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The purpose of this review is to evaluate and explain our current understanding of a very rare disorder, long-lasting autonomic symptoms with associated hemicranias (LASH). At present, there are four known cases in the literature of LASH. Its characteristics and reported response to indomethacin link it most closely to the trigeminal autonomic cephalalgias (TACs). Its pathophysiology and epidemiology remain unclear. Variance in the pain and autonomic symptom relationship in the existing TAC literature along with the reports of TAC sine headache suggests that LASH may represent a far end of the spectrum of TACs, with most similarities to paroxysmal hemicrania (PH) and hemicrania continua (HC).

Sphenopalatine ganglion (SPG) block has been used by clinicians in the treatment of a variety of headache disorders, facial pain syndromes, and other facial neuralgias. The sensory and autonomic fibers that travel through the SPG provided the scientific rationale for symptoms associated with these head and neck syndromes. Yet, despite the elucidation of this pathogenic target, the optimal method to block its pain-producing properties has not been determined. Clinicians have developed various invasive and non-invasive techniques, each of which has shown variable rates of success. We examined the available studies of sphenopalatine ganglion blockade and its efficacy in the treatment of cluster headaches, migraines, and other trigeminal autonomic cephalalgias. Studies have demonstrated that SPG blockade and neurostimulation can provide pain relief in patients with cluster headaches, migraines, and other trigeminal autonomic cephalalgias. Patients with these conditions showed varying levels and duration of pain relief from SPG blockade. The efficacy of SPG blockade could be related to the different techniques targeting the SPG and choice of therapeutic agents. Based on current studies, SPG blockade is a safe and effective treatment for chronic headaches such as cluster headaches, migraines, and other trigeminal autonomic cephalalgias. Future studies are warranted to define the optimal image-guided technique and choice of pharmacologic agents for SPG blockade as an effective treatment for chronic headaches related to activation of the sphenopalatine ganglion.

Primary headache disorders are generally characterized by the pain, time course, and associated symptoms of their attacks, but often are accompanied by milder interictal pain. Patients with chronic migraine, chronic tension-type headache, hemicrania continua, and new daily-persistent headache have constant pain more often than not. Patients with trigeminal autonomic cephalalgias such as cluster headache commonly have interictal pain as well, usually much milder and unilateral to the side of attacks. Even those with rare headache types, including hypnic headache and trigeminal neuralgia, commonly have interictal pain. This review describes the incidence of interictal pain in primary headache disorders and suggests the significance and biological meanings of this pain.

Chronic daily headache (CDH) is a group of headache disorders, in which headaches occur daily or near-daily (>15 days per month) and last for more than 3 months. Important CDH subtypes include chronic migraine, chronic tension-type headache, hemicrania continua, and new daily persistent headache. Other headaches with shorter durations (

New daily-persistent headache is a relatively uncommon type of chronic daily headache. The critical features of the original description and the subsequent Silberstein-Lipton description was the onset: daily headache starts abruptly without a background of frequent or worsening headache. In 2004, the International Headache Society classification committee excluded an abundance of migrainous features. The exclusion of patients with too many migrainous features from the International Headache Society classification was contentious from the onset and is a source of consternation for many headache experts. Many contend that the sudden onset of a daily headache raises the same issue of what turned on the headache, irrespective of the headache features. Switch-related questions about predisposing factors or precipitating events are equally valid regardless of how many migrainous features the patient has. The differential diagnosis, treatment response, or prognoses do not vary by the number of migrainous features. The current International Headache Society definition excludes more than half of patients with new onset of daily headache. This exclusion due to migrainous features could have adverse scientific, diagnostic, and treatment consequences.

Hemicrania continua (HC) is a rare primary headache syndrome, characterized by unilateral pain and an absolute response to indometacin. Since the term was first coined in 1984, more than 100 cases have been described worldwide. Most recently, detailed case series that provide more detailed information concerning the sometimes complex clinical presentation of HC have been reported. Functional imaging studies suggest a unique pattern of subcortical involvement in HC: contralateral to the pain posterior hypothalamic region, ipsilateral dorsal pons and ipsilateral ventral midbrain, which, along with the particular effect of indometacin, probably justifies its classification as a unique entity. Increasing the awareness of this primary headache form among clinicians will aid in its diagnosis while further work is being undertaken to characterize the syndrome.

The question of whether the trigeminal autonomic cephalalgias (TACs) represent primary diagnoses or points on a continuum has been debatable for a number of years. Patients with TACs may present with similar clinical characteristics, and occasionally, TACS respond to similar treatments. Prima facie, these disorders may seem to be intimately related. However, due to the current evidence, it would be challenging to accurately conclude whether they represent different primary headache diagnoses or the same primary headache disorder represented by different points on the same continuum. Ultimately, the TACs may utilize similar pathways and activate nociceptive responses that result in similar clinical phenotypes but "original and initiating" etiology may differ, and these disorders may not be points on the same continuum. This paper seeks to provide a brief comparison of TACs via diagnostic criteria, secondary causes, brief overview of pathophysiology, and the use of some key treatments and their mechanism of actions to illustrate the TAC similarities and differences.

Indomethacin has been used for the treatment of headache disorders since the 1960’s, shortly after it was introduced as a treatment for pain and joint swelling in rheumatologic conditions. A subgroup of primary headache disorders, often refractory to other pharmacologic treatment such as triptans and the usual non-steroidal anti-inflammatories, was noted to be exquisitely and absolutely responsive to the analgesic effects of indomethacin. These disorders have been better characterized over the past decade and classified into primary headache disorders of paroxysmal hemicrania (PH) and hemicrania continua (HC). Since the current ICHD-3 beta requires response to indomethacin as a diagnostic criterion, studies on alternative treatments in HC and PH generally occur in patients with intolerance to its gastro-intestinal side effects rather than loss of analgesia effectiveness. More rarely, the development of new headaches have been reported in chronic indomethacin use. In these settings, other classes of medications such as selective cyclooxygenase-2 inhibitors (celecoxib), anti-epileptic agents (topiramate), calcium channel blockers (verapamil, flunarizine), melatonin, and local nerve blocks with anesthetic and steroids have been shown to be effective in case reports and series. We review the literature and provide our clinical recommendations on alternative therapies for the “indomethacin-responsive headaches”.

Paroxysmal hemicrania and hemicrania continua are primary headache disorders characterized by unilateral attacks of severe pain around the orbit with associated autonomic features. They are unique in their absolute response to indomethacin. Diagnosis is made when patients with suspected paroxysmal hemicrania or hemicrania continua have the resolution of headache with therapeutic doses of indomethacin. Once diagnosis is made, limited data exists on the ongoing management of these patients. For patients who do not tolerate indomethacin, or wish to come off medication, there remain few options. This article will discuss the diagnosis of paroxysmal hemicrania and hemicrania continua and the ongoing management of patients on indomethacin, as well as options for patients who do not tolerate or need to come off indomethacin.

The typical aura associated with migraine is characterized by visual or sensory and speech symptoms, with a mix of positive and negative features and complete reversibility within 1 hour. However, auras are not an exclusive migraine-dependent phenomenon. There have been descriptions of aura occurring in association with cluster headache, hemicrania continua, and even with chronic paroxysmal hemicrania. In addition, the occurrence of aura without headache or followed by a headache resembling the criteria of tension-type headache is encountered in clinical practice. This paper reviews the literature about auras in non-migraine headaches and the features involving this uncommon presentation. The possibility of a specific genetic origin for the auras, not related to the primary headache type, also is raised.

Until recently, primary headache disorders such as migraine and cluster headache were considered to be vascular in origin. However, advances in neuroimaging techniques, such as positron emission tomography, single photon emission computerized tomography, and functional magnetic resonance imaging, have augmented the growing clinical evidence that these headaches are primarily driven from the brain. This review covers functional imaging studies in migraine, cluster headache, rarer headache syndromes, and experimental head pain. Together with newer techniques, such as voxel-based morphometry and magnetic resonance spectrometry, functional imaging continues to play a role in elucidating and targeting the neural substrates in each of the primary headache syndromes.

Paroxysmal hemicrania (PH) is an underreported and underdiagnosed primary headache disorder. It usually begins in the third or fourth decade of life. The recent observations indicate that it is equally prevalent in both males and females. PH is characterized by severe, strictly unilateral head pain attacks that occur in association with ipsilateral autonomic features. The attacks in PH are shorter and more frequent compared with cluster headache (CH) but otherwise PH and CH have similar clinical features. The hallmark of PH is the absolute cessation of the headache with indomethacin. However, a range of drugs may show partial to complete relief in certain groups of patients. Neuromodulatory procedures, such as greater occipital nerve blockade, blockade of sphenopalatine ganglion and neurostimulation of the posterior hypothalamus, are reserved for refractory PH.

Daily or near-daily headache is a widespread problem in clinical practice. The general term of chronic daily headache (CDH) encompasses those primary headaches presenting more than 15 days per month and lasting more than 4 hours per day. CDH includes transformed migraine (TM), chronic tension-type headache (CTTH), new daily persistent headache (NDPH), and hemicrania continua (HC). Around 40% of patients attending a specialized headache clinic meet CDH diagnostic criteria, of which 80% are women. In these clinics about 60% of patients suffer from TM, 20% from CTTH, and 20% meet NDPH criteria. Most, some 80%, overuse symptomatic medications. One should be very cautious on extrapolating these numbers to the general population. CDH prevalence in the general population seems to be around 4% to 5% (up to 8% to 9% for women). Regarding the prevalence of CDH subtypes, NDPH is rare (0.1%), whereas the prevalence of TM (1.5% to 2%) and CTTH (2.5% to 3%) is clearly higher. In contrast to data from specialized clinics, only around a quarter of CDH subjects in the general population overuse analgesics; the prevalence of CDH subjects with analgesic overuse being 1.1% to 1.9% of the general population. Most of these patients with analgesic overuse are TM patients.

Disabling headache disorders are ubiquitous in all age groups, including the elderly, yet they are under-recognized, underdiagnosed and undertreated worldwide. Surveys and clinic-based research reports on headache disorders in elderly populations are extremely limited in number. Chronic daily headache (CDH) is an important and growing subtype of primary headache disorders, associated with increased burden and disruption to quality of life. CDH can be divided into two forms, based on headache duration. Common forms of primary headache disorders of long duration (>4 hours) were comprehensively defined in the third edition of the International Classification of Headache Disorders (ICHD-3 beta). These include chronic migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua. Rarer short-duration (

Indomethacin, as a member of the non-steroidal anti-inflammatory drug class, plays a special role in the treatment of headaches. By definition, it is completely efficacious in the treatment of the primary headache disorders paroxysmal hemicrania and hemicrania continua. Therefore, indomethacin is also used as a tool for differential diagnosis in headache clinics. Indomethacin has a clear action as a cyclooxygenase inhibitor. Additional mechanisms and interactions with cell signaling pathways and inflammatory pathways are considered in this article. However, it is not known what mechanism or interaction with pathophysiological mechanisms is the key to indomethacin’s specific pharmacology in headache therapy. Focusing on headache therapy, we summarize the current knowledge of pharmacology, treatment options, and recommendations for the use of indomethacin in primary headaches. New findings from the field of headache research, as well as from Alzheimer’s disease and cancer research on the pharmacological actions of indomethacin and their potential implications on the pathophysiology of indomethacin sensitive headaches, are discussed.

Tension-type headache (TTH) is a relatively featureless headache. Many primary and secondary headache disorders can mimic TTH, particularly in its chronic form, chronic tension-type headache. This review will address both primary and secondary disorders that can present with headaches phenotypically similar to TTH, and will focus on clinical pearls that help distinguish these “mimics” from TTH.

The relation between sex hormones and migraine has been examined in a series of studies, leading to the definitions of pure menstrual migraine and menstrually-related migraine. The relation between sex hormones and other types of primary headache has been studied less extensively, but there is at least some evidence that hormones in general, and menstruation, pregnancy, or menopause in particular, also impact these disorders. This article reviews the available literature on changes of tension-type headache, cluster headache, other trigeminal autonomic cephalalgias, and hemicrania continua during women’s reproductive periods.

Primary chronic headaches of long duration include chronic migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua. This article reviews the utility of neuroimaging and other testing for diagnosis of these headaches. The presentation and diagnosis of the many secondary headaches that can mimic primary headache types are also discussed, including arteriovenous malformations, spontaneous intracranial hypotension, neoplasms, pseudotumor cerebri, cervical artery dissections, cerebral venous thrombosis, Chiari I malformation, and temporal arteritis. Although the yield of diagnostic testing is low, serious pathology as a cause of chronic headaches can be easily overlooked.

Hemicrania continua is a strictly unilateral, continuous headache of mild to moderate intensity, with superimposed exacerbations of moderate to severe intensity that are accompanied by trigeminal autonomic features and migrainous symptoms. The syndrome is exquisitely responsive to indomethacin. Its clinical phenotype overlaps with that of the trigeminal autonomic cephalalgias and migraine, in which the hypothalamus and the brain stem, respectively, have been postulated to play central pathophysiologic roles. A recent positron-emission tomography study of a cohort of patients with hemicrania continua demonstrated significant activation of the contralateral posterior hypothalamus and ipsilateral dorsal rostral pons in association with the headache of hemicrania continua. In addition, there was activation of the ipsilateral ventrolateral midbrain, which extended over the red nucleus and the substantia nigra and bilateral pontomedullary junction. No intracranial vessel dilatation was obvious.

The trigeminal autonomic cephalalgias include cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks, and hemicrania continua. While the majority responds to conventional pharmacological treatments, a small but significant proportion of patients are intractable to these treatments. In these cases, alternative choices for these patients include oral and injectable drugs, lesional or resectional surgery, and neurostimulation. The evidence base for conventional treatments is limited, and the evidence for those used beyond convention is more so. At present, the most evidence exists for nerve blocks, deep brain stimulation, occipital nerve stimulation, sphenopalatine ganglion stimulation in chronic cluster headache, and microvascular decompression of the trigeminal nerve in short-lasting unilateral neuralgiform headache attacks.