Are anti-calcitonin gene-related peptide monoclonal antibodies effective in treating migraine aura? A pilot prospective observational cohort study.

BACKGROUND: About 15% to one third of migraineurs experience aura symptoms. Aura is a reversible focal neurological phenomenon involving visual, sensory, speech, and motor symptoms that usually precede migraine pain. Monoclonal antibodies against calcitonin-related peptide (anti- CGRP mAbs) are effective in preventing chronic and episodic migraine, but little is known about their effectiveness on specifically preventing migraine with aura. METHODS: This is a pilot prospective observational cohort study, aiming at evaluating the effectiveness and safety of Erenumab, Fremanezumab or Galcanezumab for the treatment of migraine aura. We enrolled 14 patients at the Headache Centre of University Federico II of Naples. Duration of follow-up was 12 months. We assessed mean monthly days with aura symptoms, with or without subsequent headache, as well as mean monthly days with headache and mean monthly MIDAS score, by reviewing standardized paper patient headache diaries every three months. RESULTS: A significant decrease in mean monthly aura days was observed throughout the observation period (median baseline: 13, interquartile range: 4-16; after 12 months: 1, interquartile range: 0-3, p < 0.001). We observed a statistically significant decrease in mean monthly headache days as well (median baseline 21, interquartile range: 16-30; after 12 months: 5, interquartile range: 4-7, p < 0.001). During the 12-month treatment period, none of the 14 patients reported mild or serious adverse events. CONCLUSION: Our findings suggest that anti-CGRP mAbs are highly effective in migraine with aura, both in reducing mean monthly aura days and mean monthly days with headache.

Idiopathic intracranial hypertension secondary to Superior Sagittal Sinus Stenosis: a case report.

INTRODUCTION: Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) without established etiology. Venous sinus stenosis contributes to IIH; however, it is still uncertain whether the stenosis is a primary cause of IIH or a secondary result in response to elevated ICP. Transverse sinus stenosis is frequently identified in patients with IIH and it is suggestive of raised ICP. Here, we report a case of IIH caused by intrinsic superior sagittal sinus stenosis (SSS). CASE PRESENTATION: A 43-year-old man suffered from IIH with headache, papilledema, and visual impairment. Angiography demonstrated isolated SSS stenosis with a pressure gradient of 30 mmHg. SSS stenosis was resistant to revascularization by stenting alone and intrastent balloon angioplasty was then performed to overcome such resistance. The rigidity of the vein wall suggests that the vein is not collapsed and the stenosis is intrinsic, secondary to idiopathic anatomical local changes. Post-procedure headache disappeared and visual acuity improved. CONCLUSION: An isolated SSS stenosis could lead to intracranial hypertension and this condition should be taken into account in the diagnostic workup of IIH. By now, SSS stenosis is not mentioned in any current consensus guidelines or paper on the diagnostic workflow of intracranial hypertension.

Anti-calcitonin gene-related peptide monoclonal antibodies for the treatment of vestibular migraine: A prospective observational cohort study.

BACKGROUND: Vestibular migraine is considered the most common cause of recurrent vertigo for which specific treatments are missing. Monoclonal antibodies against calcitonin gene-related peptide,, are effective in preventing migraine. Since CGRP is also detected in human cochlear and vestibular organs it may also play a role in vestibular physiology. METHODS: This is a prospective observational cohort study, aiming at evaluating the efficacy of erenumab, fremanezumab or galcanezumab for the treatment of fifty vestibular migraine patients. We assessed mean monthly days with headache and dizziness/vestibular symptoms, pain intensity and migraine-related clinical burden occurring for 18 months. RESULTS: Response to treatment was excellent as 45 (90%) patients had at least a 50% reduction in vertigo frequency, 43 (86%) had at least a 50% reduction in headache frequency, and 40 (80%) a MIDAS reduction of at least 50%. Overall, 39 (78%) patients had a concomitant reduction of all three parameters. Mean monthly days with dizziness/vestibular symptoms showed an overall significant decrease from a mean of 10.3 ± 1.9 at baseline to 0.8 ± 0.3 days, difference 9.5 (CI 95% 3.6, 15.4; p < 0.001) after twelve months. CONCLUSION: We show that anti-CGRP mAbs may be effective in the treatment of Vestibular Migraine. Their use should be encouraged early in the disease course to allow for a better symptom control and quality of life improvement.

Recurrent reflex syncope in idiopathic intracranial hypertension patient resolved after lumbar puncture: pathogenetic implications.

BACKGROUND: Idiopathic intracranial hypertension is a disease characterized by increased intracranial cerebrospinal fluid volume and pressure without evidence of other intracranial pathology. Dural sinuses are rigid structures representing a privileged low-pressure intracranial compartment. Rigidity of dural sinus ensures that the large physiologic fluctuations of cerebrospinal fluid pressure associated with postural changes or to Valsalva effect cannot be transmitted to the sinus. An abnormal dural sinus collapsibility, especially when associated with various anatomical sinus narrowing, has been proposed as a key factor in the pathogenesis of idiopathic intracranial hypertension. This pathogenetic model is based on an excessive collapsibility of the dural sinuses that leads to the triggering of a self-limiting venous collapse positive feedback-loop between the cerebrospinal fluid pressure, that compresses the sinus, and the increased dural sinus pressure upstream, that reduces the cerebrospinal fluid reabsorption rate, increasing cerebrospinal fluid volume and pressure at the expense of intracranial compliance and promoting further sinus compression. Intracranial compliance is the ability of the craniospinal space to accept small volumetric increases of one of its compartments without appreciable intracranial pressure rise. In idiopathic intracranial hypertension, a condition associated with a reduced rate of CSF reabsorption leading to its volumetric expansion, a pathologically reduced IC precedes and accompanies the rise of ICP. Syncope is defined as a transient loss of consciousness due to a transient cerebral hypoperfusion characterized by rapid onset, short duration, and spontaneous complete recovery. A transient global cerebral hypoperfusion represents the final mechanism of syncope determined by cardiac output and/or total peripheral resistance decrease. There are many causes determining low cardiac output including reflex bradycardia, arrhythmias, cardiac structural disease, inadequate venous return, and chronotropic and inotropic incompetence. Typically, syncopal transient loss of consciousness is mainly referred to an extracranial mechanism triggering a decrease in cardiac output and/or total peripheral resistance. Conversely, the association of syncope with a deranged control of intracranial compliance related to cerebral venous outflow disorders has been only anecdotally reported. CASE PRESENTATION: We report on a 57-year-old woman with daily recurrent orthostatic hypotension syncope and idiopathic intracranial hypertension-related headaches, which resolved after lumbar puncture with cerebrospinal fluid subtraction. CONCLUSIONS: A novel mechanism underlying the triggering of orthostatic syncope in the presence of intracranial hypertension-dependent reduced intracranial compliance is discussed.

A head-to-head observational cohort study on the efficacy and safety of monoclonal antibodies against calcitonin gene-related peptide for chronic and episodic migraine.

OBJECTIVE: To compare the effectiveness and safety of galcanezumab, fremanezumab, and erenumab for the treatment of chronic and episodic migraine, through real-world data. BACKGROUND: Monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway have been tested extensively in several clinical trials for both episodic and chronic migraine, showing high effectiveness, safety, and tolerability; however, there are no prospective real-world studies intending to compare their efficacy and safety. METHODS: This is a prospective observational cohort study comparing the effectiveness and safety profiles of galcanezumab, fremanezumab, and erenumab for the treatment of chronic and episodic migraine. We enrolled 140 patients at the Headache Centre of University Federico II of Naples, with a history of multiple failed treatments with validated migraine preventatives. Framenezumab, erenumab, or galcanezumab were administered for 12 months. The mean monthly days with headache, Migraine Disability Assessment (MIDAS) score, and adverse events were evaluated during the run-in period and every 3 months by reviewing standardized paper patient headache diaries. RESULTS: We found a mean reduction of migraine monthly days from baseline of -12.0 (-9.8, -14.1) in the galcanezumab group, -12.3 (-10.2, -14.3) in the fremanezumab group, and -10.8 (-8.5, -13.1) in the erenumab group (for all, p < 0.001). We found a mean reduction of MIDAS score of -32.6 (-26.6, -38.5) in the galcanezumab group, -33.4 (-28.0, -38.9) in the fremanezumab group, and -29.2 (-23.0, -35.4) in the erenumab group (for all, p < 0.001). We found no significant differences between mAbs in the reduction of mean monthly days with headache and MIDAS score. We found a more rapid effect of galcanezumab and erenumab compared to fremanezumab in medication overuse headache patients after 3 months of treatment (-10.8 and -11.1 vs. -4.0 days; p = 0.029). CONCLUSION: Our results confirm the therapeutic benefits of anti-CGRP mAbs. There is no evidence that suggests that one antibody may be superior to the others in terms of effectiveness, both in chronic and episodic patients.

Multiple cranial neuropathy due to varicella zoster virus reactivation without vesicular rash: a challenging diagnosis.

Ramsay Hunt syndrome is due to reactivation of varicella zoster virus (VZV) dormant in the geniculate ganglion of the facial nerve. The diagnosis is typically based on clinical triad of ipsilateral facial paralysis, otalgia, and vesicles in the auditory canal or the auricle. However, Ramsay Hunt syndrome may occur without skin eruption in up to one third of patients. Moreover, the involvement of other cranial nerves in addition to the facial nerve has been also reported. Herein, we reported a case report of a man who developed a multiple cranial neuropathy caused by VZV reactivation without skin vesicular eruption. The present case underlines a possible diagnostic challenge that clinicians may hit when facing a common disorder such as peripheral facial palsy. Indeed, clinicians must be aware that Ramsay Hunt syndrome may develop without skin vesicular eruption as well it may be complicated by multiple cranial nerve involvement. Antiviral therapy is effective in VZV reactivation for recovery of nerve function.

Non-convulsive status epilepticus versus periodic EEG pattern in sporadic Creutzfeldt-Jakob disease: two sides of the same coin?

Sporadic Creutzfeldt-Jakob disease is characterized by rapid cognitive and neuropsychiatric impairment. The Heidenhain variant of Creutzfeldt-Jakob disease is known for isolated visual disturbance that precedes other features. Periodic sharp wave complexes on EEG are typical of sporadic Creutzfeldt-Jakob disease, but at the onset, the electroclinical pattern may be unclear and suggest the hypothesis of a non-convulsive status epilepticus. Furthermore, non-convulsive status epilepticus and sporadic Creutzfeldt-Jakob disease could coexist simultaneously. We report the case of a patient admitted to our hospital for progressive psychiatric and cognitive disorders. In the initial phase, based on clinical, EEG, and neuroradiological features, a diagnosis of possible non-convulsive status epilepticus was made. Subsequently, the rapid neurological degeneration led to the diagnosis of Creutzfeldt-Jakob disease confirmed by cerebrospinal fluid real-time quaking-induced conversion. Non-convulsive status epilepticus could mimic Creutzfeldt-Jakob disease or be present in overlap. Antiseizure drugs may be started when the etiology is unclear, but overtreatment should be avoided when invasive treatment protocols fail, and the neurological progression suggests an encephalopathy.

The putative role of trigemino-vascular system in brain perfusion homeostasis and the significance of the migraine attack.

Besides representing the place where a migraine attack generates, what is the physiological role of peptidergic control of arteriolar caliber within the trigemino-vascular system? Considering that the shared goal of most human CGRP-based neurosensory systems is the protection from an acute threat, especially if hypoxic, what is the end meaning of a migraine attack? In this paper, we have reviewed available evidence on the possible role of the trigemino-vascular system in maintaining cerebral perfusion pressure homeostasis, despite the large physiological fluctuations in intracranial pressure occurring in daily life activities. In this perspective, the migraine attack is presented as the response to a cerebral hypoxic threat consequent to a deranged intracranial pressure control aimed at generating a temporary withdrawal from the environment with limitation of physical activity, a condition required to promote the restoration of cerebral fluids dynamic balance.

Clinical features, disease progression, and use of healthcare resources in a large sample of 866 patients from 24 headache centers: A real-life perspective from the Italian chROnic migraiNe (IRON) project.

OBJECTIVE: To develop a dedicated Italian chronic migraine (CM) database (IRON project) to overcome disease misconceptions, improve clinical administration, reduce patients' burden, and rationalize economic resource allotment. BACKGROUND: Proper CM management requires a comprehensive appraisal of its full clinical, social, and economic complexity. METHODS: In this cross-sectional study, CM patients were screened in 24 certified headache centers with face-to-face interviews. Information on sociodemographic factors, medical history, characteristics of CM, and of prior episodic migraine (EM), and healthcare resource use was gathered using a semistructured web-based questionnaire. RESULTS: A total of 866 CM patients were enrolled. CM started ~20 years after EM onset (age at EM onset 17.4 ± 9.1 vs. age at CM onset 35.3 ± 12.5 [mean ± SD]). CM prophylaxis, used by 430/866 (49.6%) of the patients, was often ineffective, not tolerated, and prematurely discontinued. Medications and diagnostic workup, frequently inappropriate, were mostly subsidized by the Italian national health service. CM patients with ≥25 headache days/month revealed substantial clinical differences and heavier disability and economic burden compared with those with <25 headache days/month. CONCLUSIONS: CM is a heterogeneous headache disorder deserving more in-depth clinical characterization, sharper diagnostic criteria, and tailored treatments. CM registries are expected to improve clinical management, resulting in increased disease awareness, better healthcare resource allocation, and reduced economic burden.

Headache in idiopathic intracranial hypertension. A CGRP-dependent head pain?

Headache is the most frequent and often the most severe symptom of idiopathic intracranial hypertension (IIH) clinical presentation, although pain characteristics are very variable among sufferers and the pain may even lack in some cases. Whatever the headache features, refractoriness to treatments, pain worsening in the recumbent position, and frequent awakenings with severe headache late in the night are the specific complains of such patients. However, a migraine or probable migraine headache, mostly with a chronic headache pattern, can be diagnosed in about 2/3 of the cases. In IIH cases without papilledema (IIHWOP), this leads to a high rate of misdiagnosis with primary chronic migraine (CM). Mechanisms responsible for the shared migrainous presentation of CM and IIH/IIHWOP may rely on a pathologic CGRP release from the rich trigemino-vascular innervated dural sinuses, congested in the course of raised intracranial pressure. The possible role of IIHWOP as a powerful and modifiable risk factor for migraine progression is discussed. Further studies investigating the possible efficacy of anti CGRP/receptor antibodies in IIH/IIHWOP headache treatment are needed.

Dural sinus collapsibility, idiopathic intracranial hypertension, and the pathogenesis of chronic migraine.

Available evidences suggest that a number of known assumption on idiopathic intracranial hypertension (IIH) with or without papilledema might be discussed. These include (1) the primary pathogenetic role of an excessive dural sinus collapsibility in IIH, allowing a new relatively stable intracranial fluids pressure balance at higher values; (2) the non-mandatory role of papilledema for a definite diagnosis; (3) the possibly much higher prevalence of IIH without papilledema than currently considered; (4) the crucial role of the cerebral compliance exhaustion that precede the raise in intracranial pressure and that may already be pathologic in cases showing a moderately elevated opening pressure; (5) the role as "intracranial pressure sensor" played by the trigeminovascular innervation of dural sinuses and cortical bridge veins, which could represent a major source of CGRP and may explain the high comorbidity and the emerging causative link between IIHWOP and chronic migraine (CM). Accordingly, the control of intracranial pressure is to be considered a promising new therapeutic target in CM.

Management of epilepsy in brain tumors.

Epilepsy in brain tumors (BTE) may require medical attention for a variety of unique concerns: epileptic seizures, possible serious adverse effects of antineoplastic and antiepileptic drugs (AEDs), physical disability, and/or neurocognitive disturbances correlated to tumor site. Guidelines for the management of tumor-related epilepsies are lacking. Treatment is not standardized, and overall management might differ according to different specialists. The aim of this document was to provide directives on the procedures to be adopted for a correct diagnostic-therapeutic path of the patient with BTE, evaluating indications, risks, and benefits. A board comprising neurologists, epileptologists, neurophysiologists, neuroradiologists, neurosurgeons, neuro-oncologists, neuropsychologists, and patients' representatives was formed. The board converted diagnostic and therapeutic problems into seventeen questions. A literature search was performed in September-October 2017, and a total of 7827 unique records were retrieved, of which 148 constituted the core literature. There is no evidence that histological type or localization of the brain tumor affects the response to an AED. The board recommended to avoid enzyme-inducing antiepileptic drugs because of their interference with antitumoral drugs and consider as first-choice newer generation drugs (among them, levetiracetam, lamotrigine, and topiramate). Valproic acid should also be considered. Both short-term and long-term prophylaxes are not recommended in primary and metastatic brain tumors. Management of seizures in patients with BTE should be multidisciplinary. The panel evidenced conflicting or lacking data regarding the role of EEG, the choice of therapeutic strategy, and timing to withdraw AEDs and recommended high-quality long-term studies to standardize BTE care.

Pain cognition in migraine: from basic neurophysiology to a behavioral paradigm.

Most of the data in this review have been already reported by the authors in Neurological Science, but the goal of the present paper is to realize an integrated lecture of all the available data and look to the last achievements in pain cognition, with a special focus on migraine and chronic migraine. According to the proposed integrated perspective, migraine can be viewed as an adaptive behavioral response with evolutionistic advantages.

Intravenous mannitol in status migrainosus treatment: a clinical case series.

Status migrainosus (SM) is defined as a severe migraine attack, usually poorly responsive to treatments, lasting more than 72 h. Recurrent SM predicts chronic migraine (CM) development in 83.7% of cases. There is evidence that in most unresponsive CM patients a sinus stenosis-associated raised intracranial pressure is causatively involved in migraine chronification. To test the hypothesis that SM may reflect a sustained rise in intracranial pressure, we tested the efficacy of a 3-day treatment with intravenous mannitol 18% 250 ml b.i.d. in seven subjects presenting with a SM unresponsive to common treatments, showing unilateral or bilateral sinus stenosis at magnetic resonance venography. Mannitol infusion induced the abrupt reduction or the disappearance of pain in all patients, at least along the 3 days of treatment. While the benefit was only observed during the days of treatment in two subjects, in the remaining five patients the time to the next headache was delayed between 20 days to 5 weeks after mannitol infusion. Due to the lack of any analgesic property of mannitol, our data indicate that in this series a rise in intracranial pressure was involved in SM causative mechanisms.

Endolymphatic hydrops in idiopathic intracranial hypertension: prevalence and clinical outcome after lumbar puncture. Preliminary data.

Idiopathic intracranial hypertension is characterized by raised intracranial pressure (ICP) without any underlying pathology, presenting with (IIH) or without papilledema (IIHWOP). Headache, often on daily basis, is the most frequent symptom. Among audiovestibular symptoms, tinnitus and dizziness are commonly reported, while vertigo and hearing impairment are infrequent reports. Endolymphatic hydrops (ELH) is the typical histopathologic feature of Ménière disease, a condition featured by episodes of vertigo, dizziness, fluctuating hearing loss, tinnitus, and aural fullness. Evidences suggest that ICP is transmitted to inner ear. The aim of this study is to investigate the prevalence of ELH symptoms in IIH/IIHWOP and the relationship between the raised ICP and ELH. The prevalence of chronic headache and of ELH symptoms was investigated in a consecutive series of IIH/IIHWOP patients, and a standard audiometry with hearing threshold measurement (pure-tone average-PTA) was performed. Differences in chronic headache and ELH symptoms prevalence and changes of PTA threshold were calculated after ICP normalization by lumbar puncture (LP). Thirty-one patients (17 with IIH and 14 with IIHWOP) were included. Before LP, chronic headache was present in 93.5%. The percentages of patients reporting tinnitus, dizziness, vertigo, and aural fullness were 67.7, 77.4, 22.6, and 61.3%, respectively. Headache frequency as well as ELH symptoms and PTA significantly improved after LP. The improvement of PTA and of ELH symptoms observed after LP in this series of IIH/IIHWOP patients indicates that a raised ICP, a condition known to be involved in the progression and refractoriness of migraine pain, has also a role in ELH. We propose that intracranial hypertension may represent the shared pathogenetic step explaining the large epidemiological comorbidity between migraine and vestibular symptoms, at present conceptualized as "vestibular migraine."

An educational campaign about epilepsy among Italian primary school teachers. 2. The results of a focused training program.

A cohort of 582 Italian primary school teachers underwent a questionnaire survey to test their knowledge and attitudes toward epilepsy and verify whether an intensive and focused educational program could result in improvement of knowledge and attitudes. The program consisted of a presentation of the clinical manifestations of epilepsy and the distribution of informative brochures and an educational kit on the disease and its management to be used with their students. After several months, 317 teachers were retested using the same questions. Upon retest, the number of "don't know" answers decreased significantly for almost all questions. This was not the case for negative attitudes. The same holds true for teachers believing that epilepsy is a source of learning disability and social disadvantage. These findings support the beliefs that education on epilepsy is more likely to affect ignorance than prejudice and that stronger interventions are needed to counteract stigmatizing behaviors.

Brainstem activation in cluster headache: an adaptive behavioural response?

INTRODUCTION: The functional neuroimaging of headache patients has revolutionized our understanding of the pathophysiology of primary headaches, providing unique insights into these syndromes. Indeed, functional neuroimaging studies have shown the activation of specific brain structures, the brainstem in migraine and posterior hypothalamus in cluster headache (CH), as well as in other trigeminal autonomic cephalalgias. We describe the functional neuroimaging findings in a patient suffering from CH headache, investigated with functional magnetic resonance imaging (fMRI) during typical pain attacks. MATERIAL AND METHODS: Two typical, consecutive CH attacks were investigated by two fMRI imaging sessions on the same day. Both fMRI scans were performed at rest, during the CH attacks and the pain-free state induced by subcutaneous administration of sumatriptan. RESULTS: Significant activation of the bilateral red nucleus, ventral pons and trigeminal root entry zone ipsilaterally to the pain side was detected during the pain state, in addition to the hypothalamic region ipsilaterally to the pain side. CONCLUSION: Being that such structures are mainly involved in motor function and reactive behaviour, their activation, in our hypothesis, may be linked to pain avoidance and may well represent a defence reaction in cluster headache, which is characterised by a "fight-or-flight" type behavioural pattern during pain attacks.

Sinus venous stenosis, intracranial hypertension and progression of primary headaches.

The recently advanced hypothesis that idiopathic intracranial hypertension without papilledema (IIHWOP) is a powerful risk factor for the progression of pain in individuals prone to episodic primary headache implies that IIHWOP is much more prevalent than it is believed to be in the general population and that it can run almost asymptomatic in most of the affected individuals. In this review, we discuss the evidence available supporting that: (a) sinus venous stenosis-associated IIHWOP is much more prevalent than believed in the general population and can run without symptoms or signs of raised intracranial pressure in most of individuals affected, (b) sinus venous stenosis is a very sensitive and specific predictor of intermittent or continuous idiopathic intracranial hypertension with or without papilledema, even in asymptomatic individuals, (c) in primary headache prone individuals, a comorbidity with a hidden stenosis-associated IIHWOP represents a very common, although largely underestimated, modifiable risk factor for the progression and refractoriness of headache.

Sinus venous stenosis-associated idiopathic intracranial hypertension without papilledema as a powerful risk factor for progression and refractoriness of headache.

Data from two recent studies strongly support the hypothesis that idiopathic intracranial hypertension without papilledema (IIHWOP) could represent a powerful risk factor for the progression of pain in primary headache individuals. The first study highlights that an asymptomatic IIHWOP is much more prevalent than believed in the general population and occurs only in central venous stenosis carriers. In the second study, about one half of a large consecutive series of unresponsive primary chronic headache patients shows significant sinus venous stenosis. A continuous or intermittent IIHWOP was detectable in 91% of this subgroup and in no patient with normal venography. Moreover, after the lumbar puncture, a 2- to 4-week improvement in headache frequency was observed in most of the intracranial hypertensive patients. These findings strongly suggest that patients prone to primary headache who carry central venous outflow abnormalities are at high risk of developing a comorbid IIHWOP, which in turn is responsible for the progression and the unresponsiveness of the pain. Based on the available literature data, we propose that central sinus stenosis-related IIHWOP, although highly prevalent among otherwise healthy people, represents an important modifiable risk factor for the progression and refractoriness of pain in patients predisposed to primary headache. The mechanism could refer to up to one half of the primary chronic headache patients with minimal response to treatments referring to specialized headache clinics. Due to the clinical and taxonomic relevance of this hypothesis further studies are urgently needed.