Todd J. Schwedt

Narrative review: reversible cerebral vasoconstriction syndromes.

Key Summary Points Reversible cerebral vasoconstriction syndromes (RCVS) are characterized by multifocal areas of constriction involving the cerebral arteries that resolve within days to weeks. Patients with RCVS often present with acute onset of severe headache (thunderclap headache) with or without neurologic symptoms and signs. RCVS can occur without identifiable cause, during pregnancy or the puerperium period, as an idiosyncratic response to certain medications or illicit drugs, and in the setting of catecholamine-secreting tumors. Diagnosis is made by characteristic symptoms and signs in the setting of normal results on cerebrospinal fluid analysis, exclusion of other causes of sudden severe headache, segmental cerebral arterial vasoconstriction demonstrated by direct or indirect angiography, and reversibility of the vasoconstriction within 12 weeks. RCVS must be differentiated from primary angiitis of the central nervous system, a condition with similar angiographic abnormalities but a substantially different diagnostic and therapeutic approach. Treatment is empirical and includes observation, calcium-channel blockers (nimodipine or verapamil), and possibly high-dose corticosteroids. Prognosis is uncertain, but most patients do well. Permanent neurologic deficits and deaths have been reported. Reversible cerebral vasoconstriction syndromes (RCVS) comprise a group of disorders characterized by prolonged but reversible vasoconstriction of the cerebral arteries, usually associated with acute-onset, severe, recurrent headaches, with or without additional neurologic signs and symptoms. These syndromes are diverse (Table 1) (1) and have been given various eponymic or syndromic labels, including the Call syndrome (or the CallFleming syndrome) (2, 3), benign angiopathy of the central nervous system (4), postpartum angiopathy (5), thunderclap headache with reversible vasospasm (68), migrainous vasospasm or migraine angiitis (912), and drug-induced cerebral arteritis or angiopathy (1315). In general, these disorders have been poorly characterized and continue to be frequently confused with cerebral vasculitis because the latter condition has overlapping angiographic features, and to a certain degree, clinical features. Table 1. Conditions Associated with Reversible Cerebral Vasoconstriction Syndromes* An understanding of RCVS has been limited by the lack of a clear underlying pathologic basis and consensus definition. Furthermore, patients with RCVS have historically presented to different specialists, including stroke neurologists, headache specialists, obstetricians, and rheumatologists, and all in turn impart their own biases on nomenclature, theories of pathogenesis, and clinical approach. Some authors (1, 1618) only recently started defining the unifying features of these conditions and proposing that they be collectively called RCVS. It is likely that primary care providers, internists, emergency department physicians, neurologists, neurosurgeons, intensivists, rheumatologists, obstetricians, and other clinicians will detect RCVS in more patients because of the wider availability of newer, relatively noninvasive technologies to assess cerebral vasculature and blood flow velocity (computed tomography angiography [CTA], magnetic resonance angiography [MRA], and transcranial Doppler ultrasonography). In addition, use of vasoactive drugs, especially diet pills; exercise stimulants; certain antidepressants; nasal decongestants; and drugs of abuse, such as amphetamines, cocaine, and ecstasy, is increasing. This narrative review, by specialists in the field of rheumatology, headache, and stroke, will outline the cause and pathophysiology, symptoms and signs, diagnosis, treatment, and prognosis of RCVS and areas of uncertainty. The funding source had no role in the design, analysis, or reporting of this study or in the decision to submit the manuscript for publication. Cause and Pathophysiology Reversible cerebral vasoconstriction syndromes have been reported to occur in various clinical settings (Table 1), and although the pathophysiology is not clearly understood, a disturbance in the control of cerebral vascular tone seems to be a critical element. This alteration in vascular tone may be spontaneous or evoked by various exogenous or endogenous factors. Sympathomimetic and serotonergic drugs and tumors (3, 1315, 1922), endocrine factors, direct or neurosurgical trauma (18, 2328), and uncontrolled hypertension (29, 30) have all been implicated. The molecular pathophysiology of RCVS is unknown. It is conceivable that the numerous immunologic and biochemical factors known to be involved in subarachnoid hemorrhagerelated vasospasm (catecholamines, endothelin-1, serotonin, nitric oxide, and prostaglandins) (31, 32) play a similar role in the pathophysiology of vasoconstriction in RCVS. Ultimately, because vascular tone and caliber is dependent on vascular receptor activity and sensitivity, a spontaneous or evoked central vascular discharge may underlie the alteration and reversible nature of RCVS and contribute to the severe and acute headache seen with these disorders. The anatomical basis for this may be that cerebral blood vessels are also densely innervated with sensory afferents from the first division of the trigeminal nerve and dorsal root of C2. Symptoms and Signs The typical patient with RCVS is a woman between the ages of 20 and 50 years presenting with a hyperacute severe headache, often called a thunderclap headache. Historically, this refers to a severe headache that reaches its peak intensity within seconds, like a clap of thunder (6, 33). Thunderclap headache is most characteristic of subarachnoid hemorrhage, but it has also been described as a spontaneous and idiopathic condition and a manifestation of other intracranial or extracranial disorders, such as arterial dissection and cerebral venous sinus thrombosis (33, 34). Primary thunderclap headache is by definition not associated with cerebral vasoconstriction (34). Patients with RCVS commonly have recurrent thunderclap headache associated with cerebral vasoconstriction. As with primary thunderclap headache, the RCVS headache may be occipital or diffuse; severe and throbbing; and associated with nausea, emesis, and photosensitivity. It can recur spontaneously while the patient is at rest or can be precipitated by exertion or the Valsalva maneuver. Severe neurologic symptoms and signs, including transient or permanent visual defects, hemiplegia, dysarthria, aphasia, numbness, or ataxia, can occur secondary to ischemia in brain regions that are perfused by a severely constricted artery. Transient hypertension, which at times can be marked, is not uncommon. Generalized seizures may occur during the acute period, but epilepsy does not ensue. Major ischemic or hemorrhagic stroke, progressive brain edema, and even stroke-related death from progressive or severe, sustained cerebral vasoconstriction have been described (3541). Figure 1. Neuroimaging findings in a 46-year-old man with reversible cerebral vasoconstriction syndrome. The patient, who had a history of migraine without aura, hypertension, hyperlipidemia, and cannabis abuse, developed a severe postcoital thunderclap headache. Severe headaches recurred, and on day 3, he developed cortical blindness and mild left hemiparesis. Computed tomography angiography obtained at admission showed multifocal segmental stenosis (beading) of the bilateral middle cerebral arteries (A) and the basilar, posterior cerebral, and superior cerebellar arteries (B). These abnormalities were also present on brain magnetic resonance angiography (C). Diffusion-weighted magnetic resonance imaging (D) and apparent diffusion coefficient maps (E) showed symmetrical lesions in the bilateral occipital lobes consistent with ischemic stroke. In addition, brain magnetic resonance imaging showed small infarctions in the bilateral cerebellar hemispheres and in the right frontal lobe (not shown). Serologic tests and the results of 2 cerebrospinal fluid examinations showed no evidence for vasculitis or subarachnoid hemorrhage. The patient was treated with analgesics and verapamil. His deficits resolved completely over a period of 3 weeks, and follow-up magnetic angiography (F) showed resolution of the cerebral arterial vasoconstriction. Diagnosis Although there are no validated criteria for the diagnosis of RCVS, it is not difficult to recognize or diagnose. For the diagnosis of RCVS, the patient ideally should have all of the features that are outlined in Table 2. Although these criteria have not been prospectively validated, we believe that they have considerable sensitivity and specificity in the appropriate clinical setting and are a summary of published and personal experience to date. Table 2. Summary of Critical Elements for the Diagnosis of Reversible Cerebral Vasoconstriction Syndromes* Clinically, RCVS should be considered in patients who present with a hyperacute severe headache, with or without neurologic symptoms or signs, and without evidence of aneurysmal subarachnoid hemorrhage. Reversible cerebral vasoconstriction syndrome should also be considered in patients with cryptogenic stroke, particularly in those with severe-onset headache or thunderclap headache and symmetrical brain infarctions or edema. The initial evaluation should uniformly include unenhanced brain computed tomography (CT) to exclude subarachnoid or parenchymal brain hemorrhage. If the results of the CT scan are negative for hemorrhage, lumbar puncture should be performed to exclude CT-negative subarachnoid hemorrhage and inflammatory conditions, such as infection and cerebral vasculitis. If the results of the cerebrospinal fluid examination are benign, additional brain and neurovascular imaging to assess for other causes of severe headache, including cerebral venous sinus thrombosis, arterial dissection, unruptured saccular aneurysms, and RCVS, should be p

Occipital nerve stimulation for chronic headache - Long-term safety and efficacy

The aim of this study was to examine the safety and efficacy of occipital nerve stimulation for medically intractable headache. Electrical stimulation of large sensory afferents has an antinociceptive effect. Occipital nerve stimulation may be effective for the treatment of medically intractable headache. Retrospective analysis was performed of 15 patients with medically refractory headache who underwent implantation of an occipital nerve stimulator. Pre- and postimplant data regarding headache frequency, severity, disability, depression and post-stimulator complications were collected. Twelve patients were female and three male. Ages ranged from 21 to 52 years (mean 39 years). Eight patients had chronic migraine, three chronic cluster, two hemicrania continua and two had post-traumatic headache. Eight patients underwent bilateral and seven had unilateral lead placement. Patients were measured after 5-42 months (mean 19). All six mean headache measures improved significantly from baseline (P < 0.03). Headache frequency per 90 days improved by 25 days from a baseline of 89 days; headache severity (0-10) improved 2.4 points from a baseline of 7.1 points; MIDAS disability improved 70 points from a baseline of 179 points; HIT-6 scores improved 11 points from a baseline of 71 points; BDI-II improved eight points from a baseline of 20 points; and the mean subjective percent change in pain was 52%. Most patients (60%) required lead revision within 1 year. One patient required generator revision. Occipital nerve stimulation may be effective in some patients with intractable headache. Surgical revisions may be commonly required. Safety and efficacy results from prospective, randomized, sham-controlled studies in patients with medically refractory headache are needed.

Patent Foramen Ovale and Migraine: A Quantitative Systematic Review:

Initial studies indicate an increased prevalence of patent foramen ovale (PFO) in migraineurs with aura, and an increased prevalence of migraine and migraine with aura in persons with PFO. Retrospective analyses of PFO closure suggest clinically significant improvements in migraine patterns. The aim of this study was to examine the prevalence of migraine in patients with PFO, the prevalence of PFO in migraineurs, and the effect of PFO closure on migraine. We conducted a quantitative systematic review of articles on migraine and PFO that met inclusion criteria, then reviewed, appraised, and subjected them to data extraction. Of 134 articles identified, 18 met a priori selection criteria. The estimated strength of association between PFO and migraine, reflected by summary odds ratios (ORs), was 5.13 [95% confidence interval (CI) 4.67, 5.59], and between PFO and migraine with aura the OR was 3.21 (95% CI 2.38, 4.17). The grade of evidence was low. The association between migraine and PFO was OR 2.54 (95% CI 2.01, 3.08). The grade of evidence was low to moderate. Six studies of PFO closure suggested improvement in migraine, but had a very low grade of evidence. The low-to-moderate grade of evidence from observational studies supports an apparent association between PFO and migraine. Although PFO closure seemed to affect migraine patterns favourably, the very low grade of available evidence to support this association precludes definitive conclusions.

Guidelines for controlled trials of drugs in migraine: Third edition. A guide for investigators

International Headache Society Clinical Trials Subcommittee members: Peer Tfelt-Hansen (chairman) (Denmark), Julio Pascual (vice-chairman) (Spain), Nabih Ramadan (vice-chairman) (USA), Carl Dahlof (Sweden), Domenico D’Amico (Italy), Hans-Christopher Diener (Germany), Jakob Moller Hansen (secretary) (Denmark), Michel Lanteri-Minet (France), Elisabeth Loder (USA), Douglas McCrory (USA), Sandra Plancade (France) and Todd Schwedt (USA)

The Acute Treatment of Migraine in Adults: The American Headache Society Evidence Assessment of Migraine Pharmacotherapies

The study aims to provide an updated assessment of the evidence for individual pharmacological therapies for acute migraine treatment. Pharmacological therapy is frequently required for acutely treating migraine attacks. The American Academy of Neurology Guidelines published in 2000 summarized the available evidence relating to the efficacy of acute migraine medications. This review, conducted by the members of the Guidelines Section of the American Headache Society, is an updated assessment of evidence for the migraine acute medications. A standardized literature search was performed to identify articles related to acute migraine treatment that were published between 1998 and 2013. The American Academy of Neurology Guidelines Development procedures were followed. Two authors reviewed each abstract resulting from the search and determined whether the full manuscript qualified for review. Two reviewers studied each qualifying full manuscript for its level of evidence. Level A evidence requires at least 2 Class I studies, and Level B evidence requires 1 Class I or 2 Class II studies. The specific medications – triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan [oral, nasal spray, injectable, transcutaneous patch], zolmitriptan [oral and nasal spray]) and dihydroergotamine (nasal spray, inhaler) are effective (Level A). Ergotamine and other forms of dihydroergotamine are probably effective (Level B). Effective nonspecific medications include acetaminophen, nonsteroidal anti‐inflammatory drugs (aspirin, diclofenac, ibuprofen, and naproxen), opioids (butorphanol nasal spray), sumatriptan/naproxen, and the combination of acetaminophen/aspirin/caffeine (Level A). Ketoprofen, intravenous and intramuscular ketorolac, flurbiprofen, intravenous magnesium (in migraine with aura), and the combination of isometheptene compounds, codeine/acetaminophen and tramadol/acetaminophen are probably effective (Level B). The antiemetics prochlorperazine, droperidol, chlorpromazine, and metoclopramide are probably effective (Level B). There is inadequate evidence for butalbital and butalbital combinations, phenazone, intravenous tramadol, methadone, butorphanol or meperidine injections, intranasal lidocaine, and corticosteroids, including dexamethasone (Level C). Octreotide is probably not effective (Level B). There is inadequate evidence to refute the efficacy of ketorolac nasal spray, intravenous acetaminophen, chlorpromazine injection, and intravenous granisetron (Level C). There are many acute migraine treatments for which evidence supports efficacy. Clinicians must consider medication efficacy, potential side effects, and potential medication‐related adverse events when prescribing acute medications for migraine. Although opioids, such as butorphanol, codeine/acetaminophen, and tramadol/acetaminophen, are probably effective, they are not recommended for regular use.

Occipital Nerve Stimulation for Chronic Cluster Headache and Hemicrania Continua: Pain Relief and Persistence of Autonomic Features:

The trigeminal autonomic cephalgias (TACs) and hemicrania continua are primary headache disorders characterized by pain in a unilateral trigeminal distribution that occurs in conjunction with prominent ipsilateral cranial autonomic features (1). Cluster headache, paroxysmal hemicrania and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) are classified as TACs, while hemicrania continua is considered a separate primary headache disorder. The autonomic features and first (ophthalmic) division pain have been assumed to be interdependent. Autonomic features have been considered the result of activation of first-division nociceptive afferents, which, through a functional brainstem connection between the trigeminal nucleus caudalis and superior salivatory nucleus, leads to activation of parasympathetic efferents (2). However, this interdependence has been challenged by reports of patients with typical cluster headache without autonomic features, patients with autonomic features without cephalgia, patients with continuing autonomic features without pain after trigeminal root section and patients who report the appearance of autonomic features prior to onset of pain (3–6). Herein we report one patient with chronic cluster and one with hemicrania continua who experienced persistence of autonomic features in the absence of head pain after placement of an occipital nerve stimulator.

Advanced neuroimaging of migraine

Advanced neuroimaging has helped to increase our knowledge about migraine pathophysiology. Our perception of migraine has transformed from a vascular, to a neurovascular, and most recently, to a CNS disorder. Functional imaging has confirmed the importance of cortical spreading depression (CSD) as the pathophysiological mechanism of migraine aura in human beings, whereas novel animal studies are unravelling the mechanistic underpinnings of CSD. Altered cerebral blood flow and neurotransmitter systems have been identified during and between headaches in migraine with and without aura. Advanced neuroimaging has identified mechanisms involved in the transformation of migraine from an episodic disorder to one with near continuous symptomatology. Questions regarding the secondary effects of migraine on brain structure and function, possibly related to attack frequency and duration of illness, have been raised. New imaging techniques could lead to novel diagnostic and therapeutic interventions that will help to improve the lives of millions of patients with migraine. In this Review, we summarise the most important findings from current imaging studies of migraine.

Atypical resting-state functional connectivity of affective pain regions in chronic migraine.

Chronic migraineurs (CM) have painful intolerances to somatosensory, visual, olfactory, and auditory stimuli during and between migraine attacks. These intolerances are suggestive of atypical affective responses to potentially noxious stimuli. We hypothesized that atypical resting‐state functional connectivity (rs‐fc) of affective pain‐processing brain regions may associate with these intolerances. This study compared rs‐fc of affective pain‐processing regions in CM with controls.

Allodynia and Descending Pain Modulation in Migraine: A Resting State Functional Connectivity Analysis

OBJECTIVE Most migraineurs develop cutaneous allodynia during migraines, and many have cutaneous sensitization between attacks. Atypical pain modulation via the descending pain system may contribute to this sensitization and allodynia. The objective of this study was to test the hypothesis that compared with non-allodynic migraineurs, allodynic migraineurs have atypical periaqueductal gray (PAG) and nucleus cuneiformis (NCF) resting-state functional connectivity (rs-fc) with other pain processing regions. DESIGN Ten minutes resting-state blood-oxygen-level-dependent data were collected from 38 adult migraineurs and 20 controls. Seed-based analyses compared whole-brain rs-fc with PAG and with NCF in migraineurs with severe ictal allodynia (N = 8) to migraineurs with no ictal allodynia (N = 8). Correlations between the strength of functional connections that differed between severely allodynic and non-allodynic migraineurs with allodynia severity were determined for all migraineurs (N = 38). PAG and NCF rs-fc in all migraineurs was compared with rs-fc in controls. RESULTS Migraineurs with severe allodynia had stronger PAG and NCF rs-fc to other brainstem, thalamic, insula and cerebellar regions that participate in discriminative pain processing, as well as to frontal and temporal regions implicated in higher order pain modulation. Evidence that these rs-fc differences were specific for allodynia included: 1) strong correlations between some rs-fc strengths and allodynia severity among all migraineurs; and 2) absence of overlap when comparing rs-fc differences in severely allodynic vs non-allodynic migraineurs with those in all migraineurs vs controls. CONCLUSION Atypical rs-fc of brainstem descending modulatory pain regions with other brainstem and higher order pain-modulating regions is associated with migraine-related allodynia.

Episodic and chronic migraineurs are hypersensitive to thermal stimuli between migraine attacks

Objective: To determine if migraineurs have evidence of interictal cutaneous sensitisation. Subjects and methods: Thermal and mechanical pain thresholds in 20 episodic migraineurs, 20 chronic migraineurs, and 20 non-migraine control subjects were compared. Quantitative sensory testing was conducted when subjects had been migraine-free for at least 48 h. Heat, cold and mechanical pain thresholds, and heat and cold pain tolerance thresholds were measured. Results: Thermal pain thresholds and thermal pain tolerance thresholds differed significantly by headache group (P = 0.001). During the interictal period, episodic and chronic migraineurs were more sensitive to thermal stimulation than non-migraine controls. Conclusions: Interictal sensitisation may predispose the migraineur to development of headaches, may be a marker of migraine activity, and a target for treatment.