STOWE, VT—Deep brain stimulation, in the form of continuous stimulation of the posterior inferior hypothalamus, is an effective, safe, and well-tolerated treatment for intractable chronic cluster headache, according to Massimo Leone, MD. Already widely used to treat patients with Parkinson’s disease and other movement disorders, deep brain stimulation may be particularly beneficial in patients with chronic cluster headaches who have been unresponsive to medication and to other types of treatment.

“We have observed a long-lasting remission in implanted patients with no [major] side effects,” said Dr. Leone. “Established deep brain stimulation is a viable surgical solution to treat otherwise intractable chronic cluster headaches. This approach requires a dedicated neurosurgical team and also a dedicated neurologic team to adequately follow up these implanted patients.” Dr. Leone, of the Istituto Nazionale Neurologico Carlo Besta in Milan, Italy, addressed the 15th Annual Headache Symposium.

Dr. Leone, who has been performing deep brain stimulation in patients with chronic cluster headaches for the last five years, emphasized some key points to consider before conducting this type of procedure. “Before going into the surgery room and independently of the surgical techniques you are going to use, it’s very important that our job as clinicians has been well done. That means that the selection must have been done very carefully. That means these patients must be followed up very carefully.”

PATIENT SELECTION

A candidate for deep brain stimulation surgery must have the chronic form of cluster headache, said Dr. Leone. In addition, a patient must be completely drug resistant, and it is preferable if the pain is unilateral. As for defining the term chronic in this case, Dr. Leone pointed out that the definition is not universally agreed on. “We have to distinguish the biologic meaning of the term chronic from the lifestyle of the patient,” he said.

The diagnostic criteria of chronic cluster headache, per the International Headache Society (IHS), require that attacks occur for more than one year without a remission period or with remission periods lasting less than one month. “This in some ways is disappointing, because it means that if you are a cluster headache patient suffering two or three attacks per month, this may fit the diagnosis of chronic cluster headache,” he said “So it’s not enough to define a patient as chronic.”

Dr. Leone suggested that a more appropriate definition of chronic would require that attacks occur on a daily or on an almost daily basis within the last two years, with accompanying drug resistance. The number of pain-free days or days without attack per month also need to be factored in. “This means that these patients must be followed very strictly,” he noted. Another issue is how long follow-up should be conducted to define a patient as a true chronic cluster headache patient. “The appropriate answer arrives from clinical observation of these patients,” said Dr. Leone.

Understanding the natural history of cluster headaches is important, Dr. Leone believes, though few studies have been done on that topic. One of the most noteworthy was conducted by Manzoni et al, who followed 189 cluster headache patients for more than 10 years and classified them as either episodic or chronic cluster headache patients. After the 10-year follow-up, episodic patients maintained their episodic form (primary episodic form) in 80.7% of cases, changed to a chronic form (secondary chronic form) in 12.9%, and shifted toward an intermediate pattern (combined form) in 6.4%. For chronic patients, cluster headache was still chronic at follow-up in 52.4% of cases, while it turned into an episodic form in 32.6%, and into a combined form in 14.3%. Ten percent of patients had had no attacks for at least three years at the time of their examination.

DRUGS AND CLUSTER HEADACHES

A number of drugs are commonly used for cluster headache prophylaxis, and in many cases, the drugs are used for a very prolonged period and can cause significant side effects. This poses two problems, noted Dr. Leone. “One, these patients are not responding to these drugs. Second, [there are] limitations due to the prolonged use and to very high dosages [that are needed] to try and control these attacks. So these patients need a lot of care. The majority of these chronic patients sooner or later will start steroids. We have observed almost all of the possible side effects induced by drugs in these patients, such as diabetes, hypertension, gastrointestinal bleeding, weight increase, bone demineralization, glaucoma, and so on. We have to deal with these side effects for a long period of time. So these are real problems. We are talking about prophylaxis, but if we think in terms of prolonged daily use of triptans, particularly sumatriptan injections, we are faced with possible side effects [such as] angina, myocardial infarction, heart failure, hypertension, liver dysfunction, addiction behavior. We know that the more sumatriptan injection they use, the greater the risk for increased attack frequency.”

Many cluster headache patients undergo prolonged steroid and sumatriptan use as well. Therefore, Dr. Leone asked, “For how long do we have to wait in order to propose something that is not prolonged drug use? There is no answer at least from my point of view at this stage. Do we have to wait for dangerous side effects to appear in order to propose something else? Is it ethical to wait, or how long do we have to wait if these are young patients? We have patients 25 to 35 years old. They are in the [prime] of their life.”

HONING IN ON THE HYPOTHALAMUS

PET studies have shown that the posterior inferior hypothalamic gray matter is activated during cluster headache attacks. Voxel-based morphometric MRI has also documented alterations in the same area in cluster headache patients. This research indicates that the cluster headache generator is located in the posterior inferior hypothalamus, according to Dr. Leone. “This view is supported by the observation that high-frequency stimulation of the ipsilateral hypothalamus prevented attacks in an otherwise intractable chronic cluster headache patient previously treated unsuccessfully by repeated surgical procedures to the trigeminal nerve,” he said.

Dr. Leone and his colleagues have reported their findings from a number of trials involving deep brain stimulation in the last few years. In Neurosurgery in 2003, the researchers documented the first series of patients to undergo deep brain stimulation of the posterior hypothalamus for chronic cluster headaches. Five patients were treated with long-term, high-frequency electrical stimulation, and all five patients remained pain-free up to 22 months of follow-up. Two patients remained pain-free without any medication, and three required low doses of methysergide or verapamil.

In Brain in 2004, Dr. Leone related the case of the first patient to receive bilateral hypothalamic stimulation to control severe bilateral chronic intractable cluster headaches that initially occurred mostly on the left side. Destructive surgery to the left trigeminal nerve was contraindicated, and the attacks were resolved after electrode implantation and continuous stimulation of the left posterior inferior hypothalamus. However, after four destructive operations on the right trigeminal, right-side attacks recurred, noted Dr. Leone. Subsequent electrode implantation with continuous stimulation to the right resulted in immediate resolution of right-side pain and the hypertensive state. When the stimulators were turned off, the hypertension reappeared and then disappeared relatively quickly after the stimulation was turned back on, said Dr. Leone. Pain never recurred when ipsilateral stimulation was ongoing.

“The patient was completely relieved of all these symptoms—hypertension, abnormal sexual behavior, insomnia, and aggressive behavior. They completely disappeared during the hypothalamic stimulation,” said Dr. Leone. “Almost five years after bilateral hypothalamic stimulation, he is doing well. The main problem now, completely drug refractory, is the trigeminal stabbing pain (anesthesia dolorosa) as a consequence of the four trigeminal operations on the right side.”

More recently, Dr. Leone followed up 14 patients with severe intractable chronic cluster headache who were treated with deep brain stimulation. The patients (12 men), with a mean age of 41 (range, 25 to 63), received hypothalamic electrode implants. Sphenopalatine ganglion blockade had produced no pain relief in any of these patients who had an average of seven attacks per day and whose headaches had been chronic for a mean of 2.6 years. Two patients had bilateral cluster headache and received bilateral implantation. In all patients, stimulation was unipolar and continuous, with a frequency of 180 Hz, a pulse width of 60 msec, and mean amplitude of 2.1 V.

After a mean follow-up of 15 months (range, 0 to 40), Dr. Leone’s group found that seven patients required pharmacologic treatments such as verapamil, methysergide, and lithium. Nine patients were pain-free. Two patients had two attacks per week; in one, the attack frequency was reduced from 10 to two per day; in the other, attacks restarted after the patient was pain-free for six months. In another patient, the stimulator was switched off on eight occasions, and the mean time to headache recurrence was 59 days. When the stimulator was turned back on, the mean time to pain-free states was 7.6 days. Blood pressure, heart rate, electrolyte balance, hormone levels, and behavior were normal in all patients.

“We are obtaining information every day from each of these patients,” said Dr. Leone. “We have the total number of days of follow-up and the number of pain-free days during the follow-up and the number of stimulated days. So what we could conclude is, first of all, it is not necessary to have the stimulator on all of the time in order to have the patient pain-free. In fact, in 12 patients it had been switched off and the pain reoccurred after a mean of three months, from two to six months.

“These data are very good, because the follow-up is rather long. So we can safely conclude that deep brain stimulation is very effective for these patients. Recently, a group in Belgium published the same result in a small group of chronic, drug-resistant cluster headache patients. Four of these patients were implanted, and three achieved a completely pain-free state. The pain after many months relapsed, and they had to adjust the stimulator and then the pain went away again. The pain frequency was quickly reduced.”

SAFETY ISSUES

A patient’s ability to tolerate deep brain stimulation and the degree of risk involved are other important issues that need to be addressed, said Dr. Leone. He has encountered various problems when performing these operations, though no operation has had to be stopped. With one patient, a machine malfunctioned, and in another case there was a problem with the wire that is connected to the implanted electrode. “Another problem that we are encountering is that we are used to doing deep brain stimulation in movement disorders patients, mainly Parkinson’s disease,” said Dr. Leone. “They usually are aged patients; they do not move very much. But cluster headache patients are young; they do move, and they [lead] normal lives. So they encounter all the problems you can imagine. It is very important to give them the right proportion when you put the electrode and wires on. So we had to change a bit the technique of fixing the wire to the scalp, for instance.”

The stimulator has also switched off on its own when a patient passed by or was close to an old refrigerator or radio. “Another problem we’ve encountered is that in one case the electrode went out of position and was replaced,” said Dr. Leone. “What about the problems related to the stimulation? Once the electrode had been put into the brain, the operation went well.”

Overall, said Dr. Leone, “We have been very surprised, because [when] managed very carefully, we’ve had no problems at all. This means that the amplitude has to be increased very slowly. Of course, it depends on the level of tolerability of the patient. Because what we have been observing is that the older the patient is, the less is the tolerability. The more time that is needed to increase the amplitude, the more time to reach the therapeutic value of the stimulation.”

NR

—Colby Stong

Suggested Reading
Franzini A, Ferroli P, Leone M, Broggi G. Stimulation of the posterior hypothalamus for treatment of chronic intractable cluster headaches: first reported series. Neurosurgery. 2003;52:1095-1099; discussion 1099-1101.
Leone M, Franzini A, Broggi G, Bussone G. Hypothalamic deep brain stimulation for intractable chronic cluster headache: a 3-year follow-up. Neurol Sci. 2003;24(suppl 2):S143-145.
Leone M, Franzini A, Broggi G, et al. Long-term follow-up of bilateral hypothalamic stimulation for intractable cluster headache. Brain. 2004;127:2259-2264.
Manzoni GC, Micieli G, Granella F, et al. Cluster headache—course over ten years in 189 patients. Cephalalgia. 1991;11:169-174.

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