Curr Pain Headache Rep (2016) 20: 20 DOI 10.1007/s11916-016-0546-z

SECONDARY HEADACHE (M ROBBINS, SECTION EDITOR)

Headache and Facial Pain in Sickle Cell Disease Angeliki Vgontzas 1 & Larry Charleston IV 2 & Matthew S. Robbins 3

Published online: 15 February 2016 # Springer Science+Business Media New York 2016

Abstract Children and adolescents with sickle cell disease (SCD) have a high prevalence of recurrent headaches (24.0– 43.9 %). Acute presentation with headache can be diagnostically challenging, as the clinician must consider evaluation of several potentially devastating conditions including vascular diseases (stroke, hemorrhage, venous sinus thrombosis, moyamoya, posterior reversible encephalopathy syndrome), facial and orbital bone infarcts, dental pain, and osteomyelitis. Patients with SCD and primary headache disorders may benefit from comprehensive headache treatment plans that include abortive therapy, prophylactic therapy, and nonpharmacological modalities. Although there is limited data in adults, those with SCD are at risk for medication overuse headache secondary to frequent opioid use. Addressing headache in patients with SCD may help to reduce their use of opioids and disability and improve pain and quality of life.

This article is part of the Topical Collection on Secondary Headache * Angeliki Vgontzas [email protected] Larry Charleston, IV [email protected] Matthew S. Robbins [email protected]

1

Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, Steuben Ave., Bronx, NY 10467, USA

2

Department of Neurology, University of Michigan, Taubman Center, 1500 E. Medical Center Dr. SPC, Ann Arbor, MI 48109-5316, USA

3

Department of Neurology, Albert Einstein College of Medicine, Waters Place, Tower 2, 8th Floor, Bronx, NY 10461, USA

Keywords Sickle cell disease . Headache . Facial pain . Medication overuse . Prophylactic treatment . Abortive treatment

Introduction Sickle cell disease (SCD) refers to a clinical syndrome of genetic disorders causing mutations of the beta-globin gene. Because of the survival advantage of the HbS allele against malaria, SCD has the highest prevalence amongst populations of sub-Saharan African heritage, followed by Mediterranean, South American, and East Asian populations. In sub-Saharan Africa, 0.74 % of children are born with sickle cell disease [1]. In the USA, 0.27 % of African-American children are born with SCD and an estimated 90,000–100,000 Americans are affected [1, 2] [CDC website www.cdc.gov/ncbddd/sicklecell/ data.html]. The most common genotype, hemoglobin SS, is synonymous with sickle cell anemia and accounts for 70 % of all SCD cases in populations of African origin [3]. The next most common forms include hemoglobin SC disease and hemoglobin S–β thalassemia. The hemoglobin alleles are inherited in an autosomal recessive pattern. Hemoglobin S is the result of a single nucleotide mutation on the beta-globin gene, located on the short arm of chromosome 11. This changes the sixth amino acid in the beta-globin gene from glutamic acid to valine which results in an abnormally polymerized nucleus when the cell is stressed in a lower oxygen milieu. In a deoxygenated state, the polymerized nucleus results in a disrupted cell architecture causing the cell to dehydrate and obtain its characteristic sickled appearance [4]. Two major mechanisms result in end organ damage. One is a cycle of vaso-occlusion, ischemic reperfusion injury, and oxidative and inflammatory stress. The other is hemolytic anemia which triggers release of nitric

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oxide resulting in endothelial cell dysfunction, vasodilation, and ultimately a progressive vasculopathy [4]. Characteristic complications of sickle cell disease include pain crises, acute chest syndrome, stroke, and splenic and renal dysfunction [5]. Pain has long been recognized as the most common cause of acute morbidity in sickle cell disease and the most common reason for hospital admission for both adults and children [6]. Rapid initiation of opioids for treatment of severe pain associated with vaso-occlusive crises is strongly recommended [7]. Further disability from sickle cell associated pain and chronic moderate to severe pain crises (>3/year) are reasons to initiate treatment with hydroxyurea [7]. Headache and facial pain in SCD is a less well described and understood phenomenon. This review comprehensively examines current and past literature on secondary and primary headaches in studies of primarily children and adolescents with SCD. Secondary etiologies of acute headache and facial pain and in SCD patients often carry significant morbidity and are reported as case series/reports. However, primary headache disorders also appear to be more common in children with SCD. They are underdiagnosed clinically and thus go untreated and likely contribute to a less apparent morbidity. We conclude by providing recommendations in diagnosing and treating SCD patients with primary headache disorders. The disease is discussed as its clinical syndrome, SCD, although the literature primarily addresses patients with sickle cell anemia.

Primary Headache Disorders in Sickle Cell Disease Headache Prevalence and Demographics The prevalence of recurrent headaches in sickle cell disease patients has been estimated to be 17.8–43.9 % (Table 1) in studies of primarily children and adolescents [8, 9••, 10–13]. The lowest rates of recurrent headache may partially be explained by inclusion of very young children (as young as Table 1

1 year old) [11]. Therefore, a more likely prevalence of recurrent headaches in children and adolescents with SCD is 24.0– 43.9 %. Patients with SCD present earlier in life with headache than non-SCD controls. The largest controlled study of headache in SCD reported significantly higher prevalence of headache compared to age-matched controls in children (25.0 vs 7.3 %, p = 0.002) and adolescents (24.3 vs 14.5 %, p = 0.01), but not in adults (NS, p value not reported) [14•]. Niebanck et al. found this difference only in children under 13 years old who reported headaches at least weekly (24 vs 9.7 % in children <13 years, p = 0.013) but not in adolescents (32.4 vs 27 %, not statistically significant, p value not reported). Similarly, SCD patients with frequent headache were on average younger than controls (14.2 vs 15.9 years, p = 0.03) [10]. The prevalence of headache in SCD patients appears to remain consistent during adolescence, and thus the prevalence gap decreases.

Primary Headache Types The clinical features of primary headache disorders are balanced between tension-type headache and migraine [13] in patients with SCD, but more in favor of tension-type headache when International Classification of Headache Disorders (ICHD) criteria are strictly applied [12]. Although children <13 years old had higher rates of recurrent headache, there was no difference between the frequency of migraine between patients with SCD vs controls (22.1 v 21.1 %)—thus, most likely leaving a higher rate of tension-type headache. In contrast, Langaju et al. found that none of the children with headache reported visual phenomena, nausea, or vomiting and none of the cases fulfilled diagnostic criteria for migraine— which may partially be explained by the inclusion of children as young as 1 year old [11]. As in the general population, children that have SCD with migraine have greater functional disability compared with those who have tension-type headache [13]. It is also not well known whether attacks of such

Studies reporting headache prevalence in sickle cell disease N

Age (y)

Recurrent headaches

Migraine

36.4 % Children, 25.0 % (vs 7.3 %, p = 0.002); adolescents, 24.3 % (vs 14.5 %, p = 0.01); adults, NS All, 32.4 % (vs 27 %, NS); Children, <13 24 % (vs 9.7 %, p = 0.013) 17.8 % 43.9 % 31.2 %

15.1 % NA

SCD

Controls

Dowling 2014 Kehinde 2008

872 613

NA 616

5–15 Adults and children

Niebanck 2007

241

141

6–21

Lagunju 2012 Kossorotoff 2014 Palermo 2005

214 98 50

NA NA NA

1–16 3–18 9–17

NA not applicable, NS not shown

22.1 % (vs 21.1 %, NS) None met migraine criteria 33.7 % 15.7 %

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headaches are more common during an acute pain crisis and may result in worsening in overall pain scores.

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Secondary causes of headache and facial pain in sickle cell

Vascular

Biological Mechanisms

Ischemic arterial stroke Venous sinus thrombosis (+/− infarct)

The elevated prevalence of headaches in children with SCD invites discussion as to whether there is comorbidity with primary headache disorders. Alternatively, SCD may have unique mechanisms which ultimately result in headache and facial pain that are not well characterized by standard primary headache criteria—and thus misinterpreted when applying those criteria. SCD crises are characterized by several types of systemic pain (bony pain, acute chest syndrome) and thus may predispose to lower pain thresholds, including head pain. Children with frequent headache were more likely both to report frequent vaso-occlusive crises and to experience headache and vaso-occlusive crisis concurrently [10]. Aside from secondary causes (which are explored below), several authors have suggested a shared pathophysiology between headache and sickle cell disease which involves vascular damage and increased blood viscosity. Others have found that amongst sickle cell disease patients, those with headache appear to have an increase in biological markers of disease severity. Dowling et al. reported that children aged 5–15 years old with recurrent headaches had lower steady state hemoglobin levels. Kossorotoff et al. have suggested that increased hypercoagulability profiles in children with SCD (higher levels of coagulation factor VIII and von Willebrand factor and lower levels of protein C and S) may explain increased prevalence of migraine and recurrent headaches, which may also put them at risk for ultra-transient ischemic cerebral events [12]. Another study in adults with SCD found that although there was no correlation between headache and MRI/A abnormalities, patients with frequent and severe headache had significantly higher TCD velocities compared with those with milder or no headache [15]. The authors further proposed that increased cerebral blood flow, secondary to low hematocrit (less than 30 %) may function as a trigger for migraine [15].

Hemorrhage (subarachnoid, intraparenchymal)

Secondary Headache and Facial Pain in Sickle Cell Disease The overwhelming majority of case reports and case series in the literature describe secondary causes of headache and facial pain as well as established complications of SCD (Table 2). Frequently, patients present to an acute care setting with headache and the physician must consider whether testing of secondary causes is warranted—even more challenging in pediatric population. Here, we review the literature on secondary causes which should be considered when assessing patients with SCD and headache. These include acute stroke,

Unruptured intracranial aneurysms Silent cerebral infarcts Moyamoya syndrome Bone infarcts Facial bones (primarily mandible) Skull Subperiosteal fluid collections Orbital Orbital compression syndrome Osteomyelitis Neuropathic pain Inferior alveolar nerve Mental nerve Bnumb chin syndrome^ Dental Cavities Periodontal Disease Other Posterior reversible encephalopathy syndrome Pseudotumor cerebri syndrome

intracranial hemorrhage, moyamoya, PRES, cerebral venous thrombosis, pseudotumor cerebri syndrome, bone infarcts, neuropathic facial and dental pain, orbital compression syndrome, and osteomyelitis. Stroke and Ischemia Stroke is a major complication of sickle cell disease in childhood, with rates as high as 500–1000/100,000, equivalent to the risk of stroke in the general adult population and approximately 250–500 times greater than for children without sickle cell disease. The mechanism of stroke is usually a large vessel disease—stenosis or occlusion of the distal internal carotid (ICA) and proximal middle cerebral arteries (MCA) [16]. Monitoring of ICA/MCA velocities via transcranial Doppler and when indicated, regular transfusions, significantly reduce the risk of stroke in children [17]. Several studies have examined whether acute presentations of headache or a history of chronic headaches and migraine are associated with stroke. Twenty-two percent of children with SCD who present with ischemic stroke can present with headache [18]. Conversely, an acute presentation of headache is unlikely to be a strong predictor of ischemic stroke in children. In a chart review of 102 children with SCD presenting to the Children’s Hospital of Philadelphia solely with a chief

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complaint of headache, 6.9 % had an acute intracranial event —only one of which was ischemic stroke (two had venous thrombosis, one had a cortical vein thrombosis and skull bone marrow edema and the rest had intracranial hemorrhage) [19]. Of note, each of these children had prior stroke, silent cerebral infarcts, or TIA. Although stroke is a rare finding in children with SCD who present with acute headache, it must be considered carefully by history taking and neurologic examination with particular emphasis on subtle signs of prior vascular events. Chronic headaches or migraine have not been found to be associated with an increased number of cerebrovascular events. No association between recurrent headaches or migraine and silent cerebral infarcts was found in a large clinical trial of regular transfusions intended to prevent silent cerebral infarcts [9]. Similar results were reported in previous smaller studies [10, 15]. Furthermore, although regular transfusions (indicated by arterial (ICA/MCA) velocities) decreases both stroke and silent cerebral infarcts, it was not found to reduce headache frequency [20••]. Primary Hemorrhagic Events Primary hemorrhagic events, which often present with headache, occur in 3 % of children with SCD by 20 years of age and confer increased mortality [21]. Patients with sickle cell disease have several risk factors for intraparenchymal and subarachnoid hemorrhage including acute hypertension, venous sinus thrombosis, rupture of aneurysms—particularly in the vertebrobasilar circulation or rupture of fragile collaterals [16, 22]. A history of chronic headache or migraine is associated with intracranial aneurysms in children with SCD. The largest study found a 2.8 % prevalence of unruptured intracranial aneurysms in their sample of children with SCD—a total of five children, two of whom (age 7 and 11) had a history of chronic migraine [22]. Additional risk factors for hemorrhage include transfusion within the last 14 days, treatment with corticosteroids and possibly NSAIDs, low steady state hemoglobin concentration and high steady state leukocyte count [21, 23]. Moyamoya Sickle cell disease is one of the diseases that associate with moyamoya syndrome. Moyamoya disease is defined by an angiographic pattern of a telangiectatic network of collateral vessels secondary to large vessel stenosis—primarily of the bilateral ICAs (Fig. 1) [24]. Moyamoya is typically discovered after a stroke and its presence is associated with increased risk of future stroke in children with sickle cell disease as well as worse neurocognitive problems [25]. It has been reported that patients with SCD make up 4 % of moyamoya syndrome cases—and may explain the increased rate of moyamoya

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syndrome in African-Americans compared to Caucasians (both of which are much less frequent than in Asian populations) [8]. Headache is commonly reported by patients with moyamoya disease as one of their major symptoms—with up to 40 % of patients reporting recurrent headaches and 6 % having headache as the initial symptom of the disease [26, 27]. Revascularization surgery dramatically reduces frequent headaches [26, 28]. It has been postulated that hemodynamic changes cause by the abnormal vascularity—and its subsequent improvement with surgery—may underlie these observations [29]. Cerebral Venous Thrombosis A lesser recognized etiology of stroke in sickle cell disease is cerebral venous thrombosis. Over the last decade, there has been a steady increase in reporting typically dramatic presentations of venous sinus thrombosis in sickle cell disease patients [30–32] including in sickle cell trait [33]. These presentations have typically included severe headache and signs of increased intracranial pressure. One such case included a two year old boy who presented in a coma, secondary to straight sinus and vein of Galen thrombosis leading to bilateral thalamic infarcts [34]. SCD patients are at higher risk of thrombotic events due to imbalance in coagulation markers (low levels of C and S, higher levels of vWF and factor VIII), abnormalities in normal platelet activation and vascular endothelial damage [30]. Posterior Reversible Encephalopathy Syndrome Posterior reversible encephalopathy syndrome (PRES), is a syndrome clinically characterized by headache, vision changes, altered mental status, nausea, and seizures, often in the setting of severe hypertension. The characteristic radiographic features are widespread bilateral subcortical vasogenic edema, classically in the parietal and occipital lobes (Fig. 1). PRES has been reported in up to 10 % of patients with SCD who have had MRI brain imaging, with an average age of approximately 12 years old and with virtually all cases reporting hypertension [35]. Amongst SCD patients, PRES has been described to occur during presentation with acute chest syndrome as well as post transfusion. PRES was described in five children during hospitalization for acute chest syndrome requiring intubation— one of whom developed headache and hypertension two days after extubation [36]. Other case reports describe PRES in the setting of transfusions—both after transfusion itself as well as after erythrocytapheresis [36, 37]. In one case, a 10-year-old girl with SCD developed PRES in the setting of a lung abscess and transfusion and it appeared that her post-transfusion elevated hematocrit was associated with worse neurological symptoms and erythrocytapheresis resulted in both reduction

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Fig. 1 a, b A 23 year old woman with sickle cell disease experienced an increasing frequency of episodic attacks of severe bilateral head pain aggravated by physical activity and accompanied by nausea, photophobia, and phonophobia but without focal neurological symptoms. Though diagnosed with migraine without aura, brain MRI with axial FLAIR sequences (a) revealed hyperintensities in the bilateral anterior watershed regions, more prominent on the left (arrows). MRA of the head (b) demonstrated narrowing of the distal left internal carotid artery, a nonvisualized proximal left middle cerebral artery segment, and attenuated flow through the rest of the vessel course. Very prominent flow related signal within the collateral vessels in the cerebral convexities was also present (arrows). The constellation of findings was consistent with moyamoya syndrome. c–e A 15-year-old boy with sickle cell disease experienced severe bilateral frontal and

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temporal headache accompanied by binocular blurred vision in the setting of multiple packed red blood cell transfusions and acute hypertension. Brain MRI with axial FLAIR sequences (c–e) revealed hyperintensities in the occipital lobes (c, d arrows) and superior frontal gyri (e arrows) consistent with posterior reversible encephalopathy syndrome. f, g:A 15-year-old girl with sickle cell disease presented with severe left jaw pain and swelling. Coronal MRI of the face revealed abnormal enhancement on contrast-enhanced T1 imaging (f) of the left mandibular condyle and surrounding masseter and pterygoid muscles (arrows), with corresponding hyperintensities on T2 images (g arrows). The constellation of findings was suggestive of left mandibular osteomyelitis with surrounding myositis. (Image courtesy of Dr. Deepa Manwani, The Children’s Hospital at Montefiore.)

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in hematocrit and neurological symptoms [38]. In another case report, it was felt that hypertransfusion to a hemoglobin of 15 may have contributed to the development of PRES in a 19-year-old girl with bony crises and GI bleeding [39]. Theoretically, SCD patients may be at higher risk for PRES given multiple mechanisms which can contribute to hemodynamic changes, including increased blood viscosity or hematocrit resulting in hypertension, poor cerebral autoregulation, and endothelial dysfunction [36, 38]. Recognition of PRES may be important as its presence in SCD has been associated with elevated morbidity and mortality [35]. Pseudotumor Cerebri Syndrome There have been only a few reports of pseudotumor cerebri syndrome in children with SCD [40–42]—with many of these reports in patients with other classic risk factors (obese, female, of reproductive age). It is unclear if there is any relationship between SCD and pseudotumor cerebri syndrome. With respect to treatment, SCD patients may be more likely to have electrolyte abnormalities secondary to treatment with diuretic agents, given an impaired ability to concentrate urine due to microvascular infarctions in the kidney and subsequent renal tubular dysfunction [43]. Bone Infarcts Advances in imaging have revealed craniofacial bone infarcts to be more common than previously appreciated, although still more difficult to detect than long bone infarcts in patients with SCD [44]. In a retrospective review of 85 patients with SCD who had head and neck MRIs, 40 had undergone testing for headache or localized facial pain, of which six (15 %) had findings compatible with acute bone infarcts, including in the mandible (n = 4), the orbit (n = 1) and bilateral frontoparietal bones (n = 1) [44]. In all but one of these cases, the bone infarcts were diagnosed in the context of an acute pain crisis. Therefore, 7 % of patients with SCD who underwent MRI demonstrated acute craniofacial bone infarcts [44]. Kavadia et al. had found a similar percentage of patients (13.6 %) had radiopaque lesions, facial pain, and a negative dental exam [45]. Location of lesions seems to be greatest in the mandible [44] although multiple lesions are common (four of the six patients) [44] and have been described in case reports [46]. Disruptions of normal architecture in craniofacial bones make patients with SCD more susceptible to bone infarcts and subsequent pain. Skull and facial bones have both generalized thickness and osteoporosis. Extramedullary hematopoiesis causes a decrease in the number of trabeculae and thus a widening of the medullary spaces [47, 48]. There may be round areas of radiolucency, similar to what is present in

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metastatic cancer or multiple myeloma [48]. Bone infarcts caused by thrombosis initially appear decalcified, triggering a reactive sclerosis, which over time leads to cortical thickening. Overgrowth of the maxilla is characteristic—resulting in visible physical changes such as exposure of maxillary teeth [49]. Neuropathic Facial and Dental Pain Bone infarcts may be accompanied by paresthesia—primarily in the distributions of the maxillary nerve. Loss of sensation in the area of the inferior alveolar nerve is thought to be caused by infarction of the microvascular blood supply to nerve and branches, which may be vulnerable passing through a narrow bony canal [50]. Similarly, the mental nerve also may be susceptible during vaso-occlusive episodes of the inferior alveolar nerve at or near the mental foramen, resulting in maxillary pain, bone infarction, and hypoesthesia in the distribution of the mental nerve. This is also referred to as Bnumb chin syndrome^ and has been reported in many case studies [46, 48, 51–54]. Although pain secondary to a bony infarct has been reported to resolve within days, paresthesias in these nerve distributions typically occur for several months or longer [55]. Subperiosteal fluid collections, which may be a sequela of these infarcts, are primarily treated non-surgically and appear to resolve on subsequent imaging. Skull infarcts are less commonly reported in the literature. Arends et al. describe a case of a young man who presented with severe headache with a normal CT scan whose headache disappeared in 2 days—he then reappeared 8 days later with relapsing severe headache and MRI demonstrating an infarct in the parietal skull bone with adjacent epidural hematoma [56]. Dental complications of sickle cell disease which may present with headache and facial pain include cavities, dental pulp necrosis, and periodontal disease [57]. Socioeconomic factors may particularly influence the rate of dental complications in those with SCD. One study reported that patients with SCD with household income <$15,000 had six times as many decayed teeth as compared to those without SCD [58]. Orbital Compression Syndrome Rare case reports have reported orbital vaso-occlusive events in SCD. Abrupt headache, fever, and eyelid swelling represent the initial presentation, with symptoms progressing to proptosis, reduced visual acuity, limited ocular motility and ultimately orbital compression syndrome [59, 60]. An older review of 16 published cases of orbital compression syndrome in patients with SCD reported a median age of 12.8 years, a history of multiple vaso-occlusive events, eyelid edema at presentation, the presence of bone marrow infarcts, and frequent hematomas adjacent to the bone [60]. The majority of cases were

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treated non-surgically, with mild cases resolving on average in 2 weeks and more severe cases resolving in 4–8 weeks [60]. Osteomyelitis Although generally rare but more common in the mandible, osteomyelitis needs to be excluded in a patient with a suspected facial bone infarct. The clinical presentation of osteomyelitis (Fig. 1) may differ from that of a bony infarct in that it may also include longer history of pain and fever, leukocytosis, worse swelling at the affected site and are less likely to have more than one painful site [61]. With that said, the diagnosis can be extremely challenging. Many patients are empirically treated with antibiotics for at least 48 h, with antibiotics being discontinued if a blood culture remains negative [61].

Treatment of Primary Headache Disorders Treatment of primary headache disorders in the SCD population has clinical challenges that particularly relate to pain comorbidity and its treatment. As mentioned previously, primary headache disorders appear to be more prevalent, especially in younger children with SCD. Patients with SCD are at risk for medication overuse headache secondary to opioid use. Patients with SCD may be treated with opiates for other pain syndromes, outside of pain crises. Individualized treatment plans which can be initiated during pain crises and also address chronic use of opioids are created by pain specialists in conjunction with other health providers. Similarly, we recommend that when treating patients with SCD who have headache, care should be coordinated with the patients’ SCD health provider (hematologist, pain specialist, primary care provider) to optimize care and long-term management. Patients may need and benefit from comprehensive headache treatment plans that include abortive therapy, prophylactic therapy, and non-pharmacological modalities. Abortive Considerations In general, most abortive therapies should be limited to no more than 2–3 days per week. As mentioned previously, patients with SCD may respond to simple analgesics but these should also be limited to no more than 15 days per month to avoid MOH. Prophylaxis should be strongly considered if patients with SCD have disabling headache 2 days or more per month, particularly with the limitations on acute therapies. We would reserve the use of opioids as last resort for vasoocclusive crisis only and recommend their use not exceed more than 8 days per month if at all possible. We would generally avoid triptans and ergotamine-based compounds because of the concern for increased risk of stroke in the SCD

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population. Alternative acute therapies such as neuroleptics and muscle relaxants may need to be used. We have found peripheral nerve blocks (trigeminal, occipital [62]) to be beneficial for patients with SCD for both abortive and short term prophylactic treatment purposes. Preventive/Prophylactic Considerations The goals of prevention are to decrease the number of days with headache, the duration and severity of the headache, increase the effectiveness of abortive medications, reduce disability, and improve overall quality of life. Fortunately, a diagnosis of SCD usually does not preclude the use of prophylactic therapies. Nevertheless, it has been reported that headache and migraine appear to be significantly undertreated in SCD patients—one study found that although 15.1 % of children with SCD had migraine and 36.4 % had recurrent headache, less than 1 % were taking prophylactic medication (9, 15). Drugs that may be effective for headache prophylaxis as well as generalized musculoskeletal pain may be useful for first-line headache prophylaxis—such as tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and antiepileptics such as gabapentin. Another approach is to tailor treatment to the headache disorder or phenotype. For example, in a patient with chronic migraine and SCD, considerations may include onabotulinumtoxinA and topiramate. Medication Overuse Headache Although opiates may be reasonable for treating a sickle cell pain crisis (i.e., vaso-occlusive crisis), opioid use for migraine is associated with more severe headacherelated disability, symptomology, comorbidities (depression, anxiety, and cardiovascular disease and events), and greater need to see health care providers [63]. This has particular importance for both the patient and their providers and may lead to the search for other treatments for other pain syndromes. For example, although there has been mixed data from a single dose (1000 mg) of intravenous acetaminophen in an acute migraine attack [64–66], recent literature suggests intravenous acetaminophen to be effective in the reduction of pain, use/need for opioids, opioid-related adverse effects, extubation time, to be more efficacious when compared with oral administration, and have similar therapeutic effects as morphine sulfate in the pain of rib fractures [67, 68]. The generalizability of this data to the SCD patient population may be in question; however, the safety and use of this medication has been well established. Benefits are likely to outweigh the risk assuming no other health complications (liver disease, drug hypersensitivities, etc.). Providers may have to actively seek safe treatment alternatives.

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Data suggest that medication overuse headache (MOH) can occur with 8 or more days of opiate use over a 3-month period of time in the general population with migraine [69]. There is evidence that MOH can develop in patients who have migraine disorders even when abortive agents are used for nonheadache purposes. The SCD population would be vulnerable to this phenomenon. Optimizing nonpharmacological strategies that can be helpful for both SCD and headache disorders may be ideal (e.g. hydration, avoiding triggers). Patients with headache disorders and SCD may benefit from prophylactic therapy especially due to potential limitations in abortive therapy options (e.g. triptans, dihydroergotamine, isomethaptene, etc. particularly due to the cardiovascular risks and diseases that often accompany SCD). Caution is also advised with the use of butalbital containing medications as these combination medications can also lead to MOH with only 5 days of use per month for 3 months [69]. Non-pharmacological Considerations A diagnosis of SCD usually does not preclude the use of nonpharmacological therapies in patients’ treatment plan. The authors suggest considerations for these therapies to be tailored to the patient’s specific headache diagnoses. Sometimes, depending on the co-illnesses and comorbidities of the patient, non-pharmacological modalities may be an extremely significant part of the comprehensive headache plan. As stated above, therapies that may be beneficial to the patient for their other diagnoses may be paramount such as adequate hydration and avoiding headache and SCD crisis triggers. When available, one should strongly consider cognitive behavioral therapy and/or biofeedback for these patients as it may help multiple domains (other pain syndromes, comorbidities, and may be similarly efficacious as preventive medication without untoward effects) [70–72].

Conclusion Headache and facial pain are diagnostically challenging clinical entities in patients with SCD. There are many alarming secondary causes of headache for which SCD patients are at risk. However, SCD patients, especially younger children, appear to also suffer more from recurrent primary headache attacks, which appear to be undertreated. Opioid use—sometimes used outside of pain crises—may also place this population at risk for MOH. Specific treatment regimens for these primary headache disorders should be included as part of an overall pain management goal in SCD patients. Addressing headaches specifically may help to overall reduce their use of opioids, improve pain management, reduce disability, and improve overall quality of life.

Curr Pain Headache Rep (2016) 20: 20 Compliance with Ethics Guidelines Conflict of Interest Angeliki Vgontzas and Larry Charleston IV declare that they have no conflict of interest. Matthew S. Robbins declares book royalties from Wiley and honoraria for educational activities from both the American Academy of Neurology and the American Headache Society. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ. 2008;86(6):480–7. 2. Hassell KL. Population estimates of sickle cell disease in the US. Am J Prev Med. 2010;38(4 Suppl):S512–21. 3. Nagel RL, Fabry ME, Steinberg MH. The paradox of hemoglobin SC disease. Blood Rev. 2003;17(3):167–78. 4. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010;376(9757):2018–31. 5. Ashley-Koch A, Yang Q, Olney RS. Sickle hemoglobin (HbS) allele and sickle cell disease: a HuGE review. Am J Epidemiol. 2000;151(9):839–45. 6. Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, et al. Pain in sickle cell disease. Rates and risk factors. N Engl J Med. 1991;325(1):11–6. 7. Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. Jama. 2014;312(10):1033–48. 8. Uchino K, Johnston SC, Becker KJ, Tirschwell DL. Moyamoya disease in Washington State and California. Neurology. 2005;65(6):956–8. 9.•• Dowling MM, Noetzel MJ, Rodeghier MJ, Quinn CT, Hirtz DG, Ichord RN. Headache and migraine in children with sickle cell disease are associated with lower hemoglobin and higher pain event rates but not silent cerebral infarction. The J Pedia. 2014;164(5): 1175–80 e1. This is a large cross-sectional study of 872 children 5–15 years old with sickle cell disease which utilized both laboratory data, MRI and clinical information. Although recurrent headaches and migraine were associated with lower steady state hemoglobin, they were not associated with the presence of silent cerebral infarction on MRI. Such contributions provide further clues to the possible pathophysiology of primary headache in SCD patients. 10. Niebanck AE, Pollock AN, Smith-Whitley K, Raffini LJ, Zimmerman RA, Ohene-Frempong K, et al. Headache in children with sickle cell disease: prevalence and associated factors. J Pediatr. 2007;151(1):67–72. e1. 11. Lagunju IA, Brown BJ. Adverse neurological outcomes in Nigerian children with sickle cell disease. Int J Hematol. 2012;96(6):710–8. 12. Kossorotoff M, Lasne D, Brousse V, Desguerre I, de Montalembert M, Gaussem P. Imbalanced coagulation profile as a biomarker of

Curr Pain Headache Rep (2016) 20: 20 migraine in children with sickle cell: is this a link with cerebral ischemia? J Pediatr. 2014;165(3):645–6. 13. Palermo TM, Platt-Houston C, Kiska RE, Berman B. Headache symptoms in pediatric sickle cell patients. J Pediatr Hematol Oncol. 2005;27(8):420–4. 14.• Kehinde MO, Temiye EO, Danesi MA. Neurological complications of sickle cell anemia in Nigerian Africans—a case-control study. J National Medical Asso. 2008;100(4):394–9. This is the largest case–control study of headache prevalence of children and adults with sickle cell disease. The increased prevalence of recurrent headaches appears in children and adolescents with SCD, but not in adults with SCD. Such observations suggest a possible common pathophysiology and highlight the need to diagnose children, who may be less forthcoming with headache symptoms. 15. Silva GS, Vicari P, Figueiredo MS, Junior HC, Idagawa MH, Massaro AR. Migraine-mimicking headache and sickle cell disease: a transcranial Doppler study cephalalgia. An International J Headache. 2006;26(6):678–83. 16. Kirkham FJ. Therapy insight: stroke risk and its management in patients with sickle cell disease. Nat Clin Pract Neurol. 2007;3(5): 264–78. 17. Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998;339(1):5–11. 18. Earley CJ, Kittner SJ, Feeser BR, Gardner J, Epstein A, Wozniak MA, et al. Stroke in children and sickle-cell disease: BaltimoreWashington Cooperative Young Stroke Study. Neurology. 1998;51(1):169–76. 19. Hines PC, McKnight TP, Seto W, Kwiatkowski JL. Central nervous system events in children with sickle cell disease presenting acutely with headache. J Pediatr. 2011;159(3):472–8. 20.•• DeBaun MR, Gordon M, McKinstry RC, Noetzel MJ, White DA, Sarnaik SA. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. The New England J Med. 2014;37(8): 699–710. Despite the promising results that regular bloodtransfusion therapy decreased the incidence of both stroke and silent cerebral infarcts in children, it was not found to reduce headache frequency. Such findings stress the need for comprehensive care in patients with SCD, including targeted treatments of primary headache. 21. Ohene-Frempong K. Stroke in sickle cell disease: demographic, clinical, and therapeutic considerations. Semin Hematol. 1991;28(3):213–9. 22. Saini S, Speller-Brown B, Wyse E, Meier ER, Carpenter J, Fasano RM. Unruptured intracranial aneurysms in children with sickle cell disease: analysis of 18 aneurysms in 5 patients. Neurosurgery. 2015;76(5):531–8. discission 8-9; quiz 9. 23. Strouse JJ, Hulbert ML, DeBaun MR, Jordan LC, Casella JF. Primary hemorrhagic stroke in children with sickle cell disease is associated with recent transfusion and use of corticosteroids. Pediatrics. 2006;118(5):1916–24. 24. Stockman JA, Nigro MA, Mishkin MM, Oski FA. Occlusion of large cerebral vessels in sickle-cell anemia. N Engl J Med. 1972;287(17):846–9. 25. Dobson SR, Holden KR, Nietert PJ, Cure JK, Laver JH, Disco D, et al. Moyamoya syndrome in childhood sickle cell disease: a predictive factor for recurrent cerebrovascular events. Blood. 2002;99(9): 3144–50. 26. Ng J, Thompson D, Lumley JP, Saunders DE, Ganesan V. Surgical revascularisation for childhood moyamoya. Childs Nerv Syst. 2012;28(7):1041–8. 27. Oki K, Suzuki N. Moyamoya Disease. In: N H, editor. Report by the Research Committee on Spontaneous Occlusion of the Circle of Willis 2007. p. 4–5.

Page 9 of 10 20 28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38. 39.

40.

41.

42.

43. 44.

45.

46.

Seol HJ, Wang KC, Kim SK, Hwang YS, Kim KJ, Cho BK. Headache in pediatric moyamoya disease: review of 204 consecutive cases. J Neurosurg. 2005;103(5 Suppl):439–42. Scott RM, Smith JL, Robertson RL, Madsen JR, Soriano SG, Rockoff MA. Long-term outcome in children with moyamoya syndrome after cranial revascularization by pial synangiosis. J Neurosurg. 2004; 100(2 Suppl Pediatrics):142–9. Ciurea SO, Thulborn KR, Gowhari M. Dural venous sinus thrombosis in a patient with sickle cell disease: case report and literature review. Am J Hematol. 2006;81(4):290–3. Celikbilek A, Celikbilek M, Bozkurt A, Karakurum Goksel B, Tan M, Ozdogu H. Woman with sickle cell disease with current sigmoid sinus thrombosis and history of inadequate warfarin use during a past thrombotic event. Case Reports in Neurol. 2009;1(1):15–9. Sidani CA, Ballourah W, El Dassouki M, Muwakkit S, Dabbous I, Dahoui H, et al. Venous sinus thrombosis leading to stroke in a patient with sickle cell disease on hydroxyurea and high hemoglobin levels: treatment with thrombolysis. Am J Hematol. 2008;83(10):818–20. Feldenzer JA, Bueche MJ, Venes JL, Gebarski SS. Superior sagittal sinus thrombosis with infarction in sickle cell trait. Stroke; a Journal of Cerebral cCrculation. 1987;18(3):656– 60. Oguz M, Aksungur EH, Soyupak SK, Yildirim AU. Vein of Galen and sinus thrombosis with bilateral thalamic infarcts in sickle cell anaemia: CT follow-up and angiographic demonstration. Neuroradiology. 1994;36(2):155–6. Khademian Z, Speller-Brown B, Nouraie SM, Minniti CP. Reversible posterior leuko-encephalopathy in children with sickle cell disease. Pediatr Blood Cancer. 2009;52(3):373–5. Henderson JN, Noetzel MJ, McKinstry RC, White DA, Armstrong M, DeBaun MR. Reversible posterior leukoencephalopathy syndrome and silent cerebral infarcts are associated with severe acute chest syndrome in children with sickle cell disease. Blood. 2003;101(2):415–9. Kolovou V, Zampakis P, Ginopoulou A, Varvarigou A, Kaleyias J. Reversible posterior leukoencephalopathy syndrome after blood transfusion in a pediatric patient with sickle cell disease. Pediatr Neurol. 2013;49(3):213–7. Frye RE. Reversible posterior leukoencephalopathy syndrome in sickle-cell anemia. Pediatr Neurol. 2009;40(4):298–301. Raj S, Killinger J, Overby P. Blood transfusion in sickle cell disease leading to posterior reversible encephalopathy syndrome (PRES). J Child Neurol. 2013;28(10):1284–6. Henry M, Driscoll MC, Miller M, Chang T, Minniti CP. Pseudotumor cerebri in children with sickle cell disease: a case series. Pediatrics. 2004;113(3 Pt 1):e265–9. Segal L, Discepola M. Idiopathic intracranial hypertension and sickle cell disease: two case reports. Canadian J Ophthalmol J Canadien d'Ophtalmol. 2005;40(6):764–7. Thomas E. Recurrent benign intracranial hypertension associated with hemoglobin SC disease in pregnancy. Obstet Gynecol. 1986;67(3 Suppl):7S–9S. Brugnara C. Erythrocyte dehydration in pathophysiology and treatment of sickle cell disease. Curr Opin Hematol. 1995;2(2):132–8. Watanabe M, Saito N, Nadgir RN, Liao JH, Flower EN, Steinberg MH, et al. Craniofacial bone infarcts in sickle cell disease: clinical and radiological manifestations. J Comput Assist Tomogr. 2013;37(1):91–7. Kavadia-Tsatala S, Kolokytha O, Kaklamanos EG, Antoniades K, Chasapopoulou E. Mandibular lesions of vasoocclusive origin in sickle cell hemoglobinopathy. Odontology / the Society of the Nippon Dental University. 2004;92(1):68–72. Hamdoun E, Davis L, McCrary SJ, Eklund NP, Evans OB. Bilateral mental nerve neuropathy in an adolescent during sickle cell crises. J Child Neurol. 2012;27(8):1038–41.

20 Page 10 of 10 47.

Robinson IB, Sarnat BG. Roentgen studies of the maxillae and mandible in sickle-cell anemia. Radiology. 1952;58(4):517–23. 48. Hammersley N. Mandibular infarction occurring during a sickle cell crisis. Br J Oral Maxillofac Surg. 1984;22(2):103–14. 49. Brown DL, Sebes JI. Sickle cell gnathopathy: radiologic assessment. Oral Surg Oral Med Oral Pathol. 1986;61(6):653–6. 50. Kelleher M, Bishop K, Briggs P. Oral complications associated with sickle cell anemia: a review and case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82(2):225–8. 51. Mestoudjian P, Steichen O, Stankovic K, Lecomte I, Lionnet F. Sickle cell disease, a benign cause of numb chin syndrome. Am J Med. 2008;121(10), e1. 52. Kirson LE, Tomaro AJ. Mental nerve paresthesia secondary to sickle-cell crisis. Oral Surg Oral Med Oral Pathol. 1979;48(6): 509–12. 53. Gregory G, Olujohungbe A. Mandibular nerve neuropathy in sickle cell disease. Local factors. Oral Surg Oral Med Oral Pathol. 1994;77(1):66–9. 54. Friedlander AH, Genser L, Swerdloff M. Mental nerve neuropathy: a complication of sickle-cell crisis. Oral Surg Oral Med Oral Pathol. 1980;49(1):15–7. 55. Konotey-Ahulu FI. Mental-nerve neuropathy: a complication of sickle-cell crisis. Lancet. 1972;2(7773):388. 56. Arends S, Coebergh JA, Kerkhoffs JL, van Gils A, Koppen H. Severe unilateral headache caused by skull bone infarction with epidural haematoma in a patient with sickle cell disease. Cephalalgia : an International J Headache. 2011;31(12):1325–8. 57. Javed F, Correa FO, Nooh N, Almas K, Romanos GE, Al-Hezaimi K. Orofacial manifestations in patients with sickle cell disease. Am J Med Sci. 2013;345(3):234–7. 58. Laurence B, George D, Woods D, Shosanya A, Katz RV, Lanzkron S, et al. The association between sickle cell disease and dental caries in African Americans. Spec Care Dentist. 2006;26(3):95–100. 59. Ghafouri RH, Lee I, Freitag SK, Pira TN. Bilateral orbital bone infarction in sickle-cell disease. Ophthal Plast Reconstr Surg. 2011;27(2):e26–7. 60. Curran EL, Fleming JC, Rice K, Wang WC. Orbital compression syndrome in sickle cell disease. Ophthalmology. 1997;104(10): 1610–5. 61. Berger E, Saunders N, Wang L, Friedman JN. Sickle cell disease in children: differentiating osteomyelitis from vaso-occlusive crisis. Arch Pediatr Adolesc Med. 2009;163(3):251–5.

Curr Pain Headache Rep (2016) 20: 20 62.

Blumenfeld A, Ashkenazi A, Napchan U, Bender SD, Klein BC, Berliner R, et al. Expert consensus recommendations for the performance of peripheral nerve blocks for headaches—a narrative review. Headache. 2013;53(3):437–46. 63. Buse DC, Pearlman SH, Reed ML, Serrano D, Ng-Mak DS, Lipton RB. Opioid use and dependence among persons with migraine: results of the AMPP study. Headache. 2012;52(1):18–36. 64. Turkcuer I, Serinken M, Eken C, Yilmaz A, Akdag O, Uyan E, et al. Intravenous paracetamol versus dexketoprofen in acute migraine attack in the emergency department: a randomised clinical trial. Emerg Med J. 2014;31(3):182–5. 65. Zhang A, Jiang T, Luo Y, Zheng Z, Shi X, Xiao Z, et al. Efficacy of intravenous propacetamol hydrochloride in the treatment of an acute attack of migraine. Eur J Intern Med. 2014;25(7):629–32. 66. Leinisch E, Evers S, Kaempfe N, Kraemer C, Sostak P, Jurgens T, et al. Evaluation of the efficacy of intravenous acetaminophen in the treatment of acute migraine attacks: a double-blind, placebocontrolled parallel group multicenter study. Pain. 2005;117(3): 396–400. 67. Memis D, Inal MT, Kavalci G, Sezer A, Sut N. Intravenous paracetamol reduced the use of opioids, extubation time, and opioidrelated adverse effects after major surgery in intensive care unit. J Crit Care. 2010;25(3):458–62. 68. Pettersson PH, Jakobsson J, Owall A. Intravenous acetaminophen reduced the use of opioids compared with oral administration after coronary artery bypass grafting. J Cardiothorac Vasc Anesth. 2005;19(3):306–9. 69. Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology. 2008;71(22):1821–8. 70. Powers SW, Kashikar-Zuck SM, Allen JR, LeCates SL, Slater SK, Zafar M, et al. Cognitive behavioral therapy plus amitriptyline for chronic migraine in children and adolescents: a randomized clinical trial. Jama. 2013;310(24):2622–30. 71. Harris P, Loveman E, Clegg A, Easton S, Berry N. Systematic review of cognitive behavioural therapy for the management of headaches and migraines in adults. Br J Pain. 2015;9(4):213–24. 72. Penzien DB, Irby MB, Smitherman TA, Rains JC, Houle TT. Wellestablished and empirically supported behavioral treatments for migraine. Curr Pain Headache Rep. 2015;19(7):34.