Address all correspondence to Dr. Todd D. Rozen, Jefferson Headache Center, 111 South 11th Street, Suite 8130, Philadelphia, PA 19107.
A patient presented with a unique, stereotypical, episodic headache disorder marked by long-lasting autonomic symptoms with associated hemicrania (LASH). The autonomic symptoms clearly overshadowed the headache as the major component of the syndrome. Indomethacin controlled both the autonomic symptoms and the headache, suggesting that this is a new type of indomethacin-responsive headache. It may also complete the indomethacin-responsive headache spectrum.
short-lasting unilateral neuralgiform headache with conjunctival injection and tearing
Chronic paroxysmal hemicrania (CPH) and hemicrania continua (HC) are two unique headache syndromes that are defined by their responsiveness to indomethacin. Each has a different clinical presentation, with CPH being episodic and HC continuous, but at their root they are head pain syndromes with associated autonomic phenomena. Chronic paroxysmal hemicrania is characterized by frequent, short-lasting headache attacks with marked autonomic symptoms of conjunctival injection, tearing, ptosis, rhinorrhea, and nasal congestion. 1 Each individual attack is brief, lasting from 2 to 45 minutes. Regardless of the number of years a patient has had CPH, the headaches will be controlled by the correct dose of indomethacin. Headache and autonomic symptoms occur equally in CPH, with neither symptom complex predominating over the other.
Hemicrania continua is a unilateral, continuous headache, which is normally mild to moderate in intensity, with exacerbations of short bouts of severe head pain. 2,3 During headache exacerbations, associated symptoms of migraine (nausea, vomiting, photophobia, and phonophobia) or autonomic features of cluster headache (conjunctival injection, ptosis, tearing, nasal congestion, and rhinorrhea) can become prominent. The headache is the predominant feature of the disorder; the autonomic symptoms are generally mild and much less dramatic than in cluster headache or CPH.
A patient presented with a unique, episodic headache disorder marked by long-lasting autonomic symptoms with associated hemicrania (LASH). The autonomic symptoms overshadowed the head pain as the major component of the syndrome. Both the autonomic symptoms and the headache were controlled with indomethacin, suggesting that this is a new type of indomethacin-responsive headache that may complete the indomethacin-responsive headache spectrum.
A 38-year-old, right-handed woman presented with a stereotypical, episodic headache that she had had for the previous 2 1/2 years. It was associated with prolonged autonomic symptoms. Three to 4 hours before every headache, she would experience the acute onset of right-sided ptosis, eyelid edema, tearing, and nasal congestion. These symptoms would remain constant for up to 3 days. The headache, which was always right sided, occurred in a periorbital and retro-orbital distribution and began several hours after the onset of the autonomic symptoms, and never before the autonomic symptoms. The pain was constant and severe, usually 10 of 10 in intensity. During the headache phase, the patient would continue to have unilateral tearing, ptosis, eyelid edema, nasal congestion, and sometimes rhinorrhea. She sometimes developed nausea, vomiting, photophobia, and phonophobia. The headache and autonomic symptoms lasted from 1 to 3 days; once the headache stopped, the unilateral autonomic symptoms continued for several hours and then resolved. She never experienced headache or autonomic symptoms on the left side. She said that neck extension, chewing, and facial palpation were not triggering factors. She would remain still during an attack, denying the need to pace or move. She usually averaged one attack a week (since the onset of her symptoms), with no headaches between attacks. She never had more than one attack within a 24-hour period, and she had had no periods of remission since the headache onset. Previous acute medication included acetaminophen, aspirin, opiates, and sumatriptan, none of which proved beneficial. Verapamil, up to 400 mg per day, slightly reduced the headache duration. The results of magnetic resonance imaging (MRI) of her brain and magnetic resonance angiography (MRA) of her intracranial and carotid vessels were normal. There was no family history of migraine or cluster headache. She had smoked one pack of cigarettes a day for many years. She had a posttraumatic complex regional pain syndrome involving her left leg.
During her initial evaluation, she had a typical attack. She developed right-sided eyelid edema, ptosis, lacrimation, and nasal rhinorrhea over a period of 5 to 10 minutes, without a headache. During the 90 minutes she was monitored, her autonomic symptoms remained constant and she remained headache-free. She did develop a headache several hours after leaving the office. Neurological examination demonstrated right upper lid ptosis without anisocoria or forehead anhidrosis. The only other abnormality on examination was left leg weakness, a sequela of prior surgeries and her complex regional pain syndrome.
She was placed on 100% oxygen at 10 L/min via a face mask for 20 minutes. There was no significant change in her autonomic symptoms (she had yet to develop head pain), although her tearing may have become less prominent. Because of the atypical nature of the headache and its associated autonomic symptoms, she was instructed to take indomethacin, 50 mg three times a day, at the onset of her next attack of autonomic symptoms. This regimen completely alleviated the autonomic phenomena and prevented the headache from occurring. Based on these results, indomethacin, 50 mg three times a day, was started on a daily basis and this prevented further attacks. She was followed for 8 months during which time she remained headache-free, but then was lost to follow-up. She did not try to reduce her daily amount of indomethacin (possibly because she was fearful the attacks would return), although she was instructed to try to find the smallest possible effective dose.
The indomethacin-responsive headache syndromes, CPH and HC, while being distinct disorders, both consist of varying degrees of head pain and associated autonomic dysfunction. Headache predominates in HC with only mild autonomic symptoms, whereas in CPH there is equal prominence of autonomic symptoms and head pain.
Our patient did not appear to fit the criteria for any of the known primary headache disorders with associated autonomic phenomena, including cluster headache, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT syndrome), migraine, CPH, or HC. Our patient's most dramatic finding consisted of her prolonged autonomic symptoms both preceding and following the headache and her complete response to indomethacin. Pain duration, attack frequency, length of autonomic symptoms, and complete relief with indomethacin are not consistent with cluster headache. She does not have SUNCT because of the duration of her autonomic and headache symptoms (SUNCT attacks normally last from 5 to 250 seconds) and because SUNCT is not responsive to indomethacin. 4
She may have atypical migraine. Migraine can present with autonomic symptoms, and the patient's sex, headache frequency and duration, and associated nausea, vomiting, photophobia, and phonophobia are consistent with migraine. Against the diagnosis of migraine is the preponderance of autonomic symptoms, their duration, and complete indomethacin responsiveness. Medina and Diamond 5 described the syndrome of “cyclical migraine,” which is characterized by frequent attacks of migraine (average five attacks per week), with or without mild autonomic symptoms, occurring for 1 to 2 months and then ceasing for months to years. Cyclical migraine responds to lithium carbonate; indomethacin has not been documented to have been tried in this disorder. Against the diagnosis of cyclical migraine is the consistent weekly pattern of headache in our patient, without clustering or attack remission; the preponderance of autonomic symptoms; and the complete indomethacin responsiveness.
This could be atypical CPH or HC because of an absolute response to indomethacin, but our patient's headaches lasted too long for CPH (in which the average headache duration is 2 to 45 minutes), the autonomic symptoms were too prominent for HC, and the patient did not have a continuous headache. This may be a new, distinct indomethacin-responsive headache syndrome. It may also complete the spectrum of indomethacin-responsive headaches that have accompanying autonomic phenomena. At one end of the spectrum is HC (prominent headache, mild autonomic symptoms), in the center is CPH (prominent headache and autonomic symptoms), and at the other end is this new syndrome that I will refer to as LASH for long-lasting autonomic symptoms with hemicrania (very prominent autonomic symptoms overshadowing the headache) (Figure 1).
Goadsby and Lipton 6 suggested that headache disorders with both head pain and autonomic symptoms (cluster, CPH, HC, SUNCT) can be anatomically explained by the presence in humans of a trigeminal-autonomic reflex pathway (a brain stem connection between the trigeminal nerve and the cranial parasympathetic outflow system). In humans, stimulation of the trigeminal ganglion causes release of calcitonin gene-related peptide (CGRP) and substance P (both contained in and released from the trigeminal nerve), as well as vasoactive intestinal polypeptide (VIP), which is contained in and released from the parasympathetic nerves. 7
Through the trigeminal-autonomic reflex, trigeminal activation leads to head pain initiation and reflex parasympathetic activation leads to the production of autonomic symptoms. The hypothesized trigeminal-autonomic reflex is consistent with cluster headache, SUNCT, HC, and CPH, in which head pain, in almost all instances, precedes the autonomic symptoms. In LASH, autonomic symptoms start before the headache and outlast the head pain. The proposed trigeminal-autonomic reflex cannot easily explain this temporal profile of symptoms. A dissociation of headache and autonomic symptoms has been recognized in some of the known autonomic cephalalgias, suggesting that each arm of the trigeminal-autonomic reflex can be separately activated. 6 In LASH, the parasympathetic arm of the trigeminal-autonomic reflex would need to be triggered earlier and for a more prolonged time than the trigeminal nerve arm. One could speculate that VIP levels would increase during the initial autonomic phase, followed by an elevation of CGRP levels once the headache started. This could theoretically be tested by measuring VIP and CGRP levels in jugular venous blood during a LASH attack.
The unique effectiveness of indomethacin in the syndromes of CPH, HC, and now LASH is still a mystery. It may relate to the ability of indomethacin to decrease cerebrospinal fluid pressure or its proposed effect as a nitric oxide synthase inhibitor. 8 The syndrome of LASH appears to be rare or at least an underdiagnosed and, thus, an underreported disorder. It appears to be a unique headache syndrome and not just a variant of other primary headaches. In addition, LASH may complete the indomethacin-responsive headache spectrum.
Acknowledgment: Appreciation is expressed to Dr. Stephen D. Silberstein for reviewing this manuscript.