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The neurobiology of vascular head pain
Abstract
Nervous connections between the trigeminal ganglia and cerebral blood vessels have recently been identified in experimental animals and have been termed the trigeminovascular system. Existence of this system in humans is inferential. Trigeminovascular neurons and their peripheral unmyelinated nerve fibers contain the neurotransmitter peptide substance P. Most newly synthesized substance P is transported from ganglion cell bodies to afferent nerve fibers, where depolarization-induced release of neurotransmitter into the wall of the cerebral blood vessel occurs. Substance P dilates pial arteries, increases vascular permeability, and activates cells that participate in the inflammatory response. The relationship of trigeminovascular fibers to the pathogenesis of vascular head pain sheds light on possible mechanisms of migraine and other central nervous system conditions associated with headache and inflammation.
... Case report information and experience obtained in research and clinical practice. [10][11][12][13][14] According to the TVT, pain associated with PHD involves a vicious cycle of parasympathetically induced vasodilation and inflammation caused by inflammatory mediators in the cerebral extraparenchymal blood vessels and the meninges. 15 16 It is reasonable to argue that interrupting this pathway with a conduction block could prevent vasodilatation and inflammation (whichever phenomenon causes the other) and, thus, nociception of the PHDs and, theoretically, that of postdural puncture headaches. ...
... It is complex, and several theories attempt to explain what causes the pain of PHD. 6-10 15 29 Although the neurogenic inflammatory theory 29 has to a large extent replaced the trigeminovascular theory (TVT) as the current favorite, the TVT still adequately, although perhaps in an oversimplified manner, and comfortably explains why PPGB, by blocking the parasympathetic pathway, is successful in treating PHD and PDPH, both characterized by meningeal cerebral extraparenchymal blood vessel dilatation and meningeal inflammation, whichever is first and of whatever thus far unknown other mechanism or cause(s) [10][11][12][13][14] (please see figure 1 for an abbreviated explanation of the TVT). ...
In 1981, Devoghel achieved an 85.6% success rate in treating patients with treatment-refractory cluster headaches with alcoholization of the pterygopalatine ganglion (PPG) via the percutaneous suprazygomatic approach. Devoghel’s study led to the theory that interrupting the parasympathetic pathway by blocking its transduction at the PPG could prevent or treat symptoms related to primary headache disorders (PHDs). Furthermore, non-invasive vagus nerve stimulation (nVNS) has proven to treat PHDs and has been approved by national regulatory bodies to treat, among others, cluster headaches and migraines.
In this case series, nine desperate patients who presented with 11 longstanding treatment-refractory primary headache disorders and epidural blood patch–resistant postdural puncture headache (PDPH) received ultrasound-guided percutaneous suprazygomatic pterygopalatine ganglion blocks (PPGB), and seven also received nVNS. The patients were randomly selected and were not part of a research study. They experienced dramatic, immediate, satisfactory, and apparently lasting symptom resolution (at the time of the writing of this report). The report provides the case descriptions, briefly reviews the trigeminovascular and neurogenic inflammatory theories of the pathophysiology, outlines aspects of these PPGB and nVNS interventions, and argues for adopting this treatment regime as a first-line or second-line treatment rather than desperate last-line treatment of PDPH and PHDs.
... Among patients with BD, primary headaches, especially migraine or TTH, are common. Recurrence of symptoms is often linked to the exacerbation of systemic symptoms, primarily oral ulcers, with accompanying mild-to-moderate pain and symptoms like nausea, vomiting, or photophobia [27]. ...
Citation: Santangelo, A.; Corsello, A.; Gizzi, G.; Lancieri, M.; Diana, M.C.; Trucco, F.; Orsini, A.; Bonuccelli, A.; Peroni, D.G.; Perilli, L.; et al. Exploring Headaches in Pediatric Behçet Disease: Prevalence, Clinical Impact, and Management. J. Clin. Med. 2024, 13, 3659. https://doi. Abstract: Behçet's Disease (BD), also recognized as Behçet Syndrome, manifests uniquely in pedi-atric populations as Pediatric Behçet's Disease (PBD), characterized by multisystemic inflammatory symptoms including recurrent oral and genital aphthae, and diverse ocular, vascular, and neuro-logical involvements. This review elucidates the prevalence, burden, and management strategies of headaches in children with PBD, focusing on both primary headaches, such as migraine and tension-type headaches, and secondary headaches linked to systemic disease manifestations. It explores the pathophysiological underpinnings specific to PBD-related headaches and discusses the intricate relationship between systemic inflammatory processes and neurological symptoms. By examining the literature from 2004 to 2024, this study highlights the high frequency of headache in PBD patients, underscoring its diagnostic and clinical significance. We aim to provide a detailed understanding of headache management in PBD, emphasizing tailored therapeutic strategies that address the unique challenges faced by this patient population. This review also underscores the importance of comprehensive clinical evaluations to optimize outcomes and mitigate long-term sequelae, proposing that awareness and understanding of headache in PBD can significantly enhance both diagnosis and management.
... Based on Moskowitz and Ashina's proposals, the initiation of migraine depends on activation and sensitization of first-order trigeminovascular neurons and the afferent fibers of these neurons innervate the meninges and its vessels [2,39]. Thus, according to previous researches, continuous dural infusion of IS were used to induce meningeal nociception and activate the trigeminal neurovascular pathway, resulting in the orofacial allodynia [35,40]. ...
Background
Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) and related emotional responses. CGRP antibodies and receptor antagonists have been approved for CM treatment. However, the underlying CGRP-related signaling pathways in the pain-related cortex remain poorly understood.
Methods
The SD rats were used to establish the CM model by dural infusions of inflammatory soup. Periorbital mechanical thresholds were assessed using von-Frey filaments, and anxiety-like behaviors were observed via open field and elevated plus maze tests. Expression of c-Fos, CGRP and NMDA GluN2B receptors was detected using immunofluorescence and western blotting analyses. The excitatory synaptic transmission was detected by whole-cell patch-clamp recording. A human-used adenylate cyclase 1 (AC1) inhibitor, hNB001, was applied via insula stereotaxic and intraperitoneal injections in CM rats.
Results
The insular cortex (IC) was activated in the migraine model rats. Glutamate-mediated excitatory transmission and NMDA GluN2B receptors in the IC were potentiated. CGRP levels in the IC significantly increased during nociceptive and anxiety-like activities. Locally applied hNB001 in the IC or intraperitoneally alleviated periorbital mechanical thresholds and anxiety behaviors in migraine rats. Furthermore, CGRP expression in the IC decreased after the hNB001 application.
Conclusions
Our study indicated that AC1-dependent IC plasticity contributes to migraine and AC1 may be a promising target for treating migraine in the future.
... The trigeminovascular system is one of the key factors in migraine pathophysiology [17]. In 1984, Moskowitz premised that the pain transmission in migraine originates in activation of trigeminovascular neurons that innervate meninges and their vessels [17,23]. The process implies activation and sensitization of these neurons. ...
Novel knowledge about the interrelationships and reciprocal effects of migraine and epilepsy, migraine and mood disorders, or migraine and irritable bowel syndrome has emerged in recent decades. Over time, comorbid pathologies associated with migraine that share common physiopathological mechanisms were studied. Among these studied pathologies is epilepsy, a disorder with common ion channel dysfunctions as well as dysfunctions in glutamatergic transmission. A high degree of neuronal excitement and ion channel abnormalities are associated with epilepsy and migraine and antiepileptic drugs are useful in treating both disorders. The coexistence of epilepsy and migraine may occur independently in the same individual or the two may be causally connected. The relationship between cortical spreading depression (CSD) and epileptic foci has been suggested by basic and clinical neuroscience research. The most relevant psychiatric comorbidities associated with migraine are anxiety and mood disorders, which influence its clinical course, treatment response, and clinical outcome. The association between migraine and major depressive disorder can be explained by a robust molecular genetic background. In addition to its role as a potent vasodilator, CGRP is also involved in the transmission of nociception, a phenomenon inevitably linked with the stress and anxiety caused by frequent migraine attacks. Another aspect is the role of gut microbiome in migraine’s pathology and the gut–brain axis involvement. Irritable bowel syndrome patients are more likely to suffer migraines, according to other studies. There is no precise explanation for how the gut microbiota contributes to neurological disorders in general and migraines in particular. This study aims to show that migraines and comorbid conditions, such as epilepsy, microbiota, or mood disorders, can be connected from the bench to the bedside. It is likely that these comorbid migraine conditions with common pathophysiological mechanisms will have a significant impact on best treatment choices and may provide clues for future treatment options.
... The integral role of the trigeminovascular system in this context highlights the intricate dance between neural events and vascular changes in the migraine milieu [5,6]. As indicated in the literature, the trigeminovascular system assumes an essential function in this complicated condition, which creates an opportunity for a new migraine therapy [7]. Single-photon emission computed tomography (SPECT) imaging is extensively executed to measure reductions in regional cerebral blood flow (rCBF) when migraine attacks occur [8,9]. ...
Background:
Migraine is one of four major chronic diseases that cause disability. Decreases in regional cerebral blood flow (rCBF) occur during migraine attacks. Laser therapy is extensively employed in treating other vascular diseases; nevertheless, its effectiveness in migraine management remains largely unknown. Therefore, we evaluated the effect of low-level intravascular laser irradiation of blood (ILIB) therapy in patients with migraine.
Methods:
We performed an observational case-control study in 24 patients suffering from migraine. Patients were divided into an ILIB treatment group and a traditional rehabilitation group. This study performed clinical assessments and single-photon emission computed tomography (SPECT) prior to and after the treatment and 1 month later. Changes in rCBF-SPECT between groups and between timepoints were compared to clinical outcomes.
Results:
Nine patients undergoing rehabilitation and fifteen patients undergoing ILIB were studied from baseline to 1 month follow-up. The ILIB group, visual analog scale for pain (P = 0.001), Montreal Cognitive Assessment (P = 0.003), and Athens Insomnia Scale (P < 0.001) symptom scores significantly improved after treatment. SPECT imaging showed a 1.27 ± 0.27 fold increase in rCBF after ILIB treatment, and no significant differences in the rehabilitation group.
Conclusions:
Low-level ILIB therapy is associated with better clinical and vascular outcomes, and may be a feasible treatment option for migraine. Although our sample size was small, our data provide a starting point for migraine laser therapy research.
The article provides an analysis of modern literature sources devoted to the biochemical aspects of the pathogenesis of migraine. The role of the trigeminovascular system, etc. is described. biologically active substances involved in this process. Understanding the described processes makes it possible to increase the duration and quality of life of patients.
A 23-year-old female patient with primary vasculitis of the central nervous system simulating a brain tumor is described. The clinical picture was represented by migraine-like headaches, ataxia, transient numbness of the right leg, the lips, double vision, a slight decrease of cognitive functions. MRI of the brain revealed a tumor-like focus in the cerebellum, intensively accumulating contrast, containing micro-hemorrhages (SWI mode). Small single ischemic foci in the brain hemispheres and brain stem were also found. MR angiography (3T) did not found any pathology. Examination of the cerebrospinal fluid revealed a small cytosis (mainly T-lymphocytes) and a slight increase in protein. The results of the analysis of cerebrospinal fluid for syphilis, tuberculosis and the herpetic group of viruses were negative, type 1 oligoclonal synthesis was found. Blood tests for toxoplasmosis, antibodies to aquaporin, anti-neutrophil antibodies, markers of systemic inflammation were within normal limits. Different diagnoses were assumed: demyelinating disease, encephalitis, multiple encephalomyelitis, lymphoma. The diagnosis was established only by a brain biopsy - lymphocytic vasculitis was revealed. According to the immunohistochemical study, T-helpers predominated in the infiltrates. After pulse therapy with Metylprednisolon (1000 mg intravenously drip №. 5), the patient's condition almost returned to normal. It was recommended to take prednisolone per os (starting dose 60 mg) for 7 months.
Migraine is a chronic illness with a high economic burden. Recognizing the aetiology of migraine is crucial both from a public health and a medical point of view. Regardless of the fact that the actual cause of migraines is unidentified, trigeminal nerve fibres encompassing meningeal arteries have indeed been linked to migraine path biology. Pollution, toxicants, irritants, interior fluorescent lighting, air quality, as well as chemical exposure or aromas are other environmental factors that can trigger headaches in individuals who are sensitive. The newly found calcitonin receptor-stimulating peptides pertain to the same peptide family as calcitonin, adrenomedullin, amylin, and many others. The CGRP receptors are split into CGRP1 as well as CGRP2 predicated on one's pharmacological scientific studies that utilized the specific peptide antagonist CGRP. Is one of the main barriers to its medicinal usages? As a consequence, research on CGRP agonists as a diagnosis for troubles may expose innovative treatment and offer more options for treatment. With ongoing promotion of new and monoclonal antibodies treatments that target CGRP function, a very much younger group of migraine treatments is anticipated to be become accessible.
The scotomas characteristic of ophthalmic migraine have been described by a number of investigators.¹ The visual disturbance precedes or accompanies other symptoms of migraine and is usually of short duration. It is generally restricted to one half of the visual field, the right or the left, and ranges in size from a scarcely noticeable blind-spot to total hemianopia. A great variety of forms have been mentioned in the literature, but those which have been described in detail are of much the same type. The scotoma starts as a disturbance of vision limited to the neighborhood of the macula and spreads rapidly toward the temporal field. With increase in size the disturbed area moves or "drifts" across the visual field, so that its central margin withdraws from the macular region as its peripheral margin invades the temporal. Spread from the temporal toward the macular region has also been described and
Of the many diseases which, on therapeutic grounds, are supposed to occupy a border-line position between the provinces of the physician and surgeon, perhaps no one more than intractable epileptiform neuralgia illustrates so well the dictum of that renowned Philadelphian and friend of many doctors, Benjamin Franklin, to the effect that "he is the best physician who knows the worthlessness of the most medicines."
Granting the premise in all cases of true tic douloureux, the neuralgia quinti major of Henry Head, in which all three divisions of the trigeminal nerve are affected, that surgical measures alone can with any degree of certainty be depended on to afford relief from this horrible affliction and that the removal of the Gasserian ganglion must ultimately be contemplated, it is to be regretted that this final procedure should generally be regarded as one hazardous in its performance and uncertain in its permanent effects. Two