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Current Understanding and Treatment of Headache Disorders Five New Things

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Current Understanding and Treatment of Headache Disorders Five New Things Current Understanding and Treatment of Headache Disorders Five New Things BY MICHAEL J. MARMURA, MD gene-related peptide antagonists now appear to be STEPHEN D. SILBERSTEIN, MD effective as acute migraine treatment for patients with poor response or contraindications to triptans. s general practitioners become increas- Finally, onabotulinumtoxin A has become only the ingly adept at prescribing triptans and 6th medication approved by the US Food and Drug preventive treatment, neurologists are Administration for migraine prevention and the first more likely to see patients who are approved for chronic migraine. This article aims to refractory to standard therapies. The highlight these exciting new topics in the treatment Amost pressing concern for physicians and patients is and understanding of headache disorders, which will excluding secondary headache. Reversible cerebral help neurologists better treat and explain the disor- vasoconstriction syndrome is increasingly recognized ders to their patients. as an underdiagnosed cause of headache, and may present as a sudden-onset thunderclap headache. The REVERSIBLE CEREBRAL VASOCONSTRICTION past few years have brought exciting new advances in SYNDROME IS NOT RARE Thunderclap headache is a the understanding of migraine pathophysiology in- neurologic emergency originally defined as a severe, cluding new genes for migraine and discovery of a sudden-onset headache; ruptured intracranial aneurysm new pathway for light sensitivity. After almost 20 had to be suspected and ruled out.1 In addition to sub- years since the introduction of triptans, calcitonin arachnoid hemorrhage, many other disorders, such as spontaneous CSF leak, cerebral venous thrombosis, pi- From the Jefferson Headache Center, Thomas Jefferson University, tuitary apoplexy, sphenoid sinusitis, carotid or vertebral Philadelphia, PA. dissection, stroke, hypertensive emergency, third ventri- Address correspondence and reprint requests to Dr. Michael J. Marmura, cle colloid cyst, and even an unruptured aneurysm, can Jefferson Headache Center, 8130 Gibbon Building, 111 South 11th St., 2 Philadelphia, PA 19107; [email protected] present with thunderclap headache. Many patients Author disclosures are provided at the end of the article. with thunderclap headache have segmental cerebral va- Neurology® Clinical Practice 2011;76 (Suppl 2):S31–S36 soconstriction likely related to a disturbance in the con- Copyright © 2011 by AAN Enterprises, Inc. S31 “The past few years have brought exciting for migraine, such as ␤-adrenergic blockers, antidepres- sants, and anticonvulsants, have not been rigorously new advances in the understanding of studied for the treatment of CM. Based on recent clini- cal trials, onabotulinumtoxin A (BoNTA) is now the migraine pathophysiology” first medication with US Food and Drug Administra- tion approval for CM prophylaxis. trol of vascular tone.3 Originally called Call-Fleming The basic pharmacologic actions of BoNTA are syndrome, it is now known as reversible cerebral vaso- fairly well-understood, but the exact mechanism of ac- constriction syndrome (RCVS).4 In almost all cases, ce- tion in pain relief is unclear. BoNTA binds to nerve rebral vasoconstriction resolves within a few weeks. terminals, is endocytosed, and cleaves SNAP-25 pro- Angiography (conventional, MRI, or CT angiography) tein, inhibiting the vesicular release of acetylcholine is crucial to make the diagnosis.5 Transcranial Doppler from nerve terminals, and blocking neuromuscular has been used to monitor cerebral vasoconstriction. transmission. Similar phenomena occur in parasympa- Case reports suggest that calcium channel blockers such thetic and sensory neurons.10 Starting a few days after as nimodipine may help relieve symptoms and prevent IM injection, BoNTA produces partial chemical dener- 6 stroke. vation of the muscle, resulting in a localized reduction RCVS may be one of the most common causes of in muscle activity for months. Due to the fact that pain 7 thunderclap headache. Ducros et al reviewed 67 con- relief in cervical dystonia trials often occurred before secutive patients with angiographically confirmed any decrease in muscle tension, it has been suggested RCVS. Most (42 of 67) were women, with a mean age that BoNTA may have other distinct properties that of 42 years. Most presented with thunderclap headache: lead to pain relief. BoNTA administration appears to 63 subjects had multiple headache episodes of extreme inhibit the release of glutamate and the neuropeptides, severity peaking in less than 10 seconds. Transient neu- substance P and CGRP, from nociceptive neurons.11 By rologic deficits occurred in 11 subjects. Visual symp- blocking peripheral sensitization of nociceptive fibers, it toms were most common, followed by unilateral may also inhibit central sensitization and allodynia.12 sensory symptoms or aphasia; 2 patients had seizures. Some early studies suggested that BoNTA dem- Five patients were diagnosed with stroke: 1 ischemic, 3 onstrated effectiveness for the prevention of chronic hemorrhagic, and 1 with both types. RCVS was due to daily headache, which includes CM,13 but in other another disorder in 63% of subjects. Precipitating fac- studies did not demonstrate a significant reduction in tors included delivery or early postpartum and the use headache-free days compared to placebo.14 A large, of vasoactive substances (cannabis, selective serotonin placebo-controlled study for the treatment of episodic reuptake inhibitors, nasal decongestants, cocaine, or al- migraine failed to show superiority over placebo,15 due cohol after binge drinking). Severe headaches resolved to a greater than expected placebo response. The most in 3–6 weeks, but 24 subjects reported milder persistent common adverse events in headache trials have been headache and 7 developed depression. Based on their cosmetic (ptosis, facial asymmetry) and temporary data, Ducros et al. concluded that RCVS is greatly worsening of headache after injection.16 underdiagnosed. Two recent, large, phase 3 multicenter studies, Thunderclap headache often occurs without a the PREEMPT 1 and 2 trials, evaluated the safety proven secondary cause. Primary thunderclap head- and efficacy of BoNTA for the treatment of adults ache is recognized by the current International Clas- with CM. These 2 studies enrolled 1,384 subjects sification of Headache Disorders4 as a sudden-onset with CM in trials consisting of a 24-week, double- headache lasting from 1 hour to 10 days. Chen et al8 blind, parallel-group, placebo-controlled phase fol- suggested that primary thunderclap headache is in lowed by a 32-week open-label phase. All subjects the same spectrum as RCVS and that nimodipine is received at least a minimum dose of 155 units of also an effective treatment. BoNTA administered at 31 injection sites across 7 ONABOTULINUMTOXIN A IS EFFECTIVE IN head and neck muscles using a fixed-site, fixed-dose THE PREVENTIVE TREATMENT OF CHRONIC injection paradigm with 155 units and up to 40 ad- MIGRAINE Chronic migraine (CM) is a highly dis- ditional units using a modified follow-the-pain ap- abling form of chronic daily headache and the most proach.17,18 All patients received injections in common disorder seen in tertiary headache centers.9 Pa- frontalis, corrugator, procerus, occipitalis, tempora- tients with CM have headache at least 15 days per lis, and trapezius muscles. In PREEMPT 1, there was month and have symptoms that meet criteria for mi- no significant difference in the number of headache graine on at least 8 of those days.4 Many patients with episodes compared to baseline in the BoNTA and CM overuse acute medication to treat pain and preven- placebo groups, but in PREEMPT 2 BoNTA signif- tive treatment is essential. Most preventive medications icantly reduced the frequency of headache days com- S32 Neurology: Clinical Practice 76 (Suppl 2) February 15, 2011 pared to placebo. Based on the pooled analyses, region of the posterior thalamus, as demonstrated by subjects receiving BoNTA in the double-blind phase anterograde tracing in the rat.22 ipRGC input to this had statistically significant improvement from base- area modulates dura-sensitive pain neurons, which line after injection compared with placebo treatment also project to this region. Thalamic neurons, dually in headache episodes and multiple secondary clinical sensitive to dural pain and light input, project widely domains, including mean frequency of headache to multiple cortical regions, including the primary days and headache episodes. BoNTA-treated subjects somatosensory cortex, the primary and secondary also had fewer migraine episodes, fewer moderate or motor cortices, the parietal association cortex, and severe headache days, and less disability and triptan the primary and secondary visual cortices.21 These use than the placebo group. cortical projections may help explain other common migraine symptoms, in addition to photophobia, A BETTER UNDERSTANDING OF PHOTOPHOBIA IN such as motor weakness or incoordination, visual dis- MIGRAINE Migraineurs typically develop worsening turbances, and poor concentration. pain and migraine symptoms when exposed to light, a phenomenon known as photophobia. Photophobia CALCITONIN GENE-RELATED PEPTIDE ANTAGO- is also common in ocular disorders, such as iritis19 NISTS EFFECTIVELY TREAT MIGRAINE ATTACKS and uveitis, and intracranial disorders, such as men- Stimulation of trigeminal sensory neurons results in ingitis. In the classic visual pathway, light activates
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