Abstract
We report on clinical experience with topiramate in the prophylactic treatment of three patients with chronic and two patients with episodic, otherwise therapy-resistant, cluster headache. Patients were treated with daily doses of 75-200 mg topiramate. Topiramate was effective in three patients but proved ineffective and also caused intolerable side-effects in two patients. Topiramate may have prophylactic properties for treating cluster headache at lower doses than needed in epilepsy therapy, but its clinical value is limited due to central nervous system side-effects.
Introduction
Cluster headache is an excruciatingly severe unilateral headache characterized by ipsilateral signs of autonomic dysfunction such as ptosis, miosis, impaired sweating, rhinorrhea and lacrimation (1). Typical attacks last from 15 min to 180 min and can occur several times a day (1). Most patients suffer from an episodic course that consists of daily attacks and bouts lasting weeks or months, whereas 10–20% of patients have a chronic course without remission of attacks for more than a year (2).
The severity and frequency of cluster headache attacks demand in addition to abortive treatment above all effective prophylactic therapy. Especially the chronic form of cluster headache is sometimes refractory to standard prophylactic treatment. Therefore new treatment options are sought. Recently 10 cluster headache patients were reported to improve when they took topiramate (3). We report on our experience with five patients who received topiramate.
Patient 1
A 30-year-old man had had unremitting chronic cluster headaches since age 19. In the beginning he had one typical attack a week. During the further course the frequency of attacks increased up to five in 24 h. Attacks lasted 10 min to 2 h (mean: 1 h). Headaches were left temporal and retroorbital, excruciatingly painful, ‘hammering and stabbing’, and associated with ipsilateral lacrimation, nasal congestion, miosis, sweating, and swelling of the periorbital region.
The results of general physical and neurological examinations, as well as MRI and cerebrospinal fluid examinations, were normal. Attacks were successfully treated with 6 mg sumatriptan s.c., inhalation of ergots, and oral intake of 2.5 mg zolmitriptan.
The following prophylactic drugs failed to significantly reduce the attack frequency: indomethacin 200 mg per day for 10 days, verapamil up to 1040 mg per day, lithium (serum concentrations from 0.8 to 0.9 mmol/L), valproate 2100 mg per day, carbamazepine, budipine 80 mg per day, pizotifen 2 mg per day and methysergide 4 mg per day. During prophylactic treatment with prednisone 30 mg per day and ergotamine 2 mg per day, the frequency of attacks was significantly reduced to two per week, but side-effects (development of Cushing's syndrome and ergotism) prevented the further administration of these substances. Percutaneous neurostimulation of the trigeminal ganglion was unsuccessful. Repeated sphenopalatine ganglion blockades with bupivacaine 0.5% and buprenorphine 0.03 mg caused a moderate decrease of the attack frequency and partial pain relief.
In May 2000 we added 50 mg topiramate to verapamil (720 mg per day). After 2 days the patient had no further attacks and is still attack free (November 2001). We increased the topiramate dosage up to 150 mg per day and reduced the verapamil dose by steps. The patient now reports no side-effects during topiramate treatment.
Patient 2
A 42-year-old man had suffered from episodic cluster headache since 1984 and was treated for the first time in our department in autumn 1999. Typical episodes lasted for 6 weeks and had an average period of remission of 6–12 months. The side involved in the attacks changed from one episode to the other. During an episode the patient had one to four often nocturnal attacks in 24 h. During the first two episodes attacks lasted only 5–30 min, during further episodes the duration was between 1 and 3 h. The pain was highly intensive, strictly unilateral, located in the temporal and periorbital regions and accompanied by concomitant ipsilateral lacrimation and nasal congestion. Abortive therapy with inhalation of oxygen or sumatriptan (20 mg nasal) was effective. Prophylactic treatment was prescribed for the first time in 1999. Verapamil (up to 480 mg per day) and valproate (1600 mg per day) were ineffective and caused sleepiness, higher doses of both drugs were not tolerated. Monotherapy with prednisolone at doses of at least 40 mg per day was effective, but never induced remission. In October 2000 the patient consulted us again. He had had typical left-sided cluster headaches for 2 weeks and had taken 800 mg valproate per day without any reduction of attack frequency or pain intensity. We prescribed prednisolone (80 mg per day) and tapered the dose by 20 mg each fourth day. In parallel we administered topiramate (25 mg per day) and increased the dose by 25 mg each fourth day up to 100 mg. During monotherapy with topiramate (100 mg per day) the patient was headache free for the next weeks. He complained only of mild and tolerable sleepiness during the day while on topiramate.
Patient 3
In 1996 a 43-year-old woman developed typical right-sided cluster headache with extremely painful peri- and retroorbital, ‘pulsating and stabbing’ pain, associated with ipsilateral lacrimation, rhinorrhea, miosis, sweating, swelling of the periorbital region and restlessness. Typical attacks lasted 30–120 min and had a frequency of one to three per day. Abortive therapy with oxygen inhalation and sumatriptan s.c. were effective. Under continuos prophylactic treatment the course of cluster headache was episodic.
The following prophylactic drugs administered in monotherapy did not significantly reduce the attack frequency or else caused intolerable side-effects: verapamil (up to 360 mg per day), lithium (serum concentrations from 0.8 to 0.9 mmol/L), valproate (2400 mg per day) and methysergide (4 mg per day). Treatment with methylprednisolone in doses of at least 20 mg per day was effective but never induced remission.
During prophylactic therapy with verapamil (240 mg per day) and budipine (30 mg per day) the patient had only single, mild attacks from October 1999 to April 2000. Budipine treatment was stopped until August 2000, when another bout began during treatment with 240 mg verapamil per day. When taking a combination of budipine (60 mg per day) and (verapamil 240 mg per day) the patient had one to three attacks per day. We stopped budipine and added 50 mg prednisolone. Cluster attacks stopped but reoccurred each time the prednisolone dose was reduced below 20 mg. We added 25 mg topiramate and increased the dose by 25 mg each week up to a maximum daily dose of 125 mg. The patient was treated with topiramate for altogether 31 days. Severe attacks reoccurred with each attempt to reduce prednisolone below a daily dose of 20 mg. While on topiramate the attack frequency or intensity did not change but the patient suffered from severe and intolerable side-effects: problems with memory, attention and concentration, hesitant speech, slowed thinking, and word-finding difficulties. Because of these side-effects we stopped topiramate. All side-effects were reversible within a few days.
Patient 4
A 58-year-old man with primary chronic right-sided cluster headache since 1993 suffered from almost daily typical attacks lasting 30–45 min. He responded well to treatment with O2 inhalation and 20 mg sumatripan nasal spray. Prophylactic drugs like lithium (400 mg lithium-carbonate per day taken for 6 weeks), then verapamil in monotherapy (480 mg per day taken for 8 weeks) and in combination with budipine (up to 60 mg per day for 4 weeks) and finally valproinic acid (up to 1800 mg per day taken for 4 months) did not reduce either attack frequency or the intensity of pain. Higher doses of lithium, verapamil and valproinic acid were not tolerated due to side-effects. He had repeatedly an excellent response to steroids. Indomethacin 200 mg per day over 2 weeks was ineffective. In July 2000 we started topiramate. The patient only rarely suffered from typical cluster headache attacks while taking 75 mg topiramate. Side-effects such as sleepiness and impaired sense of smelling and taste were reversible within 6 weeks.
Patient 5
A 53-year-old man with a history of subarachnoid bleeding and clipping of a left A. carotis interna aneurysm in 1979 and an obstructive sleep-apnoea syndrome developed typical right-sided primary chronic cluster headache in May 2000. Attacks typically last 2–3 h. He responded well to inhalation of oxygen, but prophylactic treatment with steroids (75 mg prednisolone), verapamil (480 mg per day), valproinic acid (up to 2500 mg per day) and lithium were ineffective. A cranial computerized tomography (CT) scan and CT angiography and extra- and transcranial Doppler-sonography were normal. We started topiramate treatment with 25 mg two times in a day and weekly increased the dose by 50 mg up to 200 mg per day. Under this dose the patient developed serious side-effects with psychomotor restlessness, fearfulness, visual hallucinations and double vision. Once topiramate was stopped the side-effects were completely reversible within 3 days.
Discussion
Cluster headache is an uncommon primary headache disorder that is associated with considerable suffering if pharmacological treatment is ineffective. No standard surgical method has been established for treating cluster headaches (4).
New effective substances are needed for the prophylactic treatment of cluster headache. Experience with topiramate in pain therapy is limited. There has been one case report on the efficacy of topiramate in refractory intercostal neuralgia (5) and one publication on its efficacy in refractory trigeminal neuralgia in patients with multiple sclerosis (6). Wheeler and Carrazana first reported on two patients with chronic, seven patients with episodic cluster headache and one patient with cluster tic-syndrome that were treated with topiramate (3). A dosage of 50–125 mg topiramate per day shortened the cluster period duration in nine patients and the total treated cluster period duration in four patients with episodic cluster headache. Topiramate induced remission in the two patients with chronic cluster headache within 1 and 3 weeks, respectively. Only three patients reported mild side-effects while on topiramate in this study.
We report on five patients who suffered from typical cluster headache according to the IHS classification criteria. Chronic paroxysmal hemicrania (CPH) can be mixed up with CH, above all in patients with short attacks. In our patients CPH was excluded as they either responded to oxygen inhalation and sumatriptan, respectively, or were unresponsive to indomethacin treatment. Topiramate was effective in three patients but proved ineffective and also caused intolerable side-effects in two patients. In a summary of our experience three main points are worthy of discussion:
Three of five patients clearly benefited from the prophylactic treatment with topiramate. Compared with the doses needed in epilepsy treatment, effective topiramate doses were lower (75–150 mg).
Prophylactic effects were observed after a minimum of 2 days of treatment.
Two of the five patients reported severe side-effects together with no or only limited prophylactic effects. The side-effects occurred during daily topiramate doses of 125 and 200 mg, respectively, and were similar to those known from treatment of epilepsy. The side-effects of topiramate-treated epilepsy patients include emotional lability (12%), fatigue (15%), difficulty in concentrating or paying attention (12%), forgetfulness and impaired memory (7%), nervousness (21%) and behavioural problems (21%) (7, 8). Topiramate has been proven by neuropsychological testing to have an effect on the cognitive function of both patients and healthy adults (9, 10).
As the pathophysiology of cluster headache is still unclear the effects of prophylactic treatment cannot yet be explained.
Topiramate has various mechanisms of action (11). Topiramate blocks voltage-sensitive sodium channels and the kainate/d-amino-3-hydroxy-methyl-4-isoxozole propionic acid (AMPA) species of glutamate receptor, acts on the GABA neurotransmitter system (12), and increases human cerebral GABA concentrations (13). This action on the GABA system may explain its main mechanism in pain therapy.
Although topiramate appears to be a reasonable alternative treatment in patients with otherwise refractory cluster headache, its use could be limited by intolerable CNS-related side-effects. In spite of the already published encouraging results with topiramate treatment in drug-resistant cluster headache, its clinical value for treating cluster headache has to be studied in double-blind prospective trials that are either placebo-controlled or compare topiramate with standard therapy. According to our experience, treatment of cluster headache with topiramate should be restricted to neurologists who are familiar with this new anti-epileptic drug and its side-effects.