Abstract
Serotonin, 5-HT1B/1D receptor, agonists, the triptans are an established and effective abortive treatment of primary neurovascular headaches such as migraine or cluster headache and it has been assumed that these medicines work on the trigeminovascular system (1). An effect in other clinical conditions suggestive of an activated trigeminovascular system, such as in subarachnoidal haemorrhage, has been observed, but not in meningitis (2, 3).
Here, we report the case of a man with clinical and laboratory findings consistent with aseptic lymphocytic meningitis that consistently responded to the application of the 5-HT1B/1D receptor agonist naratriptan.
Case report
A 25-year-old man complained of severe throbbing and pulsating holocephalic headaches for 4 days prior to admission that evolved over 1–2 days. The pain was pronounced over the forehead and was rated 7/10 points on the analogue scale. Coughing, sneezing, straining and bending forward increased the pain. There was no history of headaches and migraine, in particular, including headaches triggered by alcohol, and no family history of migraine. He did not experience other migraineous features such as photophobia, phonophobia or nausea. Symptoms compatible with a migraine aura were not present, nor focal neurological symptoms (paresis, tingling sensations, visual symptoms).
Prior to presentation in our emergency department he had taken non-steroidal anti-inflammatory drugs for his headache with no significant relief, but was prescribed naratriptan by a general practitioner. He took naratriptan 2.5 mg three times and experienced a significant reduction of his headaches from 7/10 to 2/10 points of the analogue scale. He reported the pain relief as evolving 45 min after intake and lasting for 5–7 h without side-effects.
On neurological examination there was no neck stiffness, but tendon reflexes were pronounced on the right side. There was no clinical evidence of extrapyramidal or brainstem dysfunction. No sensory abnormalities, motor deficits or cognitive deficits were observed.
Laboratory findings
Routine laboratory tests showed normal haematological and biochemical findings including tests for HIV, borreliosis and neurotropic viruses [Adeno, Echo, Cox, herpes simplex virus (HSV), varicella zoster virus, cytomegalovirus, Epstein–Barr virus, human herpesvirus-6]. Lumbar puncture showed an opening pressure of 24 cmH2O with a pleocytosis of 491 cells/µl (normal <5), total protein was 1.100 mg/l (<500), glucose 58 mg/dL (40–65) and lactate 3 mmol/l (<2). A local synthesis of immunoglobulins in terms of oligoclonal bands was not detected. Screening tests for borreliosis were negative as well as for HSV DNA. The cytopathological study showed a lymphocytic cell picture compatible with lymphocytic meningitis. A control lumbar puncture 6 days later revealed an opening pressure of 16 cmH2O and a reduced cell count of 281 cells/µl and total protein of 870 mg/l (<500) with normal glucose and lactate.
Other laboratory findings (cranial CT, magnetic resonance imaging, EEG, somatosensory and motor evoked potentials) were normal. Due to the high cerebrospinal fluid (CSF) cell count he was prophylactically treated with ceftriaxone over 7 days. The headaches completely resolved within 3 weeks.
Discussion
We report the first case of headaches in aseptic lymphocytic meningitis that consistently responded to application of a 5-HT1B/1D receptor agonist. The patient fulfilled the International Headache Society criteria for headache attributed to lymphocytic meningitis.
The triptans are an established class of antimigraine drug that acts selectively via serotonin, 5-HT 1B/1D receptors. Experimental findings suggest different sites of action for the antimigraine effect of the triptans. They may act as vasoconstrictors in the cranial vasculature, a postjunctional effect. They may block trigeminal-induced dural plasma-protein extravasation, a prejunctional effect or inhibit release of calcitonin gene-related peptide (CGRP), and they may inhibit transmission in the trigeminal nucleus caudalis, thus blocking afferent traffic to the second order neurons (1). Further sites of action on trigeminal activation include activation of pain-modulating pathways such as the periaqueductal grey matter and the ventroposteromedial nucleus of the thalamus (4–6).
An analgesic effect of subcutaneously administered sumatriptan in subarachnoid haemorrhage has recently been reported in a small series of patients (2, 3). In contrast, a lack of effect of subcutaneously administered triptans in patients with fulminant bacterial meningitis has also been reported (7), suggesting that the state of activation and sensitization of the trigeminovascular system is a crucial factor in determining the response to 5-HT 1B/1D receptor agonists.
The clinical phenomenology in meningitis provides evidence for activation of the trigeminovascular system in meningitis. Recently, in an experimental model of acute bacterial meningitis in the mouse, the inflammatory response of the trigeminovascular system was attenuated by application of 5-HT 1B/1D receptor agonists (8). It was also observed that the neurogenic inflammation in the dura mater leading to release of vasoactive peptides such as CGRP and substance P from sensory meningeal nerve fibres was attenuated by activation of 5-HT 1B/1D receptors. Correspondingly, CGRP in the CSF was increased in patients with a bacterial meningitis. These observations provide a rationale for the effect of the triptans in these clinical conditions where the trigeminovascular system is activated, such as in aseptic meningitis and subarachoidal haemorrhage.