The lesson of chronic migraine.

The hypothesis that central sensitization/allodynia is the common final mechanism responsible for the progression of migraine pain is supported by the possibility of tracing back to allodynic mechanisms the action of the main risk factors for chronic migraine validated by the recent literature. The comorbidity between migraine and idiopathic intracranial hypertension without papilledema is emerging as a new, commonly overlooked risk factor for migraine progression whose putative mechanism might also converge on the sensitization of central pain pathways. If headache progression always occurs at the end of a pathogenetic sequence typical of an individual susceptibility to allodynia, then the primary character of chronic migraine might be debated. Allodynia is not specific to migraine but is implied in the progressive amplification of pain after repeated stimuli, a universal adaptive phenomenon. Being largely conditioned by the individual comorbidity profile, allodynia may only in part be defined as primary in itself. Many migraine comorbid conditions, including a hidden idiopathic intracranial hypertension without papilledema, may emphasize susceptibility to allodynia and promote chronic migraine. These factors and comorbid conditions require to be individually assessed and adequately treated to optimize the therapeutic response.

Cortical spreading depression and central pain networks in trigeminal nuclei modulation: time for an integrated migraine pathogenesis perspective.

The role of the cortical spreading depression (CSD)-dependent trigeminovascular activation in migraine etiopathogenesis, long considered paradigmatic, has remained substantially unproven in humans. The parallel advancement of functional neuroimaging techniques promoted the extensive exploration of the brain networks involved in pain processing in search of a possible central migraine generator. However, despite initial enthusiasms, it has not been possible to clarify whether the functional central "markers" of pain observed in primary headaches could be considered as causative or just the neural correlates of the ongoing pain. Nonetheless, our knowledge on the complex interactions between CSD, neurogenic inflammation, peripheral trigeminovascular input, central cortico-trigeminal nuclei direct modulation and pain processing and limbic system networks has enormously grown, allowing the reconceptualisation of migraine from a neurovascular to a pure neurolimbic pain disorder, therefore relocating it in the much broader frame of the brain and whole organism homeostatic control. In this work, the available evidences currently supporting the relevance of CSD, of peripheral trigeminovascular input and of direct cortico-trigeminal nuclei modulation in migraine pathogenesis are reviewed in the light of a possible integrated migraine etiopathogenetic perspective.

Pain as an evolutionary necessity.

The proposed title "Pain as an evolutionary necessity" could lead to a broad debate with implications covering many chapters of the medicine and particularly of clinical neurology. In the present perspective, the discussion will focus on migraine and cluster headache chosen as elective examples of biological and not only clinical conditions, that unveil the bond between pain and necessity. Migraine, cluster headache, and perhaps other primary headaches begin to be depicted in terms of recurrent activation of innate bio-behavioral specific patterns, with a crucial and highly conserved evolutionarily adaptive significance. The pan-mammalian sickness behavior and the fight or flight response, selectively activated by different kinds of pain, are here proposed as paradigmatic of migraine and cluster headache attacks associated behaviors, allowing to reformulate these forms as the inappropriate recurrent presentation of coordinated allostatic processes, modeled along million of years of natural evolution. In this light, all the multifaceted characteristics of migraine and cluster headache attacks can be reinterpreted as complex and integrated allostatic defensive reactions to an inescapable or to an escapable pain, respectively aimed to the restoration of biologic homeostasis through a temporary disengagement from active interaction with environment (migraine associated sickness behavior) or, on the contrary, to promote the coordinated biological changes preparatory to emergency and defensive behaviors (cluster headache-related fight or flight response).

Sinus venous stenosis-associated IIHWOP is a powerful risk factor for progression and refractoriness of pain in primary headache patients: a review of supporting evidences.

Reported prevalence of idiopathic intracranial hypertension without papilledema (IIHWOP) in series of patients with chronic or transformed migraine is significantly higher than expected; yet, IIHWOP is not included among the risk factors for migraine progression. However, several studies provided evidences suggesting that IIHWOP could represent a possible, largely underestimated, risk factor for progression of pain in migraine and, possibly, in other primary headaches. Data from two recent studies, albeit aimed to different end-points, strongly support this hypothesis. In the first study, conducted on a large series of neurological patients without any sign or symptom of raised intracranial pressure (ICP), including chronic headache, the prevalence of bilateral central venous stenosis at magnetic resonance venography (MRV) was 23% and an IIHWOP at opening pressure was found in 48% of this subgroup (11% of the whole sample) while it was not detected in any of the subjects with normal MRV. This indicates that IIHWOP may be much more prevalent than believed in general population and that it can run without any symptom or sign of raised ICP in most of affected subjects. In the second paper, sinus venous stenosis-associated IIHWOP has been found in about one half of a large chronic primary headache patients series with poor response to treatments and in none of those with normal MRV. Moreover, after the diagnostic lumbar puncture, a transient improvement of headache frequency has been observed in the majority of intracranial hypertensive chronic headache subjects. Taken together, the data of these two recent papers rise the following hypothesis: (1) asymptomatic IIHWOP is much more prevalent than expected in general population; (2) IIHWOP is a powerful and largely unrecognized risk factor for progression of pain in primary headache patients; (3) sinus venous stenosis at MRV is a reliable predictor of raised intracranial hypertension also in asymptomatic patients; (4) sinus venous stenosis has a causative role in IIH pathophysiology. These assumptions share a potential high clinical impact and need to be urgently tested in adequately designed controlled studies.

Predictive factors of neutralizing antibodies development in relapsing-remitting multiple sclerosis patients on interferon Beta-1b therapy.

The identification of predictive factors of NAbs development might have a relevant impact on clinical practice. Our objective is to look after predictive factors of NAbs development in MS IFN Beta-1b-treated patients. Database was screened for patients on IFN Beta-1b treatment with an Expanded Disability Status Scale (EDSS) at a baseline between 1 and 3.5, disease duration shorter than 15 years, and NAbs analysis performed every 6 months. The NAbs positive status was analysed in relation to baseline clinical, neuropsychological and brain imaging measures. Forty-nine patients were included. Sixteen patients had become NAbs positive at some point on IFN therapy (35%). NAbs producers differed from not producers for higher incidence of cognitive deficit and higher lesion load (OR = 5.0 and 5.6, respectively). Our study suggests that NAbs development might be a marker of a more aggressive disease and that worse outcome in NAbs producers might be biased by baseline condition.

An exploration of anger phenomenology in multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) patients are often emotionally disturbed. We investigated anger in these patients in relation to demographic, clinical, and mood characteristics. PATIENTS AND METHODS: About 195 cognitively unimpaired MS patients (150 relapsing-remitting and 45 progressive) were evaluated with the State Trait Anger Expression Inventory, the Chicago Multiscale Depression Inventory, and the State Trait Anxiety Inventory. The patients' anger score distribution was compared with that of the normal Italian population. Correlation coefficients among scale scores were calculated and mean anger scores were compared across different groups of patients by analysis of variance. RESULTS: Of the five different aspects of anger, levels of withheld and controlled Anger were respectively higher and lower than what is expected in the normal population. Although anger was correlated with anxiety and depression, it was largely independent from these mood conditions. Mean anger severity scores were not strongly influenced by individual demographic characteristics and were not higher in more severe patients. CONCLUSIONS: The presence of an altered pattern of anger, unrelated to the clinical severity of MS, suggests that anger is not an emotional reaction to disease stress. An alteration of anger mechanisms might be a direct consequence of the demyelination of the connections among the amygdale, the basal ganglia and the medial prefrontal cortex.

Redefining primary headaches.

In the light of the pathophysiologic knowledge acquired in the recent years, a tentative redefinition is now possible of some types of headache until now defined as idiopathic, and indistinctly described as primary headaches. Cluster headache and trigeminal neuralgia are known examples of diseases classified as primary, which are, in contrast, well-defined diseases to be distinguished from headaches without any recognized anatomic site of lesion or pathogenesis. Another still debated condition, chronic migraine, is proposed here as the consequence of "processes" to be ascribed to mechanisms activated by other comorbid conditions. The observations supporting the possibility that allodynia represents the implicit process leading to pain progression, which occurs in some migraineurs, are discussed.

Brain atrophy evolution and lesion load accrual in multiple sclerosis: a 2-year follow-up study.

BACKGROUND: To investigate in a large cohort of patients with multiple sclerosis (MS), lesion load and atrophy evolution, and the relationship between clinical and magnetic resonance imaging (MRI) correlates of disease progression. METHODS: Two hundred and sixty-seven patients with MS were studied at baseline and two years later using the same MRI protocol. Abnormal white matter fraction, normal appearing white matter fraction, global white matter fraction, gray matter fraction and whole brain fraction, T2-hyperintense, and T1-hypointense lesions were measured at both time points. RESULTS: The majority of patients were clinically stable, whereas MRI-derived brain tissue fractions were significantly different after 2 years. The correlation between MRI data at baseline and their variation during the follow-up showed that lower basal gray matter atrophy was significantly related with higher progression of gray matter atrophy during follow-up. The correlation between MRI parameters and disease duration showed that gray matter atrophy rate decreased with increasing disease duration, whereas the rate of white matter atrophy had a constant pattern. Lower basal gray matter atrophy was associated with increased probability of developing gray matter atrophy at follow-up, whereas gray matter atrophy progression over 2 years and new T2 lesion load were risk factors for whole brain atrophy progression. CONCLUSIONS: In MS, brain atrophy occurs even after a relatively short period of time and in patients with limited progression of disability. Short-term brain atrophy progression rates differ across tissue compartments, as gray matter atrophy results more pronounced than white matter atrophy and appears to be a early phenomenon in the MS-related disease progression.

Treatment of vascular dementia: the route of prevention.

Vascular dementia (VaD), rather than being considered as a univocal nosological entity, should be regarded as a heterogeneous clinical entity which differs in clinical-pathological phenotype as well as in pathophysiological mechanisms, but shares cerebrovascular disease (CVD), resulting from vascular or circulatory pathology, as the cause of dementia. The aim of this review is to discuss VaD treatment focusing particularly on more prevalent ischemic forms. Due to the fact that there are presently no treatments capable of obtaining considerable results once VaD is clinically established, specific emphasis will be given to the therapeutic strategies aimed at the prevention of CVD risk factors. The therapeutic strategies aimed at slowing the progression of the disease will also be discussed.

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.

Migraine and epilepsy: clinical and pathophysiological relations.

Migraine and epilepsy are both chronic disorders characterised by recurrent neurological attacks, with a partial clinical and therapeutic overlap and frequently occurring together. Although still incompletely clarified, the possible existence of a link between migraine and epilepsy has long been debated. In this paper the epidemiologic evidence of migraine and epilepsy comorbidity, the possible occurrence of both disturbances in close temporal association, possible shared physiopathologic mechanisms and the rationale for antiepileptic drug use in migraine prophylaxis will be discussed.

Validation of AIDA Cefalee, a computer-assisted diagnosis database for the management of headache patients.

AIDA Cefalee is a database for the management of headache patients developed on behalf of the Italian Neurological Association for Headache Research (ANIRCEF). The system integrates a diagnostic expert system able to suggest the correct ICHD-II diagnosis once all clinical characteristics of a patient's headache have been collected. The software has undergone a multicentre validation study to assess: its diagnostic accuracy; the impact of using the software on visit duration; the userfriendliness degree of the software interface; and patients' acceptability of computer-assisted interview. Five Italian headache centres participated in the study. The results of this study validate AIDA Cefalee as a reliable diagnostic tool for primary headaches that can improve diagnostic accuracy with respect to the standard clinical method without increasing the time length of visits even when used by operators with basic computer experience.

Headache and spontaneous low cerebrospinal fluid pressure syndrome.

We examined 59 consecutive patients presenting between 1993 and 2006 at our centre diagnosed with headache associated with spontaneous intracranial hypotension syndrome (SIH). Thirty-six (61%) patients were women; the mean age was 47 years (range 20-68). Cerebral MRI with contrast confirmed SIH in all patients. Headache characteristics were obtained by direct semistructured interview; in a minority of cases information was completed retrospectively through a phone call. All SIH patients suffered from headache. Early recognition of SIH may avoid dangerous worsening due to delayed diagnosis. Orthostatic headache, the main symptom, suggests the diagnosis.

Neurodegeneration and Alzheimer's disease: the lesson from tauopathies.

The Amyloid Cascade Hypothesis suggests that the decisive event in Alzheimer's disease (AD) is the deposition of fibrils of beta-amyloid protein (Abeta). The main objection to this hypothesis is the weak correlation between plaque load and severity of dementia. The good correlation between synaptic loss and dementia suggests that AD may be regarded as a synaptic failure. The toxicity of Abeta depends on its state of aggregation. The most important implication derived from the studies of tau gene mutations in a familial form of frontotemporal dementia (FTDP-17) is that the mutation itself is sufficient to cause neuronal loss. Several recent data suggest that apoptotic mechanisms may represent the missing link between Abeta deposition and proteolysis of tau, an early event in the pathogenic sequence of AD. Collectively, these observations suggest a model of AD whereby overproduction or reduced clearance of Abeta initiates a cascade of events that lead to neuronal loss directly or through post-translational modification of tau.

The end of the central dogma of neurobiology: stem cells and neurogenesis in adult CNS.

Until the 1990s, neurologists were practising their profession under the doctrine established in the late 19th to early 20th century by the prominent histologist Ramon y Cajal: "Once the development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably. In the adult centers, the nerve paths are something fixed, ended, and immutable. Everything may die, nothing may be regenerated. It is for the science of the future to change, if possible, this harsh decree." Similarly, Giulio Bizzozero, the most prominent Italian histologist and mentor of Camillo Golgi, classified the tissues of the human body into "labile, stable and perennial". Among the latter were the nerve cells, believed to be unable to proliferate in the postnatal brain. This classification was taught until a few years ago to generations of medical students and biologists all over the world. We have investigated the historical, methodological and technical reasons why this "central dogma of neurology", so influential in clinical and experimental neurology, has lasted so long. We examined how this dogma was broken and who contributed, and the difficulties encountered by the "heretical" researchers who contributed to this goal, especially between the 1960s and the early 1990s, when at last neurogenesis in the adult brain could no longer be denied. Finally, we propose that the understanding of the mechanisms underlying various neurological diseases and the interpretations of clinical syndromes, as well as the design of new therapies, are being revolutionised by the breaking of this dogma and the discovery of the presence of neural stem cells in the adult brain.

Hypnic headache: an update.

Hypnic headache (HH) is a rare sleep-associated primary headache disorder, usually affecting aged people, first described by Raskin in 1988. The headache attacks, single or multiple in one night, occur exclusively during sleep and tend to present at a consistent time each night, sometimes during a dream. Compared to the original description, newly reported cases have expanded the clinical spectrum of the disorder to include unilateral forms (about 40%, half of which are side-locked), forms with a longer duration (up to 3 h) and cases with onset in juvenile/adult age. The male predominance found in Raskin's series has not been confirmed by subsequent observations. To date the reported F/M ratio is 1.7/1. Pain is of severe intensity in less then one-third of cases and mild-moderate in about two-thirds. The location of pain is fronto-temporal in over 40% of cases; headache is throbbing in 38% of cases, dull in 57% and stabbing in less than 5%. Nausea is reported in 19% of cases; photophobia, phonophobia or both are present in 6.8%. Mild autonomic signs (lacrimation, nasal congestion, ptosis) may rarely be present. In 2004, HH was included in Group 4 of the International Classification of Headache Disorders-II (Other primary headaches). Sufficient evidence, mainly from polysomnographic studies, indicates that HH is a primary rapid eye movement (REM) sleep-related headache disorder of chronobiological origin. Lithium, melatonin, indomethacin and caffeine at bedtime are among the most effective therapeutic options. The pathophysiology of HH is still unclear. Available data allow speculation that, in predisposed subjects, an age-related impairment of suprachiasmatic nucleus could cyclically activate a disnociceptive mechanism leading to both a sudden awakening and headache. The mechanism may be precipitated by neurophysiologic events such as the strong reduction of firing occurring in the dorsal raphe nucleus during a REM sleep phase.

Brain atrophy and lesion load in a large population of patients with multiple sclerosis.

OBJECTIVE: To measure white matter (WM) and gray matter (GM) atrophy and lesion load in a large population of patients with multiple sclerosis (MS) using a fully automated, operator-independent, multiparametric segmentation method. METHODS: The study population consisted of 597 patients with MS and 104 control subjects. The MRI parameters were abnormal WM fraction (AWM-f), global WM-f (gWM-f), and GM fraction (GM-f). RESULTS: Significant differences between patients with MS and control subjects included higher AWM-f and reduced gWM-f and GM-f. MRI data showed significant differences between patients with relapsing-remitting and secondary progressive forms of MS. Significant correlations between MRI parameters and between MRI and clinical data were found. CONCLUSIONS: Patients with multiple sclerosis have significant atrophy of both white matter (WM) and gray matter (GM); secondary progressive patients have significantly more atrophy of both WM and GM than do relapsing-remitting patients and a significantly higher lesion load (abnormal WM fraction); lesion load is related to both WM and even more to GM atrophy; lesion load and WM and GM atrophy are significantly related to Expanded Disability Status Scale score and age at onset (suggesting that the younger the age at disease onset, the worse the lesion load and brain atrophy); and GM atrophy is the most significant MRI variable in determining the final disability.