Abstract
Newman and Solomon (1) were the first to describe headache as a well-recognized complication of haemodialysis treatment. These headaches may newly develop, however, patients suffering from primary headache syndromes before dialysis often have problems with headache of either migraine or tension type. Less often headaches occur which are exclusively associated with the dialysis procedure and are either a completely new event in the patient's medical history or express a distinctly different quality and nature from any headaches the patient had previously experienced. Only these headaches are classified as dialysis headache. According to IHS-Criteria dialysis headache is classified as a headache beginning exclusively during haemodialysis and rising to a very high intensity without substantial concomitant symptoms (2). Recently a modification of the classification criteria has been proposed (3).
Although dialysis headache is considered to be rare, Antioniazzi et al. (4) diagnosed haemodialysis headache according to the IHS-Criteria in 68% of patients developing headache during haemodialysis. The pathophysiology is unknown and the literature on this topic is spare. It has been suggested, that the headache may represent an integral part of the so-called ‘dysequilibrium syndrome’ and be one symptom among its many manifestations (5). Another common concept is, that the headache may be due or is triggered by a rising blood pressure during haemodialysis. In this context Bana et al. (6) reported a positive correlation between the severity of hypertension and the likelihood of the patient to develop a headache of one type or another. The absence of hypertension, however, would not preclude the occurrence of headache during dialysis (6).
It is intriguing that nephrectomy or transplantation may prompt a marked improvement in the headache which occurrs during subsequent dialyses. It is also known, that following dialysis the urine production may temporarily increase (7). These findings prompted us to postulate, that the Renin-Angiotensin-system may be involved in the pathophysiology of dialysis headache.
Case report
A 44-year-old women developed severe headaches during haemodialysis starting with haemodialysis in March 1998. This headache occurred every single time the dialysis took place (three times a week); 3–4 h after onset of the haemodialysis headache would increase, often up to such an intensity level that the dialysis treatment had to be interrupted. She describes the headache as biparietal with a throbbing character, sometimes accompanied by nausea and vomiting. NSAID or triptans, even when taken prophylactically, had no analgesic effect on these headaches, which continued to become worse as long as the dialysis consisted. Only after interruption of dialysis and treatment with an analgesic the headache gradually resolved in the following 4–6 h. She suffered from no other symptoms suggesting a ‘dysequilibrium syndrome’, such as blood pressure elevation, tremor, seizures and muscle cramps. She had a history of migraine without aura since puberal age according to the IHS criteria. The frequency of migraine attacks increased 1995 to one attack weekly for 1–2 days with concomitant nausea, vomiting, phono- and photophobia. When the dialysis started in 1998 the typical migraine attacks disappeared.
Renal failure began at the age of 34 and was caused by autosomally recessive transmitted, juvenile familiar nephronopthisis-type I. The disease was bioptically and moleculargenetically (homocygote mutation on chromosome 2 in the region 2q12 of the nephronophtisis-type-I-gene) diagnosed in 1996. Renal failure resulted consecutively in secondary hyperparathyreoidism and renal anaemia. The patient's medication was erythropoetin on days of dialysis, vitamins, calcium and hypericum 2 × 425 mg per day. In the past metoprolol 50 mg was taken for tachycardia but was not tolerated because of orthostatic symptoms. Metoprolol did not have any effect on headaches during haemodialysis. Neurological examination was normal.
The dialysis-protocols are thoroughly registered since 1998. At the time the patient was first seen in our headache department (2001), home dialysis was carried out three times a week. Weight was stable and blood pressure was not elevated (average 129/81 mmHg). The patient treated her dialysis headache with triptans and different NSAIDs, but with none or only little effect, taking as long as 3 h after the dialysis stopped. In fact, most of her dialysis had to be interrupted because of severe headache and her treatment regimen was on stake when she was seen in our headache department.
Following the pathophysiological considerations mentioned above, we treated her with the ACE-inhibitor fosinopril 7.5 mg on days of haemodialysis and 5 mg on the days in between. Following this regimen, the dialysis headache improved promptly and only after haemodialysis stopped, the patient reported sometimes a slight pressure. Interestingly, the patient reported as a side-effect of the medication, that under ACE-inhibitor medication the spontaneous urine production, which usually followed dialysis, decreased from about 400 ml to 100 ml. However, no significant alteration in blood pressure was documented, either during or after dialysis. Treatment with fosinopril was continued for 10 months. Unfortunately the patient then developed weakness, low blood pressure and tachycardia, which made it necessary to take her off the medication. The headache gradually recurred. Under the impression, that a different ACE-inhibitor may have less side-effects, the patient was treated with lisinopril. Even in a low dose of 2.5 mg every second day the headache improved again. However, the therapy had to be interrupted because of similar adverse events and the headaches started again, preventing her from continuing the dialysis.
At this stage we tested, whether the angiotensin receptor blocker losartan may be of benefit and the medication was succesively increased up to 100 mg daily. Initially we started with a dose of 12.5 mg/die. This dose was not tolerated in the beginning, forcing us to treat initially on days of haemodialysis only and later on the days in between. Unfortunately the dialysis headache persisted and the patient experienced the same side-effects as with the ACE inhibitors. Recently the patient tolerates higher doses of losartan, and is on 100 mg daily. Even using this high dosage, the headaches persisted. Interestingly under this medication the blood pressure reached values up to 150 mmHg, but the quality or intensity of the headaches did not change. We are intending to switch the patient on an ACE-inhibitor again, since in the meantime she tolerates a high dosage of losartan without hypotension.
Discussion
The patient in our case report suffered from a migraine-like headache which exclusively built up during haemodialysis. Often she had to interrupt dialysis because of this headache. NSAID and triptans did not have any analgesic effect. She had a previous history of migraine without aura, and when the dialysis started in 1998 the typical migraine attacks disappeared.
The pathogenesis of dialysis headache is unknown. One possibility is the presence of hypertension during haemodialysis. Bana et al. (6) found a positive correlation between the severity of hypertension and the likelihood of headache to occur during haemodialysis, even though the absence of hypertension does not necessarily preclude the occurrence of headache during dialysis (6). Our patient however, showed no elevated blood pressure during dialysis, which, compared to the days of nondialysis, would rise by maximal 10 or 20 mmHg, or, more likely, remained constant during haemodialysis procedure. Normotonic values are documented under treatment with fosinopril and lisinopril. Interestingly under therapy with high dose losartan blood pressure values sometimes were elevated up to 150 mmHg with no change in headache severity.
The headaches described by dialysis-patients may represent an integral part of the so-called ‘post–dialysis dysequilibrium syndrome’ and be one symptom among its many manifestations like restlessness, headache, nausea, vomiting, eventually accompanied by other symptoms like blood pressure elevation, tremor, seizures and muscle cramps (5). Dialysis disequilibrium syndrome was not diagnosed in our patient.
Another possible mechanism of dialysis headache may be the activation of the renin-angiotensin-system. In the literature nephrectomy and transplantation are reported to have a positive effect on dialysis-headaches (6), although in one case the blood pressure remained elevated (6). One may argue that steroids, which are usually applied following kidney transplantation, may have a beneficial effect on the headache. However this is not the case after nephrectomy, where steroids are not necessary. Our patient had a persistent spontaneous urine production of 100 ml twice/day and of 400 ml after haemodialysis, indicating the existence of a residual renal function.
Assuming a possible role of the renin-angiotensin-system in the pathogenesis of the dialysis headache we treated her with the ACE-inhibitor fosinopril. We selected this substance because of its pharmacokinetic properties, as biliar and renal excretion occurs and it is therefore most suitable for patients with renal dysfunction (8, 9). Under this treatment regimen headache during haemodialysis stopped for nearly a year and in the same period the rudimentary urine production decreased. Because of adverse events, which started after 10 months of continuous treatment (low blood pressure, dizziness and a general weakness) we stopped the treatment, after which the headache recurred with the same intensity and time pattern. After starting a new medication using another angiotensin receptor blocker, lisinopril, the headache improved again. Lisinopril was chosen because of a proven prophylactic effect in the treatment of migraine (10). However, again due to side-effects such as low blood pressure and dizziness, the medication, despite beeing efficent, had to be withdrawn. The angiotensin II-receptor blocker losartan up to 100 mg daily prompted again these side-effects, but sufficient improvement of her dialysis headache, even under high doses, was not seen. This makes it unlikely that the blood pressure, which only increased marginally during haemodialysis, is responsible for the headache.
The influence of the renin-angiotensin system on the development of dialysis headache has not been thought likely. We cannot exclude, that the headache our patient experienced during dialysis were in fact migraine attacks and the therapeutic effect of the ACE-inhibitors we have seen is due to its prophylactic effect, known for migraine. However, the headaches were exclusively triggered by dialysis, following a distinct time pattern and moreover we would not have expected such a prompt and complete relief from headache under the treatment with fosinopril and the previous treatment with metoprolol showed no effect.
It remains unknown, whether headache relief results from a drug-effect on the peripheral renin-angiotensin system or on the renin-angiotensin system present in the brain. The latter has input on several classical physiological pathways including body water balance, maintenance of blood pressure, cycling of reproductive hormones and regulation of pituitary gland hormones (11, 12). We treated our patient with two structurally diverse ACE-inhibitors. Both lipophilicity as well as carrier mediated processing may have an influence upon penetration of these drugs into the brain. Fosinopril is a lipophilic ACE-inhibitor and may penetrate the blood–brain barrier. Lisinopril has a low lipophilicity, but is orally well absorbed, suggesting involvement of factors like carrier-mediated transport processes (13). Interestingly lisinopril does not inhibit the activity of ACE in the basal ganglia, but in other circumventricular tissues, such as the organum vasculosum of the lamina terminalis where the blood–brain barrier is deficient. These tissues are rich in ACE and angiotensin II-receptors and are well known targets for induced effects on fluid, electrolyte and blood pressure homeostasis (14).
In summary we describe a case of dialysis headache with migraineous features, which was exclusively relieved following the treatment with an ACE-inhibitor and recurred after withdrawal of the treatment. The antihypertensive effect of the ACE-inhibitors seems to play no major role in its pain relieving effect, as the blood pressure never was significantly elevated and metoprolol had no effect. The fact that the angiotensin receptor blocker losartan showed no effect on the occurrence of the dialysis headache leaves room for reflections on the role of bradykinin, as the degradation of bradykinin is reduced in the presence of ACE inhibitors.
Allthough we report only a case report of this rare headache type, we draw the conclusion, that the activation of the renin-angiotensin system may play a role in the pathogenesis of dialysis headache; yet the underlying mechanism is not clear. Treatment with ACE-inhibitors may be an therapeutic option for dialysis headache, hence further studies are necessary.