Abstract
Introduction
We report a case of a young man with intractable seizures and migraine who underwent vagal nerve stimulation (VNS) as a treatment for his seizure disorder without success but with a rather striking reduction in his migraine attacks. The case is presented in detail and discussed in light of the current understanding of the putative mechanisms by which VNS reduces seizures and possibly benefits migraine.
Case report
This 42-year-old left-handed male has a history of seizures dating to childhood. He developed meningitis (aetiology unknown) at age 5 months and subsequently experienced occasional secondarily generalized tonic-clonic seizures in the months following the meningitis.
Partial complex seizures began at age 13 years and were characterized by an epigastric rising phenomenon followed by diminished responsiveness and chewing movements with a return to awareness after 2 min. By 1991 (age 31 years) he experienced 20–30 seizures monthly. By 1992 he had failed medical therapy with the following anti-epileptic drugs (AEDs): primidone, carbamazepine, phenytoin, phenobarbital, valproic acid, and clobazam.
He was evaluated for epilepsy surgery in March 1992. Scalp-derived electroencephalograms (EEGs) disclosed exclusively left temporal interictal spikes and left temporal originating seizures. Magnetic resonance imaging (MRI) demonstrated bitemporal hippocampal atrophy, maximum left with increased signal in the left hippocampus on T2 weighted images. Neuropsychology testing revealed a ‘borderline’ IQ with poor memory. Bilateral carotid amytal studies produced aphasia with the left injection and he failed the memory component of this test with both injections.
In April 1992 the patient underwent a left temporal lateral neocortical resection. The mesial temporal structures were left intact because of the preoperative neuropsychology results suggesting the risk of worsening of his memory with a hippocampal resection.
The patient was seizure-free for 6 months but his typical partial complex seizures returned with a frequency of 15–20 per month. From 1992 to August 2000 the patient was treated with varying combinations of phenytoin, carbamazepine, valproic acid, lamotrigine, vigabatrin, gabapentin, oxcarbazepine, and topiramate with no improvement in seizure frequency. In June 1998 he was restudied with scalp video-EEG telemetry. All recorded seizures had a left temporal onset; a repeat left carotid amytal study with a reduced dose of amytal again reproduced a severe memory disturbance and the expected aphasia. Further resective epilepsy surgery was declined.
A vagal nerve stimulator was implanted (Cyberonics Inc. Houston, TX, USA) on 31 August 2000 with the stimulating electrode attached to the left vagus nerve. As of October 2001 the patient continues on oxcarbazepine 1500 mg per day. Partial complex seizures continue with a frequency of 10 per month.
This patient's headache history dates to his late teens. His typical attacks begin with nausea followed by a gradually intensifying unilateral discomfort that reaches peak intensity in 30 min. The attacks occur with equal frequency on each side of the head. Photophobia, sonophobia, and vomiting are invariable concomitants. The majority of headaches onset during waking hours, but they occasionally awaken the patient from sleep. The usual duration of discomfort is 3–5 h. No other neurological features precede or accompany the headache. No specific migraine triggers have been identified, although occasional headaches coincide with days during which he also experiences multiple seizures. Migraine attacks increased in severity by age 31 years, necessitating visits to his local emergency department for intramuscular meperedine and dimenhydrinate that yield prompt relief. Treatment with simple analgesics and intranasal sumatriptan had no effect on his headaches. No medications specifically for migraine prophylaxis were ever prescribed.
Two months after VNS was initiated the patient commented that, although his seizure frequency had remained unchanged, he had been migraine-free. He continued to comment on the apparent effect of the stimulator in reducing his migraine attacks during subsequent out-patient visits for adjustment of his VNS parameters. The patient's observations prompted a detailed review of his headache history prior to the vagal nerve stimulator implant.
The emergency department records from the patient's local hospital were obtained and his personal diaries (in which he recorded his seizures and migraines) were reviewed. He averaged 2.7 migraines per month (range 0–9 with only 2 months headache-free) in the 43 months (January 1997 to August 2000) prior to initiating VNS. He attended his local emergency department for parenteral medication for more than 90% of his migraines. During the 13-month period (September 2000 to October 2001) post-VNS he has had only three migraines (December 2000, April 2001 and June 2001) with 10 months during which he was completely headache-free.
The patient's epilepsy clinic records were reviewed to assess his AED treatment from January 1997 to October 2001 because of the potential of AEDs to act as migraine-modifying agents. In January 1997 he was taking only oxcarbazepine 1500 mg/day. In April 1997 topirimate was started at 25 mg/day with a plan to increase the dose by 25 mg every 3 weeks; he could not tolerate more than 50 mg/day because of cognitive complaints. The addition of topiramate had no effect on his seizure frequency and migraines continued at one to three per month; topirimate was discontinued in April 1998. He has subsequently been treated with oxcarbazepine monotherapy.
This patient's VNS stimulation parameters were reviewed to assess their potential impact on his migraine and seizures. Initial parameters on 31 August 2000 were a current output of 0.25 mA, frequency 30 Hz, pulse width 500 µs, an ‘on’ time of 30 s every 5 min and activation by an externally applied magnet of 0.5 mA for 60 s. The apparent beneficial effect of VNS on his migraine attacks was initially noted 8 weeks after implantation of the stimulator (with the above stimulation parameters) and the anti-migraine effect has been maintained while the stimulation parameters have been adjusted because of continued seizures. The VNS stimulation parameters as of August 2001 are current output 1.75 mA, frequency 20 Hz, pulse width 250 µs, an ‘on’ time of 7 s and ‘off’ time of 12 s; his self-initiated magnet activation current output is 2.0 mA for 60 s. He has never used magnet activation in an attempt to abort a migraine attack.
Discussion
VNS for treating human epilepsy has been reported for over 10 years (1). Clinical trials suggest that approximately 30% of patients with VNS have at least a 50% reduction in seizures (2). The mechanism of action of VNS to reduce seizures is unknown but probably relates to the central projections of the vagus nerve (VN). The anatomic projections of the VN have been recently reviewed (2): the cell bodies for the sensory neurones in the VN reside in the nodose ganglion and relay sensory information to the solitary tract nucleus (NTS). The output from the NTS has three principal destinations: (i) autonomic preganglionic and related somatic motor neurones in the medulla and spinal cord for mediation of the baroreceptor reflex and the Herring–Breuer pulmonary reflex; (ii) reticular formation of the medulla for mediation of various other autonomic and respiratory reflexes; and (iii) ascending projections to the forebrain.
The majority of the output from the NTS goes to the parabrachial nucleus (PBN) located in the dorsal-lateral pons adjacent to the locus ceruleus. There are two major output pathways from the parabrachial nucleus. The first relays information to the hypothalamus, the amygdala, and the infralimbic cortex and allows vagal input to interact with autonomic, endocrine, and emotional control. The second pathway from the PBN goes to the visceral sensory relay nucleus in the thalamus and the thalamic intralaminar and midline nuclei. Some investigators have suggested, on the basis of animal experimental models, that the anti-epileptic effect of VNS is mediated by the release of noradrenaline from the locus cereleus (3).
A literature search for previous publications relating VNS to migraine disclosed a single recent case report (in abstract form) of a patient with beneficial effect on migraine by VNS (4). Kirchner et al. (5), in a study of the analgesic effects of VNS, described a patient who experienced an 80% reduction of chronic tension-type headaches after receiving a vagal nerve stimulator for epilepsy.
Our patient's diaries did not disclose an obvious relationship of migraine attacks with seizures other than occasional headaches during days with multiple seizures. We do not believe that the migraine reduction is related to improved seizure control because the patient's diaries and his emergency department records provide unique prospectively collected data that suggest VNS dramatically reduced his migraine attacks over a time period when he experienced only a very modest improvement in seizure control. Our patient had minimal alteration of his AEDs during the time period reviewed and therefore there is no evidence for an anti-migraine effect from changes in AEDs. We are unaware of any other factor(s) other than VNS that could account for the improvement in migraine.
Migraine is a neurobiological disorder with several mechanisms proposed to explain its pathogenesis and clinical symptoms. Serotonergic pathways in the brainstem and higher cortical levels (6), along with adrenergic projections, probably account for some of the biological changes that occur, and these are acted upon by the peripheral trigeminal vascular system (7) via anatomic connections of the fifth cranial nerve to its major pain sensory nucleus, the nucleus caudalis in the medulla (8). Thus pain is transmitted rostrally to thalamic and cortical levels and this system may be controlled or gated by a putative ‘migraine generator’ in the dorsal lateral midbrain demonstrated by functional imaging (9). This area is closely juxtaposed to the intrinsic opioid receptor system in the periacqueductal grey matter.
Support for a migraine generator may be seen clinically in the past, in that deep brain stimulation of the periaqueductal grey matter to treat chronic pain triggered migrainous phenomena in a patient (10). Further, recent PET evidence of functionally significant generators for cluster headache (11) have been demonstrated and in recent cases the cluster pain has been relieved by deep brain stimulation of these areas (12). These observations would suggest that there are ways that anatomically significant functional pain centres can be influenced by electrophysiological applied stimuli to relieve pain in primary headache disorders.
In light of the above, is it possible to consider possible mechanisms of how VNS could abort or reduce the migraine attacks in our patient? It is possible that the VNS directly influenced migraine attacks by acting as a direct or indirect activator or enhancer of the mechanism(s) that inhibit or turn off the migraine attack. Presumably this would somehow work by turning off the putative generator or by changing the balance between neurotransmitter activation in the brainstem or higher. Is it possible the VNS in some fashion therefore turns down the migraine generator or turns on pain inhibition or acts by some other, yet to be elucidated, neural mechanism(s)? If so, there is a possibility that VNS has a future role in migraine therapy. A retrospective review of the effect on headache from other patients undergoing VNS for epilepsy who coincidentally had migraine would be of considerable interest. A ‘positive’ result might warrant a prospective trial of VNS in migraine.