Abstract
Objective
To report a case series of hiccup as a migraine aura.
Background
Hiccup is a syndrome of inappropriate muscle contraction. To our knowledge, hiccup as a migraine aura has not been reported.
Case series
We describe series of patients who presented with hiccups as their migraine aura symptom.
Conclusion
Hiccups can present as a primary aura symptom in patients with migraine.
Introduction
The most common migraine aura symptoms are visual and sensory. Migraine with brainstem aura (MBA) is a subset of migraine with aura, with bilateral cerebral hemisphere and/or two brainstem symptoms in addition to typical visual sensory and/or speech/language symptoms but without motor weakness (1). These aura features were well described in a population-based study from Denmark, which studied 105 families with migraine with non-hemiplegic aura, including 38 patients with MBA. The most common presenting symptoms were vertigo, dysarthia and tinnitus (2). To our knowledge, hiccups have never been clearly described as an aura symptom in migraine. There have been several reports of central nervous system disorders being associated with intractable hiccups including brain stem lesions such as vascular malformations, ischemia or plaques of multiple sclerosis or neuromyelitis optica (3–5). There has been one case report of intractable hiccups associated with migraine; however, the patient had prolonged hiccups, which did not clearly precede his migraine attack (6). We describe three patients who reported hiccups as their aura symptom.
Case 1
A 24-year-old woman had episodic migraine without aura starting at age 15. Her headaches worsened at age 17. She developed mild dysphagia and tongue deviation was found on neurologic exam. Magnetic resonance imaging (MRI) revealed a Chiari malformation. She underwent posterior fossa decompression surgery with resolution of her neurological deficits. However, she continued to have episodic migraines. One year following surgery, she developed hiccups, which consistently preceded her migraine attacks. Her hiccups lasted 30–60 minutes and were followed by her typical migraine headache 30 minutes later. The rate of hiccups remained constant during their duration. On most occasions, she also had imbalance and vertigo, which could last up to 30 minutes, occurring either before or after the hiccups. The headaches started on the left side, moving to the right side and radiated to the back of her head. The pain was stabbing, shooting, throbbing and pounding. There was nausea, photophobia, phonophobia, osmophobia and worsening of headache pain with activity. The pain was rated 6 out of 10 in severity. Her severe migraines lasted 2 hours and occurred about three times weekly. She was treated with topiramate and onabotulinum toxin A injections, which decreased her headache frequency and hiccups significantly.
Case 2
A 53-year-old woman presented to our clinic with chronic migraine. She described a ‘vertiginous sensation’ (room spinning) since age 40. She was previously evaluated by an otolaryngologist and a neurologist with no clear etiology identified. In her late 40 s, she developed severe headache and other symptoms with the vertiginous spells. She related having yawning and hiccups lasting 10 minutes just prior to the onset of headache. The headaches were bi-temporal and throbbing with phonophobia but no photophobia or osmophobia. The pain worsened with activity. She reported a sensation of ‘almost passing out’ during the headaches, as well as several episodes of tinnitus lasting 5–10 minutes with them. The tinnitus would resolve after a migraine episode, though she continued to have vertigo for 2–3 days. She reported 25 severe headaches per month, lasting 24 hours or until she slept them off. A brain MRI, magnetic resonance angiography, video nystagmography and audiogram were unremarkable. Vestibular rehabilitation was not helpful. The patient had taken propranolol for migraine prevention, which worsened her aura symptoms of vertigo and tinnitus. Verapamil was recommended but declined because of concern for hypotension. Her migraines significantly improved on nortriptyline 20 mg daily. The frequency decreased to one to two migraine episodes monthly. Her aura symptoms of tinnitus, vertigo and hiccups also reduced in frequency as her headaches got better. The symptoms of hiccups and yawning decreased to one to two times per month, still preceding her migraine episodes. The vertigo persisted, though was significantly decreased in severity.
Case 3
An 18-year-old woman contacted our research group about her hiccups preceding her migraine and was interviewed by telephone. She had been having multiple aura symptoms since age 13, with hiccups as her most common preceding symptom. Her hiccups would start suddenly, lasting 20–30 minutes, followed by a throbbing, bi-frontal pain. Associated symptoms included nausea, photophobia and phonophobia. During the headache, she would often experience bilateral hand tingling lasting a few minutes. Diplopia and vertigo occurred with about half of her severe migraines, lasting 20 minutes. She also experienced visual aura symptoms, with black spots in her vision lasting less than 30 minutes. Either the visual aura or hiccups would precede the headaches but never both. At other occasions, she reported focal weakness of her face and sometimes her left arm or leg. Her headache frequency was twice per week and episodes were debilitating.
Her sister, mother, grandmother and uncle were diagnosed with familial hemiplegic migraine (FHM).
She saw a headache specialist in another state and was diagnosed with FHM (given autosomal dominant pattern of inheritance) and MBA. She treated her migraines with butalbital, aspirin and sleep. Her preventive medications included amlodipine, acetazolamide and escitalopram. Her headache frequency improved to three attacks per month on this regimen. Brain MRI and vascular imaging were reportedly normal. Genetic testing for known FHM mutations was negative.
Discussion
Intractable hiccups have been associated with various central nervous system causes including demyelinating, vascular, infectious and even described as a seizure manifestation (3–5,7). The hiccups were intractable in all these cases, unlike in our patients where hiccups clearly preceded their typical migraine headache.
Migraine with brainstem aura (ICHD-3 beta criteria).
We propose a hypothesis in the pathogenesis of migraine, which may explain hiccups as one of the aura symptoms.
The pathophysiology of hiccups is not well understood, but includes afferent, efferent and central mediators (11). The afferent limb includes the sympathetic chain, phrenic and vagus nerves. The efferent limb (phrenic nerve) includes complex interactions between the brainstem and midbrain areas, including the respiratory center, phrenic nerve nuclei, medullary reticular formation and hypothalamus (11,12). Migraine pathophysiology is complex, but studies have been shown that neurons in brainstem structures such as the periaqueductal grey matter and rostral ventromedial medulla are activated during a migraine (13). The ‘central sensitization’ hypothesis is based on the altered processing of sensory inputs in the brainstem (13,14). The reflex center for hiccups is located at C3–C5 anterior horn and medulla (11,15) and there seems to be a considerable anatomical overlap, which may explain hiccups as an aura symptom.
The aura symptoms of migraines are attributed to cortical spreading depression (CSD). which involves bilateral cerebral hemisphere and/or the brainstem in MBA. CSD has been shown to be modulated by gamma-aminobutyric acid (GABA) receptors. Even though GABA-A and GABA-B receptors are not directly involved in the initiation and propagation of CSD, they seem to have a role in maintaining the state of neuronal excitation (16). Hiccups pathophysiology also involves neurotransmitters such as dopamine and GABA and their role is poorly defined (12). GABA agonists such as baclofen are frequently used in hiccups treatment (17).
There has been a report of intractable hiccups being linked to phasic autonomic efferent activity based on respiration and cardiac cycle monitoring. To explain the relation between hiccup and heartbeat, a brain stem circuit capable of generating a slowly oscillating signal has been proposed. It is hypothesized that a hiccup is generated when this signal reaches a certain threshold of intensity (18). Migraineurs with disabling headaches may be prone to autonomic dysfunction affecting the sympathetic and parasympathetic nervous system (19). This phasic autonomic dysfunction may explain hiccups as an aura in migraine patients.
One patient in our case series met criteria for MBA. The main difference between migraine with typical aura and MBA is that MBA requires two brainstem symptoms in addition to the cerebral visual, sensory or speech/language symptoms of typical aura. In a study of migraine with aura population, at least 74% of patients described two attacks that met criteria for basilar-type migraine (20). Given the high prevalence of basilar-type migraine attacks among patients also describing typical aura, the author concluded an inability to differentiate basilar-type migraine from migraine with typical aura using clinical criteria (20).
One limitation to our study is the small number of patients in our series. Patients may not spontaneously report hiccups as an aura symptom as hiccup is fairly common in the general population. We cannot rule out that hiccups were coincidental; however, given that our patients reported the consistent occurrence of hiccups prior to their migraine pain this seems unlikely. A decrease in frequency of hiccups with migraine preventive treatment seems to support that hiccups in our patients are likely an aura symptom associated with migraine.
Conclusion
Hiccups are an uncommon aura symptom in patients with migraine.
Clinical implications
Hiccups can present as an aura symptom in migraine with aura. Cortical spreading depression and anatomical overlap of hiccup reflex center may explain hiccup as an aura symptom.
Footnotes
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest
Dr Friedman reports receives research support from the National Eye Institute, Merck, Inc., and electroCore. She is on the speaker’s bureau for Allergan and has consulted for Avanir; she is on the editorial board for Neurology Reviews.