This document provides an overview of different types of headaches including their classification, epidemiology, clinical presentation, diagnosis, pathophysiology and treatment. It discusses primary headaches such as migraines, tension headaches and cluster headaches. It also covers secondary headaches which are symptomatic of underlying conditions. Key points include migraines affecting 10-15% of the population, being more common in women, and the importance of differentiating between primary and secondary headaches to guide treatment.

5. Primary * Migraine * Thunderclap headache (TCH)-sudden onset Exertional headache Cough headache * Tension type of headache * Cluster headache Other, rare types of primary headaches * Sexual headache (Coital Cephalgia) deBruijn, SF, et al. Lancet . 1996; Lancet . 1998.

7. Tension-type headache is the most common type of primary headache. The pain can radiate from the neck, back, eyes, or other muscle groups in the body. TTH accounts for nearly 90% of all headaches. Approximately 3% of the population has chronic tension-type headaches. The precise pathophysiology is unknown, probably due to muscle tension around the head and neck, psychosocial stress, anxiety, depression. Thunderclap headache (TCH) refers to a severe headache of sudden onset. Its explosive and unexpected nature is likened to a "clap of thunder.” Sex headaches Coital Cephalgia (sef-hal-gia) are headaches brought on by sexual activity — especially an orgasm. You may notice a dull ache in your head and neck that builds up as sexual excitement increases. Or, more commonly, you may experience a sudden, severe headache just before or during orgasm. Obviously, sex raises the blood pressure. This in turn raises the pressure in the head. Also, sex causes muscle tightening and tension. Sex headaches are a combination of the blood pressure and muscle tension, for most people. Cluster headache is one of the most painful types of headache. A striking feature of cluster headache is that the attacks occur in cyclical patterns, or clusters — which gives the condition its name. Bouts of frequent attacks — known as cluster periods — may last from weeks to months, usually followed by remission periods when the headache attacks stop completely. The pattern varies from one person to another, but most people have one or two cluster periods a year. During remission, no headaches occur for months, and sometimes even years. Rare and not life-threatening.

9. Hypnic headaches Tend to occur in the elderly, women>men. Occur particularly at night, waking patient during REM stages of sleep. Characterized by throbbing, without autonomic features, may last upto 1 hr and reoccur through the night. Cold stimulus headaches Classic “ice cream headaches”. These benign headaches occur during the rapid ingestion of cold food or drink, are located in the forehead and subside within minutes without medication. Benign exertional headaches Precipitated by physical exercise, during acute straining (eg weight lifting) or after sustained exercise such as running. Usually a generalized throbbing pain. Often respond to 25-50 mg indomethacin 3 times daily taken either after the exercise or prophylactically once a typical pattern is established. B-blockers may also be used for prophylaxis. Cough headaches triggered by coughing and other types of straining such as from sneezing, blowing your nose, laughing, crying, singing, bending over or having a bowel movement.

17. Prevalence of migraine by sex and age 30 25 20 15 10 5 0 20 30 40 50 60 70 80 100 Migraine prevalence (%) Age (years) Lipton and Stewart (1993) The American Migraine Study ( n =2479 migraine sufferers) Sex ratio 2.5 (f) to 1 (m); in childhood 1 to 1 Females Males

21. Migraine with aura has been referred to as classic migraine. References to headache have been recorded as early as 3000 BC. Hippocrates, in 400 BC, described the visual aura of migraine preceding headache as “a shining light, usually in the right eye, followed by violent pain in the temple that eventually reaches the head and neck area.” Because aura is such a classic migraine phenomenon, its presence is nearly always diagnostic of this condition. Only about 1 migraine patient in 8 ever experiences an aura. These people tend to have auras with some headaches, but not with all. The migraine aura is a complex array of symptoms that reflect focal cortical or brain stem dysfunction . The aura develops gradually, over a 5 – 20 minute time period, usually lasts for less than 60 minutes, and is accompanied or followed by a headache . In some instances, particularly in late life, the aura may occur without an associated headache. The migraine aura is most commonly visual, although the aura may present as a sensory, motor, brain stem or language disturbance . International Headache Society. Cephalalgia. 1988;8;(suppl 7):1-96.

25. Bright shimmering 'stars' seen falling across the image (telischopsia). Bright-edged castellated line (fortification spectrum). Scintilating Scotoma: A blind spot surrounded by a bright starburst. It is often mobile. Loss, blanking or darkening of one half of the field of vision (Hemianopia)

36. Dubose et al (1995); Goadsby (1999); Marks and Rapoport (1997) Family history Yes Sex More females Onset Variable Location Usually unilateral in adults Character/severity Pulsatile Throbbing Frequency/ 2–72 h/attack duration 1 attack/year to >8 per month Associated Visual aura symptoms Phonophobia Photophobia Pallor Nausea/vomiting Clinical feature Migraine No More males During sleep Behind/around one eye Excruciating/ sharp Steady 15–90 min/attack 1–8 attacks/day for 3–16 weeks 1–2 bouts/year Sweating Facial flushing Nasal congestion Ptosis Lacrimation Conjunctival injection Pupillary changes Cluster headache Yes More females Under stress Bilateral in band around head Dull Persistent Tightening/pressing 30 min to 7 days 3–4 attacks/week to 1–2 attacks/year Mild photophobia Mild phonophobia Anorexia Tension headache

37. Migraine Phases Resolution Sleepy Anorexia nausea Vomiting yawning Phonophobia Photophobia Phonophobia Photophobia Osmophobia Osmophobia Vomiting Deep sleep Headache III Headache Blau (1992) I II Normal Prodromes Aura Normal Appetite Awake/sleep Light tolerance Smell Noise Fluid balance Craving Tired yawning Heightened perception Fluid retention IV Postdrome Normal Limited Light tolerance Noise Smell Fluid balance Tired Feeling high or low Diuresis Appetite Awake/sleep food tolerance Normal

48. Abatement with sleep Stereotyped premonitory symptoms Characteristic triggers Positive family history Childhood precursors (motion sickness, episodic vomiting, episodic vertigo) Osmophobia As experienced clinicians who care for patients know, pattern recognition is an invaluable diagnostic technique in clinical practice , particularly for heterogeneous disorders such as migraine. Although not included in the IHS criteria, there are a number of additional and characteristic features of the migraine syndrome that are considered to be strongly supportive of the diagnosis. These features, when present, may substantially increase diagnostic accuracy, particularly in patients who do not fully satisfy IHS criteria. For example, osmophobia (fear, aversion, or psychological hypersensitivity to smells or odors), in addition to photophobia and phonophobia, has been shown to be a highly sensitive and specific feature of migraine. Predictable timing around menstruation (or ovulation) Pryse-Phillips WEM, et al. Can Med Assoc J . 1997.

52. Material to read later: AURA MIMICS AND SECONDARY CAUSES Bousser MG et al. In: Wolff’s Headache And Other Head Pain . 2001; Campbell JK, Sakai F. In: The Headaches . 2000; Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice . 2002. Although the aura of migraine is a benign and reversible phenomenon, a number of pathologic disease states may closely mimic the migraine aura. Aura may be present without headache. This is usually seen in the elderly, and the differentiation between migraine and other disorders, such as transient cerebral ischemia, becomes difficult. Late age of onset, short duration or evolution of the focal symptoms, and negative rather than a positive visual phenomenon, particularly in a patient with vascular risk factors, should raise concern and prompt further investigations for an underlying vascular etiology. Visual hallucinations of migraine and occipital lobe epilepsy can sometimes be difficult to differentiate. The visual symptoms of both disorders may be elementary negative hallucinations (scotoma, hemianopia) or positive (phosphenes, sparks, or flashes). Perceptive illusions in which the objects appear distorted such as a change in size (macropsia, micropsia), shape (metamorphopsia), or distance may also occur in both migraine and epilepsy. The distinction between epilepsy and migraine in clinical practice is rarely difficult, however, because of the accompanying headache with migraine, and the psychic or overt seizure with epilepsy. In cases where distinction may be unclear, electroencephalography may be helpful.

55. Fisher CM. Can J Neurol Sci . 1980; Silberstein SD, Saper JR, Freitag FG. In: Wolff’s Headache And Other Head Pain . 2001. Aura without headache often occurs in patients with aura at some time but can occur even in individuals with no prior history of migraine. The distinction between this phenomenon and TIA can sometimes be difficult, particularly since both tend to occur in middle age or beyond; hence, the term late-life migraine accompaniments (LLMA). Also known as transient migrainous accompaniments (scintillating scotomata, numbness, aphasia, dysarthria, and motor weakness), LLMA may occur for the first time after the age of 45. In general, the two can usually be distinguished clinically based upon the temporal profile of the symptoms. Patients with LLMA will often describe a build-up and migration of scintillations, the “march” of paresthesias, and a progression from one accompaniment to another. These characteristics do not occur in thrombosis and embolism. Half of patients reporting LLMA also report mild headache of approximately 15 – 25 minutes’ duration. A TIA typically lasts 8 – 14 minutes. Repeat occurrences, generally two or more such attacks, aid diagnosis.

57. Although no formal guidelines exist on the use of lumbar puncture as a diagnostic test in headache, lumbar puncture is critical in a number of situations. Unless a patient is suspected of having an SAH, meningoencephalitis, or a high or low pressure syndrome, a lumbar puncture is unnecessary during a headache. Nonetheless, patients who present with thunderclap headache or their first unusually severe headache should always be considered as having an acute neurologic event, even though a variety of benign headaches may present in this fashion. If the initial CT is negative, a lumbar puncture must be performed in this situation. Patients with a subacute and progressive headache syndrome should have a lumbar puncture to exclude other disease conditions, including infections (fungal, Lyme), inflammation (vasculitis), or neoplasms (carcinomatous leptomeningeal disease). Lumbar puncture is crucial in any patient suspected of having an acute intracranial infection, as well as in patients suspected of having raised or low intracranial pressure. In patients suspected of having pseudotumor, a lumbar puncture should be performed, even in the absence of papilledema, since idiopathic intracranial hypertension has been well described in patients with normal fundoscopic examinations. Evans RE, Rozen TD, Adelman JU. In: Wolff’s Headache And Other Head Pain . 2001.

60. MR Angiography Angiography Magnetic resonance angiography (MRA) and magnetic resonance venography (MRV) are safe and noninvasive imaging modalities that are becoming increasingly sophisticated tools for visualizing the craniocerebral circulation, particularly the large cervicocephalic vessels and the circle of Willis. These are very useful screening procedures for a suspected aneurysm or AVM in patients who have not had an SAH and for patients suspected of having a carotid or vertebral dissection. It is also the preferred imaging modality for the detection of a cerebral venous sinus thrombosis. Unless aneurysm, vasculitis, or arterial dissection are highly suspected and not adequately defined by MRA, there is no reason to perform angiography in a patient with headache who has a normal neurologic examination and normal brain MRI. Acute SAH Arterial dissection CNS vasculitis Aneurysm (>5 mm) Arterial dissection Venous thrombosis (MR venography) AV malformation

66. Cortical spreading depression

68. The neurovascular theory

74. Acute migraine therapy-The cave man method The people living in the Neolithic period ( 8500-7000 BC ) used the method of trepanation , which involved removing circular chunks of skull so that the spirits causing the headache could escape . Although the scientific rationale behind trepanation is not understood, it is surprising that this procedure was performed as a treatment for migraine as late as the mid 17 th century .

75. Mechanism of current pharmacological migraine treatments

76. Preemptive treatment Migraine trigger time-limited and predictable Preventative Decrease in migraine frequency severity, and duration Acute treatment To stop pain and prevent progression Silberstein SD. Cephalalgia . 1997.

87. Triptans: Mechanisms for treatment Their action is attributed to their binding to serotonin 5-HT1B, 5-HT1D and 5-HT1F receptors in cranial blood vessels (causing their constriction) and subsequent inhibition of pro-inflammatory neuropeptide release ( CGRP and substance P). CGRP NK SP 5-HT 1F 5-HT 1D 5-HT 1B Blood vessel Trigeminal nerve Adapted from Goadsby (1997) CGRP calcitonin gene related peptide NK neurokinin A SP substance P triptan CONSTRICTION INHIBITION

90. N Engl J Med,Vol.346,N .4 · January 24,2002

91. Material to read later- Triptans dosing

94. Material to read later-TRIPTANS WORK BEST WHEN PAIN IS MILD Retrospective analysis of 3 studies confirmed triptan treatment while pain is mild provided higher pain-free response at 2 h than ergotamine plus caffeine or aspirin plus metoclopramide, and reduced need for redosing Prospective rizatriptan study of 1919 patients confirms triptan effectiveness at all levels of pain but enhanced benefit if taken while pain is mild Post-hoc analysis of Spectrum study (26 patients) showed sumatriptan provided more effective relief with less recurrence when taken while pain was still mild Cady RK et al. Headache . 2000; Cady RK et al. Clin Ther . 2000; Hu XH et al. Headache . 2002.

117. COMORBID CONDITION DRUG EFFICACY* SIDE EFFECTS* RELATIVE CONTRAINDICATION RELATIVE INDICATION Anticonvulsants Divalproex 4+ 2+ Liver disease, bleeding disorders Mania, epilepsy, impulse control Topiramate 3+ 2+ Kidney stones Epilepsy, mania, neuropathic pain Gabapentin 2+ 2+ Epilepsy, neuropathic pain Antidepressants TCAs 4+ 2+ Mania, urinary retention, heart block Other pain disorders, depression, anxiety disorders, insomnia SSRIs 2+ 1+ Mania Depression, OCD MAOIs 2+ 4+ Unreliable patient Refractory depression Silberstein SD et al. Headache in Clinical Practice . 2nd ed. 2002. Gray RN et al. Drug Treatments for the Prevention of Migraine . 1999. *On a scale of 0 to 4

118. Material to read later- COMORBID AND COEXISTENT CONDITIONS: DRUG CHOICE COMORBID CONDITION DRUG EFFICACY* SIDE EFFECTS* RELATIVE CONTRAINDICATION RELATIVE INDICATION Antiserotonin Methysergide 4+ 4+ Angina, PVD Orthostatic hypotension  -Blockers 4+ 2+ Asthma, depression, CHF, Raynaud’s disease, diabetes HTN, angina Calcium channel blockers Verapamil 2+ 1+ Constipation, hypotension Migraine with aura, HTN, angina, asthma Silberstein SD et al. Headache in Clinical Practice . 2nd ed. 2002. Gray RN et al. Drug Treatments for the Prevention of Migraine . 1999. *On a scale of 0 to 4

119. Material to read later-COMORBID AND COEXISTENT CONDITIONS: DRUG CHOICE COMORBID CONDITION DRUG EFFICACY* SIDE EFFECTS* RELATIVE CONTRAINDICATION RELATIVE INDICATION NSAIDs Naproxen 2+ 2+ Ulcer disease, gastritis Arthritis, other pain disorders Other Riboflavin 2+ 1+ Preference for natural products Feverfew Botulinum Toxin A 2+ 2+ 2+ 1+ Myasthenia gravis Dystonia or Spasticity *On a scale of 0 to 4 Silberstein SD et al. Headache in Clinical Practice . 2nd ed. 2002. Gray RN et al. Drug Treatments for the Prevention of Migraine . 1999.

121. CAUTIONS IN ACUTE MEDICATION USE Silberstein SD. Cephalalgia . 1997. PREVENTIVE CAUTION CONTRAINDICATION Methysergide Ergots, Triptans (vasospastic properties) MAOIs Sumatriptan (subcutaneous) and zolmitriptan Meperidine, Midrin, sumatriptan (po, IN) and rizatriptan (serotonin syndrome or hypertensive crisis) Propranolol Rizatriptan NSAIDs Other NSAIDs or ASA Divalproex Butalbital

126. NONPHARMACOLOGIC TREATMENT: POTENTIAL INDICATIONS Poor tolerance, response, or contraindications to drug therapy Pregnancy, planned pregnancy, or nursing History of overuse Significant life stress or deficient stress-coping skills Goslin RE et al. Behavioral and Physical Treatments for Migraine Headache . 1999. Patient preference

130. Dowson AJ, Lipscombe S, Sender J , et al. New Guidelines for the management of migraine in primary care. Current Medical Research and Opinion 2002;18(7):414-439. Summary of migraine management

131. Dowson AJ, Lipscombe S, Sender J , et al. New Guidelines for the management of migraine in primary care. Current Medical Research and Opinion 2002;18(7):414-439.

134. MRIs show hypointensities on T1-weighted images and hyperintensities on T2-weighted images , usually multiple confluent white matter lesions of various sizes, are characteristic. These lesions are concentrated around the basal ganglia, periventricular white matter , and the pons. These white matter lesions are also seen in asymptomatic individuals with the mutated gene. These infarcts usually become symptomatic at a mean age of 40 – 50 years. They are sometimes associated with mood disturbances and dementia, which occur progressively between 50 – 60 years of age and are nearly constant before death (mean age 65 years). While MRI is not used to diagnose CADASIL, it can show the progression of white matter changes even decades before onset of symptoms. The most definitive diagnostic tool is a blood test to screen for the mutated Notch 3 . No specific treatment is available. However, anti-platelet agents such as aspirin, dipyridamole, or clopidogrel might slow down the disease and help prevent strokes. CADASIL Attacks Brain Vessels

137. Diagnosis: Physical exam- Palpation of the head reveals prominent temporal arteries with or without pulsation. The temporal area may be tender. Decreased pulses may be found throughout the body. Evidence of ischemia may be noted on fundal exam. Laboratory tests- Erythrocyte sedimentation rate, an inflammatory marker, >60 mm/hour (normal 10–40 mm/hour), but may be normal in approximately 20% of cases. C-reactive protein, another inflammatory marker, is also commonly elevated. Platelets may also be elevated. Biopsy- The gold standard for diagnosing temporal arteritis is biopsy, which involves removing a small part of the vessel and examining it microscopically for giant cells infiltrating the tissue . Since the blood vessels are involved in a patchy pattern, there may be unaffected areas on the vessel and the biopsy might have been taken from these parts. Unilateral biopsy of a 1.5–3 cm length is 85-90% sensitive. So, a negative result does not definitely rule out the diagnosis. Treatment Corticosteroids, typically high-dose prednisone (40–60 mg bd), must be started as soon as the diagnosis is suspected (even before the diagnosis is confirmed by biopsy) to prevent irreversible blindness secondary to ophthalmic artery occlusion. The dose of prednisone is lowered after a 2–4 weeks, and slowly tapered over the course of 9–12 months. Oral steroids are at least as effective as iv steroids, except in the treatment of acute visual loss where iv steroids appear to offer significant benefit over oral steroids Abnormal temporal artery biopsy (TAB) characterized by mononuclear cell infiltration, granulomatous inflammation, elastic lamina fragmentation, and often the presence of multinucleated giant cells.

138. Idiopathic intracranial hypertension syn benign intracranial hypertension syn pseudotumor cerebri IIH is a neurological disorder that is characterized by increased intracranial pressure in the absence of a tumor or other diseases. The main symptoms are headache, nausea and vomiting, as well as pulsatile tinnitus (buzzing in the ears synchronous with the pulse), papilledema, diplopia (double vision) and other visual symptoms . If untreated, it may lead to swelling of the optic disc in the eye, which can progress to vision loss. Idiopathic mechanism, hypervitaminosis A, tetracyclin, minocyclin,nitrofurantoin, ampicillin, or nalidixic acid. Other medications OCP, corticosteroids, estrogens, progestational therapies, NSAIDs, amiodarone (antiarrhythmic), perehexiline (prophylactic antianginal) and the anesthtic agents ketamine and nitrous oxide. Primarily presenting in young healthy women who are usually significantly overweight

139. Idiopathic intracranial hypertension syn benign intracranial hypertension syn pseudotumor cerebri Diagnosis Neuroimaging studies are mandatory to exclude other causes of increased intracranial pressure-differential diagnosis brain tumor. The diagnosis may be suspected on the basis of the history and examination . Lumbar puncture is performed to measure the opening pressure, as well as to obtain cerebrospinal fluid (CSF) to exclude alternative diagnoses. If the opening pressure is increased, CSF may be removed for relief (see below).

140. Idiopathic intracranial hypertension syn benign intracranial hypertension syn pseudotumor cerebri Pharmacological treatment: Discontinuation of the offending medication. Acetazolamide , which acts by inhibiting the enzyme carbonic anhydrase and reduces CSF production by 6–57%. It can cause the symptoms of hypokalemia (low blood potassium levels), which include muscle weakness and tingling in the fingers. Acetazolamide cannot be used in pregnancy, as it has shown to cause embryonic abnormalities in animal studies, and in humans has been shown to cause metabolic acidosis as well as disruptions in the blood electrolyte levels in the newborn. Surgery Optic nerve sheath decompression and fenestration: making of an incision in the connective tissue lining of the optic nerve in its portion behind the eye. It is not entirely clear how it protects the eye from the raised pressure, but it may be the result of either diversion of the CSF into the orbit or the creation of an area of scar tissue that lowers the pressure. Shunting: involves the creation of a conduit by which CSF can be drained into another body cavity. A lumboperitoneal (LP) shunt, which connects the subarachnoid space in the lumbar spine with the peritoneal cavity. Acetazolamide