment of drug-refractory CM associated with depression. The aim of the study was to evaluate the efficacy of VNS in patients suffering from drug-refractory CM and depressive disorder. We selected four female patients, mean age 53 (range 43–65 years), suffering from daily headache and drug-refractory CM. Neurological examination and neuroradiological investigations were unremarkable. Exclusion criteria were psychosis, heart and lung diseases. The preliminary results in our small case series support a beneficial effect of chronic VNS on both drug-refractory CM and depression, and suggest this novel treatment as a valid alternative for this otherwise intractable and highly disabling condition.

Deep brain stimulation and cluster headache.

In recent years, neuroimaging data have greatly improved the knowledge on trigeminal autonomic cephalalgias’ (TACs) central mechanisms. Positron emission tomography studies have shown that the posterior inferior hypothalamic grey matter is activated during cluster headache attacks as well as in short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). Voxel-based morphometric MRI has also documented alteration in the same area in cluster headache patients. These data suggest that the cluster headache generator is located in this region and leads us to hypothesise that stimulation of this brain area could relieve intractable cluster headache just as deep brain stimulation improves intractable movements disorders. This view received support by the observation that high frequency stimulation of the ipsilateral hypothalamus prevented attacks in an otherwise intractable chronic cluster headache patient previously treated unsuccessfully by surgical procedures to the trigeminal nerve. So far, 16 patients with intractable cronic cluster headache (CCH) and one intractable SUNCT patient have been successfully treated by hypothalamic stimulation. The procedures were well tolerated with no significant adverse events. Hypothalamic DBS is an efficacious and safe procedure to relieve otherwise intractable CCH and SUNCT.

Neuroimaging and pain: a window on the autonomic nervous system.

Pain is one of the most common experiences of humans. Neuroimaging techniques can visualize the main brain areas involved in pain modulation, the pain matrix. It is noteworthy that many of the brain areas forming the pain matrix are also involved in modulating autonomic nervous system (ANS) activity that in turn plays a major role in determining the best adaptive response to the pain experience. The tight connection between the pain system and ANS is also evident from neuroanatomical studies indicating that the lamina 1 neurons receive both painful and visceral stimuli from all visceral organs giving rise to the spinothalamocortical pathway concerned with conveying interoceptive information to central structures. The resulting interoceptive stream projects to the viscerosensory cortex in the mid-insula and onto the right anterior insula and orbitofrontal cortices. Right anterior insula activation is involved in the sympathetic arousal associated with mental tasks. This brain region receives numerous other inputs including pain and painful stimuli are conveyed somatotopically to both insulae. A similar somatotopic organization of painful stimuli has also been shown in the basal ganglia involved in cognitive, affective, motor and autonomic states. This highly specialized organization of nociceptive information in these brain areas may subserve a number of functions, particularly of coupling pain with the most appropriate autonomic states and affective/emotional states. The anterior cingulated cortex, another brain area playing a crucial role in nociception, is also directly involved in the control of autonomic functions such as arousal during volitional behaviour, including effortful cognitive processing. It is evident that the nociceptive system and ANS closely interact in many processes involved in maintaining internal homeostatis and in order to give the most appropriate biological substrate for cognitive, affective and emotional states.

Psychopathological profile of patients with chronic migraine and medication overuse: Study and findings in 50 cases

Patients with chronic migraine (CM) have high frequence of psychiatric comorbidity or psychological distress. The presence of depression, anxiety, panic or obsessive disorders in these patients contributes to poor quality of life and can influence prognosis and treatment. A systematic investigation of psychiatric comorbidity is needed in patients with CM especially in those with medication overuse (MO), in order to reach a more comprehensive clinical management. We assessed the psychological profile of 50 patients, 40 women and 10 men suffering from CM with MO. The Spectrum Project, a complementary way of describing and assessing psychopathology with structured clinical interviews, was used for the psychological evaluation of the patients to explore personality traits. Spectrum instruments mood disorders (MOODS), panic agoraphobic disorders (PAS) and obsessive–compulsive disorder (OBS) were applied to study patients. OBS-questionnaire was positive in 28% of the patients, MOODS-questionnaire in 44%, PAS-questionnaire in 46%. 19 on 50 patients (38%) presented positivity to 2 or to all questionnaires in variable associations. None of the patients of the studied group had complete normal findings in the questionnaires. Clinical records of patients with OBS-questionnaire positivity showed a worse clinical course and tendency to relapse. These results suggest that psychological assessment is an essential step in the evaluation and treatment of patients with CM and MO. The remarkable percentage of OBS-questionnaire positivity in this group indicates that obsessive–compulsive trait represents besides depression and anxiety, a major risk of chronification and overusing.

Frovatriptan for the prevention of postdural puncture headache

Efficacy of 5–day treatment with oral frovatriptan 2.5 mg/die for the prophylaxis of post-dural puncture headache (PDPH) was tested in 50 in-patients. A mild headache occurred in 7 (14%) patients for a total of 9 days (p < 0.01 vs. no-PDPH). Most episodes of PDPH occurred in the first days of treatment (only 1 patient had headache at dismissal): 5 patients had only 1 episode, while 2 had headache for 2 consecutive days. No other symptoms were recorded. Occurrence of PDPH in a subgroup of 6 (12%) patients previously submitted to a diagnostic lumbar puncture was also examined: 4 of them reported a PDPH on the previous lumbar puncture in absence of triptans. In only 1 of these 4 patients PDPH recurred under treatment with frovatriptan. In conclusion, our non-randomized open-label study suggests efficacy of oral frovatriptan for PDPH prevention. These results need to be confirmed in a randomized, controlled, double-blind study.

Functional neuroimaging and headache pathophysiology: new findings and new prospects

In the last ten years pathophysiology of primary headaches has received new insights from neuroimaging studies. Positron emission tomography (PET) showed activation of specific brain structures, brainstem in migraine and hypothalamic grey in trigeminal autonomic cephalalgias. This brain activation suggests it may intervene both in a permissive or triggering manner and as a response to pain driven by the first division of the trigeminal nerve. Voxel-based morphometry has suggested that there is a correlation between the brain area activated specifically in acute cluster headache – the posterior hypothalamic grey matter – and an increase in grey matter in the same region. New insights into mechanisms of head pain have emerged thanks to neuroimaging obtained in experimentally induced headaches, and during peripheral and central neurostimulation.

Deep brain stimulation in craniofacial pain: Seven years' experience

Cluster headache (CH) is a primary headache with excruciatingly painful attacks that are strictly unilateral. About 10% of cases experience no significant remission, and about 15% of these do not respond to medication, so surgery is considered. Neuroimaging studies show that the posterior inferior hypothalamus is activated during CH attacks and is plausibly the CH generator. We report on 16 chronic CH patients, with headaches refractory to all medication, who received long-term hypothalamic stimulation following electrode implant to the posterior inferior hypothalamus. After a mean follow-up of 23 months, a persistent pain-free to almost pain-free state was achieved in 13/16 patients (15/18 implants; 83.3%) a mean of 42 days (range 1–86 days) after monopolar stimulation initiation. Ten patients (11 implants) are completely pain-free. A common side effect was transient diplopia, which limited stimulation amplitude. In one patient, a small non-symptomatic haemorrhage into the 3rd ventricle occurred following implant, but regressed 24 h later. Persistent side effects are absent except in one patient with bilateral stimulation, in whom stimulation was stopped to resolve vertigo and worsened bradycardia, but was resumed later without further problems. Hypothalamic stimulation is an effective, safe and well tolerated treatment for chronic drug-refractory CH. It appears as a valid alternative to destructive surgical modalities, and has the additional advantage of being reversible.

Comparison of frovatriptan plus dexketoprofen (25 mg or 37.5 mg) with frovatriptan alone in the treatment of migraine attacks with or without aura: A randomized study

Background Drugs for migraine attacks include triptans and NSAIDs; their combination could provide greater symptom relief. Methods A total of 314 subjects with history of migraine, with or without aura, were randomized to frovatriptan 2.5 mg alone (Frova), frovatriptan 2.5 mg + dexketoprofen 25 mg (FroDex25) or frovatriptan 2.5 mg + dexketoprofen 37.5 mg (FroDex37.5) and treated at least one migraine attack. This was a multicenter, randomized, double-blind, parallel-group study. The primary end point was the proportion of pain free (PF) at two hours. Secondary end points were PF at one and four hours, pain relief (PR) at one, two, four hours, sustained PF (SPF) at 24 and 48 hours, recurrence at 48 hours, resolution of nausea, photophobia and phonophobia at two and four hours, the use of rescue medication and the judgment of the treatment. Results The results were assessed in the full analysis set (FAS) population, which included all subjects randomized and treated for whom at least one post-dose intensity of headache was recorded. The proportions of subjects PF at two hours (primary end point) were 29% (27/93) with Frova compared with 51% (48/95 FroDex25 and 46/91 FroDex37.5) with each combination therapies (p < 0.05). Proportions of SPF at 24 hours were 24% (22/93) for Frova, 43% (41/95) for FroDex25 (p < 0.001) and 42% (38/91) for FroDex37.5 (p < 0.05). SPF at 48 hours was 23% (21/93) with Frova, 36% (34/95) with FroDex25 and 33% (30/91) with FroDex37.5 (p = NS). Recurrence was similar for Frova (22%, 6/27), FroDex25 (29%, 14/48) and FroDex37.5 (28%, 13/46) (p = NS), meaning a lack of improvement with the combination therapy. Statistical adjustment for multiple comparisons was not performed. No statistically significant differences were reported in the occurrence of total and drug-related adverse events. FroDex25 and FroDex37.5 showed a similar efficacy both for primary and secondary end points. There did not seem to be a dose response curve for the addition of dexketoprofen. Conclusion FroDex improved initial efficacy at two hours compared to Frova whilst maintaining efficacy at 48 hours in this study. Tolerability profiles were comparable. Intrinsic pharmacokinetic properties of the two single drugs contribute to this improved efficacy profile.

Prolonged Focal Negative Motor Seizures: A Video-EEG Study

Summary:  Purpose: Focal negative motor (akinetic) seizures are rare ictal events that are diagnostically challenging because they are difficult to differentiate from postictal Todd paresis, transient ischemic attacks, migraine events, and psychogenic episodes.

Epidemiology of fixed unilateral headaches

A fixed location unilateral headache suggests involvement of a precise nervous structure, and neuroimaging investigations are essential to seek to identify it. Nevertheless, side-locked primary headaches also occur, although they are rare. Side-locked primary headaches are more frequently found in the group of the short-lasting (≤ 4 hours) headaches but long-lasting headache forms may also present with the pain always on the same side, including migraine, tension-type headache, new daily persistent headache and cervicogenic headache. Future studies should address the issue whether patients with side-locked headache form differ from those with non-side-locked form both in terms of natural history and biological markers. Among 63 consecutive chronic cluster headache patients seen by us from 1999 to 2007, 32 (51±) had side shift. We also found that the duration of the chronic condition was significantly longer in those with side shift than those without. The high frequency of side shift in chronic cluster headache should be considered when proposing surgical treatment for severe intractable forms of the disease.