Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.315990
Source of Support: None, Conflict of Interest: None
Keywords: Cranial autonomic symptoms, SUNA, SUNCT, trigeminal autonomic cephalalgia
The syndrome of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) was first described by Sjaastad et al. in 1978. Later it was observed that not all patients with SUNCT exhibited conjunctival injection and tearing and the term short-lasting unilateral neuralgiform headache with autonomic symptoms (SUNA) was introduced for this subgroup of patients in the appendix of the second edition of International Classification of Headache Disorders (ICHD). According to ICHD-2, only one autonomic feature was required for the diagnosis of SUNA if there was no refractory period following attacks triggered by trigger areas. Recent research has shown that there are very few differences between the 2 syndromes other than the fact that SUNCT exhibits more prominent cranial autonomic features and is more easily triggerable compared to SUNA and both phenotypes are probably part of the same spectrum. As a result, in the latest version of the headache classification (ICHD-3), SUNCT and SUNA have been designated as subcategories of short-lasting unilateral neuralgiform headache attacks (SUNHA). Few systematic reviews (1997, 2013, and 2017) and metanalysis (2017) are available for primary and secondary SUNCT/SUNA.,,,, The purpose of this review is to highlight some recent developments and provide an update in terms of phenotype, pathophysiology, diagnosis, and management of SUNCT/SUNA.
Potential English language publications for the purpose of this narrative review were systematically searched in PubMed using the keywords––”short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)”, “short-lasting unilateral neuralgiform headache with autonomic symptoms (SUNA)”, “short-lasting unilateral neuralgiform headache attacks (SUNHA)”, “trigeminal autonomic cephalalgias”. The search terms were used as keywords as well as in combination and MeSH terms. In addition, relevant publications were selected from the reference list of other reviews on SUNCT and SUNA to maximize the number of articles. We excluded single case reports describing SUNCT/SUNA (other than secondary SUNCT/SUNA) and case series of fewer than 10 patients for the purpose of this review. Only the studies published in English were included. The final reference list was generated on the basis of additional topics relevant to this review such as epidemiology, pathophysiology, anatomy, and mechanisms of action of various therapeutic options.
A literature search using the defined criteria revealed potential 1103 articles. Among these 1103 articles, seven case series of at least 10 cases were identified for this review. For symptomatic/secondary SUNCT/SUNA, 49 individual case reports, one case series of secondary SUNCT/SUNA were reviewed to characterize the clinical characteristics and treatment response. We identified one placebo-controlled trial, 11 open-label case series that evaluated various medical and surgical treatments in SUNCT/SUNA.
SUNCT and SUNA are rare and as such an exact prevalence of these disorders is difficult to estimate. Only 50 cases were reported from the first description in 1978 to 2003. However, awareness of the diagnosis has led to a flurry of case reports and seven large case series of at least 10 cases each.,,,,,, Williams et al. estimated a prevalence of SUNCT/SUNA at 6.6 per 100,000 and a conservative annual incidence of 1.2 per 100,000. An epidemiological study from a town in Norway found two subjects with SUNCT-like syndromes in a population of 1838, corresponding to a prevalence of 109 per 100,000. The typical age of onset is 40 and 70 years; the mean age of onset is 57 years (older than other TACs). However, a more recent case series of SUCNT and SUNA found that the mean age of onset of SUNCT and SUNA was 45 years and 42 years, respectively. The youngest patient with SUNCT reported was 3 years old and the oldest patient was 88 years old., Earlier series and review of literature had found a male predominance for SUNCT with a male: female ratio of 1.5:1, though for SUNA, the male: female ratio was 1:1.7. A more recent study of SUNCT/SUNA found a female predominance for both SUNCT (1:1.2) and SUNA (1:2.48). Only 1 case of familial SUNCT has been reported till date.
SUNCT and SUNA are characterized by sudden brief attacks of severe unilateral pain in the distribution of trigeminal nerve (most commonly 1st division) accompanied by ipsilateral cranial autonomic symptoms. The clinical features of SUNCT/SUNA observed in case series are tabulated in [Table 1].,,,,,,
Cranial autonomic symptoms
Cranial autonomic symptoms are the defining feature of SUNCT/SUNA, though the type of autonomic symptoms and their severity may vary. By definition SUNCT patients have both conjunctival injection and tearing (with or without other CAS); while SUNA patients may have either one or none of conjunctival injection and tearing (with other CAS). Other cranial autonomic symptoms are––nasal congestion, rhinorrhea, miosis, ptosis, eyelid edema, forehead, and facial sweating and/or flushing, and a sensation of fullness in the ear. Lambru et al. in their prospective comparative study of SUNCT and SUNA found that ptosis and rhinorrhea were the only autonomic symptoms that were more common in SUNCT as compared to SUNA. More significant ptosis in SUNCT could be attributed to a stronger degree of facial parasympathetic activation leading to an ocular sympathetic deficit in SUNCT. The cranial autonomic symptoms are mostly unilateral and ipsilateral to pain, but in ~ 15% of cases, these CAS may be bilateral., In general pain in V1 distribution is associated with more severe conjunctival congestion and lacrimation, while pain in V2 and V3 distribution is associated with more rhinorrhea and nasal blockade.
Site of pain
The pain in SUNCT/SUNA is usually unilateral and typically located in the distribution of the 1st division of the trigeminal nerve (orbital, retro-orbital, supraorbital, or temporal regions). In some patients' pain may begin in another territory and radiate to V1 distribution territory. In others, pain may be maximum in intensity in the second division of trigeminal nerve (V2) or less commonly in the third division of trigeminal nerve (V3). Infrequently pain may be reported in extratrigeminal areas––particularly in C2–C3 sensory distribution [Figure 1]. Most of the patients have side-locked unilateral pain, but 10–15% may have side alternating attacks in both SUNCT and SUNA.,,
Severity and quality of pain
Pain in SUNCT/SUNA is usually severe (more severe in SUNCT than in SUNA) with most patients describing it as the most painful condition they had ever experienced, with a verbal rating scale of 8–10 in both conditions.,, However, in contrast to cluster headache (CH), most patients (70%) prefer to stay still during the attack, perhaps to avoid the cutaneous triggers that may precipitate the attack. Pain is most commonly described as stabbing, sharp, shooting, or electric shock-like pain.,, Some patients may describe the pain as pulsating or throbbing but never in isolation.
Duration, and temporal profile of individual attacks
Pareja et al. and Cohen et al. have described various patterns of attacks in SUNCT and SUNA and a clear knowledge of these patterns is essential to correctly diagnose SUNCT and SUNA, because shorter duration patterns can be misdiagnosed as trigeminal neuralgia, while longer duration patterns may be mistaken for paroxysmal hemicrania and cluster headache., The following patterns may be delineated by taking a careful history from the patients [Figure 2].,,,,
Notably, a large proportion of patients can have more than 1 attack profile and there may be wide inter-patient variation in the length of attacks and number of attacks per day.
Frequency of attacks
ICHD-3 requires at least 1 attack per day but most patients have a far greater number of attacks. The median number of attacks was found to be 20 in SUNA and 30 in SUNCT in a study by Lambru et al. In this cohort, a vast majority of patients had an attack frequency of 1–100 per day. Some patients may have nearly continuous attacks with a frequency of more than 30 attacks per hour that may cause pain for the better part of the day with minimal pain-free interval resulting in severe disability for several days––a condition named in the literature as status like presentation of SUNCT/SUNA. Therefore, for appropriate management decisions, it is pertinent to ascertain the attack load in minutes of pain per day rather than the number of attacks per day and the accompanying disability. SUNCT/SUNA can occur at any time of the day, and unlike cluster headache, it does not show a striking circadian rhythm. Most patients with SUNCT/SUNA have attacks while awake (54%) or both during waking and sleep hours (44%). Rarely (<2%) patients may have purely nocturnal attacks.,
Periodicity and chronicity
A vast majority of both SUNCT/SUNA (~ 90%) have a chronic form of disease where attacks occur for more than 1 year without remissions or with remission periods lasting less than 1 month.,, In ICHD-3 however, remission period up to 3 months is allowed. The episodic form is less common and seen in around 10% of cases with an average of 1–4 bouts per year with a duration of 1 week–10 months., The remission periods show wide variability in duration lasting 3–14 months and usually occur without circannual periodicity although there may be seasonal variations., With progression, episodic SUNA may transform to a secondary chronic form in an average of 8.4 years (range = 1–16 years).
Triggers and refractory period
In the cohort of Lambru et al., most patients with SUNCT/SUNA (49.2% of SUNA and 62.9% of SUNCT) have both spontaneous and triggered attacks. Earlier also Cohen et al. had observed that the majority (86%) of patients had both spontaneous and triggered attacks. Some patients (14%–47%) may have only spontaneous attacks., Although rare (<5%), it is useful to recognize that occasional patients with SUNCT syndrome may experience only triggered attacks. Trigger areas are almost always ipsilateral to the side of pain. Triggers include touching the face or scalp, bathing, or showering, washing or brushing hair, shaving, nose-blowing, chewing or eating, brushing teeth, talking, coughing, exercise, and light (including sunlight and fluorescent lights).,, Neck movement may precipitate attacks in some patients or abort attacks in others., Most patients with SUNCT/SUNA do not have a refractory period in contrast to Trigeminal neuralgia. In almost 80–95% of SUNCT/SUNA patients, an attack can be triggered immediately after the cessation of the previous attack.,,,
Some patients with SUNCT/SUNA may report a background featureless interictal pain on the same side as the paroxysmal pain. This interictal pain usually starts with the onset of stabbing pain but in up to 25% of cases, the interictal pain may start after the onset of paroxysmal pain. Various studies have found interictal pain in 47–50% of patients.,,,
Some patients with SUNHA may have migrainous features such as nausea and vomiting. Photophobia and phonophobia when present are ipsilateral to the side of pain and are seen in around 27% of patients. Rare patients may have an aura––more commonly a sensory aura in the form of tingling sensation in the ipsilateral side of the face but the visual aura is also described in one patient.
Pathophysiologically SUNCT and SUNA are postulated to be caused by dysfunction of the hypothalamus and the trigeminal cervical complex. So, lesions of the pituitary––hypothalamic axis and the central and peripheral connections of trigeminal nerve have been found in patients presenting with a headache resembling SUNCT and SUNA. One case series and 4 systematic reviews of symptomatic SUNCT/SUNA identified 57 cases of secondary SUNCT/SUNA, with pituitary tumors and posterior fossa lesions being the most common cause of symptomatic SUNCT/SUNA [Table 2].,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Pituitary lesions are usually prolactin or growth hormone secreting and both microadenomas and macroadenomas have been described to cause SUNCT. The causal relationship was inferred by the fact that pain was relieved in most of these cases after-treatment of the adenoma. Headache symptoms can precede pituitary symptoms by 3 to 10 years.,,,, The pituitary lesions are usually ipsilateral to the painful side and both mechanical and neurohormonal mechanisms have been postulated to cause SUNCT., Posterior fossa lesions have also been reported to cause SUNCT and SUNA. Lesions may be extraxial (vascular, tumors, or bony abnormalities) or intraaxial (infarctions, white matter lesions, space-occupying lesions) [Table 2].
Neurovascular compression in SUNCT/SUNA
Recently there has been a renewed interest in neurovascular compression of the trigeminal nerve in patients with SUNCT/SUNA. Cohen et al. found 3 patients with a vascular loop compressing on the trigeminal nerve in their cohort of 44 patients with SUNCT who had undergone MRI. Williams et al. found that of 17 patients with SUNCT/SUNA, who had dedicated views of the trigeminal nerve, 15 (88%) had an aberrant arterial loop in contact with or deforming the trigeminal nerve. A systematic literature review identified 201 cases of SUNCT/SUNA evaluated by brain MRI and found evidence of vascular compression of the trigeminal nerve in 34 patients (17%). However, it was not clear how many of these cases had dedicated views of the trigeminal nerve, which might have caused some underreporting of vascular loops in SUNCT/SUNA. The usual vessel compressing the trigeminal nerve is the anterior inferior cerebellar artery or the superior cerebellar artery.
Diagnosis of SUNCT and SUNA is primarily clinical and depends on a proper history and clinical examination. Diagnostic criteria laid down by International Classification of Headache Disorders 3rd ed.ition (ICHD-3) are enlisted in [Table 3]. The neurologic examination is usually normal in patients with short-lasting unilateral neuralgiform headache attacks, although ipsilateral trigeminal sensory findings are present in occasional patients. Cohen et al. found the abnormal sensation to pinprick (mainly hypesthesia) in trigeminal V1 or V2 distribution was present 14% of patients with SUNCT and 2 of 9 with SUNA. One SUNCT patient with persistent Horner syndrome has also been reported. Presence of significant focal neurological deficit other than mild sensory loss or Horner syndrome points towards a secondary cause. In view of the increased prevalence of symptomatic causes in patients presenting with symptoms suggestive of SUNCT/SUNA, it is imperative that all patients undergo a detailed MRI of the brain with dedicated views for pituitary, cavernous sinus, and trigeminal nerve.
Major differential diagnosis of SUNCT/SUNA is the other headache in the TAC group, namely paroxysmal hemicrania and cluster headache. Although the typical duration of SUNCT/SUNA is <10 min, there is some overlap with PH, where the usual duration is 2–30 min. Moreover, repetitive stabs or saw––tooth type of attacks may last longer and can be confused with CH. The key point in differentiating from these disorders is a good history and the clinician should try to elicit the duration of individual stabs which would be usually less than 600 s (mean of 58 s). Patients with CH or PH may report a stabbing headache, but they will not have repetitive stabs or a saw-toothed pattern. However, this differentiation may not always be eligible from the patient and lack of response to indomethacin or 100% oxygen may support a diagnosis of SUNCT/SUNA in doubtful cases. Primary Stabbing headache (PSH) is also a differential of SUNCT/SUNA because of its ultra-short duration (<1 min). However, these stabs lack autonomic features, occur at irregular intervals and location of pain changes in subsequent attacks, which helps in differentiating PSH from SUNCT/SUNA. Another cause of ultra-short-lasting headache is epicrania fugax (EF) which is characterized by short (1–50 s) paroxysms of electric, stabbing, burning pain that radiates in a linear or zig-zag pattern from front to back of the head or vice versa. The characteristic linear or zig-zag radiation and lack of CAS differentiate EF from SUNCT/SUNA.
The most important differential diagnosis of SUNCT/SUNA is trigeminal neuralgia (TN). However, there is considerable clinical overlap between TN and SUNCT/SUNA––short duration of pain, neuralgiform character of pain, high daily frequency of attacks, cutaneous triggered attacks, and evidence of vascular compression of the trigeminal nerve. Cranial autonomic symptoms are generally considered uncommon and mild in TN although in a surgical series, at least 1 autonomic symptom was reported by 67% of patients with TN, regardless of the site of pain particularly in patients with a long disease duration. While SUNCT/SUNA patients can have interictal background pain, patients with TN can also have continuous or near-continuous mild pain between attacks. Finally, to add to diagnostic confusion neurovascular contact can be seen in both SUNCT/SUNA and TN., These similarities have led to a proposal that SUNCT/SUNA may constitute a continuum of the same disorder. [Table 4] compares the clinical features of SUNCT/SUNA and TN.
The exact pathophysiology of SUNCT/SUNA is not clear and the current model is based on experiments in CH, which fails to explain all the phenotypic features of SUNCT. Functional imaging studies in SUNCT and SUNA have revealed significant activation in the region of ipsilateral or bilateral hypothalamus and brainstem.,, The principal structures involved in the pathogenesis of SUNCT are the hypothalamus, trigeminovascular system and the cranial autonomic system [Figure 3]. The trigeminovascular system consists of pseudo-unipolar trigeminal primary afferents from intra-and extracranial structures that synapse on the trigeminocervical complex (TCC) comprising of the trigeminal nucleus caudalis and C1 and C2 dorsal horns. Second-order neurons pass on to the thalamus and finally to the pain neuromatrix (collection of brain areas that modulate pain). The trigeminal autonomic reflex consists of connections of TCC with the superior salivary nucleus, which via the sphenopalatine ganglion is responsible for the autonomic symptoms associated with SUNCT/SUNA. The posterior hypothalamus is known to have a modulatory role in nociceptive and autonomic pathways via the hypothalamic trigeminal connections. The hypothalamic activation can be a permissive or triggering event and subsequently cause activation or disinhibition of the trigeminal cervical complex (TCC) and stimulate the trigeminal autonomic reflex and activate the pain pathway resulting in the typical phenotype of pain with ipsilateral CAS. In SUNCT/SUNA there may be dual pathophysiology with a peripheral component as well. The neurovascular conflict in SUNCT/SUNA may cause focal demyelination of CNV resulting in spontaneous ectopic impulses which cause short-lasting spontaneous as well as cutaneously triggered attacks. The persistent stimulation could in turn be responsible for hypothalamic activation and central disinhibition of the trigeminal autonomic reflex resulting in prominent autonomic symptoms., It is believed that TN does not have this central disinhibition which accounts for the lack of autonomic symptoms and presence of refractory period in TN.
Because of the rarity of these disorders, no randomized controlled trials are available and most of the treatment is based on observational studies, case series, and case reports. Short duration of attacks in SUNCT/SUNA makes acute treatment superfluous. Treatment is mainly preventive and transitional or short-term preventive options may be used in patients with a very high attack burden to provide some interim relief while the long-term preventive medications are up titrated [Table 5].
Intravenous lidocaine has been shown to be effective in SUNCT and SUNA when given as an intravenous or subcutaneous infusion.,, Baraldi et al. in a systematic review of literature found that lidocaine was effective in 94% of patients and 80% of them were rendered completely pain free. This has led to a suggestion by some experts that response to lidocaine infusion may be used as a diagnostic test for SUNCT/SUNA. Intravenous lidocaine has an effect on the peripheral nerve endings and may reduce central sensitization as well. A response is considered positive if the attacks are mostly or entirely suppressed for the duration of the infusion or longer. Williams et al. used subcutaneous lidocaine infusion and found it to be as effective as an intravenous infusion (79% vs 67%). Use of a short course of steroids especially methylprednisolone has also been used in SUNCT with variable success. Baraldi et al. found that the odds of having a complete response to Methylprednisolone in SUNCT and SUNA was 1.61 (95% CI: 0.34–7.66). The effect of steroids seems to be nonspecific but steroids are safer than Lidocaine. There are conflicting results for the use of GON block in SUNCT and SUNA. The premise for using GON block is that an anesthetic blockade of the occipital nerve may cause neuromodulation of TCC and relieve pain. Cohen found a good response with GON block in five of eight patients with SUNCT (68%) and one patient with SUNA. In a systematic review, Favoni et al. observed that of 25 patients with SUNCT, seven patients (28%) had a good response with patients being rendered pain-free from one week to 6 months. At the same time, the GON block has been ineffective in 11 patients with SUNCT. Based on an extensive review Baraldi et al. estimated the odds ratio of a complete response to GON block as 0.35 (95% CI: 0.07–1.76). Despite doubtful efficacy, GON block may be useful in aborting a severe and disabling attack and in patients who cannot take oral medications because of adverse effects. The procedure is minimally invasive and relatively safe with minor side effects such as paresthesias, dizziness, or localized hair loss.
Several drugs have been tried as preventive therapy for SUNCT/SUNA with variable results. Amongst this lamotrigine (LTG) is now considered as a 1st line agent in the management of SUNCT/SUNA. D'Andrea et al. reported excellent response to lamotrigine in 5 patients with SUNCT and found a dose-response relationship with maximum effect at a higher dose of 200 mg/day. Cohen observed that LTG had a favorable response in 68% of patients with SUNCT but was less effective in SUNA (25%). Williams et al. reported that response to LTG depended on the subtype of SUNCT, being more efficacious in episodic variety (100% responded) as compared to chronic variety. Favoni et al. reviewed 81 cases in the literature that had been treated with LTG and found that 64% of them had a good response. Lamotrigine seems to be more suitable in reducing attack frequency rather than abolishing them completely. Dosing and adverse effects of LTG are summarized in [Table 5]. Carbamazepine is also a commonly used drug in SUNCT/SUNA probably because of its efficacy in TN. However, only 33% of patients with SUNCT have responded to CBZ. Baraldi et al. estimated that the odds of SUNCT patients responding to CBZ were 0.16 (95% CI: 0.07–0.36). Oxcarbazepine has proven more effective in almost 59% (20/34) of patients with SUNCT/SUNA. In various open-label studies, topiramate has been found to be efficacious in about 50% of individuals with SUNCT/SUN.,, Only one small, randomized trial of topiramate in 5 patients found that a satisfactory response in 2 patients., Gabapentin has also been used and the responder rate has been 27–48%, with SUNA patients benefiting more than SUNCT patients, probably because SUNA has more of a peripheral neuropathic flavor and less autonomic symptoms as compared to SUNCT.,,, It is important to note that all these are small open-label studies and combination therapy may be required in many patients. Treatment is usually life-long because most patients with SUNCT/SUNA have chronic form. Tachyphylaxis with oral medications is uncommon. Botulinum toxin has been used in 2 cases with injections around the orbit, gum, temporal area, and cheek with good results., A recent case report reported beneficial effect of Galcanezumab, an anti-calcitonin gene related monoclonal antibody in a case of refractory SUNCT.
Surgical treatment is reserved for patients who are refractory to medical management. Findings of neurovascular contact with the trigeminal nerve kindled an interest in microvascular decompression (MVD) as a potential therapeutic option. In one case series and review of literature, MVD was effective in 75% of cases (16 patients in total).,, While more long-term studies are required, these data suggest that trigeminal MVD is a viable treatment option in patients with aberrant loops impinging on the ipsilateral trigeminal nerve. There is also a recent report where MVD was beneficial after neuromodulation approaches failed in 2 cases of refractory SUNCT. Occipital nerve stimulation (ONS) increases traffic along the trigeminovascular pathway and acts by bringing about neuroplastic changes in the pain network. In two small case series of 6 and 9 patients each almost all patients responded to ONS., More recently in a large case series of 31 patients, 50% responder rate to ONS was 77% with a 69% improvement in attack frequency at a mean follow-up of 44.9 months. The procedure is generally safe with minimal adverse effects. Deep brain stimulation (DBS) of the posterior hypothalamus or ventral midbrain tegmentum has produced good results in 3 patients with intractable SUNCT rendering them almost pain-free for 12–18 months.,, Another study of 11 patients, after an average follow up of 29 months reported the 50% responder rate of 82% and an average decrease in daily attacks of 78%. Although efficacious, serious potential adverse effects include intracranial hemorrhage, transient diplopia, and vertigo. DBS should currently be reserved for those who have been refractory to medical treatment and ONS. A very recent study involving 9 patients with refractory SUNCT/SUNA showed the promising role of minimally invasive sphenopalatine pulsed radio frequency with a responder rate of 78% at a median follow up of 6 months. [Figure 4] suggests an algorithm for the management of SUNCT/SUNA patients.
Current evidence indicates that SUNCT/SUNA are part of one spectrum, with SUNCT having more severe autonomic symptoms. Therefore, both of these disorders have been bought under the same umbrella of SUNHA in ICHD-3. Differentiation from TN is important, and prominence of autonomic symptoms and absence of refractory period is indicative of SUNCT/SUNA. There may be some overlap between TN and SUNCT/SUNA as evidenced by shared clinical features and the presence of neurovascular contact in both TN and SUNCT/SUNA. Treatment of SUNCT/SUNA is challenging and lamotrigine is generally recommended as the first-line drug. GON block and occipital nerve stimulation are promising therapeutic approaches and further studies are required to elucidate their role in the management of SUNCT/SUNA.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]