Ophthalmoplegic migraine : diagnostic criteria, incidence of hospitalization and possible etiology Hansen SL, Borelli-Merller L, Strange P, Nielsen BM, Olesen J. Ophthalmoplegic migraine: diagnostic criteria, incidence of hospitalization and possible etiology. Acta Neurol Scand 1990: 81: 54-60. Charts from patients admitted from April 1976 to March 1986 to the departments of neurology, neurosurgery, ophthalmology and pediatrics serving a population of 615,000 inhabitants in Copenhagen County were surveyed. We then examined patients with coexisting headache and ophthalmoplegia at follow-up. Many diseases may mimic a single attack of ophthalmoplegic migraine. We found 4 cases of ophthalmoplegic migraine, i.e. an annual incidence of 0.7 per million inhabitants. We added another 4 cases from the same area, but diagnosed before or after the study period. Only in 2 of the 8 cases did the ophthalmoplegic episodes fulfil criteria for pain and associated symptoms required for migraine without aura (common migraine). In contrast, the clinical characteristics of the attacks are typical of the Tolosa-Hunt syndrome. When this inflammatory disease strikes a migraineur it is likely to elicit headache with migrainous features. We postulate that such cases have been diagnosed as ophthalmoplegic migraine, whereas the proper diagnosis of Tolosa-Hunt syndrome has been made in non-migraineurs.
The literature on ophthalmoplegic migraine is mostly case studies. Within the last 30 years published studies have included between 1 and 11 cases (1-10) and only 3 articles have reported more than 3 cases (2,4,7). Materials have been collected at specialized clinics and may therefore not be representative. The condition is known to be so rare that prospective study is impossible, and its incidence is unknown. Recently, the Headache Classification Committee of the International Headache Society (11) has provide operational diagnostic criteria for all headache disorders. This makes it possible to discuss the relationship between ophthalmoplegic migraine and the main forms of migraine more meaningfully than previously. This study describes the hospitalization incidence of ophthalmoplegic migraine in a geographically defined patient population. It also provides nosographic data, including follow-up examination, on 8 representative cases, and finally discusses diagnostic criteria and whether ophthalmoplegic migraine really is a form of migraine. Material and methods
The investigation was carried out at Gentofte Hospital and Glostrup Hospital, which are affiliated with 54
S.L. Hansen, L. Borelli-Msller, P. Strange, B. M. Nielsen, J. Olesen Department of Neurology, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
Key words: ophthalmoplegic migraine; TolosaHunt syndrome Susanne Lindbjerg Hansen, Department of Neurology, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark Accepted for publication July 7, 1989
the University of Copenhagen, Denmark. The neurological, neurosurgical, ophthalmological and pediatric departments of these hospitals serve all 6 15,000 inhabitants in Copenhagen Country. Because of the socialized medical system in Denmark, it is difficult for patients to visit other hospitals. Exact information is not available, but it is estimated that few patients are seen at other hospitals. The charts of 1633 patients discharged from these departments with a diagnosis of migraine and/or paresis of one or more oculomotor nerves between April 1, 1976 and March 31, 1986 were retrieved and reviewed to estimate the incidence of ophthalmoplegic migraine. Coexisting headache and ophthalmoplegia was likely in 27 patients and these patients were offered a follow-up examination.A less complete chart survey disclosed 6 possible cases from before or after the study period who were also offered follow-up. These cases were added to strengthen the nosographic data. Of the 33 patients, 22 were examined. One patient had died and 6 could be interviewed by telephone. The remaining 4 patients are included based on information from hospital records and their general practitioner. At follow-up, all patients were asked to describe their previous episodes, using a standardized form. Patients were also questioned about any further
episodes occurring after discharge. General physical and neurological examinations were performed by a neurologist (PS). Results
At follow-up, 25 of 33 patients were excluded for the following reasons : one probably had temporal arteritis, 2 a febrile illness of uncertain nature and 1 thyreotoxic ophthalmoplegia. Three patients had diplopia or blurred vision without objective confirmation. One patient appeared not to have had headache (the chart was unclear about this). Three patients had anisocoria as the only visual sign and no visual symptoms. The anisocoria persisted at followup and was regarded as physiological. Two additional patients with anisocoria suffered from cluster headache and associated Horner’s syndrome. One patient had strabismus. In 5 patients the charts were inconclusive regarding visual symptoms, but it was clear at follow-up that the patients in fact had migraine with aura and not ophthalmoplegia. One patient who had complained of blurred vision was found to suffer from tension headache and hyperventilation. Finally, 5 patients had single episodes of headache and visual symptoms, but in addition features indicating other neurological disease. The diagnoses in these patients were: brainstem stroke, 2 patients ; MS with internuclear ophthalmoplegia, 1; posttraumatic anisocoria and headache, 1; and variable hemisensory loss in the face, possible ptosis and headache, regarded as functional, 1 patient.
moplegic migraine. They had had 5 , 2 and 1 attacks, respectively. Generally, the pain was located behind and around the affected eye or fronto-temporally on the affected side. In 7 patients the pain was nonpulsating, but in 1 patient it shifted between pressing and pulsating. Pain was severe, causing bed rest in 6 and of medium severity in 2 patients. Four patients had nausea and, of these, 3 had previously suffered from migraine. Three patients complained of photophobia, and one of phonophobia. They had all suffered from migraine previously. Angiograms, CT-scans and other laboratory tests were normal but not performed in all patients (Table 1). Inadequate initial work-up was compensated by long-term observation and follow-up examination. Only in 2 patients (cases 5 and 7) did ophthalmoplegic attacks fulfil the IHS operational criteria for migraine without aura, and none fulfilled criteria for migraine with aura (1 1). The temporal relationship between onset of pain and symptoms is shown in Fig. 1. Pain was the first symptom and preceded ophthalmoplegia by 2 h to 7 d in 7 patients. Ophthalmoplegia outlasted the headache in 7 cases. Duration of headache was more than 72 h in 4 patients. Incidence
In calculating the incidence of ophthalmoplegic migraine, 4 of the 8 cases were excluded because they had their first admission for the disorder before or after the 10-year study period. Four new cases remain, which gives an annual incidence rate of
4 x 1,000,000
Eight patients (4male, 4 female) fulfilled the mildest possible criteria for ophthalmoplegic migraine: paresis of one of the oculomotor nerves overlapping temporally with headache and no other clinical or paraclinical evidence of intracranial disorder. Three of these patients had only 1 attack, 2 had had 2 attacks, one 5, one 10, and one 50 attacks. Details about these patients are given in Table 1. Case histories for the 5 patients who had suffered 2 or more attacks are given below. Five patients had a third nerve palsy and 2 had a 6 nerve palsy, whereas the last patient had an outward deviation of the right eye so that a third nerve palsy is likely. The pupil was spared in all but one patient, who had a moderately dilated pupil with a sluggish light reaction. Four patients had previously suffered from migraine without aura (common migraine) and one from migraine with aura (classic migraine). The patient who had migraine with aura and 3 of the patients who had migraine without aura suffered from tension headache in addition. Three patients had no prior history of headache other than ophthal-
615,000 x 10
0.7 per million inhabitants peryear
Case histories Case 1
Thirty six-year-old man admitted in 1981. There was no family history of migraine, but he had had four episodes of ophthalmoplegia and headache previously in 1963, 1970 and 1975 (not leading to hospitalization here). Past medical history was unremarkable. The headache had a gradual onset 2 weeks prior to admission. The pain was experienced as steady and piercing in character of severe intensity, located around and especially behind the left eye, and fluctuating in intensity. There was no nausea, photophobia or phonophobia. Six days after onset of headache he developed drooping of the left upper eyelid and double vision, when looking up, down and to the right. The examination revealed paralysis of the left abducens and oculomotor nerves sparing the pupil, 55
Hansen et a1 Table 1. Clinical characteristics of patients with possible ophthalmoplegic migraine
Case no. 1
Age on admission and sex
Age at onset of first attack
Family history of headache
but was otherwise normal. Complete blood cell count, blood chemistries, ESR, glucose, thyroid function and VDRL were normal. A contrastenhanced CT with orbital and sinus views and left carotid angiography were normal. The patient was treated with prednisone 50 mg once a day for about 5 weeks. Pain ceased within 24 h and ptosis and double vision improved dramatically within the next few days. A follow-up examination 4 weeks later showed. normal oculomotor function but residual incomplete VI nerve palsy. At follow-up, December 1986, the neurological examination disclosed weakness of the left lateral rectus muscle with approximately 10" of residual function. There was a complaint of horizontal diplopia on left lateral gaze. The remainder of the examination was normal. 56
Prior history of other types of headache
Migraine without aura
Pain location and character Left-sided, periorbital and behind left eye non-pulsating right-sided periorbital frontal non-pulsating right-sided retro-orbital and temporal non-pulsating
Visual symptoms Diplopia
left-sided ptosis Diplopia
right-sided ptosis Diplopia
Migraine without aura tension headache
Left-sided, temporo-frontal pressing and pulsating
Migraine without aura tension headache
Diplopia left-sided ptosis
Migraine with aura tension headache
Right-sided, temporal and occipital pressing non-pulsating
No diplopia flickering hazy vision
Migraine without aura tension headache
Left-sided, retro-orbital frontal Non-pulsating
Diplopia left-sided ptosis
Left-sided, temporal, in vertex and the mandible non-pulsating
Diplopia left-sided ptosis
Ten-year-old boy admitted for the first time in 1968. The patient had a maternal family history of migraine without aura (common migraine). He was admitted after 7 days of severe, nonthrobbing headache in the right periorbital region. It was associated with nausea, vomiting and photophobia. The patient was not questioned about phonophobia. For 2 days he had experienced diplopia and drooping of the upper right eyelid. On examination there was a complete right external oculomotor nerve palsy. The right pupil was moderately dilated, and its reaction to light was sluggish. The neurological and general examinations were otherwise normal. Complete blood cell count, blood chemistries, ESR, blood glucose and urinalysis were
Ophthalmoplegic migraine Table 1 continued
Opthalmoplegia on examination
6 weeks/6 weeks
Interval between pain and onset of ophthalmoplegia
normal ESR, EEG lumbar puncture and skull X-ray
palsy ptosis 3rd nerve
Other laboratory examinations
Number of attacks
Right pupil dilated, sluggish light reaction
3rd nerve palsy ptosis
4 months/4 months
normal ESR, lumbar puncture and skull X-ray
partial 3rd nerve palsy
8 weeks/8 weeks
at the same time
partial 3rd nerve palsy ptosis
2 weeks/2 weeks
ESR not taken normal skull X-ray
"outward deviation of right eye"
normal ESR, skull X-ray, EEG
partial 3rd nerve palsy ptosis
24 hours/48 hours
partial 3rd nerve palsy ptosis
8 weeks/6 weeks
normal ESR, skull X-ray, temporal artery biopsy, EEG, acousticovestibular test
normal. Spinal fluid was normal. X-rays of skull and sinuses were normal. A right carotid arteriography one week after admission was normal. Headache remitted spontaneously within 8 days and eye symptoms within 4 months. Between 1968 and 1972 the patient had frequent episodes of right-sides supraorbital headache, drooping of the upper eyelid and diplopia with complete remission in 3 days. In the next 5 years the frequency of attacks decreased and they ceased completely in 1978. After that he has still had occasional mild non-throbbing right frontal headaches without accompanying symptoms. Right frontal mild pain with eye strain remained in exposure to cold winds. At follow-up in December 1986 the neurological examination was normal. The patient had had no further ophthalmoplegic episodes.
Thirty-nine-year-old man seen in March 1978. No personal or family history of headache or migraine. As a 2 1-year-oldhe suffered a severe head injury and was comatose for 9 days but recovered fully. He had Bell's palsy at 32 and 47 years of age. The present attack started 5 days before admission with pain located behind the right eye and in the right temporal region. The pain was of medium intensity, pressing and associated with nausea but not with vomiting, aura, phono- or photophobia. At the same time he experienced diplopia and closure of the right eye. Ophthalmological examination revealed a partial 3rd nerve palsy with normal pupil. A neurological examination 3 days later showed improvement of the 3rd nerve palsy, but was otherwise 57
Hansen et a1 Time course of symptoms Pain Diplopia Ophthalmwegia Case 1
---__ ......... --- _ -- - - - -* ......................
Vomilinglnausea Photophobia hL+-cH 3 weeks
6 weeks 6 weeks
days, the diplopia and ptosis for 7 weeks. Blood chemistries were normal, including ESR. In July 1986 she had and additional attack beginning with headache in the left temporal and frontal regions. The pain was intense; the quality was both pressing and pulsating. There was associated photophobia, but no nausea or vomiting. After 24 h the pain ceased, and the patient noticed diplopia when looking to the left. Ophthalmological examination revealed a left-sided abducens nerve palsy, but was otherwise normal. The patient was not referred to neurology. The diplopia lasted for 10 weeks and ceased gradually. No medical treatment was given. At follow-up in December 1986 no abnormality was found. She had had no further attacks. Case 5
---- -------- * ........................
Fig. 1. Time course of symptoms in 8 patients who had one or more attacks of ophthalmoplegic migraine. Note that headache
was the first symptom in all but one patient. It was severe in cases 1, 2, 4, 5 , 6 and 8 and medium in cases 3 and 7. Phonophobia was only noted in case 5. Headache was long-lasting in 4 cases and ophthalmoplegia was long-lasting in 6 cases.
normal. Complete blood cell count, blood chemistries and ESR were normal. Headache lasted 8 days, possibly shortened by aspirin treatment, but diplopia and ptosis lasted for 8 weeks. Follow-up examination revealed a slightly enlarged thyreoid gland, but no symptoms or signs of thyreotoxicosis. The neurological examination was normal. The patient had had one more attack of headache and diplopia in 1982, but was not admitted to hospital. The interval between onset of headache and diplopia was approximately 14 days. The pain was identical to the first attack. Diplopia and ptosis lasted for one month.
Seventeen-year-old woman seen in 1984. No family history of migraine. She had suffered from tension headaches and migraine without aura for at least 9 years. Migraine occurred with a frequency of 1 to 3 attacks per month. The pain was left-sided, severe, non-pulsatile, lasting for 1 or 2 days and associated with nausea, vomiting, photo- and phonophobia, but without aura. About 10 attacks of migraine after age 12 had been associated with ophthalmoplegia and diplopia, but always with complete recovery. The ptosis usually lasted for 1 to 13 days, the diplopia 1 or 2 days longer. During two of the attacks she was referred to the department of ophthalmology.Ophthalmological examinations showed a partial, left oculomotor palsy with normal pupillary reactions and size. The present attack started one week before admission to hospital. The pain was left-sided, severe, non-pulsatile and associated with nausea, vomiting, photo- and phonophobia, but without aura. After 24 h the pain subsided, and the patient experienced gradual closure of her left eye and diplopia in all directions. On examination there was a partial, leftsided, external oculomotor palsy with normal pupils. Laboratory tests were not performed. The ptosis and diplopia gradually subsided within 14 days. At follow-up December 1986both the neurological and the general physical examination were normal. She had one more attack in September 1986.
Forty-four-year-oldwoman seen in March 1984. No family history of migraine. She had suffered tension headaches for many years and had had a few migraine attacks without aura. She was admitted to the ophthalmological department with an attack of severe headache, photophobia, diplopia, ptosis and vertigo but no phonophobia or nausea beginning 3 to 4 days after pneumonia. The headache lasted for 2 58
Case 6: additional case history
One additional patient was seen 2 months after the study period. She is described here but otherwise not included because she had very variable attacks. It was a 33-year-old nurse who had been in perfect health until January 1981. She then developed double vision in the course of a few days. Ophthalmological examination revealed a complete left-sided
external oculomotor palsy with normal pupil and a complete left abducens palsy. There was no headache at any time. Carotid angiography, CT-scan and blood chemistry were all normal. The symptoms and signs disappeared completely in one month. In October 1986 she developed a left-sided temporal pressing, piercing headache, gradually increasing in intensity over 1 week. There was no associated nausea, photo- or phonophobia, but 1 week later she again developed a left-sided abducens and oculomotor nerve palsy sparing the pupil. This persisted while the headache disappeared in a few days. Two weeks later she was asymptomatic. August 1987 she had an episode similar to the one in 1981, and again without headache. A new CT-scan was normal as were hemoglobin, B 12, creatinine, electrolytes, serum-calcium, thyroid tests, tests for connective tissue disease, and chest X-ray. Four weeks later she was asymptomatic. She had recurrence of ophthalmoplegia without headache in December 1987, but on the right side. Multiple sclerosis was excluded by spinal fluid examinations for oligoclonal bands and IgG index, visual evoked potentials, somatosensory evoked potentials and MRI. The patient was finally seen in August 1988, when she had suffered from 2 weeks of increasing steady pain in her temporal regions shifting from day to day between the right and the left side. The pain was identical to the pain she had had in 1987 in association with oculomotor palsy, but this time there were no oculomotor symptoms. The headache disappeared spontaneously after 3 weeks, and the patient remains asymptomatic and with a completely unremarkable neurological examination. She does not suffer from migraine or tension headache apart from the specific episodes described above. This case history illustrates how the same patient can suffer from episodes of isolated ophthalmoplegia, isolated headache of the type usually accompanying ophthalmoplegic migraine, and finally a typical attack of ophthalmoplegic migraine with both oculomotor palsy and headache. Discussion Previous studies of ophthalmoplegic migraine
The definition of ophthalmoplegic migraine varies in the literature. Thus, Bickerstaff (2) required a complete 3rd nerve palsy, nausea and vomiting plus headache, but disregarded patients who have partial ophthalmoplegia sparing the pupil (4, 7, 9). Other reasons for headache and ophthalmoplegia should be ruled out, but the required level of paraclinical tests (CT, angiography etc.) varies. Some have required a past history of migraine or a family history of migraine and have thus disregarded similar cases without a history of migraine (4,7, lo).
Most published cases have had a history of migraine without aura (common migraine), but in the paper by Pearce (7) one patient suffered from migraine with aura (classic migraine). The sex ratio in ophthalmoplegic migraine has shown male predominance, contrasting with the female predominance in other forms of migraine. Pain has usually preceded ophthalmoplegia and has often been more long-lasting than in other types of migraine attacks. Ophthalmoplegia usually outlasted headache, most often with eventual full recovery, but our case 1 and some cases reported by others developed permanent deficits (2, 4, 7). Nosographic data and diagnostic criteria
In this study we tried to avoid selection bias by initially including all cases even vaguely resembling ophthalmoplegic migraine. Patients failing to meet our criteria at the follow-up examination were then excluded. We used the mildest possible criteria: one or more attacks of headache temporally overlapping with ophthalmoplegia in the absence of demonstrable organic lesion. Because of the retrospective nature of the study, the initial work-up was often less than optimal, but this was compensated by a long observation period and a follow-up examination. In the 8 cases fulfilling these criteria, we found an equal sex ratio. One patient suffered from migraine with aura (classic migraine) although there was no aura in association with the ophthalmoplegic attack. Pain was non-pulsating, usually long-lasting, severe, retro-orbital or periorbital and with nausea or photophobia in only half of the cases. These characteristics are different from what is usually seen in other forms of migraine, and in only 2 patients did ophthalmoplegic attacks fulfil formal criteria for migraine without aura (1 1). We report information about patients who could be suspected of having ophthalmoplegic migraine, but who had other reasons for their symptoms and thus confirm that many organic lesions can result in symptoms resembling ophthalmoplegic migraine. Extensive testing or, as in the present study, longterm follow-up are therefore necessary before the diagnosis of ophthalmoplegic migraine can be accepted. Furthermore, at least 2 attacks should be required to further reduce the possibility of overlooking an underlying organic lesion. Incidence of ophthalmoplegic migraine
The present study represents the first attempt to estimate the incidence of ophthalmoplegic migraine. It is essential whether 1 or 2 attacks are required, since 3 of 8 cases had only 1 attack. Probably because of scatter, all 4 cases from the study period 59
Hansen et al had 2 or more attacks whereas 3/4 cases from before or after the study period had only one attack as had the patient described in the additional case history. It therefore seems that approximately half of all patients are excluded if one requires 2 attacks. Accepting only cases where other reasons for ophthalmoplegia and headache have been ruled out and with at least 2 attacks, we have shown that ophthalmoplegic migraine is an extremely rare disorder, occurring about once every 2 years in a population of 1 million people. The present study is hospitalbased, and it is possible that some cases may not have been referred to a hospital and that the incidence is therefore higher than recorded. In Copenhagen County it is not customary, however, to accept the diagnosis of ophthalmoplegic migraine without referral to hospital, since practicing ophthalmologists and neurologists do not have access to CT-scanning or other advanced neuroradiological examinations. Including considerable scatter because of small numbers, the incidence found in the present study is therefore unlikely to be more than 2-3 times away from the true incidence. Is ophthalmoplegic migraine migrainous?
The characteristics of headache and the frequent lack of associated symptoms during so-called ophthalmoplegic migraine attacks indicate that the condition is not migrainous. On the other hand, what else could be responsible for the symptoms, with up to 50 recurring attacks (case2)? The most likely possibility appears to be an orbital or retro-orbital inflammatory reaction - the Tolosa-Hunt syndrome (6, 12, 13). This syndrome consists of recurring attacks of orbital and periorbital pain and ophthalmoplegia. The clinical characteristics of ophthalmoplegic migraine and Tolosa-Hunt syndrome cannot be clearly separated (6), and it is likely that diagnosing one or the other depends more on the doctor than on the patient. If ophthalmoplegic migraine is in fact a variant of the Tolosa-Hunt syndrome, why did 5 of the 8 patients have a past history of migraine? It can hardly be explained as occurring by chance, even considering the high prevalence (20%) of migraine in the population (14). Migraine patients are much more likely to respond with headache than non-migraineurs when challenged with dialysis (15) or histamine (16). We suggest that patients with a history of migraine are more likely to develop severe headache, nausea and photophobia if they are affected by the granulomatous retro-orbital inflammation of Tolosa-Hunt. Such patients will
usually be diagnosed as having ophthalmoplegic migraine. Patients who have not suffered from migraine usually will not develop severe headache, nausea and photophobia and are more likely to be diagnosed as having Tolosa-Hunt syndrome. Inflammatory genesis of ophthalmoplegic migraine is supported by our case 1 who, responded favourably to steroid treatment and several similar cases in the literature (1, 6, 8). Our “additional case” with isolated episodes of either ophthalmoplegia or pain or both, but with no family or personal history of migraine, is also more compatible with Tolosa-Hunt syndrome than with migraine. Systematic use of orbital phlebography and early steroid treatment in more cases of so-called ophthalmoplegic migraine could help to resolve this issue. However, the very low incidence of the disorder makes prospective studies difficult. References 1. ANDERSSONPG. Ophthalmoplegic migraine. Headache 1974: 14: 91-95. 2. BICKERSTAFF ER. Ophthalmoplegic migraine. Rev Neurol 1964: 110: 582-588. MP, MAZOW,ML. An unusual case of ophthal3. CRUCIGER moplegic migraine. Am J Ophthalmol 1978: 86: 414-417. 4. FRIEDMAN AP, HARTERDH, MERRITTHH. Ophthalmoplegic migraine. Arch Neurol 1962: 7: 320-327. 5. IMESRK, MONTEIROMLR, HOYTWF. Ophthalmoplegic migraine with proximal posterior cerebral artery vascular anomaly. J Clin Neuroophthalmol 1984: 4: 221-223. GW. Steroid-responsive ophthal6. KANDTRS, GOLDSTEIN moplegia in a child. Arch Neurol 1985: 45: 589-591. 7. PEARCE J. The ophthalmoplegical complications of migraine. J Neurol Sci 1968: 6: 73-81. 8. SMITHCH, REEVESAG. Amelioration of ophthalmoplegic migraine by prednisone: a case report. Headache 1986: 26: 93-94. 9. VIJAYANN. Ophthalmoplegic migraine: ischemic or compressive neuropathy? Headache 1980: 20: 300-304. 10. WALSHJP, ODOHERTY DS. A possible explanation of the mechanism of ophthalmoplegic migraine. Neurology 1960: 10: 1079-1084. 11. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988: 8 (suppl 7): 1-96. 12. HUNTWE, MEAGHER JN, LEFEVERHE, ZEMAN, W. Painful ophthalmoplegia. Neurology 1961: 11: 56-62. 13. HANNERZ J. Pain characteristics of painful ophthalmoplegia (the Tolosa-Hunt syndrome). Cephalalgia 1985: 5: 103-106. 14. NIKIFOROW R, HOKKANEN E. An epidemiological study of headache in a rural population in northern Finland. Headache 1978: 18: 137-145. 15. BANADS, YAPAE, GRAHAM JR. Headache during dialysis. Headache 1972: 12: 1-14. 16. KRABBEAW, OLESENJ. Headache provocation by continuous intravenous infusion of histamine; clinical results and receptor mechanisms. Pain 1980: 8: 253-259.