From basic mechanisms to therapeutic perspectives in cluster headache.

PURPOSE OF REVIEW: The pathophysiological understanding of cluster headache has evolved significantly over the past years. Although it is now well known that the trigeminovascular system, the parasympathetic system and the hypothalamus play important roles in its pathomechanism, we increasingly understand the functional role several neurotransmitters and hormones play in the communication between these structures. RECENT FINDINGS: This work will give an overview of the current understanding of the role of calcitonin gene-related peptide, vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, melatonin and orexins in cluster headache. On the basis of recent evidence, this study will also review the relevance of the monoclonal calcitonin gene-related peptide antibody galcanezumab as well as the sleep-regulating hormone melatonin in the treatment of cluster headache. SUMMARY: Herein, we aim to review the basic mechanisms implicated in the pathophysiology of cluster headache and how the increased mechanistic understanding may lead to the discovery of novel therapeutic targets.

Targets for migraine treatment: beyond calcitonin gene-related peptide.

PURPOSE OF REVIEW: Despite the development of several medications for the acute and preventive treatment of migraine, there are still many patients in whom lack of efficacy, tolerability, interactions or contraindications make other options necessary. CGRP-based drugs have opened the door to a new era of migraine-targeted treatments. Beyond CGRP, there are other promising targets covered here. RECENT FINDINGS: For the acute treatment of migraine, 5-HT1F receptor agonists, ditans, are now available. Unlike triptans, 5-HT1B/1D receptor agonists, cardiovascular disease is not a contraindication for the use of ditans. The first study on a monoclonal antibody targeting PAC1 receptor was negative, although this may not be the end for the pituitary adenylate cyclase-activating polypeptide (PACAP) pathway as a target. SUMMARY: Following positive phase-III clinical trials, lasmiditan is the first ditan to be FDA-approved. PACAP has experimental evidence suggesting a role in migraine pathophysiology. As for CGRP, the presence of PACAP in key migraine structures along with positive provocative tests for both PACAP-38 and PACAP-27 indicate this pathway may still be a pharmacological target. Glutamate-based targets have long been considered in migraine. Two clinical trials with memantine, an NMDA-R antagonist, for the preventive treatment of migraine have now been published. The hypothalamus has also been implicated in migraine pathophysiology: the potential role of orexins in migraine is discussed. Acid-sensing ion channels, as well as amylin-blocking drugs, may also become migraine treatments in the future: more research is warranted.

Elevated circulating metalloproteinase 7 predicts recurrent cardiovascular events in patients with carotid stenosis: a prospective cohort study.

BACKGROUND: Major adverse cardiovascular events are the main cause of morbidity and mortality over the long term in patients undergoing carotid endarterectomy. There are few reports assessing the prognostic value of markers of inflammation in relation to the risk of cardiovascular disease after carotid endarterectomy. Here, we aimed to determine whether matrix metalloproteinases (MMP-1, MMP-2, MMP-7, MMP-9 and MMP-10), tissue inhibitor of MMPs (TIMP-1) and in vivo inflammation studied by 18F-FDG-PET/CT predict recurrent cardiovascular events in patients with carotid stenosis who underwent endarterectomy. METHODS: This prospective cohort study was carried out on 31 consecutive patients with symptomatic (23/31) or asymptomatic (8/31) severe (> 70%) carotid stenosis who were scheduled for carotid endarterectomy between July 2013 and March 2016. In addition, 26 healthy controls were included in the study. Plasma and serum samples were collected 2 days prior to surgery and tested for MMP-1, MMP-2, MMP-7, MMP-9, MMP-10, TIMP-1, high-density lipoprotein, low-density lipoprotein, high-sensitivity C-reactive protein and erythrocyte sedimentation rate. 18F-FDG-PET/CT focusing on several territories' vascular wall metabolism was performed on 29 of the patients because of no presurgical availability in 2 symptomatic patients. Histological and immunohistochemical studies were performed with antibodies targeting MMP-10, MMP-9, TIMP-1 and CD68. RESULTS: The patients with carotid stenosis had significantly more circulating MMP-1, MMP-7 and MMP-10 than the healthy controls. Intraplaque TIMP-1 was correlated with its plasma level (r = 0.42 P = .02) and with 18F-FDG uptake (r = 0.38 P = .05). We did not find any correlation between circulating MMPs and in vivo carotid plaque metabolism assessed by 18F-FDG-PET. After a median follow-up of 1077 days, 4 cerebrovascular, 7 cardiovascular and 11 peripheral vascular events requiring hospitalization were registered. Circulating MMP-7 was capable of predicting events over and above the traditional risk factors (HR = 1.15 P = .006). When the model was associated with the variables of interest, the risk predicted by 18F-FDG-PET was not significant. CONCLUSIONS: Circulating MMP-7 may represent a novel marker for recurrent cardiovascular events in patients with moderate to severe carotid stenosis. MMP-7 may reflect the atherosclerotic burden but not plaque inflammation in this specific vascular territory.

Facial solitary morphea profunda presenting with painful trigeminal neuropathy: A case report.

BACKGROUND: Localized facial scleroderma usually presents as frontal linear morphea or progressive hemifacial atrophy. Only isolated cases of trigeminal painful neuropathy have been described. CASE REPORT: A 43-year-old woman developed an oval lesion on the right cheek. After 1 year, she noticed constant "pulling" pain and episodes of lancinating pain, both spontaneous and triggered by chewing and cold drinks. She was diagnosed with solitary morphea profunda and CT scan, ultrasonography, cranial MRI and biopsy were completed. Methylprednisolone (1 gr/day for 3 days) was prescribed. For pain, gabapentin, oxcarbazepine, amitryptiline, pregabalin and eslicarbacepine were all ineffective. A capsaicin patch was placed with prolonged benefit. Later on, the pain slightly worsened; occipital blockade was effective and methotrexate was recommended. CONCLUSION: This is the first case of solitary morphea profunda associated with painful trigeminal neuropathy. Treatment should include immunosuppressants and treatment of neuropathic pain, in which local therapies seem particularly beneficial.

HTLV-1 myelopathy after renal transplant and antiviral prophylaxis: the need for screening.

The human T-lymphotropic virus type 1 (HTLV-1) is a RNA retrovirus that infects a minimum of 5-10 million people worldwide. Transmission by cell-containing blood products and solid organ transplantation has been reported. Clinical disease occurs in about 5-10% of infected individuals and consists mainly in adult T cell leukemia and HTLV-1-associated myelopathy (HAM). We present a 54-year-old woman who underwent kidney transplant from cadaveric donor in March 2015. Donor also underwent cornea extraction for another recipient (corneal transplant protocol includes HTLV-1/2 serology). Twenty-four hours after completion of kidney transplant donor, HTLV-1 serology was revealed positive. Following experts' recommendations, once donor seropositivity was demonstrated, antiviral prophylaxis including zidovudine and raltegravir was initially given to our patient, in spite of which the patient developed HAM. Once the diagnosis of HAM was established, antiretroviral therapy was restarted, and intravenous pulses of methylprednisolone were periodically administered with transient initial improvement. Later on, the patient experienced neurological deterioration becoming wheelchair dependent. Since the occurrence of this case, HTLV-1 screening has become mandatory for solid organ transplantation in the Spanish province of Navarra, and the same should happen worldwide.