Two Forms of Unilateral Consistent Headache and Its Sources

Abstracts & Commentary

Sources: Bahra A, et al. Neurology. 2002;38:354-361; Pringsheim T. Can J Neurol Sci. 2002;29:33-40; Pareja JA, et al. Cephalalgia. 2001;21:940-946.

These 3 reports individually discuss partial reviews of classic paroxysmal headache (CH), its source, and its difference from hemicrania continua (HC). Bahra and colleagues discuss the broad clinical aspects of CH on the basis of clinical symptoms alone. Pringsheim provides an interesting and informative description of the pathophysiology which describes the genetic factors as well as some of the patterns behind the development of CH. Pareja and colleagues focus on a specific cluster disorder called HC which consistently responds to the single, sustained effective treatment of indomethacin.

Classic Paroxysmal Headache. Bahra et al evaluated 230 patients with unilateral CH. One hundred sixty-six (72%) were men, 64 (28%) women. Pain affects men and women equally and frequently involves mostly the retro-orbital, temporal, dental, forehead, jaw and, less frequently, lower areas of the face. All patients suffer only a consistently unilateral pain with 60% located on the right side of the head. Associated with the pain, autonomic activity includes tearing, conjunctival injection, lid ptosis, and rhinorrhea. Half the patients become nauseated and 93% become physically restless during the attack. Less intense symptoms include nausea, photophobia, vomiting (few), annoyance by light, noise, or drinking alcohol. CH occurs during large time periods once or twice a year. Average individual bouts last a maximum-minimum of 159-72 minutes and the mean number of attacks can occur 4-5 times in 24 hours. Most sieges of CH lasted about 8.6 weeks once a year with 43% of patients suffering their bouts in spring or autumn. The use of either tobacco smoking or any alcohol stimulates severe bursts. Nevertheless, most patients with cluster headache (67%) have continued to smoke, and 90% who took alcohol reported a triggered attack. Sixty of the 230 patients with CH reported previous symptoms of migraine and a third claimed a family history of migraine. Five percent indicated a close family member who had migraine. No principal symptomatic differences affected males or females in any quality except by the overall number of men 2.5:1 to women. Only 5 women had cluster headache during pregnancy, but menopause had only a small effect on their suffering. Sumatriptan was ingested by oral (61%), subcutaneous (45%), or intranasal (14%) routes; half of the group had taken oral ergotamine agents.

Unfortunately, the only effective drug that acutely ameliorates cluster headache consists of subcutaneously injected sumatriptan immediately upon the onset of headache (Ekbom K. N Engl J Med. 1991;325:322-326). Gobel and colleagues, however, found 88% successful injection therapy during 2031 attacks in 52 affected sufferers (Gobel H, et al. Neurology. 1998;51:908-911). Inhalation of high concentrations of oxygen will quiet the attack, but clumsiness of the apparatus usually prevents its readiness. No oral drug has yet met the noninvasive challenge, although intranasal application of sumatriptan apparently halts cluster headache in less than an hour. Methysergide and lithium provide a certain degree of prevention against successive bouts of cluster headache, but methysergide may injure cardiopulmonary tissues if sustained more than a month or so. Oral verapamil carries some protection against close serial bursts.

Dr. Pringsheim has summarized from the past literature that the ultimate source of cluster headaches comes from the period (PER) gene located on the X chromosone and the timeless (TIM) gene, both in the chromosone suprachiasmatic (STC) nucleus of the hypothalamus. This nucleus generates the proteins of PER and TIM which synthesize and bind together in retinal-delayed darkness (mostly sleep). As light appears in wakefulness, the TIM protein begins to degrade gradually until it ceases. When darkness reappears, TIM becomes maximally synthesized and, with PER, the circadian molecule pattern repeats its cycle. In the 4 annual, equal dark/light zones, the hypothalamic STC reaches its largest cell numbers near the Ides of March and September, thereby anticipating day/night equality of light. The suprachiasmatic nucleus regulates the melatonin protein generated by the pineal gland. Melatonin feeds from the pineal body to the STC nucleus that stimulates the superior cervical ganglia which sends more epinephrine back to the pineal gland. This then stimulates increased melatonin, which shifts the circadian clock. Recently, PET scanning has identified the specific area of the active STC circadian pacemaker in the hypothalamus.

About half or more of patients who suffer classic episodic cluster headaches do so in relation to the influence of the sunlight on their retinas and thalamic STC nucleus. Typical are the active bouts during the 7-10 days in early July or the similar period following the early days of January. Their "off" months usually come in April and October. Two thirds suffer nocturnal attacks with many relating to REM sleep. Most suffer abnormal sleep patterns even without the headaches. Leone and associates, however, have recently reported that 10 mg daily of melatonin significantly improved the intensity and number of attacks associated with cluster headaches (Leone M, et al. Cephalalgia. 1996;16:494-496).

Classic Hemicrania Continua (HC). HC is a relatively rare, spontaneously appearing year-round disorder consisting of the following: 1) HC, if not treated, consists of a moderate-to-severe regular, unilateral, and spontaneous head pain that is almost daily expressed throughout the year. 2) The pain consistently appears over their trigeminal sensory area and can be absolutely ameliorated only by steady, daily ingestion of indomethacin (Goadsby P, Lipton R. Brain. 1997;120:193-209). When headache and focal autonomic dysfunction appear, trigeminal autonomic activity may generate ipsilateral pupillary mitosis, tearing, lid ptosis, and rhinorrhea along with the resurgent pain. 3) Other patients with unilateral head-face pain (HP) that continuously appears throughout long periods of the year may not receive relief from indomethacin. Pareja et al and your editor can identify examples of such unilateral headaches that may occur every day or so but are not responsive to indomethacin. These include repetitive unilateral migraine, recurrent dental problems, supraorbital neuralgia, cervicogenic headache, post-traumatic dysautonomic cephalalalgia, unilaterial tension-anxiety type headache, atypical facial pain, and temporal-mandibular joint disorders. Moderate psychological depression or anger also may evoke unilateral steady muscle pain. Many of these patients can be helped by other available non-narcotic drugs and over-the-counter medications. Like many patients with functional back pain, however, many patients with chronic bilateral headaches and some with unilateral ones, go on and on without finding any apparent particular agent of cause. —Fred Plum

Dr. Plum, University Professor, Weill Medical College, and Attending Neurologist, New York Presbyterian Hospital, is Editor of Neurology Alert.