Paroxysmal Hemicrania: An Update
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.315982
Source of Support: None, Conflict of Interest: None
Keywords: Chronic paroxysmal hemicrania, cluster headache, hemicrania continua, paroxysmal hemicrania, trigeminal autonomic cephalalgia
In 1974, 0ttar Sjaastad and Inge Dale reported two female patients in their fifties with daily, side-locked headaches involving the temporal region, around the orbit, forehead, and face for 10 to 15 years. The headache was short-lasting (15–45 minutes) and the attacks of pain were occurring 6 to 18 times per day. Each episode was associated with conjunctival injection, epiphora, and nasal stuffiness on the side of pain. The attacks were different from cluster headache by shorter duration, higher frequency of attacks, no preference for attacks in the night and no precipitation of attacks with alcohol. Both patients showed a complete response to 50 to 75 mg/day of indomethacin. A detailed report of patients was published in 1976 by 0ttar Sjaastad and Inge Dale and they referred to this headache as chronic paroxysmal hemicrania. Some of the subsequent cases did not have the chronic unremitting course as seen originally by the authors. They rather had episodic and discrete attacks. The later classification (ICHD 2nd edition) divided paroxysmal hemicrania into episodic and chronic variants. However, the phrase “paroxysmal hemicrania” was retained in the International Classification of Headache Disorder (ICHD).
Paroxysmal hemicrania (PH) is characterized by recurrent paroxysms of unilateral headache associated with cranial autonomic symptoms. Episodes are characteristically short-lasting and absolutely responsive to indomethacin. PH is phenotypically closer to cluster headache. However, it does not respond to oxygen as seen with cluster headache attacks. Due to its resemblance to cluster headache (and later showing activation of hypothalamus on functional MRI), PH is placed in the group of trigeminal autonomic cephalalgias along with hemicrania continua, SUNCT and SUNA.
The exact prevalence of paroxysmal hemicrania is not known. It may not be as rare as it is thought to be. There is no population-based study to know the epidemiology of PH. In 1989, Fabio Antonaci and Ottar Sjaastad compared the total number of reported patients of PH with those of cluster headache (CH). The patients of PH were reviewed from three published case series. Authors came to the conclusion that the prevalence of PH is one to three percent of that of CH. The estimated prevalence of PH is 1 per 50,000 as opposed to cluster headache that has a prevalence of 1 per 1000. The authors reviewed 84 cases of PH with a female: male ratio of 2.36:1. The mean age of onset was 34.1 ± 16.7 years (range 11-81 years), mean age at diagnosis was 47.4 ± 14.4 years (22 to 82 years) and the mean duration of illness at the time of diagnosis was 13.3 ± 12.2 years. Though the estimated prevalence of PH was quite low, the authors in their paper said “CPH, seems to be much more frequently occurring than originally observed. Headache specialists particularly interested in cluster headache and seeing many such cases would be likely to see CPH cases as well.”
In this review, we focussed on the overview of clinical features of PH based on the published case series of PH, the evolution of ICHD criteria for PH, secondary causes of PH, presumed pathophysiology of PH in view of recent functional neuroimaging studies and treatment options in PH.
PH may occur in any age group [Table 1].,,,,,,,,, Patients from the age of one year to 80 years have been reported to have PH.,, Mean age in most series varied from 30 to 45 years. PH seems to be equally prevalent in males and females. However, the earlier reports showed a slight female preponderance. PH is a strictly unilateral and side-locked headache. Rarely, it may change sides or it may simultaneously involve both sides. In the majority of case series, the most common location of pain was in the orbital, periorbital, temporal, and frontal area. In a minority of patients, Pain also involved parieto-occipital region. During the peak intensity of headache, pain may spread to the vertex region, ipsilateral neck, shoulder, and arm. Pain is variably described as sharp, shooting, throbbing, boring, or band-like. Most PH attacks are short-lasting and rarely go beyond 30 minutes. Attack frequency may also be quite variable and range from two to 50 attacks per day. Very brief attacks (lasting one to two minutes) and very long attacks lasting a few hours may produce a diagnostic confusion between SUNCT/Trigeminal neuralgia and cluster headache respectively.,,,
The most characteristic feature of PH is the presence of an ipsilateral autonomic feature. Conjunctival redness and lacrimation are reported most frequently. Other autonomic features like nasal stuffiness, ptosis, eyelid edema, forehead sweating and flushing, miosis and rhinorrhoea have also been reported in a variable percentage of patients.
Phenotypic similarities between PH and cluster headache
Cluster headache and PH share many pain characteristics., Both have unilateral, side- locked-headaches, mainly involving the ophthalmic division of the trigeminal nerve. Cluster headache is considered one of the most painful conditions known to mankind. Patients with PH report pain severity of their most severe attacks ranging from eight to ten on visual analog scale (VAS). However, all patients with PH may not have such high VAS ratings. Like cluster headache, a minority of patients with PH also report suicidal ideation during severe pain attacks., The duration of headache in cluster headache ranges from 15 minutes to three hours and PH attacks last two to 30 minutes suggesting an overlap in the attack duration of both headaches. Both have abrupt onset and cessation of pain. Both have agitation and restlessness associated with pain attacks. Alcohol may also trigger attacks in PH (in minority) as with cluster headache.,
There are important differences in the PH and CH. The circadian and circannual periodicity of episodic CH is missing in PH. PH attacks may occur in the day and night. However, they do not have a preference of attacks at the night as in CH. Motor restlessness was considered an important feature of CH. Restlessness is recently added to the diagnostic criteria for PH in ICHD-3. Attacks of cluster headache are aborted by oxygen inhalation and prevented by verapamil, steroids, lithium, or anti-epileptics. Attacks of PH are prevented by therapeutic doses of indomethacin. Also, unlike CH, the chronic form is more commonly seen in PH than the episodic form.
PH and HC are indomethacin responsive headaches. HC is characterized by continuous, unilateral, side-locked pain in the ophthalmic division of trigeminal nerve. Similar to PH, pain in HC is associated with cranial autonomic features like conjunctival injection, lacrimation, nasal stuffiness, rhinorrhoea, miosis, ptosis, or eyelid edema. However, the cranial autonomic features may not be as severe as they are seen in attacks of PH. Patients with HC have brief periods of severe attacks overlying continuous pain. These severe attacks may also have more severe cranial autonomic features. A sub-group of patients with PH have continuous unilateral pain in the inter-ictal period. Many headache experts believe that the PH with inter-ictal low-grade continuous pains and HC with intermittent acute severe pain attacks are indistinguishable from each other. The natural history of HC and PH also suggests that they are not exclusive and inert entities. HC and PH may transform into each other in a minority of patients. O. Sjaastad and F. Antonaci in 1993 reported two females who transited between paroxysmal hemicrania and hemicrania continua while responding to indomethacin in both stages. We also found in our series, a subgroup of patients with HC having preceding short-lasting headaches and a small group of patients with PH having continuous unilateral headaches with autonomic features prior to the onset of PH. There is a report of change from continuous headache to paroxysmal pain attacks in two patients with HC after the use of Cox-2 inhibitors. These observations suggest that PH may be phenotypically closer to CH but it may be more closely related to HC based on its natural history and response to indomethacin.
PH and other short-lasting headaches
Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache with autonomic features (SUNA) are characterized by very brief (one to 600 seconds), unilateral, side-locked pain attacks usually involving ophthalmic division of trigeminal nerve.,, They are characteristically associated with cranial autonomic features as seen in patients with PH. Patients with SUNCT/SUNA can have up to 100 such attacks per day. They do not respond to indomethacin. These attacks can be prevented by anti-epileptic drugs like lamotrigine.
Primary stabbing headaches
These headaches are characterized by very brief, single or multiple stabs of severe pain that lasts only a few seconds. These attacks are usually unilateral and side-locked and they are not associated with cranial autonomic features. Only when the attacks are multiple, preventive medicine is required. Primary stabbing headaches respond completely to indomethacin.
This headache occurs during sleep and usually produces awakening. It lasts a few minutes to a few hours and usually presents in patients 50 years of age or more. The headache is of migraine or tension-type quality and is devoid of any cranial autonomic features. It responds to indomethacin.,
Primary cough headache and headache related to exercise or sexual activity
These are short-lasting headaches related to any Valsalva maneuver (primary cough headache), post-exercise, or during or after sexual activity. These are not associated with cranial autonomic features. These may be prevented by therapeutic doses of indomethacin.,,
The first edition of the ICHD in 1988 referred PH to chronic paroxysmal hemicrania [Table 2]. Subsequently, PH was classified into episodic and chronic variants in ICHD 2nd edition [Table 3]. The remission period of 1 month was required by ICHD 2nd ed.ition for episodic PH. It was subsequently increased to three months by ICHD 3rd ed.ition., The universal requirement for the diagnosis of PH was a pain in the distribution of orbital, supra-orbital, or temporal region with at least one of the several cranial autonomic features. The cranial autonomic features have largely remained the same across all classifications. The duration of headache attacks required by ICHD 1ST edition was two to 45 minutes that was reduced to 30 minutes in subsequent classifications. It was because of the fact that the mean duration of attack in PH was found to be less than 20 minutes in most case series of PH. Similarly, the ICHD 2nd ed.ition and the later classifications reduced the number of pain attacks from 50/day to 20/day that a patient should have for the diagnosis of PH. Another important change was the addition of restlessness/agitation to one of the optional requirements for the diagnosis of PH by ICHD 3rd ed.ition in 2018. This change was made after observing that up to 80% of patients with PH had restlessness associated with acute attacks. The ICHD has been universally accepted and appreciated for reliably differentiating PH from CH and SUNCT/SUNA.
Varied structural pathologies are reported in patients with PH.,, In our literature search, we found 27 case reports of secondary or symptomatic paroxysmal hemicrania after removal of duplicate studies. However, many of the cases were not fulfilling ICHD criteria either due to discrepancy of location, duration and frequency of pain or due to non-responsiveness to indomethacin. We identified seven cases conforming to ICHD criteria of PH including indomethacin responsiveness.,,,,,, The underlying pathology included pituitary macroadenoma, gangliocytoma in sella turcica, maxillary cyst, cavernous sinus meningioma, demyelinating lesions at the trigeminal sensory nucleus and root entry zone [Table 4]. Though the cause-to-effect relationship of the underlying pathology to PH was not clear, yet most of these patients improved after the treatment of underlying pathology and could discontinue indomethacin
Association of PH with other primary headaches
In a retrospective case series of 74 patients with PH by Christopher J. Boes and David W. Dodick, 16% patients had a concomitant migraine, seven percent had tension-type headache and five percent had headaches not specified. There are reports of CH and trigeminal neuralgia in patients suffering from PH. Transition from PH to HC and vice versa has already been discussed. A higher prevalence of migraine in PH and other trigeminal autonomic cephalalgias has been reported by some other studies.,
Pathophysiology of PH
The precise pathophysiology of PH is not known. However, most of the experimental work in the last three decades on CH and other trigeminal autonomic cephalalgias (TACs) have shed some light on the presumed peripheral and central mechanisms of pain and cranial autonomic symptoms in TACs. To understand the pathway of TACs, we need to understand the pathway of pain, pathogenesis of parasympathetic and sympathetic manifestations, and pathway responsible for circadian/circannual rhythms, nocturnal attacks, triggers, and systemic/hormonal changes seen with TACs.
The genesis of pain is most likely related to the activation of the trigeminal nerve, mainly the ophthalmic division. The afferent loop of the trigeminal nerve provides the sensory innervation to the cranial, extracranial structures, meninges, and the cranial blood vessels. All of them are pain-sensitive structures. The afferent loop ends in the trigeminal nucleus caudalis (TNC). The trigeminal nucleus extends from the medulla to the upper cervical spinal cord. The nociceptive signals from TNC go to the ipsilateral brainstem and reach the hypothalamus, thalamus, and finally to the cortex for the perception of the pain.,
The cranial autonomic symptoms are mediated through the trigmenio-autonomic reflex., The afferent loop of the trigeminal nerve also makes a connection with the superior salivatory nucleus (SSN) in the pons. The parasympathetic fibres that originate from the SSN pass through the facial nerve and through the geniculate ganglion and the sphenopalatine ganglion supplies through vasomotor efferent to cranial and extracranial vasculature and through secretomotor efferent supplies the lacrimal and nasal mucosal glands. This pathway explains the lacrimation, conjunctival injection, nasal stuffiness, and rhinorrhea with pain in PH.,
The presence Horner's syndrome is explained by the lack of sympathetic tone with pain attacks. The sympathetic fibers are present on the outer surface of the internal carotid artery. It is hypothesized that the pain attack produces the swelling of the carotid wall that compresses the sympathetic fibres producing a transient lack of sympathetic tone resulting in the various manifestation of Horner's syndrome.
The elevated levels of calcitonin gene-related peptides (CGRP, a biomarker of trigeminal afferent activation) and vasoactive intestinal peptide (VIP, a marker of parasympathetic activation) in the jugular bulb in patients with CH and PH during acute attacks is strong evidence in favor of an activation of trigemino-autonomic reflex in patients with PH. The abolition of attacks by CGRP inhibitors, oxygen in CH (inhibits parasympathetic tone), 5HT (1B/1D) inhibitors, sphenopalatine ganglion block, or neurostimulation are concordant with the trigemino-autonomic reflex activation in TACs.,,,,
The functional imaging studies (PET and functional MRI) have shown the activation of the posterior hypothalamus in CH and other TACs. Hypothalamus is connected to the TNC and SSN in the brainstem through the trigemino-hypothalamic tracts., This pathway regulates the function of the brainstem nuclei and therefore, the hypothalamus is thought to have a “permissive role” in TACs. Hypothalamus also regulates the sleep-wake cycle, pain processing, and other chronobiological functions. The relationship of pain with circadian and circannual rhythm, altered pain processing resulting in a lower threshold for pain during cluster periods, presence of nocturnal attacks, endocrinal changes especially the blunting of melatonin surge during cluster period are explainable due to the activation of the hypothalamus. The good response to deep brain stimulation in drug-refractory TACs possibly modulates the hypothalamic functions negating the “permissible role” of hypothalamus in CH, PH. and SUNCT syndrome.,,,
Indomethacin is the mainstay of treatment in PH. The usual method of prescribing indomethacin is to start at a dose of 25 mg thrice daily and gradually escalate the dose to 75 to 100 mg thrice daily in the per dose increments of 25 mg every three to five days. The majority of patients with PH respond to a low daily dose (<150 mg) of indomethacin.,, However, a minority of patients may require a high dose of 225 to 300 mg at the beginning of the treatment. Indomethacin remains effective for years and tahyphylaxis to indomethacin is rare. It is advisable to try to reduce the dose of indomethacin after discussing it with the patient. In our experience, an early de-escalation may be tried. If unsuccessful, increasing the dose of indomethacin again produces prompt relief. Early de-escalation helps in reducing pill burden, improves compliance, and prevents gastrointestinal side-effects of indomethacin, which are quite troublesome in some patients. Many patients achieve remission for variable periods and others are invariably able to reduce the daily dose.
Other partially effective drugs are Cox-2 inhibitors like celecoxib and refecoxib. Rofecoxib was withdrawn from the market due to cardiovascular side effects. Celecoxib also has a black-box warning by FDA for cardiovascular side-effects. Other NSAIDs have variable effectiveness in PH.
Calcium channel blockers (verapamil, flunarizine), acetazolamide, topiramate have been found to be effective in some patients.,, Various epi-cranial nerve blocks have been tried effectively in anecdotal reports., Hypothalamic deep brain stimulation has worked in patients with drug-refractory PH.,,
PH is a rare headache that is phenotypically similar to CH but it does not respond to oxygen therapy but improves with the therapeutic doses of indomethacin. The PH is more frequently seen by those physicians who frequently see CH. Most patients with PH report severe headache to the tune of 8/10 on VAS. The headache duration is usually less than 30 minutes unlike CH that usually have longer attacks. The absence of circadian/circannual periodicity and response to indomethacin reliably differentiate PH from CH. PH may be pathophysiologically closer to hemicrania continua due to phenotypical similarity of acute attacks of PH and acute exacerbation of HC, response to indomethacin, and possible transition to and from HC in its natural course. The precise pathophysiology of PH is not known, but like other TACs, pain and cranial autonomic symptoms are related to activation of trigeminal nerve afferents and activation of trigemino-autonomic reflex respectively. Activation of the hypothalamus as evidenced from functional imaging studies may serve the central “permissive” role in the occurrence of PH and other TACs. Indomethacin is the most effective and time-tested drug for PH. The other COX-2 inhibitors, topiramate, and calcium channel blockers may be tried in patients with unbearable side-effects of indomethacin. Hypothalamic deep-brain stimulation may be reserved for drug-refractory PH.,
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[Table 1], [Table 2], [Table 3], [Table 4]