Headache: Trends in Treatment

Educational Objectives

The goal of this program is to improve diagnosis and treatment of headaches. After hearing and assimilating this pro­gram, the clinician will be better able to:

1.   Recognize common and serious causes for headache in the emergency department.

2.   Distinguish clinical features of cluster headache from those of migraine.

3.   Treat cluster headache using abortive agents and long- and short-term preventive agents.

4.   Explain the autonomic system pathogenesis of cluster headache.

5.   Describe mechanisms and outcomes of sphenopalatine ganglion stimulation in patients with chronic refractory cluster and migraine headaches.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. The following has been disclosed: Dr. Freitag is a visiting lecturer for GlaxoSmithKline. Drs. Huff and Tepper and the planning committee reported nothing to disclose. In their lectures, Drs. Freitag and Tepper present information related to off-label or investigational use of a therapy, product, or device.

Acknowledgments

Dr. Huff was recorded at the 15th Annual Scientific Assembly of the American Academy of Emergency Medicine, held March 2-4, 2009, in Phoenix, AZ. Drs. Freitag and Tepper were recorded at Headache Update 2009, jointly sponsored by the Diamond Headache Clinic Research and Educational Foundation, the Diamond Inpatient Headache Unit of St. Joseph Hospital, and the Rosalind Franklin University of Medicine and Science, Chicago, IL, and held July 13-18, 2009, in Lake Buena Vista, FL. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Headache: The View from the ER

J. Stephen Huff, MD, Associate Professor of Emergency Medicine and Neurology, University of Virginia Health Systems, Charlottesville

Causes of headache: benign in most cases; Texas observational study  —  in 455 patients, <1% with subarachnoid hemorrhage (SAH); headache common  emergency department (ED) presentation in young women; primary cause  —  no other (secondary) cause detectable; biochemical and cellular, not gross anatomic; challenge  —  normal neurologic examination in patient with tumor

Approach to patient 

Ask whether headache isolated: lone acute severe headache (LASH)  —  consider lumbar puncture (LP) without im­aging; if patient has fever, altered mental status, weakness or numbness, gait difficulty, then not LASH

Sudden onset or onset with exertion: concern about SAH, but retrospective study shows 10% of SAH patients wake up with headaches;  »33% have nonexertional headaches

New, progressive, or frequent headaches: “first or worst?” oversimplification; Diaz  (2007)  —  patients asked whether this is worst headache, and when was last episode of headache this severe; questions logically exclusive, but found that order of questions influenced agreement in answers; historical "red flags"   —  trauma (in elderly, may be trivial); cancer (classic tumor-related headaches worse in morning and improve as day progresses; often resemble benign [tension-type headaches); immunosuppression, eg, HIV, transplant, long-term steroid therapy (even low dose); anticoagulant use; hypercoagulability

Recurrent or chronic headache: migraine; cluster headache; patient with migraine  —  if typical or recurrent, no fur­ther work-up needed; new pattern or new onset more concerning; pain often unilateral but may change sides sometimes

Worst headache: "worst" should be weighted for individual patient; red flags  —  focal or lateralizing signs; aggrava­tion by exertion; fever; nuchal rigidity and stiff neck; anisocoria; cranial nerve abnormalities; papilledema (not common); focal deficits; drift; altered mental status; nuchal rigidity (jolt accentuation of headache)  —  test for meningitis; ask patient to turn head rhythmically »1 time/sec; if this worsens neck pain, test positive

Subarachnoid Hemorrhage

Incidence: of ED patients with chief complaint of headache,  »1%  have SAH; of sudden onset headache, 10%; 25% to 50% of SAH cases missed on first visit

Reasons for missed diagnosis

Failure of clinicians to appreciate spectrum of clinical presentation: history should trigger evaluation if abrupt on­set, and maximum intensity reached over seconds or 1 min, investigate further; nausea and vomiting in majority; nuchal rigidity and altered mental status in some; “sentinel headache” difficult to identify; warning leaks with smaller headaches  —investigate aggressively if identified; aneurysms  —  most common cause of SAH in middle age; arteriovenous malformations  —  more common in younger patients; computed tomography (CT) >90% sen­sitive

Failure to understand limitations of CT: 90% to 95%sensitivity for SAH and decreases with time (several days); low pretest probability and normal CT can cause error; if SAH suspected, perform LP after normal CT; LP ab­normal early in case; traumatic LP  —  spectrophotometric examination of cerebrospinal fluid for xanthochromia more specific than visual determination

Other Causes of Headache

Environmental: carbon monoxide; cluster event  —  key for recognition; typically occurs during first use of heating system

Giant cell arteritis (GCA): not commonly found; headaches last days; polymyalgia rheumatica  —  common in GCA; erythrocyte sedimentation rate  —  >2-hr turnaround; relatively specific; elevated in most GCA patients; important to consider in elderly patient; responds to steroids; preventable cause of blindness

Pseudotumor cerebri: occurs in young, overweight women, and in those taking oral contraceptives; visual complaints  —  may be common, visual loss in severe cases; papilledema  —  may be present; CT  —  may show tight ventricles; LP opening pressure  —  diagnostic

Central venous thrombosis: natural history unclear; common in women; many have coagulopathy; headache may be nonspecific; D-dimer  —  usefulness debated; some people with pseudotumor have elevated D-dimer (>500 ng/mL; »80% sensitive); with low pretest probability, may rule out central venous thrombosis; if pretest probability higher, may need image (eg, magnetic resonance angiography)

Arterial dissections: cause of stroke in younger patients; natural history uncertain; headache  —  may be abrupt and unilateral; typically retro-orbital; Horner’s syndrome  —  may be present

Cluster Headache

Frederick G. Freitag, DO, Clinical Assistant Professor, Department of Family Medicine, Chicago Medical School at Rosalind Franklin University of Medical Science, North Chicago, IL, and Clinical Associate, Depart­ment of Family Medicine, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL

Clinical features of cluster headaches: compared to migraine, starts later (in 20s for most individuals) and runs later in life; occur in groups over defined period (eg, 5-6 attacks/day, 1-2 times/yr, for 2-3 mo); attacks brief (average 30-45 min); pain rarely switches sides between or during series; pain  —  localized to frontal temporal orbital area; sometimes occurs in occipital region; lifestyle  —  smoking and alcohol

Circadian features: periodicity  —  peak times in mid-December and mid-June, within 2 wk; time changes in spring and fall; 24-hr cycle  —  majority of headaches occur during same time of day in given cycle and  across cycles; at night, usually near end of first sleep cycle; awakens patient (unlike migraine); staying awake may suppress tempo­rarily

Physical examination: facial characteristics  —  leonine; previously used to distinguish; during headache  —  many pa­tients have partial Horner’s syndrome (residual may persist after attack)

Pathogenesis

Vasodilation: many patients flushed during attack, with distended superficial temporal arteries; carotid blood flow may increase (150%-300%) during attack

Autonomic system: alterations in shape of hypothalamus (seen in magnetic resonance image [MRI]); may be genetic predisposition; evidence of both increase in parasympathetic (PS) phenomena that would explain symptoms (eg, lacrimation, nasal congestion, flushing), but might also be explained by sympathetic paresis; hypothalamus involvement  —  may be related to circannual features; hormonal components  —  cluster patients tend to have reduc­tion in hypothalamus-regulated hormones (eg, testosterone) may be associated with cycles, but may also be chronic; prolactin also involved; serum enkephalin  —  starts to decrease »2 wk before onset of cluster cycle; reach 50% of normal; levels restored as cycle ends; endorphin  —  spikes to 2- to 4-fold during cycle, then fall dramati­cally; affects pain regulation

Chronic cluster headache:  »10% of cluster population; continuous and episodic forms; episodic to chronic transformation  —loss of circannual features; increasing number of attacks; diminished response to therapy; can re­verse process by controlling cluster

Treatment

Abortive agents: not uniformly effective; oxygen  —  100% delivered from 8 to 20 L/min via face mask; first-line ther­apy; patients should be seated and breathing normally; stops 70% to 80% of attacks; triptans  —  includes sumatrip­tan and zolmitriptan; delivered by nasal spray or injection; need rapid onset of activity; oral formulations not successful; dihydroergotamine mesylate  —  serotonergically active agent; ergotamines  —   oral sublingual form used; local anesthetics  —  4% aqueous lidocaine intranasal spray or drip to anesthetize sphenopalatine ganglion (SPG; in back of posterior pharynx); 5% to 10% cocaine solution more effective but more drawbacks

Preventive agents: episodic cluster headache  —  older ergotamines may be effective (less risk of developing retroper­itoneal, cardiac or pulmonary fibrosis); methylergonovine  —   first metabolic breakdown product of methysergide; effective for cluster headache and well tolerated; ergotamine tartrate  —effective for some patients; low bioavail­ability; triptans — use those with longer half-life; rebound unlikely; safe and effective; do not use in patients at risk for coronary artery disease; long duration required because of pharmacy limits on amounts dispensed (need ³1 dose/day, sometimes 2); corticosteroids  —rapid relief (4-24 hr)  headache returns after tapering; 40 mg prednisone; depot injection effective alternative to oral; dose £10 days

Long-term preventives: verapamil  —  robust evidence for efficacy in treating cluster headache; 360 mg optimal for most patients, but necessary dose varies; check electrocardiograms if using >480 mg (because of risk for prolonga­tion of AV interval); nimodipine  —  calcium channel blocker approved for treatment of SAH; effective for cluster and migraine headaches; fall-back agent (cost considerations); cyproheptadine  —antihistamine; potent blocker at the 5-hydroxytryptamine 2 (5-HT2) receptor sites; well tolerated in patients with serotonin syndrome and cluster headaches; 16 to 32 mg/day in divided doses for cluster; lithium carbonate  —  previously drug of choice; prone to adverse events; divalproex  —  mood-stabilizing agent; may be more effective than topiramate; 250 to 500 mg/day; use direct release form and give at bedtime to avoid side effects;  indomethacin  —  not as effective as others for pre­vention; melatonin  —  9 to 15 mg once daily at bedtime; related to hypothalamic alterations; occipital nerve blocks  —  efficacy may relate to injection of local anesthetic or corticosteroid; botulinum toxin  —  results not robust in literature; clonidine (a-agonist)  —  used successfully; tizanidine — useful because of a-agonist effects; baclofen  —  muscle relaxant; useful in some patients; testosterone  —  consider obtaining serum level in patients with resistant cluster headache; if suppressed, consider replacement therapy; effective in some patients

Intractable Chronic Cluster Headache

Histamine desensitization: 4 placebo-controlled trials comparing histamine to other standard agents as therapy for and prevention of migraine; robust results; likely mechanism  —  down-regulation of cyclic guanosine monophos­phate/nitric oxide/L-arginine pathway that modulates perivascular inflammatory response; use small dose and grad­ually increase infusion rate, based on tolerability and suppression of attacks; if administered too quickly, can bring on full headache; seems to restore responsiveness of patient to standard preventive agents; stopping after histamine alone leads to headache reappearance; IV dihydroergotamine  —  less effective than histamine

Surgical options: ganglionectomies, radiofrequency techniques, sectioning trigeminal nerve, glycerol injections, and gamma knife procedures; challenges  —  headache can switch sides; complications, eg, anesthesia dolorosa, anesthe­sia of cornea

Indomethacin-Responsive Syndromes

Features: high frequency of attacks (10-20 per day) but very brief (moments); higher number of attacks resembles short-lasting, unilateral, neuralgiform headache attacks with conjunctival injection and tearing (SUNCT); auto­nomic features; headaches always on same side; aspirin may provide minimal relief; other anti-inflammatory drugs not effective

Hypnic headache: like cluster, awakens patients from sound sleep; occurs in older individuals; devoid of autonomic symptoms; caffeine  —  drug of choice (100-200 mg before bedtime); ablates headache attacks and does not affect sleep cycles; lithium  —  give 300 mg at 7 pm; not well tolerated in older patients

Trigeminal Neuralgia

Features: cluster pain more temporal; neuralgias lower on face; attacks cyclical in nature but high frequency group­ing; pain more stabbing and burning; rarely occurs in younger individuals (if seen at <30 or 40 yr of age, consider multiple sclerosis and obtain MRI); trigger zones  —  in face on same side as trigeminal neuralgic pain; specific for individual; well localized areas (eg, touch or temperature); brief attacks

Therapies: medical therapies not usually first choice (because of adverse events); antiseizure drugs  —  first choice, if tolerated; neurosurgical procedures  —  appropriate in majority of cases (eg, microvascular decompression of poste­rior fossa)

Electrical Stimulation for Acute Treatment of Medically Refractory Cluster Headache

Stewart J. Tepper, MD, Professor of Medicine (Neurology), Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, and Director of Research, Center for Headache and Pain, Neurological Institute, Cleveland Clinic, OH

Background: parasympathetic (PS) outflow may account for many features of cluster headache (eg, scleral injection, lacrimation, rhinorrhea, vasodilation, pain, edema surrounding eye); in migraine, meningeal pain mechanisms (neurogenic inflammation and vasodilation) might be mediated by PS outflow; PS outflow from brainstem tra­verses sphenopalatine ganglion (SPG); some evidence that SPG blocks and ablation useful in treating refractory cluster headache and migraine through interruption of efferent pathways; cluster  —  ipsilateral hypothalamic gener­ator activates pathways that turn on PS (causing lacrimation, release of vasoactive intestinal peptide and vasodila­tion); migraine  —  central generator in periaqueductal gray matter or dorsal raphe region turned on from brainstem and activates superior salivatory nucleus from whence PS outflow goes to SPG and from SPG to meninges, causing vasodilation and neurogenic inflammation; peripheral pain mechanisms activate afferents that go back to brainstem for processing; hypothesis  —  blocking SPG may abort peripheral pain mechanisms of cluster and migraine

SPG Stimulation Studies

Methods: induced cluster headaches or migraine; turned on stimulator or sham, and assessed whether attacks termi­nated; stimulator needle  —  inserted through sphenopalatine fossa and below maxillary division of trigeminal nerve; correct placement  —  activates greater and lesser palatine nerves to posterior soft palate and nasopharynx; patients report paresthesia in back of throat and nose; too high placement  —activates alveolar branches; patient reports par­esthesias in teeth; fluoroscopic and physiologic confirmation of location

Results: with good electrode placement, rapid termination (30-60 sec) of attacks; no adverse events, except pain on insertion of stimulator

Conclusion: termination of cluster and migraine attacks possible with SPG stimulation; success linked to optimal an­atomic and physiologic localization; for episodic migraine, efficacy unclear; need less invasive technique for inser­tion of stimulator

Suggested Reading

Bartsch T et al:&n