Indomethacin-responsive trigeminal autonomic cephalgias: a review of key characteristics and pathophysiology.

Trigeminal autonomic cephalgias (TACs) are a well-defined subset of uncommon primary headaches that share comparable onset, pathophysiology and symptom patterns. TACs are characterised by the presentation of one-sided and high-intensity trigeminal pain together with unilateral cranial autonomic signs, which can include lacrimation, rhinorrhea, and miosis. The International Classification of Headache Disorders 3rd Edition recognises four different headache entities in this group, with cluster headache as the most recognised among them. Hemicrania continua (HC) and paroxysmal hemicrania (PH) are both distinctive cephalgias of which the diagnostic criteria include an absolute response to indomethacin. Consequently, for this reason they are often referred to as 'indomethacin-responsive' TACs. The main focus of this review was to discuss the state of knowledge regarding the pathophysiology and key characteristics of PH and HC. Given the limited understanding of these conditions, and their exceptionally uncommon prevalence, a correct diagnosis can pose a clinical challenge and the search for an effective treatment may be prolonged, which frequently has a serious impact upon patients' quality of life. The information provided in this review is meant to help physicians to differentiate indomethacin-sensitive cephalgias from other distinct headache disorders with a relatively similar clinical presentation, such as cluster headache, trigeminal neuralgia, and various migraine conditions.

Hemicrania continua in a family: A report of two cases.

OBJECTIVE: To report two cases of hemicrania continua (HC) in a mother and daughter. BACKGROUND: HC is a rare primary headache disorder belonging to the family of trigeminal autonomic cephalalgias (TACs). Unlike migraine, familial cases of TACs are rare, and we know relatively little of their inheritance pattern and genetic mechanisms. METHODS: We present a mother and daughter with HC. We compare the similarities and differences between this family and the first report of familial HC and discuss the implications for future studies. RESULTS: Both the mother and daughter presented with a constant, side-locked headache of moderate intensity, with episodic exacerbations of more severe pain that are associated with ipsilateral cranial autonomic activation. After negative workup, both patients were started on indomethacin and achieved absolute response at different doses, confirming HC. CONCLUSIONS: Our report further corroborates other reports of familial TACs that TACs are primary headaches possibly attributable to genetic factors, albeit detailed mechanisms remain elusive. Nevertheless, whether clinical presentation and treatment responses would be substantially different between sporadic and familial HCs remain unclear.

[Cluster headache and other trigeminal autonomic cephalalgias]. / Clusterhoofdpijn en andere trigeminale autonome cefalalgieën.

Trigeminal autonomic cephalalgias (TACs) are a group of 4 different primary headache syndromes that have a lot of pathophysiological and clinical features in common. The 4 different TACs are: cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks and hemicrania continua. TACs are characterized by frequent, strictly unilateral, (very) intense headache attacks with ipsilateral cranial autonomic symptoms or intrinsic restlessness or both. A distinction can be made between the 4 TACs on the basis of the duration and frequency of the headache attacks. The treatment of cluster headache consists of an acute treatment and a maintenance treatment. Headache attacks in the context of paroxysmal hemicrania and hemicrania continua (almost) always respond to treatment with indomethacin. More and more neuromodulation therapies are becoming available, such as vagus nerve stimulation, stimulation and blocking of the sphenopalatine ganglion, stimulation and blocking of the occipital nerve and deep brain stimulation.

Diagnostic Testing for Migraine and Other Primary Headaches.

Most primary headaches can be diagnosed using the history and examination. Judicious use of neuroimaging and other testing, however, is indicated to distinguish primary headaches from the many secondary causes that may share similar features. This article evaluates the reasons for diagnostic testing and the use of neuroimaging, electroencephalography, lumbar puncture, and blood testing. The use of diagnostic testing in adults and children who have headaches and a normal neurologic examination, migraine, trigeminal autonomic cephalalgias, hemicrania continua, and new daily persistent headache are reviewed.

Trigeminal Autonomic Cephalalgias.

The trigeminal autonomic cephalalgias (TACs) are a group of primary headache syndromes all marked by unilateral headache and ipsilateral cranial autonomic features. The TACs include cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, and hemicrania continua. Pathophysiology includes the trigeminal pain system, autonomic system, hypothalamus, and more recently an identified role for the vagus nerve. Diagnosis is made after looking at headache frequency, duration, and accompanying symptoms. Each TAC has its own unique treatment, which is discussed in depth.

Do paroxysmal hemicrania and hemicrania continua represent different headaches? A retrospective study.

OBJECTIVE: Hemicrania continua and paroxysmal hemicrania are considered different headaches belonging to a group of trigeminal autonomic cephalalgias. However, they share many clinical features. Both headaches also show complete response to indomethacin, which is a mandatory criterion for their diagnosis. Are they really different headaches? To answer this question, we compared the pain characteristics and autonomic features between two headaches. We also determined whether paroxysmal hemicrania transforms into hemicrania continua or vice versa in their natural history. METHODS: The patients with hemicrania continua and paroxysmal hemicrania were compared for severity, location, character, and mean effective indomethacin dose. The number of autonomic features and their severity was also compared. The natural history of headache was looked into to see the evolution of hemicrania continua and paroxysmal hemicrania from episodic and chronic pains, respectively. RESULTS: We included 35 patients with hemicrania continua and 27 patients with paroxysmal hemicrania from July 2015 to March 2017. The mean age of patients with paroxysmal hemicrania was 34.42 years, and hemicrania continua was 37 years. Both groups were similar for majority of pain characteristics and number/severity of autonomic features. However, paroxysmal hemicrania had higher pain severity. Five patients transformed from paroxysmal hemicrania to hemicrania continua, and 3 patients transformed from hemicrania continua to paroxysmal hemicrania. CONCLUSION: Paroxysmal hemicrania and hemicrania continua were similar on majority of pain characteristics and autonomic features. The paroxysmal hemicrania and hemicrania continua are not exclusive headaches and can transform into each other.

LASH syndrome: New cases with a broadening clinical phenotype.

OBJECTIVE: To describe three new cases of the headache syndrome of long-lasting autonomic symptoms with hemicrania (LASH), and to establish a clinical phenotype utilizing all LASH cases noted in the medical literature. METHODS: A case series of patients was evaluated in an academic headache clinic over a two-year time period. LASH syndrome was defined by episodic headache attacks with associated cranial autonomic symptoms that start before headache onset, last the entire duration of the headache and continue on for a period of time after the headache ceases. RESULTS: Three patients were noted to have LASH syndrome in a two-year time period (2017-2018). One patient was diagnosed with primary LASH, while two others had probable secondary LASH from a secretory pituitary tumor. The primary LASH patient was female. She had on average one headache per week lasting 1-3 days in duration. She experienced migrainous associated symptoms along with their cranial autonomic symptoms. She also developed a fixed Horner's syndrome along with a typical headache attack, which was present for 6 months at the time of consultation. She had complete headache relief with indomethacin and her miosis and ptosis also resolved with treatment. Secondary LASH was diagnosed in two patients (one male, one female) both with prolactin secreting pituitary microadenomas. One of the patients had his headaches abolish with dopamine agonist therapy while the other patient did not respond to hormonal modulation but became pain free on indomethacin. Secondary LASH patients had less frequent headache episodes and lacked any migrainous associated features, but exhibited agitation with headache. CONCLUSION: LASH syndrome may be rare, but more reported cases are entering the headache literature. The temporal profile of onset and offset of cranial autonomic symptoms is key to making the diagnosis. Primary and secondary LASH may present differently based on gender predominance, the presence of migrainous associated features, and attack frequency. Secondary LASH appears to be indomethacin responsive, suggesting that medication effectiveness should not obviate the need to do testing for secondary etiologies.

The unique role of the trigeminal autonomic reflex and its modulation in primary headache disorders.

PURPOSE OF REVIEW: The trigeminal autonomic reflex is a physiological reflex with an important protective function which also plays a role in pathophysiological conditions, such as primary headache. It is not understood whether the autonomic symptoms in trigeminal autonomic cephalalgias and migraine are the consequence of severe trigeminal discharge or indeed directly driven by central generators as part of the pathophysiology, underlying these syndromes. RECENT FINDINGS: Modulating this reflex, and particularly the parasympathetic reflex arc, has been shown to be effective in treating headache. Among these modulators, left noninvasive vagal nerve stimulation has been shown to bilaterally inhibit the parasympathetic output of the reflex. Furthermore, the peripheral activation of the reflex, resulting in parasympathetic discharge, is not sufficient to provoke headache attacks in cluster headache patients, suggesting a central modulation. SUMMARY: Here, we review the anatomy and physiology of the trigeminal autonomic reflex and its involvement in primary headache. Possible candidates who have a modulating effect, including neurostimulation and pharmacological approaches, are described.

Cluster Headache and Other Trigeminal Autonomic Cephalalgias.

PURPOSE OF REVIEW: This article covers the clinical features, differential diagnosis, and management of the trigeminal autonomic cephalalgias (TACs). The TACs are composed of five diseases: cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA), and hemicrania continua. RECENT FINDINGS: New classifications for the TACs have two important updates; chronic cluster headache is now defined as remission periods lasting less than 3 months (formerly less than 1 month), and hemicrania continua is now classified as a TAC (formerly classified as other primary headache). The first-line treatments of TACs have not changed in recent years: cluster headache is managed with oxygen, triptans, and verapamil; paroxysmal hemicrania and hemicrania continua are managed with indomethacin; and SUNCT and SUNA are managed with lamotrigine. However, advancements in neuromodulation have recently provided additional options for patients with cluster headache, which include noninvasive devices for abortive therapy and invasive devices for refractory cluster headache. Patient selection for these devices is key. SUMMARY: The TACs are a group of diseases that appear similar to each other and to other headache disorders but have important differences. Proper diagnosis is crucial for proper treatment. This article reviews the pathophysiology, epidemiology, differential diagnosis, and treatment of the TACs.

Hints on Diagnosing and Treating Headache.

BACKGROUND: Headache, like dizziness, is one of the more common presenting complaints in outpatient care and in the emergency room. More than 200 varieties of headache have been described, and the false impression may arise that the diagnosis and treatment of these syndromes is a highly challenging task. METHODS: This review is based on pertinent articles retrieved by a selective search in PubMed. RESULTS: In primary headache, the headache is not a symptom but a disease in its own right. There are four types of primary headache: migraine, tension headache, trigeminal autonomic cephalalgia, and other primary headache disorders. By definition, the physical examination is normal, including the neurological examination. Secondary headache, in contrast, is a symptom of another disease (e.g., a tumor or cerebral hemorrhage). Triptans and nonsteroidal anti-inflammatory drugs (NSAID) are the drugs usually given for the acute treatment and prophylaxis of migraine. In tension headache, NSAID are given acutely, and tricyclic drugs for prophylaxis. There are various options for the treatment of trigeminal autonomic cephalalgia syndromes such as cluster headache and paroxysmal hemicrania. For group 4 headaches (other primary headache disorders), the treatment must be chosen on an individual basis; indomethacin is often effective. CONCLUSION: If the patient is clearly suffering from none of the four types of primary headache, the problem must be a headache of a secondary nature, potentially reflecting a dangerous underlying disease. The treatment of headache is usually successful and thus highly rewarding for physicians of all medical specialties.

Trait- and Frequency-Dependent Dysfunctional Habituation to Trigeminal Nociceptive Stimulation in Trigeminal Autonomic Cephalalgias.

We investigated whether the stimulation frequency (SF), the pain phases, and different diagnoses of trigeminal autonomic cephalalgias (TACs) may influence the habituation to pain. We studied the habituation of the nociceptive blink reflex R2 responses at different SFs (.05, .1, .2, .3, .5, and 1 Hz), in 28 episodic cluster headache (ECH) patients, 16 during and 12 outside the bout; they were compared with 16 episodic paroxysmal hemicrania (EPH) during the bout and 21 healthy subjects. We delivered 26 electrical stimuli and subdivided stimuli 2 to 26 in 5 blocks of 5 responses for each SF. Habituation values for each SF were expressed as the percentages of the mean area value of second through fifth blocks with respect to the first one. A significant lower mean percentage decrease of the R2 area across all blocks was found at .2 to 1 Hz SF during ECH, outside of the ECH, and EPH compared with healthy subjects. We showed a common frequency-dependent deficit of habituation of trigeminal nociceptive responses at higher SFs in ECH and EPH patients, independently from the disease phase. This abnormal temporal pattern of pain processing may suggest a trait-dependent dysfunction of some underlying pain-related subcortical structures, rather than a state-dependent functional abnormality due to the recurrence of the headache attacks during the active period. PERSPECTIVE: TACs showed a frequency-related defective habituation of nociceptive trigeminal responses at the higher SFs, irrespectively of the diagnosis and/or the disease phase. We showed that the clinical similarities in the different subtypes of TACs are in parallel with a trait-dependent dysfunction in pain processing.

Therapeutic Approaches for the Management of Trigeminal Autonomic Cephalalgias.

Trigeminal autonomic cephalalgia (TAC) encompasses 4 unique primary headache types: cluster headache, paroxysmal hemicrania, hemicrania continua, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms. They are grouped on the basis of their shared clinical features of unilateral headache of varying durations and ipsilateral cranial autonomic symptoms. The shared clinical features reflect the underlying activation of the trigeminal-autonomic reflex. The treatment for TACs has been limited and not specific to the underlying pathogenesis. There is a proportion of patients who are refractory or intolerant to the current standard medical treatment. From instrumental bench work research and neuroimaging studies, there are new therapeutic targets identified in TACs. Treatment has become more targeted and aimed towards the pathogenesis of the conditions. The therapeutic targets range from the macroscopic and structural level down to the molecular and receptor level. The structural targets for surgical and noninvasive neuromodulation include central neuromodulation targets: posterior hypothalamus and, high cervical nerves, and peripheral neuromodulation targets: occipital nerves, sphenopalatine ganglion, and vagus nerve. In this review, we will also discuss the neuropeptide and molecular targets, in particular, calcitonin gene-related peptide, somatostatin, transient receptor potential vanilloid-1 receptor, nitric oxide, melatonin, orexin, pituitary adenylate cyclase-activating polypeptide, and glutamate.

The pathophysiology of the trigeminal autonomic cephalalgias, with clinical implications.

The hallmark of primary headaches belonging to the group known as the trigeminal autonomic cephalalgias is unilateral headache accompanied by cranial autonomic symptoms. Being relatively rare and poorly understood, they represent a clinical challenge, leading to underdiagnosis and undertreatment. While the headache is the most obvious and disabling symptom, it is only part of a complex symptomatology which hints at the involved pathophysiological mechanisms. Activation of the trigeminal-autonomic reflex results in the aforementioned cranial autonomic symptoms, which are well understood; however, it is obvious that this brainstem reflex is regulated by higher centers that seemingly play a pivotal role in the attacks and the wide range of other symptoms indicating a homeostatic disturbance. These symptoms, as well as a number of well-validated findings, implicate the hypothalamus in the pathophysiology. over the course of the past 2-3 decades, novel therapies and technological advances have helped increase our knowledge of these clinical syndromes, and will likely continue to do so in the coming years as we witness the arrival of new drugs and neurostimulation options. In this review, the clinical presentation for cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing, and hemicrania continua is covered, along with our current understanding of the common pathophysiology and clinical manifestations.

Primary Headache Disorders Part I- Migraine and the Trigeminal Autonomic Cephalalgias.

In Primary Headache Disorders, Part 1, we discuss three of the primary headache disorders using the headache definitions from ICHD-III (Beta): Migraine, with and without aura; its pathophysiology and treatment are discussed. We then discuss the Trigeminal Autonomic Cephalalgias (TACs), including Cluster Headache and Hemicrania Continua, two more primary headache disorders, as well as the other TAC Headaches. We discuss pathophysiology as well as diagnosis, treatment, and pharmacotherapeutic management of these headache diatheses.

LASH: A Review of the Current Literature.

PURPOSE OF REVIEW: 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). RECENT FINDINGS: 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).

Tics in TACs: A Step into an Avalanche? Systematic Literature Review and Conclusions.

BACKGROUND: Trigeminal autonomic cephalalgias (TACs) comprise cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks, and hemicrania continua. In some cases, trigeminal neuralgia (TN, "tic douloureux") or TN-like pain may co-occur with TACs. AIM: This article will review the co-occurrence and overlap of TACs and tics in order to contribute to a better understanding of the issue and an improved management of the patients. METHODS: For performing a systematic literature review Pubmed was searched using a total of ten terms. The articles identified were screened for further articles of relevance. SUMMARY: TACs are related to tics in various ways. TN or TN-like paroxysms may co-occur with CH, PH, and HC, labeled as cluster-tic syndrome, PH-tic syndrome, and HC-tic syndrome. Such co-occurrence was not only found in the primary TACs but also in secondary headaches resembling TACs. The initial onset of TAC and tic may be simultaneous or separated by months or years. In acute attacks, tic and TAC may occur concurrently or much more often independently of each other. The term "cluster-tic syndrome" was also used in patients with a single type of pain in a twilight zone between TACs and TN fulfilling none of the relevant diagnostic criteria. Short-lasting neuralgiform headache attacks overlap with TN in terms of clinical features, imaging findings, and therapy.

SUN: Short-Lasting Unilateral Neuralgiform Headache Attacks.

PREMISE: Short-lasting unilateral neuralgiform headache attacks (SUN) are part of the group of primary headaches called trigeminal autonomic cephalalgias (TACs). They are characterized by unilateral attacks of pain with associated ipsilateral cranial autonomic symptoms. PROBLEM: Recently the classification of these attacks has changed, to incorporate the different types of autonomic symptoms such as conjunctival injection and tearing (or lack thereof). Previously considered to be rare and rather refractory to treatment, there is an increasing awareness of this syndrome and the therapeutic possibilities. DISCUSSION: This article discusses the clinical aspects of the syndrome, pathophysiology, current, and future treatments.

Trigeminal autonomic cephalalgia as a presenting feature of Neuromyelitis Optica: "A rare combination of two uncommon disorders".

Neuromyelitis Optica (NMO) can have atypical presentations like hiccups, vomiting, etc. which is classically described as the area postrema syndrome. Here we report a case of a 39 year old male patient who presented with features of Trigeminal Autonomic Cephalalgia (TAC). MRI spine showed long segment myelitis. Diagnosis of NMO was confirmed by a positive Anti aquaporin 4 antibody assay. TACs are a rare group of headache disorders characterized by severe unilateral headache in the V1 distribution of the trigeminal nerve and autonomic symptoms. This presentation in NMO is hitherto unreported in literature.