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  • ✓ A research team in Milan, Italy, reported that hypothalamic stimulation eliminated cluster headaches in 10 of 16 patients who had the procedure, and drastically reduced the frequency, intensity, and duration of headaches in the other six.

Cluster headaches cause such excruciating pain that people have killed themselves to escape it. Yet, the cause of this malady remains a mystery, and a cure has remained elusive. Now it appears that implanting an electrode in the hypothalamus to deliver continuous electrical stimulation may offer reliable relief to people who suffer chronic cluster headaches that have defied all other treatments.

A research team in Milan, Italy, reported that hypothalamic stimulation eliminated cluster headaches in 10 of 16 patients who had the procedure, and drastically reduced the frequency, intensity, and duration of headaches in the other six (Neurology 2006:67:150–152).

Cluster headaches, according to criteria published by the International Headache Society in 2004, involve at least five attacks occurring often, from once every other day to eight per day.

“Before the operation, none of the patients were able to work,” lead author Massimo Leone, MD, of the Instituto Nazionale Neurologico Carlo Besta, told Neurology Today. “As a result of stimulation, most patients lives have gradually returned to normal; most have resumed work.”


To test for a placebo effect, Dr. Leone turned off the pacemaker in nine of the patients without their knowledge. Five of the patients experienced full-blown recurrences of their cluster headaches, which disappeared when the pacemaker was turned back on. In four patients, the headaches returned only sporadically, so the pacemaker was not turned back on.

“These findings indicate that hypothalamic stimulation does not work by a placebo effect,” Dr. Leone concluded in the paper. “In all cases when the stimulator has been switched off unknown to the patient, the crises have returned.”

Neurology Today asked several experts to comment on whether the lack of a sham procedure could have led to a placebo effect. “I think implanting the first few on compassionate grounds was understandable, but I do think a controlled trial needs doing,” said Peter Goadsby, MD, of the Institute of Neurology in London. “I think it would be an ethical undertaking.”

“I actually do not think cluster headache is improved by belief, but I do not think medical practice should be driven by beliefs,” Dr. Goadsby added. “So for a different reason I would support such a trial.”


Dr. Leone noted that all participants in the trial were informed about possible side effects from the procedure. Investigators in Belgium enrolled six patients in a pilot study of hypothalamic stimulation, and one patient died of a cerebral hemorrhage after the electrode was implanted (Brain 2005;128: 940–947). Two patients, however, were pain free, and one had fewer than three attacks per month. (One patient had only transient remission of the headaches, and another patient dropped out.)

“We conclude that hypothalamic stimulation has remarkable efficacy in most, but not all, patients with treatment-resistant chronic cluster headache,” wrote Jean Schoenen, MD, of the Headache Research Unit at the University of Liege, Belgium, in Brain. Because of the risks, Dr. Leone asserts that hypothalamic stimulation “is to be regarded as an extreme remedy to be used only in the worst cases.”

Stephen Silberstein, MD, Director of the Headache Center at Thomas Jefferson University Hospital in Philadelphia, agrees. He would reserve hypothalamic stimulation for “the worst of the worst,” he said, those “people who do not respond to aggressive treatment, and who have frequent cluster headaches that are interfering with their life to the point where they have no life left.”


Dr. Stephen Silberstein said that he would reserve hypothalamic stimulation for “the worst of the worst” — those “people who do not respond to aggressive treatment, and who have frequent cluster headaches that are interfering with their life to the point where they have no life left.”

Such patients are often completely disabled, according to David W. Dodick, MD, a neurologist at the Mayo Clinic in Scottsdale, AZ. “Patients with chronic cluster headaches suffer daily and nightly attacks of excruciating pain, and often do not respond well to medication,” said Dr. Dodick. “It is among the most painful conditions that physicians confront. Considering that, deep-brain stimulation does not seem like such an extreme a treatment.”


The most radical method of preventing cluster headaches involves cutting the trigeminal nerve, which sends branches to the eye socket, the nose, and the jaw. But this procedure causes facial numbness, including loss of corneal sensation, which can lead to corneal abrasions because the patient can no longer feel anything irritating the eye. The abrasions can lead to corneal ulcers and even blindness.

“Furthermore, any operation that damages the trigeminal nerve may produce anesthesia dolorosa, a continuous burning pain that is nearly impossible to treat,” said Arne May, MD, of the Department of Systems Neuroscience at the Universitéts-Krankenhouse Eppendorf in Hamburg, and the author of a 2005 paper on cluster headaches (Lancet 2005:366:843–855).

Moreover, cutting the trigeminal nerve doesn't always end the headaches. Dr. Goadsby described a 59-year-old man who, after having the trigeminal nerve cut, continued to have cluster headaches just as often, although they tended to be of shorter duration (Brain 2002; 125:976–984).

“That case illustrates that cluster headache may be generated primarily from within the brain,” Dr. Goadsby concluded. Although the cause of cluster headaches remains unknown, circumstantial evidence strongly implicates the hypothalamus.


The hypothalamus controls circadian rhythms, which could explain the clock-like regularity and seasonal variation of cluster headaches. Also, PET and MRI show that the hypothalamus is highly active during cluster headache attacks. The structure also tends to be smaller on the side of the pain. Such evidence drew Dr. Leone's attention to the hypothalamus as a treatment target.

“We reasoned that stimulation of the ipsilateral posterior inferior hypothalamus in chronic, intractable cluster headache patients might prevent neuronal activation there and relieve pain,” he wrote in the Neurology paper.

But how does hypothalamic stimulation work? Dr. Leone can only propose a theory: “High-frequency stimulation is thought to exert an immediate inhibitory effect on neurons, which may explain the disappearance of tremor in Parkinson disease as soon as stimulation is started,” he said. “The hypothalamus is directly connected to the trigeminal nucleus caudalis (TNC), which is responsible for processing information arising from pain-sensitive structures of the head. The hypothalamus is also connected to brain areas involved in pain modulation, the so-called pain matrix. The neuromodulatory effect induced by continuous hypothalamic stimulation may restore the control exerted by the hypothalamus and the pain matrix on the TNC.”

While just a theory, Leone's explanation carries with it the promise of other approaches to ending cluster headaches, which is why neurologists have been enthusiastic about his follow-up study.

“It's an important article that presents results from a cutting-edge approach to treating a devastating neurological problem,” said Dr. Goadsby. “The work highlights an emerging area of treatment – neuromodulatory approaches. It's an exciting time!”


• Leone M, Franzini A, Blissone G. Hypothalamic stimulation for intractable cluster headache: Long-term experience. Neurology 2006:67: 150–152.
    • May A. Cluster headache: Pathogenesis, diagnosis, and management. Lancet 2005;366:843–855.
      • Coppola G, Vandenheede M, Schoenen J, et al. Somatosensory evoked high-frequency oscillations reflecting thalamo-cortical activity are decreased in migraine patients between attacks. Brain 2005;128: 940–947.