Headache. Steven J. Scrivani, Steven B. Graff-Radford, Shehryar N. Khawaja, and Egilius L. H. Spierings. Contents

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1 Headache Steven J. Scrivani, Steven B. Graff-Radford, Shehryar N. Khawaja, and Egilius L. H. Spierings Abstract Headache is defined as a pain in the region above the orbitomeatal line. Headache disorders are common and considered a major health problem that affects a large percentage of the population worldwide. The International Headache Society (IHS) has an updated classification of headache referred to as the International Classification of Headache Disorders III (ICHD-III). This classification divides headache into primary and secondary headache and, additionally, categorizes painful cranial neuralgias and other facial pain S.J. Scrivani (*) Chief, Division of Oral and Maxillofacial Pain, Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Boston, MA, USA sscrivani1@partners.org S.B. Graff-Radford Director, Division of Headache and Orofacial Pain, Pain Center, Cedar Sinai Medical Center, Los Angeles, CA, USA steven.graff-radford@cshs.org S.N. Khawaja Resident, Orofacial Pain Program, Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Boston, MA, USA khawajashehryar@gmail.com E.L.H. Spierings Professor, Craniofacial Pain Center, Tufts University School of Dental Medicine, Headache and Facial Pain Program, Department of Neurology, Tufts Medical Center and Tufts School of Medicine, Boston, MA, USA spierings@medvadis.com # Springer International Publishing AG 2017 C.S. Farah et al. (eds.), Contemporary Oral Medicine, DOI / _33-1 conditions. This chapter discusses the epidemiology, clinical presentation, and management of the most common primary headache disorders (migraine headache, tension-type headaches, and trigeminal autonomic cephalgias) and important secondary headache disorders (headaches attributed to ischemic stroke or transient ischemic attack, trauma or injury to head and neck region, nontraumatic intracranial hemorrhage, giant cell arteritis, increase or decrease in cerebrospinal fluid, and intracranial neoplasia). In addition, it reviews the association between headache and temporomandibular disorders. Keywords Primary headache disorders Migraine Tension-type headaches Trigeminal autonomic cephalgias Secondary headache disorders Cluster headache Hemicrania continua Paroxysmal hemicrania Short-lasting unilateral neuralgiform headache attacks Contents Introduction... 2 Epidemiology and Classification of Headache Disorders... 2 Evaluation of Headache... 4 History... 4 Physical Examination... 4 Diagnostic Studies

2 2 S.J. Scrivani et al. Diagnosis and Treatment of Primary Headache Disorders... 9 Migraine... 9 Tension Type Headache Trigeminal Autonomic Cephalgia Diagnosis and Treatment of Important Secondary Headache Disorders Headache Attributed to Ischemic Stroke or Transient Ischemic Attack Headache Attributed to Trauma or Injury to the Head and/or Neck Headache Attributed to NonTraumatic Intracranial Hemorrhage Headache Attributed to Giant Cell Arteritis Headache Attributed to Increased Cerebrospinal Fluid Pressure Headache Attributed to Low Cerebrospinal Fluid Pressure Headache Attributed to Intracranial Neoplasia Headaches Attributed to Cervicogenic Disorders Headaches Associated with Disorders of Nose and Paranasal Sinuses Medication Overuse Headache Temporomandibular Disorders and Headache Conclusion and Future Directions Cross-References References Introduction Headache is defined as a pain in the region above the orbitomeatal line. Headache disorders are common and considered a major health problem that affects a large percentage of the population worldwide (Rasmussen et al. 1991; Lipton et al. 2007). It may affect the individual s daily activities, psychosocial functioning, and quality of life. Headache is one of the leading causes of absence from work and accounts for millions of workdays lost each year (La Jolla Donald 2001; Bigal et al. 2006). The International Headache Society (IHS) has an updated classification of headache referred to as the International Classification of Headache Disorders III (ICHD-III). This classification divides headache into primary and secondary headache and, additionally, categorizes painful cranial neuralgias and other facial pain (Society 2013). (Tables 1, 2, 3, and4). Each of the categories is further subdivided and provides specific criteria for the diagnoses listed. Secondary headache is due to a specific and identifiable underlying pathology (Table 3). Epidemiology and Classification of Headache Disorders The lifetime prevalence of headache (irrespective of type) has been reported to be 93% in men and 99% in women. The point prevalence of headache is 11% in men and 22% in women. Tension-type headache (TTH) and migraine are the most common types of headache affecting the population (Rasmussen et al. 1991, Rasmussen et al. 1991; Lipton et al. 2007). TTH is more prevalent than migraine and its lifetime prevalence is 85%. In a cross-sectional population study of 740 adult subjects, 74% had experienced TTH within the previous year and 31% had experienced TTH for more than 14 days. In another study, the 1-year prevalence rate of TTH was 63% in males and 86% in females. The onset is usually between 20 and 40 years of age with peak prevalence in the fifth decade of life. However, up to 25% of school children report TTH and in the mature population (60 years), the prevalence is 20% to 30%. There is evidence that chronic TTH (15 days of headaches, for at least 3 months) has a genetic predisposition. It is estimated that first-degree relatives of chronic TTH patients are three times more likely to suffer from headache in comparison to the general population (Rasmussen et al. 1991, Rasmussen et al. 1991). The American Migraine Study found the overall 1-year prevalence of migraine in the United States to be 17% to 18% for women and 6% for men, increasing with age among both genders, reaching a maximum at ages 35 to 45 years and declining thereafter (Lipton et al. 2007). Aura symptoms may be experienced by 20% to 36% of adult migraine patients (Bigal et al. 2006; Lipton et al. 2007). Before puberty, migraine is slightly more common in boys, with the highest prevalence between 6 and 10 years of age. In girls, the peak prevalence is between 14 and 19 years of age. Migraine prevalence is inversely related to income, with low-income groups having the highest prevalence. Race and geographic region

3 Headache 3 Table 1 The International Headache Society Classification of Headache Disorders (ICHD) III-Beta Part one: the primary headaches (1 4) Part two: the secondary headaches (5 12) Part three: painful cranial neuropathies, other facial pains and other headaches (13 14) Appendix Table 2 The ICHD-III classification of primary headache disorders 1. Migraine a. Migraine without aura b. Migraine with aura c. Chronic migraine d. Complications of migraine e. Probable migraine f. Episodic syndromes that may be associated with migraine 2. Tension type headaches a. Infrequent episodic tension type headache b. Frequent episodic tension type headache c. Chronic tension type headache d. Probable tension type headache 3. Trigeminal autonomic cephalgias a. Cluster headache b. Paroxysmal hemicrania c. Short-lasting unilateral neuralgiform headache attacks d. Hemicrania continua e. Probable trigeminal autonomic cephalgias 4. Other primary headache disorders a. Primary cough headache b. Primary exercise headache c. Primary headache associated with sexual activity d. Primary thunderclap headache e. Cold-stimulus headache f. External-pressure headache g. Primary stabbing headache h. Nummular headache i. Hypnic headache j. New daily persistent headache are also determining factors. The prevalence of migraines is highest in North America and Western Europe and among those of European descent. Migraine with aura has a stronger genetic background than migraine without aura. The American Migraine Study estimates that 23 million US residents have severe headaches. Table 3 The ICHD-III classification of secondary headache disorders 5. Attributed to trauma or injury to the head and/or neck 6. Attributed to cranial or cervical vascular disorder 7. Attributed to nonvascular intracranial disorder 8. Attributed to a substance or its withdrawal 9. Attributed to infection 10. Attributed to disorder of homeostasis 11. HA or facial pain attributed to disorder of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial structures 12. Attributed to psychiatric disorder Table 4 The ICHD-III classification of painful cranial neuropathies, other facial pains and other headaches 13. Painful cranial neuropathies and other facial pains 14. Other headache disorders Twenty-five percent of women experience four or more severe attacks per month, 35% experience one to three severe attacks per month, and 40% experience one or less than one per month. The study also found that more than 85% of women and more than 82% of men with severe migraine have some migraine-related disability (La Jolla Donald 2001; Bigal et al. 2006; Lipton et al. 2007). Trigeminal autonomic cephalgias (TACs) are relatively rare primary headache disorders. Prevalence estimates are 1%. Cluster headache is proposed to have a prevalence between 0.09% and 0.32% (Sjaastad and Bakketeig 2003). This particular disorder primarily affects men, with a male to female ratio of approximately 4:1. In a population-based sample in Germany, the 1-year prevalence of cluster headache was estimated to be 119/100,000. The mean age of onset of cluster headache is approximately 27 to 31 years of age which is nearly 10 years later than that of migraine. Approximately 73% of cluster headache patients are smokers or former smokers and half note that alcohol can trigger an attack during a cluster period. There is strong evidence for a genetic background in cluster headaches, as well. First-degree relatives of cluster headache patients are up to 39 times more likely to experience cluster headaches than the general population, whereas second-degree relatives are only 8 times

4 4 S.J. Scrivani et al. more likely (Manzoni 1999a, b; Ekbom and Hardebo 2002; Sjaastad and Bakketeig 2003). Paroxysmal hemicrania (PH) is a rare disorder and has an estimated prevalence of 0.021% to 0.07%. The female to male ratio is estimated to be approximately 1.6:1. There is no evidence for a genetic background on the prevalence of PH. The average age of onset is usually between 34 and 41 years, with an average duration of illness of 13 years (Boes and Swanson 2006). Similar to PH, hemicrania continua (HC) is a rare headache disorder. Little is known regarding its true prevalence. Only few hundred cases of HC have been reported in literature. However, recent studies indicate that it may be more common than previously estimated (Peres et al. 2001). HC is more common in women than in men. The female to male ratio is estimated to be approximately 2.8:1. There is no evidence of genetics in the onset or prevalence of the condition. The average age of onset is similar to that of PH. Short-lasting unilateral neuralgiform headache is another rare form of TAC. Epidemiological investigation suggests an estimated prevalence and annual incidence of 6.6 and 1.2 per 100,000 (Williams and Broadley 2008). The preponderance of these headaches is more common in men than in women. The male to female ratio is approximately 7:1 (Boes and Swanson 2006). Evaluation of Headache History Headache disorders have unique and distinctive features that typically characterize them. Hence, in order to accurately diagnose the headache disorders, a careful and thorough analysis of the headache history is required with special emphasis on the description; associated neurological, gastrointestinal, and systemic symptoms are also required (Table 5). It is important to note the location of the headache and whether it is unilateral or bilateral. The site where the headache begins and any radiating pattern of the pain may be important, along with the timing and duration of the headache. Additionally, the quality (pressure, squeezing, throbbing, stabbing) and intensity (mild, moderate, severe) of the headache should be documented. Note should also be made of photophobia, phonophobia, osmophobia, and any associated autonomic phenomenon (sweating, redness, swelling, eyelid ptosis, periorbital edema, conjunctival injection, excessive tearing, congestion or runny nose, fullness in the ears). Other important qualities may include restlessness or a feeling of fatigue and wanting to lie down in a dark, quiet room, as well as nausea or vomiting. Some headache disorders are associated with an aura (a transient neurological event), which may be visual, sensory, or motor. The more common are visual auras in the form of visual abnormalities such as photopsia, fortification spectrum, and scotomas (Fig. 1). There also may be specific predromal and postdromal symptoms that may be specific for a headache type. Additionally, one should inquire about any triggers (food and drink related, weather changes, sleep pattern, dietary habits, hydration status) as well as modifying factors (physical activity, positional changes, jaw function). Especially, note any history of trauma to the head or neck. Identify current and past medications, relevant family history, and the use of overthe-counter medications, supplements, and alternative or complementary therapies. A comprehensive psychosocial history is imperative for all patients with headache disorders. Establish the details of any pending or planned disability claims or litigation. Note should be made of any unusual or atypical signs and symptoms (i.e., red flags). Intracranial and extracranial pathology may cause headache. The American Headache Society s mnemonic tool, SNOOP for secondary headache (Table 6) (Dodick 2003), outlines aspects of a patient s symptoms and signs that suggest the presence of a life-threatening disorder (Table 3). Physical Examination The purpose of the physical examination is to discover any possible cause of the headache. Therefore, it is important to proceed systematically. The physical examination should include a

5 Headache 5 Table 5 History and clinical features of primary headache disorders Parameter Age of onset (yrs) Gender ratio (M:F) Clinical features Pain location Migraine headache without aura Migraine headache with aura Tension type headache Cluster headache Paroxysmal hemicrania Hemicrania continua :3 1:3? 4:1 1: 1.6 1:2.8 7:1 Fronto-temporal, orbital, and occipital region Fronto-temporal, orbital, and occipital region Fronto temporal, holocephalic Temporal, periorbital, maxillary Temporal, periorbital, maxillary Fronto temporal, parietal, occipital Short lasting unilateral neuralgi form headache attack Temporal, periorbital Laterality Unilateral a Unilateral a Bilateral Unilateral Unilateral Unilateral Unilateral Pain quality Pain intensity Pain duration Additional features Throbbing Throbbing Dull/Aching Boring / sharp / stabbing / throbbing Moderate severe Moderate severe Mild moderate 4 72 h 4 72 h 30 min to days Photophobia Phonophobia Osmophobia Nausea Vomiting Worsened by exercise Photophobia Phonophobia Osmophobia Nausea Vomiting Worsened by exercise Pre-headache aura symptoms b Mild nausea Stabbing / throbbing / boring Pressure / dullness / throbbing Severe Moderate severe Moderate Severe Sharp / electric / stabbing 15 min 180 min c 2 min 30 min d Continuous s e Ptosis/miosis Periorbital edema Facial or forehead sweating Facial or forehead redness Conjunctival injection or tearing Nasal congestion or rhinorrhea Ear fullness Pacing the floor or agitation Photophobia Phonophobia Ptosis/miosis Periorbital edema Facial or forehead sweating Facial or forehead redness Conjunctival injection or tearing Nasal congestion or rhinorrhea Ear fullness Ptosis/miosis Periorbital edema Facial or forehead sweating Facial or forehead redness Conjunctival injection or tearing Nasal congestion or rhinorrhea Ear fullness Pacing the floor or agitation Photophobia Phonophobia Ptosis/miosis Periorbital edema Facial or forehead sweating Facial or forehead redness Conjunctival injection or tearing Nasal congestion or rhinorrhea Ear fullness (continued)

6 6 S.J. Scrivani et al. Table 5 (continued) Parameter Migraine headache without aura Migraine headache with aura Tension type headache Cluster headache a Headaches may take place bilaterally as well b Visual, sensory, and speech abnormality c Once every other day to maximum of 8 attacks per day d At least 5 attacks per day more than half of the time e Single stabs, series of stabs, or in a saw-tooth pattern, at least one headache per day for more than half of the time Paroxysmal hemicrania Hemicrania continua Short lasting unilateral neuralgi form headache attack

7 Headache 7 head to toe assessment of the major organ systems, including a comprehensive neurological examination, with specific attention to the cranial nerves, and a complete head and neck examination. All four principles of physical examination should be included: inspection, palpation, percussion, and auscultation. The physical examination should start with taking of the vital signs. This provides indication of the physiological state of the patient. Some form of numerical pain rating scale should be used to register the intensity of the headache present. This indicates the severity of pain and later aids in the evaluation of management strategies, progression of pain, and outcomes assessment. The clinician should note facial expression, general demeanor, dress, posture, gait, and speech of the patient and assess the mood, cognitive, and physical state. This aids in determining any neurological signs or symptoms that might be accompanied with the headache. In addition, presence of abnormal signs may indicate an underlying organic disorder, warranting urgent care. Note should also be made of whether the patient is currently experiencing a headache during the office visit and the physical examination. Examine the head, face, and neck for hyperesthesia or allodynia. Inspect the head, face, and neck for any asymmetry, swelling, redness, discoloration, or skin lesion(s). Presence of such signs may be suggestive of an underlying pathology and necessitate further evaluation. Palpate the head, occiput, posterior neck, shoulders, and upper back, as well as the lateral and anterior neck for muscle tenderness, tender or trigger points, joint tenderness, or any areas of tactileprovoked, sharp, shock-like pain. Assess the masticatory muscles (temporalis, masseter, medial pterygoid, inferior and superior lateral pterygoid) and temporalis tendon insertion extraorally and intraorally for tenderness, pain, and trigger points. Examine the mandibular range of motion and assess for any pain or dysfunction associated with mandibular motion. Examine the temporomandibular joints for swelling or tenderness as well as for audible noises with jaw movements (clicking, cracking, popping, or crepitation). Examine the oral cavity for any evidence of gross dental decay, gingival inflammation, swelling, and painful and/or mobile teeth. Examine the oral mucous membranes for lesions and areas of swelling or discoloration. Examine the floor of the mouth and palpate and the submandibular glands for tenderness and masses. Examine the tongue for lesions, masses, and areas of discoloration. Examine the hard and soft palate as well as the posterior and lateral oropharynx. Examine the parotid glands for enlargements, masses, or areas of tenderness. Presence of any lesions, masses, or areas of discoloration in the oral cavity may indicate presence of an underlying disorder, particularly autoimmune disorders or malignancy. Also make note of the pattern of the filiform and fungiform papillae on the tongue. Similarly, alteration in the distribution of tongue papillae may indicate presence of a localized oral mucous membrane disease or a systemic condition. Examine the anterior and lateral neck for palpable lymphadenopathy or other swellings or masses. Palpate the carotid arteries and examine the pulsations as well as auscultate for bruits. Inspect and palpate the superficial temporal arteries for nodules, pulsations, or areas of tenderness. Inspect and palpate the thyroid gland for any masses, nodules, or areas of tenderness. Examine the eyes for external structural swellings, lesions, or discolorations. Also, examine the eyes for upper lid ptosis, conjunctival injection, and excessive tearing. Such features are common in patients with trigeminal autonomic cephalgias. However, they may present secondary to intracranial pathology as well. Perform an examination of the full range of motion of the globes looking for any alteration in extraocular muscle function. Examine the pupils for size and shape and perform pupillary light reflexes, examining for direct and consensual light reflexes. Additionally, test for visual acuity. Lastly, perform a funduscopic examination, looking, in particular, for papilledema of the optic disc (Fig. 2). This is important to rule out any secondary causes of headaches, particularly inflammatory disorders, demyelinating disorders, or disorders of intracranial pressure. Perform a comprehensive examination of cranial nerve function, with particular attention to the trigeminal system. Test for sensory

8 8 S.J. Scrivani et al. Fig. 1 Typical presentation of visual aura symptoms associated with the migraine with aura. Figure illustrates scintillating scotoma (a partial loss of vision or a blind spot in an otherwise normal visual field with crescent of shimmering zigzags), and digitolingual paresthesias (abnormal sensory sensation) Table 6 SNOOP: Acronym for signs and symptoms of concern Systemic symptoms or disease Fever, weight loss, HIV, systemic cancer Neurologic signs or symptoms Confusion, clumsiness, weakness, aphasia, visual problems Onset sudden Thunderclap, progressive, positional Onset after age 40 years Vascular (temporal arteritis), tumor, infection Pattern change Any new or changed headache pattern or quality or increase in frequency or intensity abnormalities to light touch, sharp touch (pin-prick), pressure, temperature (hot and cold), contact detection (Von Frey filaments), direction sense, and 2-point discrimination. Make note of hyperesthesia or allodynia to any of these sensory modalities. Also, test for motor function strength of the masticatory complex. Look for any alteration in speech pattern, swallowing, or tongue movements. Examine head and neck movements for range of motion and strength. In addition, perform a thorough sensory and motor examination of the rest of the body. Test for coordination and balance as well to rule out any underlying pathology. Diagnostic Studies Contingent upon findings on history and physical examination, the clinician should consider additional diagnostic studies. These may include imaging studies, blood studies, lumbar puncture, diagnostic injections, electrocardiogram (ECG), electroencephalogram (EEG), polysomnography (PSG), or electromyography (EMG). The more common diagnostic studies to perform would be either computerized tomography (CT) or magnetic resonance imaging (MRI) of the head. In addition, MR angiogram (MRA) and MR venogram (MRV) may be needed. A number of blood studies may be helpful, including blood tests such as erythrocyte sedimentation rate (ESR) to rule giant cell arteritis, lumbar puncture to rule out pressure induced or infection headache, complete blood count/full blood count (CBC/FBC) to rule out anemia and serious blood dyscrasias, thyroid screen (FT3, FT4, TSH) to rule out thyroid disease, and a Lyme titer.

9 Headache 9 Diagnosis and Treatment of Primary Headache Disorders The primary headache disorders are: 1. Migraine 2. Tension-type headache 3. Trigeminal autonomic cephalgias 4. Other primary headache disorders Migraine Clinical Presentation, Pathophysiology, and Diagnosis Migraine is a disorder of the brain and the trigeminal system with widespread effects on other bodily systems. It is divided into multiple subtypes (Table 7). However, there are two major subtypes. Migraine without aura is a clinical syndrome characterized by headache with specific features and associated symptoms (IHS 1.1). Migraine with aura is primarily characterized by the transient focal neurological symptoms that usually precede or sometimes accompany the headache (IHS 1.2) (Fig. 1) (Society 2013). Furthermore, in some patients there may be a premonitory phase, occurring hours or days before the headache, and a headache resolution phase. Premonitory and resolution symptoms include hyperactivity, hypoactivity, depression, cravings for particular foods, repetitive yawning, fatigue, difficulty concentrating, emotional changes, difficulty reading or writing, and neck stiffness or pain. Almost 90% of migraine patients report triggers or precipitating factors that may initiate a headache attack. However, exposure to a trigger or precipitant may not always result in the onset of a headache attack. Common triggers are stress, anxiety, foods (such as chocolate, cheese), alcoholic beverages (such as beer, red wine), menstruation, fatigue, alteration in sleeping pattern, missed meals, changes in weather, head trauma, and strong lights or smells. Migraine headache disorder is considered to be a neurobiological disorder. The pathophysiology of migraine involves activation of the trigeminovascular system. This results in release of vasoactive Fig. 2 Fundal examination of eye demonstrating blurred disk margins (arrows). This is indicative of papilledema neuropeptides including substance P, calcitonin - gene-related peptide (CGRP), and neurokinin A from trigeminal C fibers (Goadsby et al. 1988). Other mediators considered to play a key role include 5-hydroxytryptamine, nitric oxide, and glutamate. When released, the neuropeptides result in a cascade of events, including mast cell degranulation, platelet aggregation, vasodilation, and plasma extravasation, leading to neurogenic inflammation in the region (Izumi 1999). Neurogenic inflammation is suggested to be vital in the prolongation and intensification of pain associated with migraine. Furthermore, it may result in peripheral and central sensitization (phenomena in which neurons become progressively responsive to nociceptive and nonnociceptive stimulation). Functional brain imaging suggests that the periaqueductal gray region of the dorsal raphe nucleus, the dorsal pons, and locus coeruleus play an important role in the pathogenesis of migraine headache, probably acting as central generators, or in modulation of pain associated with migraine. In migraine with aura, a phenomenon known as cortical spreading depression of Leão is considered to play a vital role in the mechanism of aura symptoms. Cortical spreading depression is a self-propagating wave of neuronal and glial depolarization that spreads across the cerebral cortex

10 10 S.J. Scrivani et al. corresponding to the clinically affected region. It results in oligemia (reduction in blood flow) followed by hyperemia (increase in blood flow) (Charles 2009; Leao 1947). In addition to propagation of aura symptoms, it is suggested to activate trigeminal nerve afferents and alter bloodbrain barrier permeability (Charles 2009). Cerebral blood flow imaging studies indicate no such changes suggestive of cortical spreading depression during attacks of migraine without aura. However, blood flow alterations may take place in brainstem and cortex secondary to pain activation. The diagnosis of migraine without aura may be confirmed when certain IHS criteria are met and after organic disease is excluded: (80) Patient needs to have had at least five attacks, each lasting between 4 and 72 h (untreated or unsuccessfully treated); (87) headache has at least two of the following four characteristics: unilateral location, pulsating quality, moderate or severe pain intensity, and aggravation by or causing avoidance of routine physical activity (e.g., walking or climbing stairs); (92) and the headache must be accompanied by nausea or vomiting or photophobia and phonophobia (Society 2013). Migraine headache in children and adolescents (under 18 years) is most often bilateral, unlike the case in adults. Similarly, headache attacks in children may last between 2 and 72 h. Migraine headache is usually located in the frontotemporal and occipital regions; however, headaches in other areas of the head have also been described. In the majority of cases, headaches are unilateral, switching sides. Some patients may experience bilateral headaches. In addition to headaches, some may develop cutaneous allodynia of the scalp or pain in the neck and shoulders. For the diagnosis of migraine with aura, the patient needs to fulfill the following criteria: (80) In addition to the criteria for migraine without aura, the patient needs to have at least two attacks with aura symptoms; (87) fully reversible aura symptoms (visual, sensory, speech or language, motor, brainstem, or retinal); (92) the aura Table 7 Classification of migraine headache disorders 1.1. Migraine without aura 1.2. Migraine with aura Migraine with typical aura Typical aura with headache Typical aura without headache Migraine with brainstem aura Hemiplegic migraine Familial hemiplegic migraine (FHM) Familial hemiplegic migraine type Familial hemiplegic migraine type Familial hemiplegic migraine type Familial hemiplegic migraine, other loci Sporadic hemiplegic migraine Retinal migraine 1.3. Chronic migraine 1.4. Complications of migraine Status migrainosus Persistent aura without infarction Migrainous infarction Migraine aura-triggered seizure 1.5. Probable migraine Probable migraine without aura Probable migraine with aura 1.6. Episodic syndromes that may be associated with migraine Recurrent gastrointestinal disturbance Cyclical vomiting syndrome Abdominal migraine Benign paroxysmal vertigo Benign paroxysmal torticollis symptoms have at least two of the following four features: at least one aura symptom spreads gradually over 5 min and/or two or more symptoms occur in succession, each individual aura symptom lasts for 5 to 60 min, at least one aura symptom is unilateral, and aura is accompanied, or followed within 60 min, by headache. An aura may also occur in the absence of a typical migraine headache (IHS ). It most often takes form of positive visual phenomena that move across the visual field over minutes, migrating paresthesia, or dysphasic speech (Society 2013).

11 Headache 11 If headache occurs on more than 15 days per month for at least 3 months, which has the features of migraine on at least 8 days per month and in the absence of medication overuse, it is called chronic migraine (IHS 1.3) (Society 2013). It is estimated that chronic migraine (CM) occurs between 2% and 6% of the population. Most patients start as having intermittent headache, characteristic of migraine, and then transform into CM. The evolution from intermittent headache to chronic headache may be subtle. Attacks may initially take longer to recover, with the emergence of a lingering low-grade headache. The headache proneness increases and even minor perturbations may trigger an attack. In retrospective studies, this transition may take an average of 10.8 years to evolve. This progressive shift is considered to be neurological and is often accompanied by other central effects, such as depression, anxiety, insomnia, and other generalized body pains. It is possible that this is directly due to the pain or due to the medications taken by the patients to treat the pain. If a headache lasts for more than 3 days in succession, it is called status migrainosus (IHS 1.4.1). Serious complications of migraines are rare and include persistent aura without infarction (IHS 1.4.2), migrainous infarction (IHS 1.4.3), and migraine aura-triggered seizure (IHS 1.4.4). If migraine without aura is strongly associated with menstrual onset, it may be pure menstrual migraine without aura or menstrually related migraine without aura. In pure menstrual migraine, women suffer from attacks similar to migraine without aura, over at least three consecutive cycles. The attacks occur exclusively on day 1 2 (i.e., days 2 to +3) of menstruation in at least two out of three menstrual cycles and at no other times of the cycle. In contrast, in menstrually related migraine, women experience migraine attacks without aura, with attacks occurring exclusively on day 1 2 (i.e., days 2 to +3) of menstruation in at least two out of three menstrual cycles, as well as at other times of the cycle (Society 2013). Treatment There are numerous potential treatments for migraine. Treatment may commence with a number of lifestyle alterations, so-called protective factors, such as regular sleep and meals, exercise, smoking cessation, and change in the use of alcohol. In addition, elimination of headache triggers, such as caffeine, dietary supplements (nitrites, preservatives, and monosodium glutamate), specific alcoholic beverages, weather factors, bright lights, loud noises, and irritating smells. In addition, there may be certain medications that may trigger headache, particularly analgesic agents. Reduction in physical and emotional stressors may also play an important protective role. Physical and behavioral medicine therapies have been shown to be effective preventative treatments and may also inhibit worsening of headache. In particular, there is very good evidence to support a variety of behavioral medicine treatments for migraine (Silberstein et al. 2012). Pharmacological treatment of migraine may be abortive or prophylactic. Patients who experience frequent severe migraine attacks often require both approaches. The choice of treatment should be guided by the frequency of the attacks. Individuals with fewer than 4 headache days per month and no impairment, or those with no more than 1 headache day per month regardless of impairment, can be treated with abortive medications (Lipton et al. 2007). Individuals with more frequent attacks, such as those with 6 or more migraine days per month with normal functioning, 4 or more migraine days with some impairment, or 3 or more migraine days with severe impairment, should be considered for prophylactic treatment (Lipton et al. 2007). If there is a comorbid illness, a prophylactic agent that can treat both should be used when possible, and agents that might aggravate a comorbid illness should be avoided. Nonpharmacologic methods, such as biofeedback, relaxation techniques, acupuncture, and other behavioral interventions, can be used as adjunct therapy (Holroyd and Drew 2006). Patient preferences should also be considered.

12 12 S.J. Scrivani et al. Several medications are used for acute migraine treatment, including selective 5-HT (serotonin) 1B/D receptor agonists (ergots, triptans), analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen (APAP)/paracetamol, dopamine-antagonistic antiemetics, and opioids (Table 8). Caution is advised with use of abortive agents, because overuse of such agents, especially compounded medications (such as NSAIDs with caffeine and/or barbiturate), may enhance the risk of medication-overuse headache (Silberstein 2000). In general, it is advised that APAP and NSAIDs should be taken for no more than 15 days per month, while other abortive and compound agents are suggested to be taken for less than 10 days per month (Silberstein 2000). Drugs with proven benefit, as per the American Academy of Neurology (Silberstein 2000; Silberstein et al. 2012), are listed in Table 9. Prophylactic treatments include a broad range of medications (Loder et al. 2012; Silberstein et al. 2012). Beta-blockers (propranolol, timolol, metoprolol) and anticonvulsants (topiramate, sodium valproate, divalproex sodium) have relatively the strongest evidence of effectiveness (Table 10). However, other medications such as tricyclic antidepressants (amitriptyline) and serotonin-norepinephrine reuptake inhibitors (venlafaxine) have also shown to be effective (Silberstein et al. 2012). These medications are started at low doses and titrated to the desired effect to minimize side effects and arrive at the minimal dose needed. In refractory cases, polypharmacy is often necessary. Similarly, botulinum toxin type A (Onabotulinum toxin A) has been shown to be effective preventive treatment for chronic migraine (headaches occurring for at least 4 h per day, 15 or more days per month, for 3 months) (Jackson et al. 2012). For the preventive treatment of menstrually related migraine, there is strong evidence for the prophylactic use of long-acting triptans (frovatriptan, naratriptan). Emerging abortive and preventive treatments include selective 5-HT 1F agonist, calcitonin gene-related peptide (CGRP) receptor antagonist, nitric oxide synthase (NOS) inhibitors, and glutamate receptor antagonist (Table 11). There is also some evidence for the use of natural products, herbal remedies, and supplements for migraine. The most evidence supports the use of magnesium, vitamin B2 (riboflavin), coenzyme Q10, and butterbur (pedasites). Tension Type Headache Clinical Presentation, Pathophysiology, and Diagnosis Tension type headache (TTH) is described as a dull ache or nonpulsating pain, lasting from 30 min up to 7 days, mild to moderate in intensity, often manifesting as tightness, pressure, or soreness in a band-like distribution (Society 2013). The pain location is nonspecific, though it is often bilateral and may extend into the neck. Temporalis and masseter muscle involvement may be present, and mastication may be affected in some patients. Unlike migraine, TTH is usually not aggravated by routine physical activity, such as walking or climbing stairs. It is not associated with nausea or vomiting and is associated with no more than one of photophobia and phonophobia. However, in chronic TTH, headache may be associated with mild nausea (Society 2013). TTH may be aggravated by a number of factors, such as stress, anxiety, fatigue, menstruation, alcohol, and sleep disturbances. The precise pathophysiology of TTH is unknown. However, it is considered to be multifactorial. Environmental influences such as peripheral activation of myofascial nociceptors are considered to play a role in etiology of episodic TTH, while sensitization of nociceptive pathways appear to be important for the development of chronic TTH (Bendtsen 2000). Functional brain imaging investigations indicate reduced gray matter density in regions of pons and cingulate, insular, and orbitofrontal cortices (Schmidt-Wilcke et al. 2005). These changes correlate with the duration of symptoms in chronic TTH. Similarly, sensory testing investigations report reduced pain, thermal, and electrical threshold in chronic TTH, suggestive of alteration in the central pain processing (Bendtsen et al. 1996). On the contrary, based on similar demographic and

13 Headache 13 Table 8 Classes of migraine abortive agents Pharmacotherapy Triptans Dihydroergotamines Nonsteroidal anti-inflammatory drugs Opioids Antiepileptic drugs Corticosteroids Injection therapy Neurotoxins (onbotulinumtoxin A) Supplements Vitamins Herbs Minerals clinical features, response to pharmacotherapy, and genetic influences it has been suggested that TTH and migraine headache disorder are part of a same disorder, but represent opposite ends of a continuum, varying in severity, intensity, and frequency of symptoms (Vargas 2008). The IHS primarily classifies TTH based on the frequency of headache occurrences (Table 12). It is classified as Infrequent episodic TTH (IHS 2.1) if headache occurs on 1 day or more per month (less than 12 days per year), and Frequent episodic TTH (IHS 2.2) if they occur on less than 1 day per month but less than 15 days per month for at least 3 months. Chronic TTH evolves from episodic TTH and is diagnosed when the headaches occur more often than 15 days per month for at least 3 months. The categories are typically subdivided according to the presence or absence of pericranial tenderness as assessed by manual palpation. Treatment Patients with TTH tend to self-medicate with over-the-counter analgesics and caffeine. Rarely do they consult their physicians for relief unless the frequency or intensity of the headaches increases. Treatment of TTH may also include behavioral methods, such as relaxation training, biofeedback techniques, and physical therapy. Pharmacotherapy may be needed, but the patient should be aware of the potential complications. Recent practice guidelines based on very limited published and controlled data recommend NSAIDs and acetaminophen for acute care, while the drugs of choice for the prevention of TTH are amitriptyline (first choice); mirtazapine or venlafaxine (second choice); and clomipramine, maprotiline, and mianserin (third choice) (Bendtsen et al. 2010). For acute as well as preventive care, side effects associated with these drugs may limit their tolerability. No preventive drugs are FDA approved for this indication (Bendtsen et al. 2010; Jackson et al. 2012). Trigeminal Autonomic Cephalgia Cluster Headache Clinical Presentation, Pathophysiology, and Diagnosis Cluster headache (CH) is an episodic headache disorder associated with severe pain and major autonomic activation. The headache is considered the most severe pain that humans can endure. The pain is typically unilateral stabbing, throbbing, located in the eye or temple and sidelocked from attack to attack (Society 2013). Approximately 15% of patients will experience a side shift between cluster periods. Attacks are relatively brief, varying from 15 to 180 min, with a mean of less than 1 h. They may occur daily or near daily, with up to 8 attacks per day, often occurring at the same time each day, particularly during sleep. The attacks occur during cluster periods lasting from 2 weeks to a few months, and these periods will often reoccur on an annual or biannual basis during the same seasons. Cluster attacks are associated with autonomic features ipsilateral to the pain and with a sense of restlessness or agitation. The autonomic features consist of at least one of the following: conjunctival injection or lacrimation; nasal congestion or rhinorrhea; eyelid edema; forehead and facial sweating; forehead and facial flushing; sensation of fullness in the ear; and miosis or ptosis. In certain patients, cluster headache attacks may be associated with photophobia or phonophobia, which may complicate the assessment and result in diagnostic delay. Cluster headache attacks may be provoked by alcohol, histamine, or

14 14 S.J. Scrivani et al. Table 9 Recommendation of American Academy of Neurology/American Headache Society for abortive therapy for migraine headaches Level A drugs: Established efficacy 2 RCTs showing efficacy Triptans Almotriptan (12.5 mg PO) Eletriptan (20 mg, 40 mg, 80 mg PO) Naratriptan (1 mg, 2.5 mg PO) Rizatriptan (5 mg, 10 mg PO a ) Sumatriptan (25 mg, 50 mg, 100 mg PO; 20 mg IN; 4 mg, 6 mg SC; iontophoretic patch) Zolmitriptan (2.5 mg, 5 mg PO; 2.5 mg, 5 mg IN) Ergots Dihydroergotamine (2 mg IN; 1 mg pulmonary inhaler) Non-steroidal anti-inflammatory drugs Aspirin (500 mg PO) Diclofenac (50 mg, 100 mg PO) Ibuprofen (200 mg, 400 mg PO) Naproxyn (500 mg, 550 mg PO) Refocoxib (25 mg PO) Acetaminophen (1000 mg PO) Opioids Butrophanol (1 mg IN) Combinations Sumatriptan/naproxyn (85 mg/500 mg PO) Acetaminophen/aspirin/caffeine (500 mg/500 mg/ 130 mg PO) Codeine/acetaminophen (25 mg/ 400 mg PO) Level B drugs: Probably effective 1 RCT or 2 non-rct Ergots Ergotamine (1 mg, 2 mg PO) Dihydroergotamine (1 mg IV) Opioids Tramadol (75 mg PO) Non-steroidal anti-inflammatory drugs Ketoprofen (100 mg PO) Ketorolac (30 mg IV) Dopamine antagonists Prochlorperazine (5 mg, 10 mg PO; 25 mg PR) Chlorpromazine (10 mg, 25 mg oral; 12.5 mg IM) Metoclopramide (10 mg IV) Other agents Metimizole (1 mg PO) Isometheptene (65 mg PO) Supplements Magnesium (1000 mg, 2000 mg IV) Level C drugs: Possibly effective 1 non-rct showing efficacy Corticosteroids Dexamethasone (4 mg, 16 mg PO) Antiepileptic drugs Valproic acid (400 mg, 1000 mg PO) Combination Butalbital/acetaminophen (50 mg/650 mg PO) a Also available in oral disintegration tablets PO per oral, SC subcutaneous, IN intranasal spray, IV intravenous

15 Headache 15 Table 10 Classes of migraine preventive agents Pharmacotherapy Antiepileptic drugs Antidepressant Beta-adrenergic blockers Calcium channel antagonists Serotonin (5-HT) antagonists ACE inhibitors/angiotensin II receptor antagonist Injection therapy Neurotoxins (onbotulinumtoxin A) Supplements Vitamins Herbs Minerals nitroglycerin. They are often associated with premonitory and prodromal symptoms. These may occur minutes to days before the onset of headache. Local prodrome includes autonomic symptoms, mild pain, and nonspecific symptoms such as pressure, tingling, heaviness, and pulsating. Some may also describe sensitivity to smell, nausea, vomiting, tiredness, irritability, hunger, dry mouth, metallic taste, and feeling of tightness in the teeth (Boes and Swanson 2006). The pathophysiology of CH is complex. The clinical presentation of circannual and circadian periodicity, the neuroendocrine alterations, and functional brain imaging investigation findings indicate that posterior region of hypothalamus plays an important role in the pathogenesis of CH (May et al. 1998; May and Goadsby 1998; Leone and Bussone 2009). Similarly, the clinical distribution of pain in the ophthalmic division and changes in the concentration of neuropeptides are suggestive of activation of trigeminovascular system during the period of CH (May et al. 1998; Leone and Bussone 2009). It has been postulated that metabolic activity in the hypothalamic region can consequently result in activation of the trigeminal nucleus, using the anatomical pathways present between hypothalamic nuclei and the trigeminal nucleus (trigemino-thalamic pathways) (Leone and Bussone 2009). In addition, trigeminovascular stimulation can result in reflex activation of the parasympathetic outflow from the superior salivatory nucleus (SSN). Likewise, stimulation of the trigeminovascular system leads to vasodilation of the peripheral blood vessels, which can cause neuropraxic injury to the perivascular sympathetic plexus, resulting in sympathetic dysfunction. This explains the strong autonomic component of these headache attacks (May and Goadsby 1998; Leone and Bussone 2009). Cluster headache can be episodic or chronic. The IHS classifies cluster headache as episodic if there is greater than 1 month of headache-free days per year. For cluster headaches to be considered chronic, the headache attacks occur for more than 1 year without remission or with remission periods lasting less than 1 month. Between 80% and 90% of cluster headache patients have the episodic form, but 13% of them will progress to chronic. Approximately one third of chronic cluster headache patients will spontaneously remit to an episodic form. Treatment The treatment of cluster headache is essentially pharmacologic. The goal is to shorten and alleviate the cluster headache attacks, as well as to shorten and prevent the period of attacks. The pharmacotherapy can be divided into abortive and prophylactic. Due to the intensity of the headache attacks, the abortive therapy has to be rapid in onset. Acute agents that are most effective are oxygen and the serotonin 1B/D receptor agonists (triptans). Pure 100% oxygen is delivered via non-rebreathing mask at rates from 12 to 15 L per minute for approximately 15 to 20 min. For rapid relief of symptoms, sumatriptan has been FDA approved and can be delivered subcutaneously (Pascual et al. 2007). Headaches refractory to pharmacotherapy agents may require interventional procedures, such as sphenopalatine ganglion or occipital nerve block. Prophylactic therapies should be initiated as soon as a cluster period begins. However, the FDA has approved none of the pharmacotherapies for this indication. Verapamil appears to have the strongest evidence of effectiveness. Other medications include lithium, divalproex sodium, and topiramate. Corticosteroids can also be beneficial in the management of cluster headache. However, the use is limited as initiation or bridging therapy

16 16 S.J. Scrivani et al. Table 11 Recommendation of American Academy of Neurology/American Headache Society for preventive therapy for migraine headaches Level A drugs: Established efficacy 2 RCTs showing efficacy Beta-blockers Metoprolol ( mg per day) Propranolol ( mg per day) a Timolol Antiepileptic drugs Topiramate ( mg per day) a Divalproex ( mg per day) Sodium valproate Triptans Frovatriptan b Supplements Butterbur c Level B drugs: Probably effective 1 RCT or 2 non-rct Antidepressants Amitriptyline ( mg per day) Venlafaxine ( mg per day) Beta-blockers Atenolol ( mg per day) Nadolol Triptans Naratriptan b Zolmitriptan b Non-steroidal anti-inflammatory drugs Supplements Riboflavin (vitamin B2) Feverfew Level C drugs: Possibly effective 1 non-rct showing efficacy ACE inhibitors Lisinopril Angiotensin receptor blockers Candesartan α-agonist Clonidine Guanfacine Antiepileptic drugs Carbamazepine Beta-blockers Nebivolol Pindolol Antihistamines Cyproheptadine (2 8 mgper day) Supplements Coenzyme Q10 Level U drugs: Inadequate or conflicting data to support or refute medication use Methodological shortcomings or conflicting data Antidepressants Fluvoxamine (continued)

17 Headache 17 Table 11 (continued) Fluoxetine Protriptyline Antithrombotics Acenocoumarol Warfarin Picotamide Beta-blockers Bisoprolol Calcium channel blockers Nicardipine Nifedipine Nimodipine Verapamil ( mg per day) Antiepileptics Gabapentin ( mg per day) Direct vascular smooth muscle relaxants Cyclandelate Other drugs: Medications that are established as possibly or probably ineffective Antiepileptics Lamotrigine d Oxcarbazepine e Antidepressants Clomipramine f Antihypertension Acebutolol e Telmisartan e Other medications Clonazepam e Nabumetone e Montelukast a FDA indication b Short-term prophylaxis of menstrually related migraine c Some developing safety concerns d Established as not effective e Possibly not effective f Probably not effective for short periods of time (Pascual et al. 2007). The prophylactic medications are often continued for 1 month after the last cluster attack and then discontinued until the next cluster period begins. Due to chronicity of the attacks (annual or biannual) patients may start prophylactic therapy 1 month before the usual time period of onset of headache attacks. Headaches refractory to preventive therapy may require surgical intervention. Gamma-knife radiation, occipital nerve stimulation, and deep brain stimulation of the hypothalamus in patients with intractable chronic cluster headache have yielded promising results (Ford et al. 1998; Burns et al. 2007; Leone et al. 2010). Paroxysmal Hemicrania Clinical Presentation, Pathophysiology, and Diagnosis Paroxysmal hemicrania (PH) is a headache disorder with clinical characteristics similar to those of cluster headache. However, it is characterized by relatively short duration attacks (2 to 30 min), more frequent (at least 5 attacks per day more

18 18 S.J. Scrivani et al. Table 12 Classification of tension-type headache disorder 2. Tension type headache 2.1. Infrequent episodic tension-type headache Infrequent episodic tension-type headache associated with pericranial tenderness Infrequent episodic tension-type headache not associated with pericranial tenderness 2.2. Frequent episodic tension-type headache Frequent episodic tension-type headache associated with pericranial tenderness Frequent episodic tension-type headache not associated with pericranial tenderness 2.3. Chronic tension-type headache Chronic tension-type headache associated with pericranial tenderness Chronic tension-type headache not associated with pericranial tenderness 2.4. Probable tension-type headache Probable infrequent episodic tension-type headache Probable frequent episodic tension-type headache Probable chronic tension-type headache than half of the time), and has an absolute response to indomethacin therapy. Furthermore, unlike cluster headache, paroxysmal hemicrania is more common in women than in men (Society 2013). The headache attacks are strictly unilateral, predominantly limited to the periorbital region. Like cluster headache, the diagnosis is confirmed when the headache is accompanied by at least one ipsilateral autonomic sign (lacrimation, conjunctival injection, rhinorrhea, nasal congestion, forehead and facial sweating, forehead and facial flushing, miosis, ptosis, fullness in the ear, and eyelid edema) (Boes and Swanson 2006, Society 2013). The pathophysiology of PH is similar to that of cluster headache. It is suggested that there is metabolic activation of the posterior portion of the hypothalamus, with concurrent activation of the trigeminovascular system, resulting in subsequent parasympathetic activation and sympathetic dysfunction (May and Goadsby 1998; Leone and Bussone 2009). Attacks occurring in periods lasting 7 days to 1 year separated by pain-free periods lasting for 1 month or more are classified as episodic paroxysmal hemicrania and attacks occurring more than 1 year without remissions or with remission lasting less than 1 month are classified as chronic paroxysmal hemicrania (Society 2013). Treatment Paroxysmal hemicrania has an absolute response to indomethacin therapy. Oral indomethacin should be used, initially in a dose of at least 150 mg daily and increased if necessary up to 225 mg daily. The dose by injection is 100 to 200 mg. There are reports in the literature of cases refractory to indomethacin. However, based on the current IHS guidelines, in order for a headache to be classified as paroxysmal hemicrania, it has to have an absolute response to indomethacin (Society 2013). Nevertheless, some reports have suggested mild to moderate relief with sumatriptan or topiramate (Pascual and Quijano 1998; Boes and Swanson 2006; Camarda et al. 2008). Hemicrania Continua Clinical Presentation, Pathophysiology, and Diagnosis Hemicrania continua (HC) is a rare persistent headache disorder. Headache is strictly unilateral and is often associated with the presence of ipsilateral autonomic symptoms, such as conjunctival injection or lacrimation, nasal congestion or rhinorrhea, eyelid edema, forehead and facial swelling, forehead and facial flushing, sensation of fullness in the ear, or miosis or ptosis (Society 2013). In certain individuals, there may be sense of restlessness or agitation associated with the headache, which may be aggravated by movement or there may be the presence of ipsilateral photophobia and phonophobia. Another characteristic feature of this particular headache disorder is that it has an absolute response to therapeutic doses of indomethacin. The headache is commonly located in the frontal, temporal, and periorbital region. The headache is described as a sensation of pressure, dullness, or throbbing. It is of mild to moderate intensity; however, there may be periods of severe pain during which headache

19 Headache 19 may become stabbing in quality. Furthermore, during periods of exacerbation it may be associated with a feeling of sand particles in the eyes. These periods of severe exacerbated pain usually take place at night and may awake the patient from sleep. Similar to other headache disorders, hemicrania continua may be worse with physical activity, menses, strong smells, and stress (Boes and Swanson 2006). The pathophysiology of HC is similar in mechanism to that of other trigeminal autonomic cephalgias. Functional brain imaging suggests activity in the posterior hypothalamus, dorsal rostral pons, and ventrolateral midbrain. This corresponds to the clinical presentation of HC, which is similar to other trigeminal autonomic cephalgias and migraine headaches (Matharu and Goadsby 2005). Posterior hypothalamic activation is observed in other trigeminal autonomic cephalgias. It is proposed that presence of autonomic symptoms and distribution of pain in the trigeminal region is due to posterior hypothalamic activity, with secondary activation of trigeminovascular response and trigemino-autonomic reflex. The role of activation in the dorsal rostral pons and ventrolateral midbrain is unclear. However, as indicated earlier in this chapter, these regions are activated during migraine headaches and may play a role in disinhibition of the trigeminal nociceptive pathways, as well as explain clinical features of HC that it shares with migraine headache (May et al. 1998; Matharu and Goadsby 2005). The IHS further classifies hemicrania continua into two subcategories, remitting subtype (IHS 3.4.1) and unremitting subtype (HIS 3.4.2) (Society 2013). The remitting subtype is characterized by headache that is not daily or continuous but is interrupted by remission periods of at least 1 day without treatment. Correspondingly, the unremitting subtype is characterized by headache that is daily and is continuous for at least 1 year without remission periods of 1 day or more (Boes and Swanson 2006; Society 2013). Treatment Hemicrania continua have an absolute response to indomethacin. The therapeutic dosage is 150 to 225 mg daily for oral indomethacin and 100 to 200 mg daily for injectable indomethacin (Society 2013). The results are dramatic with a rapid onset of relief occurring within hours. However in some cases, it may require up to 1 to 2 days. The maintenance dosage of indomethacin is usually less than the initial therapeutic dosage. Other NSAIDs, in particular aspirin, ibuprofen, piroxicam, diclofenac, or selective COX-2 inhibitors, have shown to be less effective in providing absolute relief (Boes and Swanson 2006). Short-Lasting Unilateral Neuralgiform Headache Attacks Clinical Presentation, Pathophysiology, and Diagnosis Short-lasting unilateral neuralgiform headache attacks are a primary headache disorder with clinical features resembling cluster headache, paroxysmal hemicrania, and trigeminal neuralgia. It is characterized by headache attacks that are moderate to severe in intensity, strictly unilateral, short duration (lasting from 1 to 600 s), and occurring as single stabs, series of stabs, or in a saw-tooth pattern. The headache has a frequency of at least one per day for more than half of the time when the disorder is active. The location of the pain is often orbital, supraorbital, or temporal. However, it may involve or be limited to other areas of the trigeminal distribution. The attacks are accompanied by ipsilateral autonomic symptoms (lacrimation, conjunctival injection, rhinorrhea, nasal congestion, forehead and facial sweating, forehead and facial flushing, miosis, ptosis, fullness in the ear, and eyelid edema). Based on the type of ipsilateral autonomic features, it is further subclassified into short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with autonomic symptoms (SUNA) (Boes and Swanson 2006; Society 2013). The pathophysiology of short-lasting neuralgiform headache attacks is similar to that of other trigeminal autonomic cephalgias. Clinical features, functional brain imaging, and neuroendocrine investigations suggest activation in the

20 20 S.J. Scrivani et al. posterior hypothalamic region (Bussone and Usai 2004). It is hypothesized that presence of autonomic symptoms in short-lasting neuralgiform headache attacks is secondary to signal generation in the hypothalamic region, with secondary activation of the trigeminovascular response and trigemino-autonomic reflex (Bussone and Usai 2004; Goadsby et al. 2010). The differential diagnosis of SUNCT and SUNA prominently includes trigeminal neuralgia (TN). Compared to TN, SUNCT, and SUNA attacks are more likely to be located in the ophthalmic division of the trigeminal nerve. While both TN and SUNCT and SUNA may be triggered by cutaneous stimuli, SUNCT and SUNA are less likely to demonstrate a refractory period immediately after an attack. Attacks occurring in periods lasting 7 days to 1 year separated by pain-free periods lasting for 1 month or more are classified as episodic. Attacks occurring for more than 1 year without remission, or with remission lasting less than 1 month, are classified as chronic (Society 2013). Treatment Short-lasting unilateral neuralgiform headache is typically treated with anticonvulsant agents, such as lamotrigine, topiramate, or gabapentin, although no data from large-scale, controled trials are available. It is not responsive to indomethacin (as compared to paroxysmal hemicrania) or to high-flow oxygen or subcutaneous sumatriptan (by contrast to cluster headache) (Boes and Swanson 2006; Goadsby et al. 2010). Diagnosis and Treatment of Important Secondary Headache Disorders Secondary headache disorders are defined as headaches that occur in close temporal relation to another disorder that is known to cause headache or fulfills criteria for causation by that disorder (Society 2013). The IHS classification divides the secondary headache disorders into the following categories: 1. Headaches attributed to trauma or injury to the head and/or neck 2. Headaches attributed to cranial or cervical vascular disorder 3. Headaches attributed to nonvascular intracranial disorder 4. Headache attributed to a substance or its withdrawal 5. Headache attributed to infection 6. Headache attributed to disorder of homoeostasis 7. Headache or facial pain attributed to disorder of the cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or facial or cervical structure 8. Headache attributed to psychiatric disorder It is not within the scope of this chapter to discuss all of these disorders. However, the important and relatively prevalent disorders are listed in Table 13 and outlined briefly below. Headache Attributed to Ischemic Stroke or Transient Ischemic Attack Headache associated with acute ischemic cerebrovascular disease is well recognized but poorly understood. Although the pain is usually mild to moderate in intensity, there is nothing pathognomonic about the quality of the pain, its intensity, or location. This diagnosis should be considered based on the accompanying neurologic deficits that present in an acute fashion, often in a person older than 50 years. It seems temporally related to the head pain that will typically be of a different type than previously experienced by the patient. Posterior circulation dysfunction (in the vertebral and basilar artery distribution) is more likely to cause headache than carotid artery dysfunction. Neurologic deficits include visual obscurations, diplopia, weakness, numbness, altered cognition, dysarthria, aphasia, and ataxia. Transient ischemic attacks present with neurologic deficits that might be seen in an acute ischemic stroke, most commonly amaurosis fugax, and weakness or numbness on one side. These deficits resolve, by definition, within 24 h and usually within 20 min. Symptoms or signs

21 Headache 21 Table 13 Important types of secondary headache disorders 1. Headache attributed to ischemic stroke or transient ischemic attack 2. Headache attributed to trauma or injury to the head and/or neck 3. Headache attributed to nontraumatic intracranial hemorrhage 4. Headache attributed to giant cell arteritis 5. Headache attributed to increased cerebrospinal fluid pressure 6. Headache attributed to low cerebrospinal fluid pressure 7. Headache attributed to intracranial neoplasia consistent with cerebral ischemia warrant emergent care. This cause of headache typically affects older individuals with vascular risk factors (such as diabetes, coronary disease, hypertension, hypercholesterolemia, and tobacco use). However, stroke can occur at any age. A head CT may be sufficient for the diagnosis, especially if there is a question of acute bleeding, but MRI will have a much higher sensitivity and specificity. The differential diagnosis for a patient with headache and neurologic symptoms must include migraine. An older migraineur who develops a headache with new neurologic symptoms or signs should be considered to be vascularly compromised until proven otherwise. Treatment for the headache must be individualized and typically this pain lasts for a few days at most. Vasoactive drugs are contraindicated. Headache Attributed to Trauma or Injury to the Head and/or Neck Headaches secondary to traumatic intracranial hematoma may be due to an epidural or subdural hematoma (Fig. 3). Headache secondary to nontraumatic intracranial hematoma may be due to an intracerebral hemorrhage or subarachnoid hemorrhage (SAH) (Society 2013). Like pain associated with ischemia, pain stemming from hemorrhage is best diagnosed according to its accompanying symptoms. An epidural hematoma is most often caused by severe blunt trauma to the skull, causing fracture and subsequent rupture of the middle meningeal artery. The patient may experience a so-called lucid interval, which refers to a period of time during which the patient apparently recovers for the most part after head trauma only to become somnolent and then comatose in short order (Lobato et al. 1988). Lucid interval is, however, more the exception than the rule; more frequently, patients will continue to have severe pain followed by a change in cognition. Rapid surgical drainage of the epidural hematoma is necessary to prevent mortality. A subdural hematoma may present acutely, subacutely, or even with chronic symptoms. The subdural space fills with blood after a bridging vein ruptures, usually from a fall or other type of head trauma. Older patients are at greater risk because they are more likely to have gait instability and their bridging veins are stretched. Often there is a history of minimal head trauma, with neurologic symptoms beginning several hours or even days later. Patients on anticoagulation therapy and those taking frequent aspirin or (NSAIDs) are particularly at risk. Pain is not always the chief complaint. Symptoms may include any neurologic deficit, such as gait disturbance, personality change, somnolence, visual disturbances, or focal changes such as hemiparesis, hemisensory changes, and visual field defects. Surgical evacuation of the hematoma is sometimes necessary, while in other cases careful observation of a small subdural hematoma without brain shift or pressure can be an effective treatment. Headache due to a subarachnoid hemorrhage (SAH) is fairly characteristic. Patients with an SAH typically present with a very sudden-onset, thunder clap headache. This pattern of headache reaches its maximal intensity in less than 1 min, often within seconds. It is commonly associated with nausea and vomiting, a stiff neck, or, frequently, rapid loss of consciousness. A ruptured saccular aneurysm is the most common cause of spontaneous SAH. Whenever an SAH is suspected, the patient should be sent to an emergency room by an ambulance, where a head CT can be performed. If the suspicion of SAH is high

22 22 S.J. Scrivani et al. and the head CT is unremarkable, the patient should undergo a lumbar puncture for blood or xanthochromia (which takes several days to develop). A head MRI should also be considered, as it may show an aneurysm or arteriovenous malformation (Fig. 4). Management includes, maintaining hemodynamic stability and neurosurgical consultation for either aneurysmal clipping or endovascular coiling, and treatment of vasospasm (Bousser et al. 2001). Headache Attributed to NonTraumatic Intracranial Hemorrhage Head pain associated with nontraumatic intracerebral hemorrhage (Society 2013) most typically presents with acute neurologic deficits. Intracerebral hematoma may be due to several etiologies (hypertension, neoplasm, arteriovenous malformation). If large enough, it can extend into a ventricle. An intracerebral hematoma may result in coma or death, contingent upon the cause and volume of the bleed, causing destruction of cerebral tissue and mass effect. Headache Attributed to Giant Cell Arteritis Giant cell arteritis (GCA) is a disease in which there is inflammation of cranial arteries (Society 2013), resulting in occlusion of blood vessels. In temporal arteritis, the superficial temporal artery is affected. Other arteries commonly affected by GCA include the maxillary, ophthalmic, and posterior ciliary arteries. The involved artery may be enlarged and tender to palpation. Patients often complain of intense or deep headache that worsens upon lying flat and of malaise, weakness, and weight loss. Jaw claudication is a common finding, which can impersonate the much more common temporomandibular disorders. Furthermore, patients may complain of pain on combing their hair because of allodynia. Patient with GCA may have polymyalgia rheumatica, causing pain, stiffness, and weakness in the proximal arms and legs. Occlusion of the optic artery may result in blindness. On examination, there may be presence of an enlarged, tender temporal artery or abnormal funduscopy (Fig. 5). Women over the age of 50 years are most commonly affected (Levine and Hellmann 2002). Fig. 3 Images of intracranial head computed tomography. (a) Demonstrates right side frontal traumatic subarachnoid hemorrhage (arrow). (b) Demonstrates right side epidural hematoma following head injury (arrow)

23 Headache 23 Fig. 4 Intracranial magnetic resonance angiography illustrating an intracranial aneurysm Laboratory studies reveal an elevated (ESR) and C-reactive protein (CRP). Temporal artery biopsy is required for a definitive diagnosis. GCA results in skipped lesions along the vessel walls. Due to this, a sample of at least 2 to 2.5 cm of blood vessel is suggested with thin sectioning for microscopic examination. Treatment with high-dose corticosteroid (e.g., prednisone 40 to 60 mg per day) should begin immediately, followed by referral for biopsy and long-term management. A delay in treatment may result in blindness, which is irreversible. GCA is usually self-limited but relapse can occur (Levine and Hellmann 2002). Headache Attributed to Increased Cerebrospinal Fluid Pressure Increased intracranial pressure may yield a nonspecific headache involving the entire head. The patient may have a mass that exerts pressure or have a process often wise that impairs the normal circulation and egress of cerebrospinal fluid (CSF). This headache typically worsens with Valsalva maneuver or recumbency and may be associated with nausea or vomiting, visual problems, and neurological deficits. The examiner should watch for extraocular eye movement abnormalities, especially diplopia, and evidence of papilledema (Fig. 2). Idiopathic intracranial hypertension (previously referred to as pseudotumor cerebri) occurs most often in young, obese, females. Hormonal contraceptives and certain other medications, such as tetracycline, may also be risk factors. Typically, this condition produces a generalized daily headache with intermittent visual disturbances and possibly pulsatile tinnitus. Neuroimaging should be unremarkable, except for slit-like ventricles and sometimes stenosis of both transverse sinuses, especially apparent on MRV. Examination may reveal papilledema (Fig. 2) and abducens (sixth cranial nerve) palsy. Increased opening pressure on lumbar puncture, usually higher than 200 to 250 mm H 2 O, with a normal head MRI, confirms the diagnosis. If left untreated, blindness may ensue (La Jolla Donald 2001). After proper referral, treatment consists of risk factor modification (weight loss) and with acetazolamide, which decreases the production of CSF, or corticosteroids (La Jolla Donald 2001; Chaaban et al. 2013). Some patients may require multiple lumbar punctures to lower the pressure, optic nerve sheath fenestration for relief of papilledema, or lumboperitoneal shunting to reduce headaches and prevent visual loss (La Jolla Donald 2001). Headache Attributed to Low Cerebrospinal Fluid Pressure Headache due to low CSF pressure is worsened within few minutes of standing and relieved by recumbency. It may be accompanied by neck stiffness or pain, tinnitus, hypoacusis, paraesthesia of the neck and arms, photophobia, or nausea. Low CSF pressure may be iatrogenic after lumbar puncture or occur postoperatively or spontaneously. The latter may be associated with rupture of meningeal diverticula, or weakened dura mater, as a result of connective tissue disease, such as Marfan syndrome (Marcelis and Silberstein 1990; Mokri 2003). The positional component of the headache becomes less evident over time. The

24 24 S.J. Scrivani et al. Headache brought on acutely by coughing or Valsalva maneuver is usually indicative of a benign condition. However, in rare cases, it can be due to a tumor causing increased intracranial pressure. This takes place if a neoplastic process intermittently occludes normal CSF flow, producing a ball-valve mechanism that manifests as posture-dependent headache (Vázquez- Barquero et al. 1994; Pfund et al. 1999). Fig. 5 Enlargement of temporal artery (arrows) headache is produced by traction by the sagging when standing on the dura mater and its painsensitive vasculature. Head MRI typically reveals postcontrast pachymeningeal enhancement of the dura and perhaps descent of the cerebellar tonsils, with flattening of the prepontine cistern and distortion of the brainstem. The headache may resolve spontaneously or within 48 to 72 h of treatment. Treatment may involve complete bed rest without head elevation for 2 or 3 days, mild analgesics, caffeine or theophylline, or an epidural blood patch. The blood patch has a pain relief success rate of over 90% (Marcelis and Silberstein 1990; Mokri 2003). Headache Attributed to Intracranial Neoplasia Intracranial neoplasm is accompanied by headache in approximately 50% and is one of the primary presenting symptoms in approximately 20%. However, patients usually presents with focal neurologic symptoms or seizure. Headache may be attributed to increased intracranial pressure or hydrocephalus caused by the neoplasm, to the pressure from the neoplasm itself or to carcinomatous meningitis (Society 2013). Other associated symptoms include morning headaches, weight loss, personality changes, seizure, or neurologic deficits, such as focal weakness or numbness, trouble walking, or visual disturbances. Headaches Attributed to Cervicogenic Disorders The prevalence of cervicogenic headaches is estimated to be 0.4% to 2.5% in the general population, and 15% to 20% in patients with chronic headache (Haldeman and Dagenais 2001). It is more prevalent in females, with a female to male ratio of 4:1. The mean age of onset is around 40 years. The pain is mostly unilateral in location; however, bilateral headaches can also occur. The pain is distributed over the occipital region, and it tends to radiate anteriorly toward the frontal region. Pain can be continuous or intermittent, of nonthrobbing quality, and aggravates with cervical functional and parafunctional movements. In addition, there is a positive history of cervical disorders. There have been reports of accompanying signs of associated nausea, vomiting, phonophobia, photophobia, and periorbital edema or flushing (Haldeman and Dagenais 2001). The pathophysiology of cervicogenic headaches is associated with presence of trigeminocervicogenic complex that provides an anatomical connection between trigeminal and cervical structures (Haldeman and Dagenais 2001). The ICHD-III diagnostic criteria for cervicogenic headaches requires that there be clinical, laboratory, and/or imaging evidence of a disorder or lesion within the cervical spine or soft tissues of the neck that is known to cause a headache. In addition, the guidelines suggest that there should be evidence of at least two of the following: