Headache and Methemoglobinemia

Article type : Headache Currents

Title: HEADACHE AND METHEMOGLOBINEMIA

Author:

Fawad Ahmed Khan, MD1,2,3 [email protected] Caley McIntyre, MD4,2 [email protected] Abdul Mukhtadir Khan, MD5 [email protected] Alexander Maslov, MD2 [email protected]

1The McCasland Family Comprehensive Headache Center, Ochsner Neuroscience Institute, Ochsner Clinic Foundation, New Orleans, LA, USA 2The University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA, USA 3Tulane University School of Medicine, New Orleans, LA, USA 4Department of Hospital Medicine, Ochsner Clinic Foundation, New Orleans, LA, USA 5Department of Pulmonary and Critical Care Medicine, Ochsner Clinic Foundation, New Orleans, LA, USA

Corresponding Author: Fawad Ahmed Khan, MD, Ochsner Neurosciences Institute, 1514 Jefferson Highway, 7E222, New Orleans, LA, USA 70121. Tel: (504) 842-3980. Email: [email protected] Tel: (504) 842-3980 Author Manuscript

Abstract: This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/HEAD.13696

Aim: This basic review is intended to summarize the current knowledge of methemoglobinemia as an important cause of secondary headache with the hope of generating a growing interest in studying this phenomenon. Background: We describe the pathological underpinnings of headaches generated by hypoxia. Possible mechanisms include cerebral vasodilation associated stretching of the vessel nociceptors, sensitization of perivascular nociceptors mediated by nitric oxide, cerebral calcitonin gene-related peptide (CGRP), activation of the cyclic adenosine monophosphate pathway, cortical spreading depression, disruption of the blood-brain barrier, and neurogenic inflammation. We review the clinical features, pathophysiology and management of methemoglobinemia. We conducted a literature review of reports of symptomatic methemoglobinemia with headache. In addition, we describe a case report of a patient who presented with an acute onset of severe holocranial headache associated with rapidly progressive perioral paresthesia, cyanosis in lips and hands, nausea, and mild dyspnea on exertion. These features can be misinterpreted as an acute attack of migraine with pain related hyperventilation syndrome and anxiety leading to clinically detrimental delay in the management of the progressive hypoxia. Her symptoms resolved following treatment with methylene blue. The complex relationship of migraine and hypoxia related headaches is also reviewed. We propose that methemoglobinemia associated headaches are possibly generated by stretching of the nociceptor nerve endings during cerebral vasodilation and hypoxia mediated oxidative stress. Conclusions: The case highlights the need to broaden the formulated differential diagnosis of an acute onset severe holocranial headache and pay careful attention to other signs and symptoms that may provide hints on potential mechanism(s) for secondary headaches. We provide justification for the need to incorporate ‘Headache attributed to Methemoglobinemia’ as a subtype under the section “Headache attributed to hypoxia and/or hypercapnia” of the International Classification of Headache Disorders (ICHD) to support clinical decision making.

Key words: secondary headaches

methemoglobinemiaAuthor Manuscript cyanosis hypoxia methemoglobin percentage

ICHD

Conflict of Interest Statement: Fawad Ahmed Khan has received funding for research from Amgen; funding for travel and speaking from Amgen, Allergan, Teva Pharmaceuticals, Eli-Lilly and Company, Electrocore, Promius Pharma, and Depomed; holds a patent for a diagnostic device with Ochsner Health System (not related to the content of this review). Caley McIntyre, Abdul Mukhtadir Khan, and Alexander Maslov declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

HEADACHE AND METHEMOGLOBINEMIA

Methemoglobinemia is a pathological clinical entity characterized by an increased fraction of methemoglobin in the blood, leading to impairment of normal oxygen exchange with tissues.

Pathophysiology and Epidemiology

Methemoglobin is a form of hemoglobin where the iron contained in the heme moiety has been oxidized from ferrous (++) to ferric (+++) state, preventing the reversible binding of oxygen.1 Under normal physiological conditions, only small amounts of methemoglobin are present in circulation, as the ferric iron is reduced primarily via nicotinamide adenine dinucleotide + hydrogen (NADH)-cytochrome b5 reductase, with a secondary pathway via Nicotinamide adenine dinucleotide phosphate + hydrogen (NADPH)-methemoglobin reductase.2,3 However, in the presence of persistent oxidative stress or impaired reduction of iron back to a ferrous state, levels of methemoglobin can rise into a pathological range, leading to Author Manuscript functional anemia and decreased oxygen caring capacity.4

Both congenital and acquired forms of methemoglobinemia have been recognized. Congenital causes include gene mutations causing NADH-cytochrome b5 reductase deficiency5 or NADH- cytochrome b5 deficiency,6 both of which lead to impairment of methemoglobin reduction. Additionally, several known genetic mutations lead to abnormal hemoglobin variants, collectively termed Hemoglobin M, which are resistant to normal enzymatic reduction.7

Acquired methemoglobinemia occurs in the setting of oxidative stress, most frequently due to medications or other chemicals. Commonly implicated exposures include dapsone, topical anesthetics (e.g. benzocaine), nitrates/nitrites, and aniline dyes.8,9,10,11,12,13

Limited data exists on the incidence of methemoglobinemia, though both acquired and congenital forms are considered rare clinical entities. Retrospective studies of patients undergoing endoscopic procedures with the use of topical anesthetics have shown rates of diagnosed methemoglobinemia in less than 0.1% of cases.14,15

Clinical presentation and Diagnosis

Signs and symptoms of methemoglobinemia are largely attributable to tissue hypoxia from ineffective delivery of oxygen in the setting of elevated methemoglobin levels. Symptom severity correlates with methemoglobin percentage (see Table 1).4,16 Underlying comorbidities affecting tissue oxygenation, such as anemia, chronic pulmonary disease, or heart failure can lead to more severe symptomatology at lower methemoglobin levels. Patients with congenital methemoglobinemia, in contrast to those with acquired methemoglobinemia, may remain asymptomatic or present with isolated cyanosis at relatively elevated baseline methemoglobin levels.

While most findings are relatively non-specific, several features are suggestive of methemoglobinemia. Chocolate brown blood, which does not change color with exposure to air, Author Manuscript is a unique finding associated with elevated levels of methemoglobin. A “saturation gap”, measured as the difference between the oxygen saturation measured by pulse oximetry and arterial blood gas analysis, is often present (a difference of >5% is considered

Diagnosis is confirmed by arterial or venous blood gas with co-oximetry, which additionally quantifies the concentration and percentage of methemoglobin.

Treatment

Management of methemoglobinemia depends on the severity of symptoms, level of methemoglobin, and reversibility of its cause. In general, suspected causative agents should be discontinued, and high flow oxygen should be provided. In cases with limited clinical findings and methemoglobin levels below 20%, no further treatment may be required.

Patients with acquired methemoglobinemia who are symptomatic or who have methemoglobin levels above 20% should be considered for treatment with methylene blue, which enhances heme reduction via the secondary NADPH-methemoglobin reductase pathway to rapidly decrease levels of methemoglobin. Methylene blue can be given intravenously at a dose of 1 to 2 mg/kg for 5 minutes.4 The maximum effect of methylene blue occurs quickly, at 30 minutes.17. Additional doses may be repeated if further reduction of methemoglobin is required.18,19 Incomplete discontinuation of the inciting exposure such as the offending agent in the gastrointestinal tract, or alternative diagnoses should be considered if methemoglobin levels do not decline rapidly in response to methylene blue treatment.20

Possible complications of treatment with methylene blue include hemolysis (particularly in patients with G6PD deficiency),21 serotonin syndrome in patients taking serotonergic medications (due to inhibition of monoamine oxidase A),22 and benign blue or green discoloration of the urine.23 Additionally, methylene blue is labeled by the FDA as pregnancy category X due to teratogenic and fetotoxic effects.24 Author Manuscript

Case Report of a Patient with Methemoglobinemia and Acute Headache

We describe a patient with a history of methemoglobinemia who was recently hospitalized at our institution for the symptomatic management of acute onset of headache that accompanied the symptoms of methemoglobinemia. She is 38-years-old and has a past medical history of attention deficit disorder, hypothyroidism, anemia, chronic migraine headaches without aura on topiramate 200 mg per day and scheduled onabotulinumtoxinA injection therapy, and cervicogenic headaches following whiplash injury. In the last 6 years leading up to the current evaluation she experienced 6 episodes of methemoglobinemia secondary to various external causes. Glucose-6-phosphate dehydrogenase mutation testing was negative. The causes of methemoglobinemia included dapsone treatment for urticaria, an unknown source of arsenic exposure, use of a local anesthetic, ingestion of food containing nitrates, topical cosmetics containing nitrates, and one unknown trigger. During five of the six documented hospital admissions related to methemoglobinemia, she described rapid onset of diffuse cyanosis (involving lips, hands, and feet), progressively worsening hypoxia, and holocranial headache. All the symptoms abated with methylene blue infusion and supplemental oxygen during each episode.

We reviewed her most recent episode of methemoglobinemia. She presented to the emergency room with rapidly progressive perioral paresthesias, cyanosis in lips and hands, holocranial headache with intensity of 10 on a 0-10 scale described a deep pressure sensation (“as if I was deep under water / scuba diving”), nausea, and dyspnea on exertion. She denied any new medication use, exposure to herbal compounds, fever, chest pain, visual disturbances, cognitive, or neurological symptoms. She quickly recognized that her symptoms were related to methemoglobinemia and attributed the exacerbation to ingestion of bacon during breakfast on the day of the presentation. Her physical examination revealed tachycardia, labored breathing, and acral cyanosis, and peri-oral cyanosis. The remainder of her exam was unremarkable. Her arterial blood gas parameters were pH 7.415, PCO2 39.1 mmHg, PO2 34.4 mmHg, bicarbonate 24.5 mmol/L, oxygen saturation 90% on room air, and methemoglobin level of 30.6% (normal reference range:0.0 - 1.5 %). Blood hemoglobin and hematocrit were 12.2 g/dL and 37%, Author Manuscript respectively. She was immediately treated with oxygen supplementation with nasal canula and 50 mg of intravenous methylene blue. The repeat arterial blood gas 3 hours later revealed the

This article is protected by copyright. All rights reserved 7 following: pH 7.411, PCO2 37.3 mmHg, PO2 43.2 mmHg, bicarbonate 23.2 mmol/L, oxygen saturation 95% on 2-liter oxygen, and methemoglobin level of 10%.

She was admitted to the hospital. The methemoglobin level increased from 10% to 22.7% on the following day. This prompted treatment with an additional dose of 50 mg of intravenous methylene blue on day two of the hospitalization. Within 6 hours of the treatment the methemoglobin level decreased to 6.4%. On day three the methemoglobin level was 6.1%.

For the symptomatic management of the headache she received four doses of 1 mg intravenous hydromorphone on the day of admission followed by 1000 mg of intravenous acetaminophen every 8 hours. In addition, she was initiated on a patient-controlled analgesia (PCA) with intravenous morphine with provision for 1 mg intravenous boluses every 12 minutes. For the symptomatic management of nausea, she received 4 mg of oral ondansetron every 8 hours. She also received 2000 mg of ascorbic acid daily.

Her clinical presentation improved during the hospitalization, and she was discharged home in stable condition with counselling on dietary habits on day three. Oxygen supplementation was successfully weaned off by day two. Her headache, cyanosis and shortness of breath dramatically improved by the end of day two and coincided with the decrease in the methemoglobin level. The morphine and acetaminophen were successfully discontinued. On discharge she reported resolution of shortness of breath and nausea and a minimal headache ranging from 0 to 2 on a 0- 10 scale. On a follow up clinic visit 7 days after discharge she reported complete resolution of headache.

Discussion

Our patient presented with acute onset of methemoglobinemia within hours of ingestion of nitrate containing food. Her symptoms included perioral paresthesias, cyanosis in lips and hands, Author Manuscript severe holocranial headache, nausea, and dyspnea on exertion. Fortunately, she was able to quickly identify her symptoms as an episode of methemoglobinemia based on previous presentations. Had this not been the case, her clinical presentation would have been easily

This article is protected by copyright. All rights reserved 8 misdiagnosed as an acute migraine attack (common practice patterns) supported by the medical history of migraine headaches. The paresthesias, cyanosis, and shortness of breath would have been misinterpreted as pain related hyperventilation syndrome and anxiety. The working diagnosis would have led to symptomatic migraine management and clinically detrimental delay in the management of the progressive hypoxia. This case highlights the need to broaden the differential diagnosis of an acute onset of severe holocranial headache as a secondary headache and pay careful attention to other signs and symptoms that may provide hints on potential etiologies of secondary headaches.

During five of the six documented hospital admissions related to methemoglobinemia, she described an associated rapid onset severe holocranial headache. The headache resolved with the resolution of the cyanosis and coincided with the decline in the methemoglobinemia levels. The progressive hypoxia may have been the primary contributor of the reported holocranial headaches, which were different from her typical migraine headaches. It is possible that the pathophysiological underpinnings of migraine rendered an increased susceptibility to the reported hypoxia generated headache. Mechanisms that may play a role in this phenomenon include a relatively greater reactivity and sensitivity of intracranial vessels to hypoxia in migraine sufferers25,26,27,28 and/or amplified responses to changes in blood oxygenation of brain areas implicated in the processing of head and neck pain.29,30,31,32 Future controlled studies on this select population are needed to improve our understanding of the complex relationship of migraine and cortical responses to decline in oxygenation.

Literature Review of Methemoglobinemia Cases with Headache

We identified references in Medline (Pubmed) using the search terms “Methemoglobinemia” AND “Headache” in the subsections of title search from a period of January 1, 1969 through July 1, 2019. The PubMed search was limited to English language and human literature only. Case reports and letters were included only if they added significant information. Author Manuscript We initially identified 34 reports from Medline (Pubmed) database. We included 8 studies in this review after assessing the content for the reporting of cases wherein headache was explicitly reported during the clinical presentation of methemoglobinemia. Three reports describing acute

onset of headache with methemoglobinemia were excluded as the cause of the headache may have been confounded by the precipitating factor for methemoglobinemia. These included attempted suicide by ingestion of copper fungicide,33 rapid increase in serum dapsone levels,34 and toxic inhalation of aniline and p-toluidine vapor.35

Two case series and 6 case reports were reviewed (see Table #2). No patients in this review had a reported prior history of migraine. The age range spanned 4 to 72 years. No study provided any descriptive details of the nature or features of the headache. In 5 case reports, a near immediate improvement of the headache and other symptoms was noted following the treatment of the methemoglobinemia. Three case reports provided no information on the clinical resolution of the reported headaches.

Pathophysiology of Headache in Methemoglobinemia

Methemoglobinemia is characterized by the conversion of iron from ferrous (++) to a ferric (+++) state in the hemoglobin. To defend this process, the body reduces iron back to a ferrous (++) state. If this balance is disrupted, the body accumulates methemoglobin, leading to a methemoglobinemia state.13,36 With the inability to properly transport oxygen, tissue and cellular hypoxia develop, thus leading to the myriad of clinical symptoms including headache. Headache is also commonly associated with other conditions that are characterized by hypoxia. Headaches in high-altitude induced hypoxia, obstructive sleep apnea with oxygen desaturation, and chronic obstructive pulmonary disease related chronic hypoxemia have been described.37,38,39 Headache was also reported in an experimental model of normobaric hypoxia in healthy volunteers. Eighty one percent and seventy one percent of the participants developed headache at six or 12 hours, respectively, after the start of normobaric hypoxia.40

The origin of the headache from hypoxia is proposed to be in the intracranial blood vessels. Brain hypoxia is hypothesized to increase cerebral blood flow via increased cerebral blood vessel

41 dilation. The cerebralAuthor Manuscript vasodilation in response to hypoxia may lead to temporary stretching of the vessel nociceptors, producing a temporary headache that can be reversed with reversal of vasodilatation.42,43,44 Additionally, sensitization of perivascular nociceptors may be the primary underlying mechanism of the headache, in conjunction with the vessel mechanical dilation. The

This article is protected by copyright. All rights reserved 10 sensitization may occur via release of nitric oxide (which also contributes to the vasodilatation),45 cerebral calcitonin gene-related peptide levels (which may contribute to both neuro-inflammation and vasodilatation),46 and activation of the cyclic adenosine monophosphate pathway.47 Other proposed mechanisms that can provoke headache in the setting of hypoxia include cortical spreading depression, disruption of the blood-brain barrier, and neurogenic inflammation mediated by pro-inflammatory mediators such as bradykinin, cytokines, and oxidative stress.44

The pathophysiology of headache in methemoglobinemia remains largely unknown. We propose that in methemoglobinemia two mechanisms may play a role in the generation of headache. One may be the stretching of the nociceptor nerve endings associated with cerebral vasodilation in response to hypoxia. A second would be hypoxia-related oxidative stress activating a domino cascade leading to neuronal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, a potent pro-oxidant that has been reported to produce neuroinflammation and migraine headaches.48

The mechanisms responsible for headache in patients with migraine may be more complex. In migraine the trigeminovascular/trigemino-autonomic model of headache offers greater credibility in explaining the mechanisms of pain as the model directly translates to humans. According to this model the vessel (artery or dural sinus), is an agent in the generation and transmission of headache pain, through sensory, effector, and vasomotor functions.49,50 Methemoglobinemia induced hypoxia may trigger the cerebral vessels to initiate migraine processes, thus explaining the acute onset of headache and nausea. It must be noted that the influence of migraine and other primary headache disorders in the generation of methemoglobinemia associated headache, and the susceptibility thereof, has not been reported in the literature. Systematic research targeted at exploring these associations and factors responsible is warranted.

Methemoglobinemia and the Scope of the International Classification of Headache

Disorders (ICHD)Author Manuscript

The recent advances in the science and discovery of systemic influences on the trigeminovascular complex, the meninges, and the various pain efferent structures in the head

This article is protected by copyright. All rights reserved 11 and neck has broadened our understanding of secondary headaches. This review is intended to further enhance the comprehensiveness and generalizability of the ICHD-351 as it pertains to secondary headaches related to hypoxia, specifically from methemoglobinemia.

We propose that the addition of ‘Headache and Methemoglobinemia’ as a sub class in the classification of secondary headache is warranted and justified by the current literature. The recognition of this entity serves the purpose of allowing for an accurate classification of headaches that present in patients with symptomatic methemoglobinemia. Furthermore, the awareness and accessibility of this sub class in a universally accepted classification of headache disorders can support the clinical decision making and diagnostic planning for headaches associated with cyanosis, thus allowing for early intervention to improve the clinical outcome.

We emphasize the need to incorporate headache associated with cyanosis as a ‘red flag’ in the systematic evaluation of patients presenting with headaches. We are optimistic and fully support the scientific community’s future efforts to develop the ICHD-4. For this endeavor, we strongly urge the designated committee members to incorporate ‘Headache attributed to Methemoglobinemia’ in the proposed classification. In the current structure of the classification an appropriate addition of this entity would be listed as: subtype ‘10.1.5 Headache attributed to Methemoglobinemia’ under subtype section 10.1 Headache attributed to hypoxia and/or hypercapnia.

Evaluating Acute Secondary Headaches and the Role of the Headache Specialist

In accordance with principles of good clinical practice, an astute clinician with a sound knowledge of primary and secondary headaches should be equipped with the skills to seamlessly characterize the subtleties of common and uncommon headache presentations. Headache specialists are expected to be well versed with the ICHD. Cognizance of the classification of headaches aids in the conceptualization of the various systemic pathological processes that may Author Manuscript impact head and neck pain. In the evaluation of an acute headache without features of a primary headache disorder, the availability of a headache specialist, at the time of the initial presentation

or during subsequent consultation, is undoubtedly invaluable in rendering a time sensitive working differential diagnosis that can guide the employment of emergent treatment strategies. The lack of knowledge of secondary headaches, on the other hand, often leads to oversight of systemic disease processes and other contributing factors responsible for the generation of headaches. Such oversight can have unintended consequences in emergent settings.52

Clinical Highlights

1. Methemoglobinemia can be associated with neurological manifestations including headache, anxiety, altered sensorium, seizures, and coma. 2. Headache as a clinical presentation of symptomatic methemoglobinemia may be acute in onset and holocranial in nature and tends to resolve with normalization of methemoglobin levels. 3. Knowledge of methemoglobinemia as a secondary cause of headache in a patient presenting with acute headache and cyanosis is critical in the timely diagnosis of methemoglobinemia and can mitigate the consequences of rapidly progressive hypoxia. 4. We support the addition of ‘Headache attributed to Methemoglobinemia’ under the ICHD classification subtype - 10.1 Headache attributed to hypoxia and/or hypercapnia. 5. The underpinnings of hypoxemia related headaches are complex. An understanding of the role of methemoglobinemia on the brain and cerebral blood vessels will shed light on mechanisms involved in the pathogenesis of headache attributed to disorder of homoeostasis.

References.

1. Jaffé ER. Methemoglobin pathophysiology. Progress in Clinical and Biological Research. 1981;51:133-151. 2. Mansouri A and Lurie AA. Methemoglobinemia. Amer J Hematol (1993;42:: 7-12. 3. Barclay JA, Ziemba SE, Ibrahim RB. Dapsone-induced methemoglobinemia: a primer for

clinicians. Ann Pharmacother.Author Manuscript 2011;45:1103-15. 4. Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: etiology, pharmacology, and clinical management. Ann Emerg Med. 1999; 34: 646–656. 5. Percy MJ, Lappin TR. Recessive congenital methaemoglobinaemia: cytochrome b(5) reductase deficiency. Br J Haematol.2008;141:298-308.

6. Hegesh E, Hegesh J, Kaftory A. Congenital methemoglobinemia with a deficiency of cytochrome b5. N Engl J Med. 1986; 314:757-61. 7. Marengo-Rowe AJ. Structure-function relations of human hemoglobins. Proc (Bayl Univ Med Cent). 2006;19:239–245. 8. Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine. 2004;83:265–73. 9. Hegedus F, Herb K. Benzocaine-induced methemoglobinemia. Anesth Prog. 2005;52:136– 139. 10. Walley T, Flanagan M. Nitrite-induced methaemoglobinaemia. Postgrad Med J. 1987;63(742):643–644. 11. Fawns HT, Aldridge AG. Methaemoglobinaemia due to nitrates and nitrites in drinking- water. Br Med J. 1954;2(4887):575–576. 12. Fairbanks VF. Blue gods, blue oil, and blue people. Mayo Clin Proc. 1994;69:889–892. 13. Skold A, Cosco DL, Klein R. Methemoglobinemia: pathogenesis, diagnosis, and management. South Med J 2011; 104: 757-761. 14. Chowdhary S, Bukoye B, Bhansali AM, Carbo AR, Adra M, Barnett S Aronson MD, Leffler DA.. Risk of topical anesthetic-induced methemoglobinemia: a 10-year retrospective case- control study. JAMA Intern Med. 2013;173:771-776. 15. Kane GC, Hoehn SM, Behrenbeck TR, Mulvagh SL. . Benzocaine-induced methemoglobinemia based on the Mayo Clinic experience from 28 478 transesophageal echocardiograms—incidence, outcomes, and predisposing factors. Arch Intern Med. 2007;167:1977-82. 16. Price DP. Methemoglobin inducers. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR, editors. Goldfrank's Toxicologic emergencies. 10th ed. New York: McGraw-Hill; 2015. 17. Clifton J, Leikin JB. Methylene blue. Am J Ther 2003;10:289Y291. 18 Bradberry SM. Occupational methaemoglobinaemia. Mechanisms of production, features, diagnosis and management including the use of methylene blue. Toxicol Rev. 2003;22:13-27. 19. El-Husseini A, Azarov N. Is the threshold for treatment of methemoglobinemia the same for all? A case report and literature review. Am J Emerg Med 2010;28:e5Ye10. 20. Cortazzo JA, Lichtman AD. Methemoglobinemia: a review and recommendations for management. J Cardiothorac Vasc Anesth. 2014;28:1043-7. 21. Curry S. Methemoglobinemia. Ann Emerg Med 1982;11:214Y221. 22. U.S. Food and Drug Administration. FDA Drug Safety Communication: Updated information about the drug interaction between methylene blue (methylthioninium chloride) and serotonergic psychiatric medications. https://www.fda.gov/drugs/drug-safety-and- availability/fda-drug-safety-communication-updated-information-about-drug-interaction- between-methylene-blue. Accessed September 9, 2019. 23. Clifton J, Leikin JB. Methylene blue. Am J Ther 2003;10:289Y291. 24. Kidd SA, Lancaster PA, Anderson JC, Boogert A, Fisher CC, Robertson R, Wass DM.. Fetal

death after exposureAuthor Manuscript to methylene blue dye during mid-trimester amniocentesis in twin pregnancy. Prenat Diagn. 1996;16:39-47. 25. Solomon S, Lipton RB, Harris PY. . Arterial stenosis in migraine: spasm or arteriopathy? Headache 1990;30: 52-61. 26. Dodick DW. Dodick, David W. A phase by phase review of migraine pathophysiology. Headache 2018;58: 4-16. ‐ ‐ This article is protected by copyright. All rights reserved 14

27. Amin FM, Hougaard A, Schytz HW, Asghar MS, Lundholm E, Parvaiz AI, de Koning PJ, Andersen MR, Larsson HB, Fahrenkrug J, Olesen J, Ashina M. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain. 2014;137(Pt 3):779-94.

28. Thomsen LL, Iversen HK, Brinck TA, Olesen J. Arterial supersensitivity to nitric oxide (nitroglycerin) in migraine sufferers. Cephalalgia 1993; 13: 395–399. 29. Pietrobon D. Moskowitz MA. Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nature Reviews Neuroscience 2014;15: 379. 30. Singhal AB, Maas MB, Goldstein JN, Mills BB, Chen DW, Ayata C, Kacmarek RM,Topcuoglu MA. High-flow oxygen therapy for treatment of acute migraine: A randomized crossover trial. Cephalalgia. 2017;37:730-736.

31. . Arngrim N, Schytz HW, Britze J, Amin FM, Vestergaard MB, Hougaard A, Wolfram F, de Koning PJ, Olsen KS, Secher NH, Larsson HB, Olesen J, Ashina M. Migraine induced by hypoxia: an MRI spectroscopy and angiography study. Brain. 2016;139(Pt 3):723-37.

32. Schoenen J. Hypoxia, a turning point in migraine pathogenesis? Brain 2016;139: 644-647. 33. Yang CC, Wu ML, Deng JF. Prolonged hemolysis and methemoglobinemia following organic copper fungicide ingestion. Vet Hum Toxicol. 2004;46:321-3.

34. Elonen E, Neuvonen PJ, Halmekoski J, Mattila MJ. Acute dapsone intoxication: a case with prolonged symptoms. Clin Toxicol. 1979;14:79-85.

35. Smith PA, Lodwick J, Dartt J, Amani JR, Fagan KM. Methemoglobinemia resulting from exposure in a confined space: Exothermic self-polymerization of 4,4'-methylene diphenyl diisocyanate (MDI) material. J Occup Environ Hyg. 2017;14:D13-D21.

36. David SR, Nora M, Rajan R. The blood blues: A review on methemoglobinemia. Journal of Pharmacology and Pharmacotherapeutics 2018;9: 1. 37. Luks AM, Swenson ER, Bärtsch P. Acute high-altitude sickness. Eur Respir Rev. 2017;26(143).

38. Alberti A, Mazzotta G, Gallinella E, Sarchielli P. Headache characteristics in obstructive sleep apnea syndrome and insomnia. Acta Neurol Scand. 2005;111:309-16.

39. Ozge A, Ozge C, Kaleagasi H, Yalin OO, Unal O, Ozgür ES. Headache in patients with chronic obstructive pulmonary disease: effects of chronic hypoxaemia. J Headache Pain. 2006;7:37-43.

40. Broessner G, RohreggerAuthor Manuscript J, Wille M, Lackner P, Ndayisaba JP, Burtscher M. . Hypoxia triggers high-altitude headache with migraine features: A prospective trial. Cephalalgia 2016; 36: 765–771. 41 41. Harris AD, Murphy K, Diaz CM, Saxena N, Hall JE, Liu TT, Wise RG. Cerebral blood flow response to acute hypoxic hypoxia. NMR Biomed. 2013;26:1844-52.

42. Britze J, Arngrim N, Schytz HW, Ashina M. Hypoxic mechanisms in primary headaches. Cephalalgia. 2017;37:372-384.

43. Arngrim N, Schytz HW, Britze J, Amin FM, Vestergaard MB, Hougaard A, Wolfram F, de Koning PJ, Olsen KS, Secher NH, Larsson HB, Olesen J, Ashina M. Migraine induced by hypoxia: an MRI spectroscopy and angiography study. Brain. 2016;139(Pt 3):723-37.

44. Birk S, Petersen KA, Kruuse C, Guieu R, Jonassen O, Eisert W, Olesen J. The effect of circulating adenosine on cerebral haemodynamics and headache generation in healthy subjects. Cephalalgia. 2005;25:369-77.

4545. Van Mil AH, Spilt A, Van Buchem MA, Bollen EL, Teppema L, Westendorp RG, Blauw GJ. Nitric oxide mediates hypoxia-induced cerebral vasodilation in humans. J Appl Physiol (1985). 2002;92:962-6.

46. Hasbak P, Lundby C, Olsen NV, Schifter S, Kanstrup IL. . Calcitonin gene related peptide and adrenomedullin release in humans: Effects of exercise and hypoxia. Regul Pept 2002; 108:89–95. 47. Ben-Haim G, Armstead WM. Stimulus duration-dependent contribution of k(ca) channel activation and cAMP to hypoxic cerebrovasodilation. Brain Res. 2000;853:330-7.

48. Borkum JM. Migraine Triggers, Oxidative Stress, and the Thyroid. Headache. 2016;56:784- 5.

49. Brennan KC, Charles A. An update on the blood vessel in migraine. Curr Opin Neurol. 2010;23:266-74.

50. Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol. 1988;23:193–196. 51. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018; 38: 1–211. 52 Do, Thien Phu, et al. "Red and orange flags for secondary headaches in clinical practice: SNNOOP10 list." Neurology92.3 (2019): 134-144. Author Manuscript

Table #1 Common findings by methemoglobin level in otherwise healthy patients

METHEMOGLOBIN PERCENTAGE CLINICAL FINDINGS OF TOTAL HEMOGLOBIN <1% Normal physiological level 10-20% Cyanosis 20-30% Anxiety, headache, lightheadedness, tachycardia 30-50% Fatigue, confusion, tachypnea, dizziness 50-70% Arrythmias, acidosis, seizures, coma >70% Death

Author Manuscript

Table #2 Studies on Patients Reporting Headache Associated with Methemoglobinemia

Study History of Mean Age Type Description Methemoglobin Treatment Resolution Notes (year) Migraine in years of percentage of Headache (SD) Headache correlating in relation to with headache Treatment Masavkar NR 9.6 (1.88) CS NR 3-15 MB NR (2017)1 Sajal NR 52.3 (12.5) CS NR 39.8-64.8 None NR (2011)2 mg/mL*

Murphy NR 57 CR NR 24.2 MB Yes, near (2018)3 immediate improvement Allister NR 4 CR NR 8 AA NR Patient had (2017)4 G6PD Author Manuscript deficiency

Nappe NR 29 CR NR 27.4 MB Yes, near (2015)5 immediate improvement Kilicli NR 30 CR NR 14.1 AA Yes, near (2013)6 immediate improvement Kaushik NR 72 CR NR 9 MB, AA, Yes, near Required 4 (2004)7 Riboflavin immediate treatments improvement (all of which improved symptoms) Armstrong NR 60 CR NR 48.7 MB Yes, near (2004)8 immediate improvement

CS, case series; CR, case report; MB, methylene Blue; AA, ascorbic acid; NR, not reported.

*The average hemoglobin level of the study population was 11.2±1.7g/dL%. Information on methemoglobin percentage was not provided. The authors referenced that the normal methemoglobin in blood is less than 1.5% of the total hemoglobin (<2.4mg/mL).

Author Manuscript 1 Masavkar, Sanjeevani Satish, et al. "Acquired methemoglobinemia–A sporadic Holi disaster." Indian pediatrics 54.6 (2017): 473- 475.

2 De, Sajal. "Assessment of severity of methaemoglobinemia following fibreoptic bronchoscopy with lidocaine." Indian Journal of Chest Diseases and Allied Sciences 53.4 (2011): 211. 3 Murphy, Travis, and Melinda Fernandez. "Acquired methemoglobinemia from phenazopyridine use." International journal of emergency medicine 11.1 (2018): 45. 4 Allister, L, Torres, C, Schnall, J, Bhatia, K, Miller E. Case Reports of the Harvard Emergency Medicine Residency: Jaundice, Anemia and Hypoxemia. Journal of Emergency Medicine. 2017 Jan; 52(1):93-97. 5 Nappe, Thomas M., Anthony M. Pacelli, and Kenneth Katz. "An atypical case of methemoglobinemia due to self-administered benzocaine." Case Reports in Emergency Medicine 2015 (2015). 6 KILICLI, Elif, et al. "Cost of beauty; prilocaine induced Methemoglobinemia." Turkish journal of emergency medicine 14.4 (2014): 185-187. 7 Kaushik, Prashant, et al. "Celecoxib-induced methemoglobinemia." Annals of Pharmacotherapy 38.10 (2004): 1635-1638. 8 Armstrong, C., K. W. Burak, and P. L. Beck. "Benzocaine-induced methemoglobinemia: a condition of which all endoscopists should be aware." Canadian Journal of Gastroenterology and Hepatology 18.10 (2004): 625-629. Author Manuscript