Trigeminal autonomic cephalgias: diagnosis, therapy, atypical forms and pathophysiology

Trigeminal autonomic cephalgias; cluster headache, paroxysmal hemicrania, hemicrania continua and SUNCT (short-lasting unilateral neuralgiform headache attacks with conjuctival injection and tearing) syndrome are characterized by unilateral trigeminal distribution of pain and accompanying ipsilateral autonomic symptoms. Other than cluster headache, all of these syndromes have been described within last twenty years, and are found relatively less frequent and less known forms. Diagnosis of paroxysmal hemicrania and hemicrania continua, especially atypical forms, essentially depends on indomethacin responsiveness. For SUNCT syndrome, there is not such a drug which provides a practical approach to both diagnosis and therapy and its diagnosis depends on clinical features. So far, case reports from various countries helped us realize the existence of secondary forms of these syndromes and the necessity of imaging techniques, especially for recently described autonomic cephalgias.     

Headaches with (ipsilateral) autonomic symptoms

Abstract. Primary short-lasting headaches broadly divide themselves into those associated with autonomic symptoms, so called trigemino-autonomic cephalgias (TACs), and those with little autonomic syndromes. The trigeminoautonomic cephalgias include cluster headache and paroxysmal hemicranias, in which head pain and cranial autonomic symptoms are prominent. The most striking feature of cluster headache is the circadian and circannual periodicity of the attacks. Inheritance may play a role in some families. The attacks are of extreme intensity, of short duration, occur unilaterally, and are accompanied by symptoms of autonomic dysfunction. Medical treatment includes both acute therapy aimed at aborting individual attacks and prophylactic therapy aimed at preventing recurrent attacks during the cluster period. Some types of trigemino-autonomic headaches, such as paroxysmal hemicrania and hemicrania continua have, unlike cluster headaches, a very robust response to indomethacin, leading to a consideration of indomethacin-sensitive headaches.     

Short-lasting primary headaches: focus on trigeminal automatic cephalgias and indomethacin-sensitive headaches

Short-lasting primary headache syndromes provides both a diagnostic challenge and considerable therapeutic reward. Primary short-lasting headaches broadly divide themselves into those associated with auto nomic symptoms, trigeminalautonomic cephalgias and those with little autonomic syndromes. The trigeminal-autonomic cephalgias include cluster headache and paroxysmal hemicranias, in which head pain and cranial autonomic symptoms are prominent. Consideration of short- lasting headaches, particularly in the context of the differential diagnosis between cluster headache and paroxysmal hemicrania leads to a consideration of indomethacin-sensitive headaches. There are a group of headaches, such as paroxysmal hemicrania and hemicrana continua , which have a curious and a very robust response to indomethacin. These headaches tend to be referred to neurologists as they are refractory to other treatments and thus are useful to know about.     

Trigeminal autonomic cephalalgias: diagnostic and therapeutic developments

PURPOSE OF REVIEW: The review was designed to summarize recent research relevant to the trigeminal autonomic cephalalgias, which include cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing/cranial autonomic features (SUNCT/SUNA). Hemicrania continua is included for completeness. RECENT FINDINGS: Cluster headache has the longest attack duration and relatively low attack frequency. Paroxysmal hemicrania has intermediate duration and intermediate attack frequency. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing have the shortest attack duration and the highest attack frequency. Hemicrania continua has a continuous pain with exacerbations that can include cranial autonomic symptoms as part of the phenotype. The importance of diagnosing these syndromes resides in their excellent but highly selective response to treatment. SUMMARY: Considerable advances have been made in the diagnostic and therapeutic approaches to trigeminal autonomic cephalalgias and these are important for neurologists to consider.     

Pathophysiology of cluster headache: a trigeminal autonomic cephalgia

Cluster headache is a form of primary neurovascular headache with the following features: severe unilateral, commonly retro-orbital, pain accompanied by restlessness or agitation, and cranial (parasympathetic) autonomic symptoms, such as lacrimation or conjunctival injection. It occurs in attacks typically of less than 3 h in length and in bouts (clusters) of a few months during which the patient has one or two attacks per day. The individual attack involves activation of the trigeminal-autonomic reflex; thus, such headaches can be broadly classified with the other trigeminal-autonomic cephalgias, such as paroxysmal hemicrania and the syndrome of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. Observations of circadian biological changes and neuroendocrine disturbances have suggested a pivotal role for the hypothalamus in cluster headache. Functional neuroimaging with PET and anatomical imaging with voxel-based morphometry have identified the posterior hypothalamic grey matter as the key area for the basic defect in cluster headache.     

Trigeminal autonomic cephalalgias: Diagnosis and treatment

The trigeminal autonomic cephalalgias (TACs) are a group of primary headache disorders characterized by unilateral head pain that occurs in association with ipsilateral cranial autonomic features. The TACs include cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and its close relative short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). These syndromes cause patients considerable disability and certainly very significant suffering. They are distinguished by the frequency of attacks of pain, the length of the attacks, and very characteristic responses to medical therapy, such that the diagnosis can usually be made clinically, which is important because it completely dictates therapy. The management of TACs can be very rewarding for physicians and highly beneficial to patients.     

Paroxysmal hemicrania responding to topiramate

Chronic paroxysmal hemicrania (CPH) is a rare primary headache syndrome, which is classified along with cluster headache and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) as a trigeminal autonomic cephalalgia. CPH is exquisitely responsive to indomethacin so much so that the response is one of the current diagnostic criteria. The case of a patient with CPH, who had marked epigastric symptoms with indomethacin treatment and responded well to topiramate 150 mg daily, is reported. Cessation of topiramate caused return of episodes, and the response has persisted for 2 years. Topiramate may be a treatment option in CPH.     

Neurostimulation in primary headache syndromes

Neurostimulation therapy involves the use of peripheral or central nerve electrical stimulation approaches for the treatment of medically intractable headache. Currently, for peripheral stimulation the main approach is that of occipital nerve stimulation, while for central stimulation deep-brain approaches with the target of the region of the posterior hypothalamic gray matter have been explored. Target conditions include migraine and the trigeminal autonomic cephalalgias: cluster headache, paroxysmal hemicrania and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing/cranial autonomic features (SUNCT/SUNA), as well as hemicrania continua. The initial results are encouraging and given the very significant disability of medically intractable primary headaches, this is a very promising area for patients and physicians alike.     

Trigeminal autonomic cephalalgia sine headache

Cluster headache without headache (CH-H) has been described several times. We add three new CH-H patients and a patient with (probable) paroxysmal hemicrania without headache (PH-H). We searched the literature and found some more cases of CH-H and PH-H. CH-H attacks may have a shorter minimal attack duration than CH attacks. We propose the term trigeminal autonomic cephalalgia without headache (TAC-H) for autonomic attacks and/or extracephalic pain or sensory symptoms with an attack duration and distribution and/or response to therapy suggesting one of the trigeminal autonomic cephalalgias, but without accompanying headache. Secondary TAC-H may develop after treatment for painful TAC attacks. We discuss pathophysiological issues, particularly the central role of the hypothalamus and the suggestion that the superior salivatory nucleus (SSN) might be triggered by the diencephalic pacemaker without nociceptive activation.     

Trigeminal autonomic cephalgias due to structural lesions: a review of 31 cases

Trigeminal autonomic cephalgias (TACs) include cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing. Associated structural lesions may be found, but a causal relationship is often difficult to establish. We sought to identify clinical predictors of underlying structural abnormalities by reviewing previously described and new TAC and TAC-like cases associated with a structural lesion. We found that even typical TACs can be caused by an underlying lesion. Clinical warning signs and symptoms are relatively rare. We recommend neuroimaging in all patients with a TAC or TAC-like syndrome.     

Ictal video-polysomnography and EEG spectral analysis in a child with severe Panayiotopoulos syndrome.

OBJECTIVE: To describe the ictal polysomnographic features of a patient with Panayiotopoulos syndrome, a peculiar epileptic syndrome characterized by infrequent, often single, prolonged, nocturnal, focal seizures comprising an unusual constellation of autonomic symptoms (malaise, nausea, pallor, tachycardia, vomiting) and unilateral deviation of the eyes at the onset of seizures. These clinical, ictal manifestations are rarely followed by post-ictal headache. In the literature, there is little information on the ictal EEG characteristics of Panayiotopoulos syndrome and, in particular, on certain autonomic manifestations, such as tachycardia, as the sole ictal phenomena at the onset of seizures. METHODS AND RESULTS: One, all-night videopolysomnography, during which one seizure was recorded. Video-EEG data were evaluated visually and by means of quantitative spectral analysis. The spectral analysis of the recorded seizure showed a complex ictal pattern of cortical involvement with focal onset in the right occipital area followed by the recruitment of widespread extra-occipital cortical regions. CONCLUSIONS: This is the first such analysis of this peculiar epileptic condition. Most of the symptoms were consistent with a diagnosis of severe Panayiotopoulos syndrome, although the patient also presented "atypical findings": a relatively high frequency of seizures, post-ictal headache, no spontaneous remission of seizures with age, and late onset of visual hallucinations; this last finding is more frequent in "Gastaut-type childhood occipital epilepsy", in which onset typically occurs later than in Panayiotopoulos syndrome. [Published with video sequences].     

Trigemino-autonomic cephalalgias. Report of two cases

Trigemino-autonomic cephalalgias (TAC) constitute a rare group of primary headache conditions associated with unilateral fluctuating head pain and autonomic symptoms. These syndromes, including cluster headache, hemicrania continua, paroxysmal hemicrania and SUNCT, are much less prevalent than migraine and tension-type headache. The pathogenesis of TAC is unknown. Similar neuropeptide changes seen in all TAC syndromes suggest a shared underlying pathophysiology in these headaches. Some of them respond to the treatment with indomethacin and sumatriptan. Two patients suffering from one of the trigemino-autonomic cephalalgias are presented in the paper.     

Diagnostic difficulties of paroxysmal symptoms in a boy with Parry-Romberg syndrome

Parry-Romberg syndrome is characterized by progressive unilateral facial atrophy affecting subcutaneous tissue, cartilage and bone structures. Headache attacks and epilepsy are commonly associated with this syndrome but the underlying pathophysiology is still unknown. A case of a 12-year-old boy with Parry-Romberg syndrome and syringomyelia suffering from severe headache attacks and epileptic seizures is reported herein.Headache attacks were associated with bilateral autonomic symptoms and hyperventilation and were usually followed by complex partial and sometimes by secondary generalized tonic seizures. Detailed neuroimaging examinations were performed (magnetic resonance imaging [MRI] of the head, orbits, and spinal cord, MR angiography, and MR spectroscopy of the cerebellum). The EEG pattern revealed localized discharges contralaterally to the affected side. Antiepileptic treatment with carbamazepine was instituted with minimal effect. Modification of treatment (replacement with oxcarbazepine) was successful.In the reported patient interesting correlation of headache attacks, autonomic symptoms and epileptic seizures was observed. Additionally we believe it is the first report of coincident syringomyelia and Parry-Romberg syndrome.     

Idiopathic facial pain other than vascular pain

Cluster Headache associates a severe pain generally unilateral and autonomic symptoms with a remarkable periodicity. In the first part we tried to explain the conception of physiopathology of these short lasting headache syndromes and in the second part we described the clinical features. The short lasting primary headaches are divided into two groups: those with marked autonomic activation which comprise chronic and episodic paroxysmal hemicrania, short lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT syndrome) and cluster headache. The second group includes two entities, one without autonomic activation: Hypnic Headache and one with mild autonomic features: Hemicrania Continua. The paroxysmal hemicranias are characterized by attack frequency ranges from 15 to 20 per day of short lasting attacks of unilateral pain that typically last 2 to 10 minutes, the severe pain is associated with autonomic symptoms and responds to treatment with indomethacin. The SUNCT syndrome has a less severe pain but marked autonomic activation during attacks, this syndrome is actually resistant to proposed therapy. The Hypnic Headache and the Hemicrania Continua have yet less severe pain with very mild or without autonomic features.     

Trigeminal autonomic cephalalgias. Pathophysiology and classification

Trigeminal Autonomic Cephalalgias (TACs) is a grouping of headache syndromes that includes cluster headache, paroxysmal hemicrania and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). They are recognized clinically by their episodic, stereotypic attack profile and very often prominent cranial autonomic symptoms, such as lacrimation, conjunctival injection or rhinorrhea. They involve afferent activation of the trigeminal innervation of intracranial pain-producing structures, or the perception of that activation, and reflex activation of the facial, seventh cranial, nerve outflow pathway. This excess reflex trigeminal-autonomic activation seems to be permitted by dysfunction in the brain, specifically in the posterior hypothalamic gray matter. Understanding the anatomy and physiology of these disorders has greatly facilitated their management and the development of exciting new strategies such as neuromodulatory approaches to the management of the more intractable cases.     

Post-traumatic chronic paroxysmal hemicrania (CPH) with aura

The authors describe a patient who developed chronic paroxysmal hemicrania (CPH) in close temporal relationship to a head injury. The subsequent attacks of CPH were associated with a typical migrainous sensory and motor aura. Administration of indomethacin 75 mg daily resulted in isolated occurrence of autonomic and aura symptoms in the absence of pain symptoms. The patient became completely asymptomatic on indomethacin 100 mg daily. Migrainous aura may be seen with trigeminal-autonomic headaches and may represent the expression of an aura-susceptibility gene rather than typical migraine headache biology.     

Sinus venous stenosis-associated IIHWOP is a powerful risk factor for progression and refractoriness of pain in primary headache patients: a review of supporting evidences

According to the diagnostic criteria of International Headache Society classification, hemicrania continua is a strictly unilateral continuous headache of moderate intensity with painful exacerbations associated with ipsilateral autonomic signs without pain-free periods. We report a case of a 42-year-old woman suffered of a remitting form of hemicrania continua evolved from a strictly unilateral migraine without aura.     

Epileptic seizures and headache/migraine: A review of types of association and terminology

PurposeThere are different possible temporal associations between epileptic seizures and headache attacks which have given rise to unclear or controversial terminologies. The classification of the International League Against Epilepsy does not refer to this type of disorder, while the International Classification of Headache Disorders (ICHD-2) defines three kinds of association: 1. migraine-triggered seizure (“migralepsy”), 2. hemicrania epileptica, and 3. post-ictal headache.MethodsWe performed an extensive review of the literature, not including “post-ictal” and “inter-ictal” headaches.ResultsOn the basis of well-documented reports, the following clinical entities may be identified: (A) “epileptic headache (EH)” or “ictal epileptic headache (IEH)”: in this condition headache (with or without migrainous features) is an epileptic manifestation per se, with onset, and cessation if isolated, coinciding with the scalp or deep EEG pattern of an epileptic seizure. EH maybe followed by other epileptic manifestations (motor/sensory/autonomic); this condition should be differentiated from “pure” or “isolated” EH, in which headache/migraine is the sole epileptic manifestation (requiring differential diagnosis from other headache forms). “Hemicrania epileptica” (if confirmed) is a very rare variant of EH, characterized by ipsilateral location of headache and ictal EEG paroxysms. (B) “Pre-ictal migraine” and “pre-ictal headache”: when a headache attack is followed during, or shortly after, by a typical epileptic seizure. The migraine attack may be with or without aura, and its seizure-triggering role (“migraine-triggered seizure”) is still a subject of debate. A differentiation from occipital epilepsy is mandatory. The term “migralepsy” has not been used uniformly, and may therefore led to misinterpretation.ConclusionsOn the basis of this review we suggest definitions and a terminology which may become the basis of a forthcoming classification of headaches associated with epileptic seizures.     

Psychogenic Elaboration of Simple Partial Seizures

Summary: Seizures that cause loss of consciousness (LOC) can be classified as epileptic or nonepileptic based on evaluation of ictal semiology and analysis of changes in EEG events, recorded with continuous scalp EEG and video monitoring. We report 3 patients who had hippocampal electrographic seizures documented with intracranial EEG recording with no accompanying scalp EEG change immediately preceding psychogenic unresponsiveness. Each patient also had complex partial seizures (CPS) originating in the hippocampus. Some individuals can have complex interactions of epileptic and nonepileptic seizures.     

Gastroesophageal reflux disease vs. Panayiotopoulos syndrome: An underestimated misdiagnosis in pediatric age?

Autonomic signs and symptoms could be of epileptic or nonepileptic origin, and the differential diagnosis depends on a number of factors which include the nature of the autonomic manifestations themselves, the occurrence of other nonictal autonomic signs/symptoms, and the age of the patient.Here, we describe twelve children (aged from ten months to six years at the onset of the symptoms) with Panayiotopoulos syndrome misdiagnosed as gastroesophageal reflux disease.Gastroesophageal reflux disease and Panayiotopoulos syndrome may represent an underestimated diagnostic challenge. When the signs/symptoms occur mainly during sleep, a sleep EEG or, if available, a polysomnographic evaluation may be the most useful investigation to make a differential diagnosis between autonomic epileptic and nonepileptic disorders. An early detection can reduce both the high morbidity related to mismanagement and the high costs to the national health service related to the incorrect diagnostic and therapeutic approaches. To decide if antiseizure therapy is required, one should take into account both the frequency and severity of epileptic seizures and the tendency to have potentially lethal autonomic cardiorespiratory involvement.In conclusion, we would emphasize the need to make a differential diagnosis between gastroesophageal reflux disease and Panayiotopoulos syndrome in patients with “an unusual” late-onset picture of GERD and acid therapy-resistant gastroesophageal reflux, especially if associated with other autonomic symptoms and signs.