Headache 2012 American Headache Society

ISSN 0017-8748 doi: 10.1111/head.12019 Published by Wiley Periodicals, Inc.

Resident and Fellow Section

Morris Levin, MD, Section Editor Department of Neurology Dartmouth Hitchcock Medical Center, Lebanon, NH

TEACHING CASE: DIALYSIS HEADACHE Barbara Nye Resident in Neurology, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA Deborah E. Tepper, MD Cleveland Clinic Lerner College of Medicine, Center for Headache and Pain, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA This is a 61-year-old right-handed white female with past medical history of diabetes mellitus type 2, hypertension, obstructive sleep apnea, rheumatoid arthritis, psoriatic arthritis, non-alcoholic steatohepatitis, chronic anemia, nephrolithiasis, pyleonephritis with recent right nephrectomy, and end-stage renal disease (ESRD) (recently initiated on hemodialysis) who presented with 3 weeks of an intractable headache. She reported that the headache started several months prior to admission, approximately the time she started receiving hemodialysis. Prior to this, she did not get headaches and has no family history of migraines. She described the headaches as bifrontal, throbbing in quality, and lasting all day with associated nausea and vomiting, photophobia, and phonophobia. She denied any aura or focal neurological complaint associated with the headache. She had been admitted to outside hospitals 2 previous times and was treated with high-dose opiates, which caused excessive sedation, encephalopathy, and respiratory depression. Her previous work-up was negative for the most common secondary causes of headache. A computed tomography scan of the head was negative for infarction, hemorrhage or mass lesion. Magnetic resonance imaging/magnetic resonance venography of the brain
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were also negative, with no evidence of venous sinus thrombosis or meningitis. Spinal uid analysis showed no evidence of infection but was notable for a slightly elevated protein of 69. An electrocardiogram revealed atrial brillation (relatively new to the patient) that was rate-controlled on admission. Prior to transfer from the outside hospital to our facility, the patient received 2 g intravenous (IV) magnesium and had completed 5 days of high-dose methylprednisolone with no relief. Recent medications that had been trialed and discontinued included topiramate, lisinopril, amlodipine, and combination acetaminophen-butalbital-caffeine. Her medications on admission included aspirin 81 mg, uticasone, metoprolol tartrate 25 mg twice daily, nortriptyline 25/25/50 mg, gabapentin 100 mg three times daily, hydromorphone, and lorazepam. Patient is married and lives with her husband; she has never smoked and denied both alcohol and drug use. On admission, the patient had a low-grade fever of 100.6, blood pressure 98/48, pulse 99, and oxygen saturation 99% on room air. On physical examination, the patient appeared uncomfortable sitting in a darkened room. There were no signs of meningismus, with full range of motion in her neck and no occipital nerve tenderness. Heart had a regular rhythm with no murmurs rubs or gallops, and her lungs were clear to auscultation. She had an arteriovenous stula in the left arm. Neurological examination showed normal mental status and no cranial nerve abnormalities. Fundoscopic examination was also unrevealing. She had normal symmetric strength, normal reexes, and normal sensory exam; gait was stable. Basic labs on admission were remarkable only for an elevated blood urea nitrogen and creatinine.

182 The patient was initiated on a modied Raskin protocol consisting of diphenhydramine 25 mg, metoclopramide 10 mg IV, and dihydroergotamine (DHE) 1 mg IV administered 3 times daily. She responded well, with a reduction in headache pain from 7/10 on admission to a 4/10 the following day. She had an exacerbation of her headache during dialysis on hospital day 2 but otherwise continued to improve. Patient was titrated off both the hydromorphone and lorazepam to remove any possible effects of a medication overuse headache that could be contributing to her status migrainosus. Gabapentin was discontinued as well. She was initiated on treatment with topiramate 25 mg qhs with plans to increase by 25 mg weekly to a nal dose of 200 mg qhs. As an additional preventative measure, she was pretreated with chlorpromazine (CPZ) 50 mg PO prior to dialysis to help reduce the intensity of the headaches she developed during dialysis. The patients hospital course was prolonged because she developed atrial brillation with rapid ventricular response, pulmonary edema, and hypoxia. She required transfer to the medicine service for further management. She continued to have good response to her regimen. The topiramate was discontinued during the hospitalization as she developed a leukopenia. She was discharged home after a 2-week hospitalization on a regimen of nortriptyline 50 mg at night and magnesium oxide 200 mg twice a day for headache prevention, and CPZ 50 mg to be taken prior to dialysis. On follow-up, 6 months after admission, the patients headaches were well controlled. She continued to take the magnesium oxide for prevention but had to discontinue the nortriptyline as she felt it was causing her to be loopy. She continued to premedicate with CPZ prior to her dialysis treatments.

January 2013 and vascular disease have increased, combined with people living longer. Between 1980 and 2009, the prevalence of ESRD increased by almost 600%, and by December 2009, more than 871,000 people were being treated for ESRD. Since 2009, with more aggressive treatment of chronic kidney disease, the incidence rate of ESRD has actually plateaued.1 ESRD patients predialysis are likely to have the same prevalence of migraine as the general population, about 11.7% (17.1% in women and 5.6% in men).2 It is estimated that about 70% of patients undergoing dialysis develop headaches.3 This means that doctors treating headache disorders will probably be evaluating and treating more patients than ever with dialysisrelated headaches, as well as those on dialysis with pre-existing headache disorders. In a study of dialysis-related headache in 123 patients in Brazil, 50 developed headaches during the dialysis session, of which 34 were classied as dialysisrelated headaches and only 7 of which were said to have migraine. However, of the 34 hemodialysis headaches, 19 resembled migraine without aura.4 The authors concluded that the current overlap between dialysis-related headache and other headache disorders suggests the need for more precise diagnostic categories within the dialysis-related headache disorder classication. Others have suggested that the dialysis-related headache disorder be abandoned entirely, as dialysis is just another stressor likely to trigger headaches of all kinds, including migraine and tension-type. These authors feel that dialysis-related headache is not a reliable diagnosis because headaches with dialysis are most often seen in those with a history of headaches, the headaches similar in quality to those on and off dialysis, and not resolving with kidney transplantation.5 Diagnostic Conundrums.The patient in this case was not said to have a history of migraine, but her headaches, which started with her dialysis, met the criteria for migraine by the International Classication of Headache Disorders, 2nd edition criteria (ICHD-2) in that they were throbbing, moderate to severe, and accompanied by photophobia, phonophobia, and nausea, and lasted 4-72 hours.6 The diagnostic criteria for 1.1 migraine without aura per ICHD-2 criteria require:

EXPERT COMMENTARY Deborah E. Tepper, MD Clinical Instructor, Cleveland Clinic Lerner College of Medicine, Center for Headache and Pain, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA Renal failure and resulting dialysis are increasingly prevalent, as the rate of obesity, diabetes type 2,

Headache A. 5 attacks with B. Headache 4-72 hours duration with C. 2 of: 1. Unilateral 2. Throbbing 3. Moderate or severe 4. Worsened by routine physical activity and D. 1 of: 1. Nausea 2. Photophonophobia E. Not attributed to another disorder6 The last criterion not attributed to another disorder is problematic because the patient in question never had migraine before dialysis and only had her headaches with dialysis. Therefore, one cannot say that this is a primary headache disorder, required in the diagnosis of migraine without aura. Instead, her attacks could be classied as a secondary headache disorder, despite meeting criteria for A-D criteria for primary migraine. In fact, in the ICHD-2, there is a secondary headache disorder that ts this patient. Postdialysis headache is a headache attributed to the secondary trigger of dialysis, coming under the ICHD-2 category of headaches attributed to disturbances in homeostasis (Chapter 10, ICHD-2) 6. 10.2 Dialysis Headache Diagnostic criteria: A. 3 attacks of acute headache with B. The patient on hemodialysis C. Headache develops during 50% of hemodialysis sessions D. Headache resolves within 72 hours after each hemodialysis session or stops after successful transplant We are left with 2 headache disorders. Because she meets all criteria for 10.2 Dialysis Headache, that diagnosis comes rst, but then add 1.1 Migraine without aura as a secondary diagnosis. Her migraine without aura actually is probable migraine without aura; in that, it is missing 1 criterion, that of excluding secondary causes. Treatment of Dialysis Headache.There is a paucity of controlled data on how to treat dialysis-

183 related headaches. There are case reports only for amitriptyline and angiotensin-converting enzyme inhibitors.7 There are consistent suggestions to maintain a euvolemic state, correct any metabolic derangement, and avoid a caffeine-withdrawal headache, likely to occur if a patient takes in a great deal of caffeine and has it dialyzed off.8 Treatment might take into account another theory for etiology of dialysis-related headache, that is, the increase in nitric oxide that peaks between the third and fourth hour of dialysis, along with other pain inducers, such as bradykinin.9 For this patient, the doctors chose to pursue treatment typical for migraine prevention in general, and this appears to have been successful. She was given topiramate, nortriptyline, and magnesium as preventive medications and was treated acutely at dialysis sessions with CPZ. Nortriptyline caused side effects, as did topiramate, and gabapentin apparently did not show benet. The potential benet of magnesium in dialysis patients is supported by a study of 75 patients with hemodialysis-related headache per ICHD-2 criteria. This study excluded all patients with a primary headache disorder. The principle risk factor for the dialysisrelated headache appeared to be lower magnesium levels both predialysis and postdialysis, and higher sodium levels. The authors found these risks in dialysis-related headache patients compared with controls who did not have headaches associated with their dialysis.10 The magnesium as a sole preventive medication worked, and there is no need to go further, but if she begins to break through despite the regimen, another potential treatment might be onabotulinumtoxin A, as her headaches are just at a frequency of 15 or more days per month, the suggested threshold for chronic migraine. Onabotulinumtoxin A would have the advantage of avoiding systemic side effects or medication interactions, although its use has not been tested in dialysis-related chronic daily headache. I agree with the authors that the hydromorphone and benzodiazepines should be discontinued, as they add the potential complications of medication overuse headache and cognitive impairment. If she were getting these medications with each dialysis session, it would be more than enough to result in rebound, given the

184 thrice weekly treatments. Using opioids 8 or more days per month can induce chronication of migraine, and it would be important to rule this out as a contributing factor in her current pattern of headaches.11 The use of CPZ has been examined for acute treatment of multiple types of headaches. In a small, double-placebo trial in 2002, Bigal et al found that IV CPZ was effective for tension-type headache.12 Also in 2002, these authors conducted a double-blind placebocontrolled trial of 68 patients in the Emergency Department who had been diagnosed with migraine with and without aura. They found a statistically signicant improvement in pain, photophobia, phonophoia, and nausea (P < .01) using a single IV injection of CPZ at 1 mg/kg dosage.13 CPZ has also been used successfully for acute treatment of post-traumatic headache,14 meningitis-related headache,15 and headaches associated with subarachnoid hemorrhage and subdural bleed.16 Although explicit studies are lacking on the use of CPZ in dialysis headache, it can be surmised that CPZ works on multiple headache types without specicity to etiology. Neuroleptic pain relief is believed to stem from several sources, including agonist action on the postsynaptic dopamine receptors in the limbic system and basal ganglia. CPZ has antihistaminergic, antiadrenergic, anticholinergic, and antiserotonergic actions, serving as a non-narcotic pain agent and anti-emetic.17 In summary, this patient developed a dialysisrelated headache with de novo probable migraine. Her successful treatment with magnesium as a preventive medication and CPZ as an acute treatment has experimental and experiential basis in the literature, although there is a paucity of randomized, control trial literature specic to the treatment of dialysis headache.

January 2013
2. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68:343-349. 3. Bana DS, Yap AU, Graham JR. Headache during hemodialysis. Headache. 1972;12:1-14. 4. Antoniazai AL, Bigal ME, Bordini CA, Tepper SJ, Speciali JG. Headache and hemodialysis: Prospective study. Headache. 2003;43:99-102. 5. Binik YM, Baker AG, Kalogeropoulos DK, et al. Pain, control over treatment, and compliance in dialysis and transplant patients. Kidney Int. 1982;21: 840-848. 6. Headache Classication Subcommittee of the International Headache Society. The International Classication of Headache Disorders: 2nd Edition. Cephalalgia. 2004;24(Suppl. 1):9-160. 7. Leinisch-Dahlke E, Schmidt-Wilcke T, Kramer BK, May A. Improvement of dialysis headache after treatment with ACE inhibitors but not angiotensin II receptor blocker: A case report with. Cephalalgia. 2004;25:71-74. 8. Nikic PM, Zidverc-Trajkovic J, Andric B, Milinkovic M, Stojimirovic B. Caffeine-withdrawal headache induced by hemodialysis. J Headache Pain. 2009;10: 291-293. 9. Antoniazzi AL, Evans RW. Headaches and hemodialysis. Headache. 2009;49:463-466. 10. Goksel BK, Torun D, Karaca S, et al. Is low blood magnesium level associated with hemodialysis headache? Headache. 2006;46:40-45. 11. Bigal ME, Lipton RB. Overuse of acute migraine medications and migraine chronication. Curr Pain Headache Rep. 2009;13:301-307. 12. Bigal ME, Bordini CA, Speciali JG. Intravenous chlorpromazine in the acute treatment of episodic tension-type headache. Arq Neuropsiquiatr. 2002;60: 537-541. 13. Bigal ME, Bordini CA, Speciali JG. Intravenous chlorpromazine in the emergency department treatment of migraines: A randomized controlled trial. J Emerg Med. 2002;23:141-148. 14. Herd A, Ludwig L. Relief of posttraumatic headache by intravenous chlorpromazine. J Emerg Med. 1994;12:849-851. 15. Fernandes CM. Parenteral chlorpromazine and a meningitis headache. J Emerg Med. 1995;13:577-579. 16. Barclay CL, Shuaib A, Montoya D, Seland TP, Thomas HG. Response of non-migrainous

REFERENCES
1. National Kidney and Urological Diseases Information Clearing House. Kidney Disease Statistics for the United States. Bethesda: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; 2012:NIH Publication No. 123895.

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headaches to chlorpromazine. Headache. 1990;30: 85-87. 17. Kelley NE, Tepper DE. Rescue therapy for acute migraine, part 2: Neuroleptics, antihistamines, and others. Headache. 2012;52:292-306.

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QUESTIONS FOR DISCUSSION

1. Should the concept of dialysis-related headache disorder be abandoned and reframed as just another trigger for headaches including migraine? Would this case support that? Why? 2. Was the diagnostic work-up for this patients persistent headaches appropriate? Is there other diagnostic testing that might have been important? 3. What considerations must be kept in mind regarding pharmacological treatment of headache patients with renal disease? Patient undergoing hemodialysis? 4. Does the probable migraine label make sense when it occurs only following an instigating factor, such as trauma, infection, or, in this case, presumed metabolic disturbance? This case presentation and discussion meets the ACGME requirements for residency training in the following core competency areas: patient care, medical knowledge, practice-based learning and improvement, and systems-based practice.

EDITORS COMMENTS Dr. Teppers comprehensive review of dialysisrelated headaches is an excellent summary of the state of knowledge about these headaches. This condition serves as a not-uncommon cause for inpatient neurology consultation, not to mention a great deal of suffering on the part of dialysis patients who certainly need no more disincentives for undergoing this procedure several times each week.The case presented here by Dr. Nye is interesting in its close resemblance to typical migraine with aura in many ways, and response to IV DHE, a reliable migraine treatment. Presumably, clues to the mechanisms behind these headaches might be found here, but data is so sparse at present we cannot yet draw rm conclusions. Fortunately, despite this, many of these patients respond well to creative approaches to treatment as illustrated by Drs. Nye and Tepper.