Introduction

One of the most outstanding contributions to modern medicine has been the introduction of therapeutic organ transplantation. Despite their spectacular and resolutive nature, these procedures are not free of complications in transplant recipients. Neurological problems in particular, occur with a frequency of 20–60%, depending on the organ transplanted [1]. The percentage is higher for heart and bone marrow transplants, and lower in kidney recipients [1]. Neurological complications can be subdivided into those common to all transplants and those specific for a given type of transplant. Headache, in particular, is a non-specific complication with a prevalence that varies between 3.2 and 35.2% according to the studies [2, 3]. Whereas major complications occurring after transplantation have been investigated [4–6], headaches are infrequently discussed as a clinically significant problem in the transplant literature, since they are generally considered less important than other complications such as encephalopathy, infectious diseases of the central nervous system, blood hypertension, organ rejection, therapy with cyclosporine or FK 506 [1, 7–10]. However, headaches have an important negative effect on life satisfaction of these patients according to Matas et al. [11]. To the best of our knowledge, only one study specifically dealt with headaches, and in particular migraine [3]. Other publications involve only case reports [12–17]. Table 1 summarises data published on the incidence of neurological complications and, when reported, of headache and migraine for different transplant types [18–29]. Results are quite variable, but it is difficult to compare them owing to the different methods used. In this study we considered the occurrence of different headache types in a group of renal transplanted patients before and during renal failure (RF), during dialysis, after transplantation.

Table 1 Occurrence of neurological complications in heart, kidney, liver, lung and heart-lung transplants in some studies
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Methods

A total of 83 consecutive patients (55 males, 28 females; mean age 41.7 ± 11.8, range 18–63) at least 6 months after transplantation were included in the study. All the patients underwent orthotopic renal transplant at the General Surgery Department of our University. Data on patient age at the time of transplantation and the course of the illness are summarised in Tables 2 and 3. The most frequent diseases underlying RF were glomerulonephritis (53% of patients) and polycystic kidney disease (13%), followed by diabetes mellitus, ureteral malformation and systemic lupus erythematosus. A patient questionnaire was used to collect anamnestic information, with specific regard to pharmacological history and headache characteristics during distinct periods: before RF; during RF; during dialysis treatment; after the transplant. The headaches were classified according to ICHD-II criteria [30]. All the patients underwent a general and neurological examination. Blood pressure, weight, blood biochemistry parameters and cyclosporine dosage were measured and records of the same parameters from previous visits were obtained. All the patients were on immunosuppressive therapy with cyclosporine and corticosteroid; in addition, a large group was being treated with anti-hypertensive therapy.

Table 2 Age at transplantation (n = 83)
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Table 3 Time elapsed in the different conditions (n = 83)
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Considering that all analysed variables were qualitative, a non parametric analysis was performed with the Pearson’s χ2 and the McNemar’s χ2 tests. The significant level was set at P < 0.05.

Results

The pattern of headache in the 83 patients during the various periods of their history is shown in Table 4. In group A (before RF), 27 patients suffered from headache: 17 migraines without aura (MO), eight episodic tension-type headache (ETTH) and two hypertension-related (HR). In group B (during RF), the 36 patients suffering from headache comprised 20 MO, two ETTH, 13 HR, one metabolic headache (MH). Of those with MO, 12 patients had suffered before RF and eight were new cases. For the other five MO patients in group A, MO ceased in four and one developed HR. The two ETTH cases had also suffered before RF; of the six remaining ETTH patients in group A, three developed HR, whereas in three headache ceased. Out of HR group, 11 were new cases and two patients had already suffered before RF. In group C (during dialysis) (Table 4c), the 33 headache sufferers comprised seven MO, one ETTH, three HR, 22 dialysis headache (DH). All the group C MO patients had been in the same category in group B; of the remaining 13 group B MO patients, MO ceased in eight and five developed DH. The group C ETTH patient had been in the same category in group B. Of the 22 DH patients 13 were new cases and nine had been categorised in group B (five MO, three HR and one ETTH). In group D (after transplantation), 37 patients suffered of headache: 15 MO, 10 ETTH, two ETTH + MO, two HR, four not classifiable (NC), two cyclosporine related (CY), one OKT3 related headache (OKT3), one primary stabbing headache (PSH). Twenty three of whom were new cases (six MO, seven ETTH, two ETTH + MO, four NC, two CY, one OKT3, one PSH). Conversely, 26 patients suffering from headache (10 MO) before transplant were free of attacks at 6–12 months follow up.

Table 4 Occurrence of headache during the different periods of the history of the patients (n = 83)
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In order to evaluate a possible significance of the different headache occurrence before and after transplant, we subdivided the headache patients into two groups, considering in the first only migraine patients and in the second all the other kind of headaches. In the first group, 17 (20%) patients suffered of MO before the transplant, 15 (18%) MO post transplant, without statistical significance (McNemar’s χ2P = 0.79). In the second group, 10 (12%) patients presented headache before transplant, 22 (26.5%) after, with statistical significance (McNemar’s χ2P = 0.004).

All patients received immunosuppressive therapy of both cyclosporine and prednisone at dosages depending on the time elapsed since transplantation and clinical condition. To investigate a possible correlation between the headache and levels of cyclosporine and/or creatinine, we examined the post transplant follow-up results at 7 days and 1–3–6–12 months for patients who had cyclosporine and creatinine levels above the normal range. There were no significant differences for both between patients with and without headache (Pearson’s χ2P = 0.43 for cyclosporine and P = 0.73 for creatinine). We were able to establish a definite relationship with cyclosporine administration only in two cases in which the lowering the high cyclosporine level within the normal range, was followed by headache disappearance.

Furthermore, 64 patients received azotioprine, 73 antihypertensive therapy; among the latter, 25 were treated with the beta-blockers, 18 with metoprolol, seven with atenolol. Table 5 summarises the data on the occurrence of MO in transplant patients with and without beta-blocker treatment. Comparison of the data reveals that administration of these anti-hypertensive agents, which are known to protect against migraine, did not influence MO development. Indeed, the onset or disappearance of MO showed no relation with doses nor with the type of beta-blocker used (metoprolol 50–200 mg, atenolol 50–100 mg). Tables 6 and 7 list the patient characteristics and the pattern of migraine attacks for subjects who developed MO after transplantation.

Table 5 MO patients treated and not treated with beta-blockers in the different conditions
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Table 6 Patients who developed MO after transplant
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Table 7 Attack features, treatments and associated headache in the patients with MO developed after transplant
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Finally, the group of patients suffering from MO that persisted after transplantation (n = 10) showed no relevant change in the pattern of attacks in either frequency or intensity.

Discussion

The results show that headache is a diffuse problem in the transplant patients, affecting 44.5% of the study subjects and requiring specific treatment or diagnostic procedure in 8%. Comparing with the literature, the percentage of patients with headache is higher, respect to both liver and kidney transplant patients 31% and to liver transplant patients 7–35% [3, 23]. We found no reports on the prevalence of migraine after isolated kidney transplantation. In the only paper available on kidney transplant, headache affects only 3% of patients but this result is not comparable with ours, since this study considers only the acute complications occurring in the first 3 days after the surgical procedure [2]. Steigler et al. 1994 [3] reported migraine in 18% of liver transplanted patients, in agreement with the results found here.

According with IHS diagnostic criteria of headache induced by substance use or exposure (30), cyclosporine seems not to be a relevant factor in the development of headache and specifically of migraine; in the only two cases with a definite relationship, the headache was described as continuous, tightening, bilateral in location, and without neurovegetative symptoms, which disappeared on a decrease in cyclosporine dosage. However, we cannot exclude a role of cyclosporine in the genesis of headache not directly related to its high level; since in particular some patients may be predisposed to develop headache. About this point, if we consider that after transplant four patients presented no classifiable headache, condition not present before RF, during RF or during DH periods and situation de novo in four patients, seem possible that this therapy could somehow favour the development of headache, perhaps related to its vasoactive properties [31]; however, the exact mechanisms by which the immunosuppressive drugs could induce or exacerbate headache are unknown. Six of the eight cases who developed MO after transplantation had a low frequency of attacks, which does not seem to be related to the use of a drug taken continuously. In none of these cases, the symptomatology was considered so important as to require modification of cyclosporine use. In two cases, the age on presentation of migraine was relatively advanced (46 and 47 years) and the first attack occurred within 1 month after transplant, casting doubt on a causative mechanism different from simply casualness.

None of the patients reported migraine with aura (MA), a finding that differs from that of Steiger et al. [31], who reported that 5/34 liver transplant patients developed MA after surgery; among different hypothesis, this could possibly be related to the different transplant organ.

During dialysis, the number of patients with headache attributable to this procedure, without correlation with pre-existing headache or migraine, was remarkable. On the other hand, we observed a decrease in the number of MO patients during dialysis. Furthermore, no new MO cases occurred during this period, which was long enough (dialysis duration at least 1 year in 70% of patients and at least 6 months in >98%) to exclude bias due to too short an observation period. We can hypothesise possible mechanisms related to the procedure of dialysis or to biochemical plasma changes in calcitonin gene-related peptide and substance P as recently demonstrated [32].

An important point is the antihypertensive therapy taken by patients, in particular beta-blockers, which represent an important prophylactic treatment. There are no differences for beta-blocker treatment in the distribution of patients who developed MO after transplantation, those with pre-existing MO, or those for whom MO disappeared after transplant. In the three groups of patients with MO, the distribution of the cases with MO developed after transplant, with pre-existing MO or indeed in which disappeared is the same. The new cases with MO in therapy with beta-blockers are four, in three the introduction of the drug was after transplant in one was pre-existing the transplant. Of the 10 patients in whom MO disappeared, beta-blocker treatment was started after transplantation in four and the remaining six patients were not treated. In conclusion, the treatment with beta-blockers may be a cause that produces some difficulties in the interpretation of the data, but the detailed analysis of the results seems to indicate that the distribution of the patients regarding the appearance or disappearance of MO in the various groups of patients is random.

After kidney transplant, we did not find an increase of MO cases, but a significant increase in the number of non specific headache such as “non classifiable” or ETTH.

Further studies on the occurrence of neurological complications in transplanted patients should take in account also the development of headache specifically of migraine. Besides clarifying the extent of this problem, such investigations could give clues on its causative mechanisms, particularly with regard to immunosuppressive therapy.