Abstract
This case study concerns a patient with primary chronic cluster headache, who was unresponsive to all treatments and consecutively underwent hypothalamic deep brain stimulation (DBS). DBS had no effect on the cluster attacks, but cured an existing polydipsia as well as restlessness. However, hypothalamic DBS produced a constant, dull headache without concomitant symptoms and a high-frequent tremor. All of these effects were repeated when the stimulation was stopped and than started again. DBS had no effect on a pathological weight gain from 70 kg to 150 kg due to bulimia at night, usually during headache attacks. This case illustrates that cluster headache is, in some patients, only one symptom of a complex hypothalamic syndrome. This case also underlines that the stimulation parameters and anatomical target area for hypothalamic DBS may be too unspecific to do justice to the clinical variety of patients and concomitant symptoms. Hypothalamic DBS is an exquisite and potentially life-saving treatment method in otherwise intractable patients, but needs to be better characterised and should only be considered when other stimulation methods, such as stimulation of the greater occipital nerve, are unsuccessful.
Introduction
Deep brain stimulation (DBS) in cluster headache is an innovative, new method for treating otherwise intractable patients. The target point was chosen based on clinical considerations and functional studies that revealed the crucial role of the posterior hypothalamus in cluster headache (1–3). Despite the fact, that these studies could strengthen the clinical impression of the posterior hypothalamus as a key player in the generation of cluster headache attacks (4,5), the responder rate of DBS in this region varies between 50–70% (6–8) and there are several patients with cluster headache that do not respond (6,9). Until now, no predictors for success have been identified. We report a case of chronic cluster headache with failure of DBS for treatment but with contingent effects on other, concomitant symptoms.
Case report
A 34-year-old woman developed a primary, chronic, strictly left-sided cluster headache according to IHS-criteria (10) at the age of 28 years. Medical treatment with high doses of Verapamil (760 mg/day), lithium (lithium carbonate, 1600 mg/day), topiramate (300 mg/day), sodium valproate (2700 mg/day) and steroids (250 mg/day) was entirely without success. Oxygen was effective in about 20% of the attacks and only triptans (sumatriptan 6 mg s.c.) were able to stop most of the attacks; however, the maximum dose per day was routinely exceeded. The patient suffered up to eight attacks daily, so that the decision for hypothalamic DBS, following international guidelines (11), was made. In May 2006, an electrode was implanted stereotactically in the left posterior hypothalamus (anterior periventricular region of the triangle of Sano; Figure 1) according to published co-ordinates (2 mm lateral, 3 mm posterior and 5 mm inferior referenced to the mid-AC–PC line) (1,4). Of note, a quadripolar electrode model 3387 (Medtronic, Minneapolis, MN, USA) was used for macrostimulation. This lead contains four electrodes, each with a length of 1.5 mm and spaced 1.5 mm apart. The deepest and the highest active points are spaced 10.5 mm overall which covers mid-brain tegmentum and the posterior inferior hypothalamic area. Although, at first, the frequency of attacks was slightly reduced, it quickly reached prior levels despite several adjustments of the stimulation parameters.
MRI orientation of the stimulator tip in the hypothalamus.
DBS-parameters and clinical correlations
In January 2008, the patient came to our out-patient clinic. The stimulation parameters at that time were unipolar on electrode 1 with amplitude of 2.9 V, a frequency of 185 Hz and a pulse width of 210 µs. The cluster headache attacks were unaltered under stimulation, but the patient reported several symptoms which exceeded the clinical picture of cluster headache.
The first effect of the stimulation was a new permanent headache without additional attacks. It was characterised as pressing and dull and was localised predominantly frontal and bilaterally behind the eyes with accentuation on the left (symptomatic) side. This headache was not accompanied by any autonomic or vegetative features. It is noteworthy that the patient had no previous history of headaches. She reported that the unusual pulse width of 210 µs had been chosen earlier, because smaller pulse widths had aggravated this headache type.
Second, the patient had suffered from polydipsia since 2004. The polydipsia occurred during an (unsuccessful) treatment with steroids, but did not stop after the end of the therapy. Endocrine dysfunction could not be detected and the polydipsia was classified as psychogenic. The polydipsia stopped soon after starting deep brain stimulation and did not re-occur until the stimulator was turned off.
Third, since the beginning of the cluster headache, the patient gained 80 kg (from 70 kg to 150 kg). This increase was not influenced by DBS. The patient described an enhanced appetite, particularly at night, while suffering from cluster attacks.
These symptoms (polydipsia, weight increase) are rather unusual for a cluster headache and were suggestive of a more complex ‘hypothalamic syndrome’. Of note, the first published patient receiving DBS also showed symptoms atypical of cluster headache (5), such as oculofacial swelling.
In order to see the patient in an untreated condition and to later optimise the stimulation parameters, we turned the stimulator off for 2 weeks. During this period, only a preventative medication of 720 mg Verapamil daily was given. Within 3 days of turning off the stimulation, the polydipsia returned and the permanent headache disappeared. No change of cluster headache attacks was noticed. Furthermore, the patient presented a so-far unknown restlessness of movements and irregular tremor, especially concerning her legs and her chin, which decreased over the day and disappeared during cluster attacks. As we did not perform EMG recordings, the frequency cannot be exactly defined. The chin tremor was a resting tremor which stopped immediately during talking or eating. It was of high frequency and varying amplitude. The leg tremor affected the right leg more than the left. It also presented mainly as a resting tremor but it was also detectable holding the legs stretched out. It did not interfere with walking or standing as orthostatic tremor usually does. There was no intentional component. The frequency of the leg tremor was lower than that of the chin tremor and the amplitude also varied. All of the above symptoms confirmed the impression of a rather complex hypothalamic syndrome.
We carried out a new test stimulation of all four electrode contacts on consecutive days to avoid overlap effects using standard parameters with a frequency of 130 Hz and a pulse width of 60 µs. Besides the well-known side-effects of hypothalamic stimulation (like dizziness and vertigo), repeated stimulation of all four electrodes evoked the new headache of pressing quality localised bilaterally with a significantly lower threshold of about 2.5 V at the deeper electrodes. We recognised this problem from another patient with DBS in the posterior hypothalamus, who also developed a new headache exclusively under stimulation of this contact (data not published). As before, these parameters prompted the polydipsia and the restlessness to disappear after 3 days of stimulation on all electrodes, but no effect on cluster headache frequency, duration or severity of attacks could be achieved, despite concurrent medication.
Discussion
Our patient demonstrates that the syndrome ‘cluster headache’ may be embedded in a more complex clinical entity which can, in part, be influenced through hypothalamic DBS. Cluster headache, polydipsia, restlessness of movements and the excessive increase in weight may be attributed to a hypothalamic dysfunction. Some of these symptoms were directly and repeatedly stopped, whereas others were even triggered by the stimulation. Why are the results of this method so heterogeneous and why does electrical stimulation of this area provides such an unpredictable clinical picture?
The target point for hypothalamic DBS in cluster headache was chosen because of results of pooled group analyses using positron emission tomography (H2O-activation-PET) (1). It has to be said that H2O-PET has a low spatial (4–5 mm) and temporal (1-min sample time) resolution and, being a statistical method, requires group analysis. In addition, to achieve a statistically significant result in regional cerebral blood flow, a smoothing kernel of at least 10 mm is required. It cannot be overstated that this PET study is the first time that results from functional imaging was translated into deep brain stimulation; likewise, it needs to be pointed out that these patients have been intractable to medical treatment (12). On the other hand, a failure rate up to 50% seems quite high for an invasive treatment that even contains the risk of invalidity or death (9). One possible approach to diminish the failure rate could be individual pre-operative PET- or fMRI-scans during cluster headache attacks for each patient. Single case studies are, in principle, possible (2) and it would be easier to define the individual target point for each patient (13). This does not change the fact that hypothalamic DBS should be the last therapeutic option in cluster headache patients.
It needs to be added that other surgical treatments for cluster headache have recently been introduced, including: (i) the stimulation of the greater occipital nerve (n = 16) (14,15); (ii) the ophthalmic branch of the trigeminal nerve (n = 1) (16); (iii) vagus nerve stimulation (n = 6) (17); and (iv) the higher cervical stimulation (n = 1) (18). The underlying mechanism of all of these methods is not known but it has been suggested that they may modulate the trigeminocervical neurons in the brain stem. Currently, only data for the stimulation of the greater occipital nerve have been published in numbers that allow a rough estimation of its effect, suggesting that the success rate may be comparable to that of DBS (14). However, there are less side effects and the risk of a permanent injury is minimal. Until we have entirely understood how hypothalamic DBS unfolds its effect, the uncritical use of DBS has to be made with caution. Given that patients are operated who are medically intractable and consequently suicidal, effective hypothalamic DBS can achieve phenomenal results and may well save lives. However, a better and, above all, individual definition of the stimulation target is crucial for improved results. This could be achieved using event-related functional MRI in each single patient before operation. Given that an operation for deep brain stimulation costs around Euros 20,000 in Germany (including stimulation device (unilateral) and operation (excluding post-stationary care, supervision and further treatment on an out-patient basis), it is economically incomprehensible that so little funding goes into the understanding of the scientific basis and improvement of this method.
Regarding the efficacy of hypothalamic DBS in ameliorating cluster headache attacks, there seems to be a discrepancy between the original reports (7,19), a recent update on German patients (6) and a recent double-blind trial (8). How can this be explained? It is certainly not as simple as blaming the technical details of the devices, the operation, or the target region used, as these are identical. It seems clear that the selection of patients and overall care may have a huge impact on the outcome. Doctors are certainly called upon to re-check patient selection criteria (20) as well as their personal attitude to medical care of these patients. The current procedure of telling the patient that this method (i.e. hypothalamic stimulation) is the ‘ultima ratio’, and only applicable when every other treatment has failed, is not without a catch. It is indeed a difficult new issue to consider what that information policy (DBS as a last resort) means psychologically to these patients before the operation – and even more so when it fails. Most doctors seem to shut their eyes towards intractable pain conditions and even more so when invasive methods have failed. If we are ever to help these rare but devastated patients, we need to: (i) define better which patients should be operated; (ii) define better the anatomical target point; and (iii) intensify the patient–doctor relationship.
Cluster headache is a devastating disease. In our quest to help the patients, our primary goal is still not to harm the patients: ‘nil nocere’.
Footnotes
Acknowledgements
This work was supported by grants from the DFG (MA 1862/2-3) and BMBF (371 57 01 and NeuroImageNord).