Abstract
Pathological laughter is defined as laughter arising with non-specific stimuli in absence of a corresponding change in affect, of a voluntary control of the extent or duration of the episode and of a corresponding change in mood lasting beyond the actual laughing (1). This condition has been described to date only as a consequence of central nervous system (CNS) lesions in several neurological disorders such as motor neuron disease, vascular pseudobulbar paralysis, extrapyramidal disorders, demyelinating diseases, gelastic epilepsy and fou rire prodromique (1). Lesion localization includes ventral and tegmental brainstem, hypothalamus, frontal and temporal cortex, striatocapsular regions, basal ganglia, corticobulbar motor tract and many other regions (1). Laughter and merriment have also been described after deep brain stimulation of subthalamic nucleus in parkinsonian patients (2).
We report a unique case of transient acute pathological laughter as a drug-induced phenomenon after sumatriptan use in a patient with episodic cluster headache.
Case report
The patient was a 38-year-old, right-handed man, an employee. His family and past medical history were unremarkable. No neuropsychiatric disorder had been reported. For 10 years he had suffered from recurrent periods of episodic headache attacks recurring about every 2 years, lasting 6–8 weeks, and characterized by multiple bouts (from one to four per day) of excruciating left orbital pain lasting 30 min, associated with homolateral tearing, conjunctival injection, eyelid oedema and nasal congestion. These episodes had been classified by his general practitioner as ‘trigeminal neuralgia’ and left untreated.
On examination at our Unit, the patient reported three to four attacks per day in the previous 5 weeks. Over the past 5 days the attacks had diminished in frequency to one a day at around 14.00 h. The patient was triptan naive. General and neurological examination, brain magnetic resonance imaging and blood chemistry findings were normal. A diagnosis of episodic cluster headache was made. As acute therapy subcutaneous sumatriptan (6 mg) was recommended. As an alternative, we also prescribed O2 inhalation (100%, 8 l/min). No prophylaxis was given because the reduced frequency of the attacks suggested that the active period was coming to an end.
On follow-up examination 15 days later, the patient reported being headache free for 4 days. On the nine occasions when he had taken sumatriptan the drug had completely relieved the symptoms within about 5–10 min. On two occasions when sumatriptan had been unavailable, O2 had also provided relief, although more slowly (15 min) than sumatriptan. Surprisingly, the patient reported that about 5 min after every sumatriptan injection he experienced episodes of involuntary mirthless laughter, not elicited by other external or internal stimuli. These episodes lasted 4–5 min and were witnessed by his wife. No such episodes appeared after he inhaled O2, nor did the patient report other symptoms associated with sumatriptan apart from a mild and transient tightening sensation in the neck.
Discussion
To our knowledge no published reports have described pathological mirthless laughter as a drug-induced phenomenon. Nor is pathological laughter listed as a possible adverse effect of sumatriptan. Because our patient experienced pathological laughter only after sumatriptan injection and never when he received O2 or was left untreated, we attribute these events to sumatriptan.
Subcutaneous sumatriptan is the reference standard for the acute treatment of cluster headache (3). Sumatriptan, a selective 5-HT1B/1D receptor agonist, penetrates poorly into the CNS and is believed to act peripherally by inducing vasoconstriction in large cerebral blood vessels and by blocking neurogenic inflammation within the trigeminovascular system. Nevertheless, sumatriptan may, at least in some circumstances, act centrally, as suggested by reports of acute oral, neck and trunk dystonia, akathisia (4–8), and resolution of essential and symptomatic palatal myoclonus after subcutaneous and oral (but not intranasal) administration (9–11). Interestingly, 3H-sumatriptan-binding sites are widely diffused throughout the human brain, especially in the basal ganglia, where they seem to be involved in the presynaptic regulation of excitatory (glutamate), inhibitory (GABA) and peptidergic neurotransmitters (12–15). In fact, besides the visual cortex (layers II–III), the highest density of specific 3H-sumatriptan-binding sites has been found in the substantia nigra and medial globus pallidus, where their density is almost threefold that in areas crucially involved in migraine pathogenesis, such as the trigeminal nucleus caudalis, nucleus tractus solitarius, area postrema and periacqueductal grey (12–14).
How sumatriptan caused spontaneous laughter in our patient remains unclear. Spontaneous emotional laughter involves the amygdala, thalamic/hypothalamic and subthalamic areas and the dorsal tegmental brainstem and is coordinated by a centre located in the dorsal area of the upper pontine mesencephalon, an area inhibited by motor frontal afferents (1). Pathological laughter arises from chronic disinhibition of the laughter-generating circuitry by lesions involving the internal capsule and basal ganglia, substantia nigra, caudal hypothalamus and (double-sided) pyramidal tract (1). In our patient sumatriptan could therefore have caused pathological laughter by stimulating 5-HT1B/1D receptors within the basal ganglia. 5-HT1B receptors are highly expressed presynaptically on striatonigral projecting neurons containing dynorphin, on striatopallidal projecting neurons containing dynorphin, substance P and enkephalin, and on cortical glutamatergic outflow to subcortical areas (12–14). Acute sumatriptan stimulation of 5-HT1B/1D receptors within the basal ganglia might therefore have subcortically suppressed the cortical frontal inhibitory afferents, thereby exerting a releasing effect on brainstem areas generating laughter. An interesting question in our patient is whether genetic factors might have increased the susceptibility of 5-HT1B/1D receptors within the CNS.
Our report of sumatriptan-induced pathological laughter in a patient with cluster headache therefore confirms that sumatriptan can act on the extrapyramidal circuitry and underlines that as well as arising from CNS lesions or stimulation, pathological laughter can appear as an acute, transient drug-induced phenomenon.