David W. Dodick

New appendix criteria open for a broader concept of chronic migraine.

After the introduction of chronic migraine and medication overuse headache as diagnostic entities in The International Classification of Headache Disorders, Second Edition, ICHD-2, it has been shown that very few patients fit into the diagnostic criteria for chronic migraine (CM). The system of being able to use CM and the medication overuse headache (MOH) diagnosis only after discontinuation of overuse has proven highly unpractical and new data have suggested a much more liberal use of these diagnoses. The International Headache Classification Committee has, therefore, worked out the more inclusive criteria for CM and MOH presented in this paper. These criteria are included in the appendix of ICHD-2 and are meant primarily for further scientific evaluation but may be used already now for inclusion into drug trials, etc. It is now recommended that the MOH diagnosis should no longer request improvement after discontinuation of medication overuse but should be given to patients if they have a primary headache plus ongoing medication overuse. The latter is defined as previously, i.e. 10 days or more of intake of triptans, ergot alkaloids mixed analgesics or opioids and 15 days or more of analgesics/NSAIDs or the combined use of more than one substance. If these new criteria for CM and MOH prove useful in future testing, the plan is to include them in a future revised version of ICHD-2.

A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease.

There are no established treatments for patients with acute, severe neurological deficits caused by multiple sclerosis or other inflammatory demyelinating diseases of the central nervous system who fail to recover after treatment with high‐dose corticosteroids. We conducted a randomized, sham‐controlled, double‐masked study of plasma exchange without concomitant immunosuppressive treatment in patients with recently acquired, severe neurological deficits resulting from attacks of inflammatory demyelinating disease, who failed to recover after treatment with intravenous corticosteroids. Patients who did not achieve moderate or greater improvement after the first treatment phase crossed over to the opposite treatment. Moderate or greater improvement in neurological disability occurred during 8 of 19 (42.1%) courses of active treatment compared with 1 of 17 (5.9%) courses of sham treatment. The primary analysis was positive. Improvement occurred early in the course of treatment, and was sustained on follow‐up. However, 4 of the patients who responded to the active treatment experienced new attacks of demyelinating disease during 6 months of follow‐up. Moderate or greater improvement occurred during follow‐up in only 2 of 13 patients who failed to improve during the treatment phase. Plasma exchange leads to functionally important neurological recovery in an important proportion of severely disabled patients with acute attacks of idiopathic inflammatory demyelinating disease.

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

OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial.

Objectives: This is the first of a pair of studies designed to assess efficacy, safety and tolerability of onabotulinumtoxinA (BOTOX®) as headache prophylaxis in adults with chronic migraine. Methods: The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 (PREEMPT 1) is a phase 3 study, with a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxinA (155 U–195 U; n = 341) or placebo (n = 338) (two cycles). The primary endpoint was mean change from baseline in headache episode frequency at week 24. Results: No significant between-group difference for onabotulinumtoxinA versus placebo was observed for the primary endpoint, headache episodes (−5.2 vs. −5.3; p = 0.344). Large within-group decreases from baseline were observed for all efficacy variables. Significant between-group differences for onabotulinumtoxinA were observed for the secondary endpoints, headache days (p = .006) and migraine days (p = 0.002). OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few subjects discontinued due to adverse events. Conclusions: There was no between-group difference for the primary endpoint, headache episodes. However, significant reductions from baseline were observed for onabotulinumtoxinA for headache and migraine days, cumulative hours of headache on headache days and frequency of moderate/severe headache days, which in turn reduced the burden of illness in adults with disabling chronic migraine.

OnabotulinumtoxinA for Treatment of Chronic Migraine: Pooled Results From the Double‐Blind, Randomized, Placebo‐Controlled Phases of the PREEMPT Clinical Program

(Headache 2010;50:921‐936)

Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial

BACKGROUND Calcitonin gene-related peptide (CGRP) probably has a role in migraine pathophysiology, and antagonism of its receptors might provide treatment without the vasoconstrictor effects of triptans. We aimed to assess the clinical profile of MK-0974 (telcagepant), an orally bioavailable antagonist of CGRP receptor. METHODS In a randomised, parallel-treatment, placebo-controlled, double-blind, trial at 81 sites in the Europe and the USA, adults with migraine diagnosed by International Headache Society criteria treated moderate or severe attacks with either oral telcagepant 150 mg or 300 mg, zolmitriptan 5 mg, or placebo. The five co-primary endpoints were pain freedom, pain relief, or absence of photophobia, phonophobia, or nausea at 2 h after treatment. Analysis was by the full analysis set and multiplicity was controlled for with a step-down closed-testing procedure. This trial is registered with ClinicalTrials.gov, number NCT00442936. FINDINGS 1380 patients were randomly assigned to receive telcagepant 150 mg (n=333) or 300 mg (354), zolmitriptan (345), or placebo (348). Telcagepant 300 mg was more effective than placebo for pain freedom (95 [27%] of 353 patients vs 33 [10%] of 343 [p<0.0001]), pain relief (194 [55%] of 353 vs 95 [28%] of 343 [p<0.0001]), and absences of phonophobia (204 [58%] of 353 vs 126 [37%] of 342 [p<0.0001]), photophobia (180 [51%] of 353 vs 99 [29%] of 342 [p<0.0001]), and nausea (229 [65%] of 352 vs 189 [55%] of 342 [p=0.0061]). Efficacy of telcagepant 300 mg and zolmitriptan 5 mg were much the same, and both were more effective than telcagepant 150 mg. Adverse events were recorded for 31% taking telcagepant 150 mg, 37% taking telcagepant 300 mg, 51% taking zolmitriptan 5 mg, and 32% taking placebo. INTERPRETATION Telcagepant 300 mg is effective as an acute treatment for migraine with efficacy comparable to that of zolmitriptan 5 mg, but with fewer associated adverse effects. FUNDING Merck Research Laboratories.

Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society

Objective: To provide updated evidence-based recommendations for the preventive treatment of migraine headache. The clinical question addressed was: What pharmacologic therapies are proven effective for migraine prevention? Methods: The authors analyzed published studies from June 1999 to May 2009 using a structured review process to classify the evidence relative to the efficacy of various medications available in the United States for migraine prevention. Results and Recommendations: The author panel reviewed 284 abstracts, which ultimately yielded 29 Class I or Class II articles that are reviewed herein. Divalproex sodium, sodium valproate, topiramate, metoprolol, propranolol, and timolol are effective for migraine prevention and should be offered to patients with migraine to reduce migraine attack frequency and severity (Level A). Frovatriptan is effective for prevention of menstrual migraine (Level A). Lamotrigine is ineffective for migraine prevention (Level A).

Efficacy and Safety of Topiramate for the Treatment of Chronic Migraine: A Randomized, Double-Blind, Placebo-Controlled Trial

Objective.—To evaluate the efficacy and safety of topiramate (100 mg/day) compared with placebo for the treatment of chronic migraine.

A self-administered screener for migraine in primary care The ID Migraine™ validation study

Background: Migraine is a highly prevalent and disabling illness that remains substantially undiagnosed in primary care. Because of the potential value of a screening tool, the current study was designed to establish the validity and reliability of a brief, self-administered migraine screener in patients with headache complaints in the primary care setting. Methods: A total of 563 patients presenting for routine primary care appointments and reporting headaches in the past 3 months completed a self-administered migraine screener. All patients were then referred for an independent diagnostic evaluation by a headache expert, of whom 451 (80%) completed a full evaluation. Migraine diagnosis was assigned based on International Headache Society criteria after completing a semi-structured diagnostic interview. Results: Of nine diagnostic screening questions, a three-item subset of disability, nausea, and sensitivity to light provided optimum performance, with a sensitivity of 0.81 (95% CI, 0.77 to 0.85), a specificity of 0.75 (95% CI, 0.64 to 0.84), and positive predictive value of 0.93 (95% CI, 89.9 to 95.8). Test-retest reliability was good, with a kappa of 0.68 (95% CI, 0.54 to 0.82). The sensitivity and specificity of the three-item migraine screener was similar regardless of sex, age, presence of other comorbid headaches, or previous diagnostic status. Conclusions: The three-item ID Migraine™ migraine screener was found to be a valid and reliable screening instrument for migraine headaches. Its ease of use and operating characteristics suggest that it could significantly improve migraine recognition in primary care.

Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM feasibility study

Background: Medically intractable chronic migraine (CM) is a disabling illness characterized by headache ≥15 days per month. Methods: A multicenter, randomized, blinded, controlled feasibility study was conducted to obtain preliminary safety and efficacy data on occipital nerve stimulation (ONS) in CM. Eligible subjects received an occipital nerve block, and responders were randomized to adjustable stimulation (AS), preset stimulation (PS) or medical management (MM) groups. Results: Seventy-five of 110 subjects were assigned to a treatment group; complete diary data were available for 66. A responder was defined as a subject who achieved a 50% or greater reduction in number of headache days per month or a three-point or greater reduction in average overall pain intensity compared with baseline. Three-month responder rates were 39% for AS, 6% for PS and 0% for MM. No unanticipated adverse device events occurred. Lead migration occurred in 12 of 51 (24%) subjects. Conclusion: The results of this feasibility study offer promise and should prompt further controlled studies of ONS in CM.