Other primary headaches: Distinct clinical features and uncertain pathophysiology

Chapter 4 of the International Classification of Headache Disorders encompasses a clinically diverse group of headache entities whose etiology and pathophysiology are vaguely understood (1). Many of these headaches are, relatively, rare. This further increases the difficulty of conducting clinical research. In this special issue, experienced experts specialized in specific headache entities were invited to provide state-of-the-art updates on these headaches. Some of these findings may shed light on the pathophysiology and stir thoughts and bring new insights for future research.

This special issue starts with headaches associated with physical exertion, a group that encompasses headaches associated with cough, exercise, or sexual activities. González-Quintanilla et al. revisited the historical records of headaches associated with physical exertion back to 1932 and described how the diagnostic has changed entities over the years (2). Once considered ominous and pathognomonic of intracranial pathology, i.e., posterior fossa lesions, accumulating evidence suggests that the majority of headaches associated with physical exertion are benign and primary in nature. Even though secondary causes accounted for less than 20% of these patients, it remains critical to properly identify such patients. The advances in neuroimaging over the last few decades provide further diagnostic clues. Besides, certain demographic features and treatment responses differ between subtypes. The authors provided a clinical summary of the differentiation between primary and secondary etiologies, the separation between subtypes of these headaches, and up-to-date treatment options.

Thunderclap headache is a well-recognized “red flag” sign and is considered a neurological emergency. Lin et al. reviewed primary headache attributed to sexual activity (HSA) and primary thunderclap headache (3). In this paper, the authors provided their clinical experience on these two disorders and a new perspective on the classification and diagnosis of these two disorders. Reversible cerebral vasoconstriction syndrome is a major differential diagnosis, and the authors suggested a similarity between probable (angiogram-negative) reversible cerebral vasoconstriction syndrome and primary HSA in terms of proposed pathophysiology, clinical manifestation, and treatment.

Certain diagnostic entities are featured by a specific distribution of the headaches, such as epicranial headaches, defined as headaches originating outside the skull. Primary stabbing headache (PSH) belongs to this group and is perhaps the most common primary headache after migraine and tension-type headache in the general population. Kwon et al. reviewed the epidemiology and symptomatology of stabbing headaches (4). Even though secondary headaches may sometimes present with stabbing features, the majority of patients have a primary headache and self-limiting disease course. In a well-illustrated figure, the authors proposed a diagnostic flowchart on how to exclude potential secondary causes. Red flags and potential PSH mimics are well summarized. Based on the extremely short attack duration and superficial distribution, the authors revisited the physiology of trigeminal pain processing and provides potential disease mechanisms and how peripheral nerve ending, Schwann cells, and central sensitization may contribute synergically to the development of the PSH.

In the second part of epicranial headaches, Cuadrado reviewed nummular headache and epicrania fugax (5). Both headaches are featured by specific clinical presentations that demarcate themselves from stabbing headaches. Contrary to the stabbing headache, nummular headache (usually) features continuous pain during the attack. The author described the phenotypes in detail and proposed how secondary lesions that lead to a nummular headache mimic may provide clues to potentially peripheral pathophysiology. Epicrania fugax is an even rarer subtype of epicranial headache featured by its usually linear trajectory of short-lasting shooting pain. Unlike nummular headache, cranial autonomic symptoms may be accompanied. In contrast to nummular headaches, epicrania fugax might have an (additional) central generator. The comorbidities and differentiation among stabbing headaches, nummular headaches, and epicrania fugax were well summarized.

Chapter 4 has two miscellaneous primary headache disorders: hypnic headache and new daily persistent headache (NDPH). These two disorders are considered benign but need special attention as secondary pathologies should be carefully differentiated. Lindner et al. provided an extensive review of the current knowledge about hypnic headache and secondary conditions that can mimic hypnic headache (6). Brain tumors, vascular pathologies, obstructive sleep apnea, hypoglycemia, medication withdrawal, nocturnal arterial hypertension, and medication-overuse headache have been reported as presenting like hypnic headache. The authors also provided an excellent summary of the acute and prophylactic medications for hypnic headache reported so far, although well-designed randomized clinical trials are lacking. Peng and Rozen reviewed NDPH with the most updated findings (7). They provided new insight into pathogenesis- and clinically-driven sub-classification of NDPH (“3Ts model”) and treatment strategies based on the 3Ts model. Authors argued on the hot debates regarding NDPH: i) is NDPH a primary headache disorder? and ii) is NDPH just a quick chronification of primary headache disorders? They provided their expert opinions on these issues based on clinical experience and studies.

Advances in novel migraine therapeutics opened a new era in the headache field. While focusing on new insights into migraine pathophysiology and treatments based on neuropeptides and intracellular signaling, we hope this special collection would stimulate research on other primary headaches which include rare but distinct, common but less recognized, and benign but difficult-to-treat headache disorders.