Headaches Lecture

Lecture Outline Headaches Introduction Epidemiology Clinical Presentation Diagnosis Patho-physiology Treatment Acute therapy Prophylactic therapy Migraine management Secondary headaches Exam prep-what to know!

Classification of headaches Primary headaches OR Idiopathic headaches THE HEADACHE IS ITSELF THE DISEASE NO ORGANIC LESION IN THE BEACKGROUND TREAT THE HEADACHE! Secondary headaches OR Symptomatic headaches THE HEADACHE IS ONLY A SYMPTOM OF AN OTHER UNDERLYING DISEASE TREAT THE UNDERLYING DISEASE! The differentiation between 1  and 2  is critical as it dictates diagostic approach and guides treatment and prognosis.

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.

Episodic headache disorder characterised by combinations of changes: Neurological, Gastrointestinal, Autonomic Definition A neurologic disorder characterised by idiopathic, paroxysmal, recurrent attacks of headache lasting from 2-72 hours Typical characteristics: Unilateral (sometimes bilateral) pulsating quality mod or severe intensity may be accompanied by either nausea & vomiting or photophobia & phonophobia aggravated by physical activity may be preceded by an aura Definition of Migraine headache

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.

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.

Migraine Triggers Stress Emotion-(anger, anticipation, anxiety, depression, emotional letdown, exhilaration/excitement, frustration, stress) Sex Glare-flickering lights/light glare Hypoglycemia Altered Sleep Pattern-fatigue/sleep deprivation or excessive sleep Menses Physical exertion Alcohol Smoking/second hand tobacco smoke Excess caffeine / withdrawal Odours (perfume, exhaust fumes, paint, solvents) Foods containing MSG tyramine nitrates phenylethylamine Aspartame chocolate Drugs Estrogen (eg. OCP) Nitroglycerin Excess analgesic use or withdrawal (cocaine, cimetidine, oestrogens, theophylline)

Material to read later: SECONDARY, SYMPTOMATIC HEADACHES THE HEADACHE IS A SYMPTOM OF AN UNDERLYING DISEASE, LIKE : Hypertension Sinusitis Glaucoma Eye strain Fever Anaemia CADSIL P seudotumor cerebri Temporal arteriitis Infection - Meningitis, encephalitis Brain tumor, meningeal carcinomatosis Haemorrhagic strok e head (SAH) and/or neck trauma cranial or cervical vascular disorder non-vascular intracranial disorder a substance or its withdrawal- caffine, drugs disorder of homoeostasis disorder of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth or other facial or cranial structures psychiatric disorder cranial neuralgias and central causes of facial pain

Migraine affects 10-15% of general population Migraine accounts for 10-20% of all headaches in adults 1% chronic migraine (>15 days/months) Mean frequency 1.2/month Mean duration 24 h (untreated) 10% always with aura, >30% sometimes with aura Usual age at onset is 15-35 years Family History: 70% of patients have relatives with Headache history Prevalence highest in 25-55 year age group Largely undiagnosed or self-diagnosed (85% of men, 72% of women) Often self-treated by sufferer; 30% Treated by physicians Economic impact hard to quantify (est. $US18 Billion) Relates to: Absenteeism, Decreased work productivity, Cost of treatment Migraine: epidemiology

World prevalence of migraine 1-year prevalence rates Population-based studies IHS criteria (or modified) USA 12% Chile 7% Japan 8% Italy 16% Denmark 10% France 8% † Switzerland 13% Rasmussen and Olesen (1994); Rasmussen (1995); Lipton et al ( 1994); Lavados and Tenhamm (1997); Sakai and Igarashi (1997) † Prevalence measured over a few years

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

Migraine in Women Migraine 2-3x more common than in men Possibly some hormonal association 14% of women experience migraine associated with periods Usually during first 3 days Risk of migraine increased 10x in women on OCP OCP increase frequency of migraines Attacks occur during placebo week rather than during active weeks Almost half women experience improvement in migraine during pregnancy. Migraine frequency decreases in 2/3 women after menopause

Migraine in childhood Prevalence 5% Sex ratio 1:1 Abdominal symptoms often predominant Semiology of attacks as in adulthood except shorter duration of attacks Short sleep very effective

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.

Although the aura usually precedes the headache in each attack, it may continue into the first several minutes of the headache or begin in the middle of an attack. Typically the auras are visual and often take the form of photopsias, formless visual obscurations (“like heat waves rising off the road”), bright silver or colorful fortification spectra, or scintillating scotomata. Sensory aura is the second most common and usually occurs in a “cheiro-oral” distribution, often involving these areas in a sequential fashion over a short period of time, rather than affecting both areas simultaneously. Tingling may begin, for example, in one hand and then, over a period of minutes, ascend the arm to the elbow and then jump to the ipsilateral side of the face (cheiro-oral), recapitulating in the cortical homunculus. Sometimes mild hemiparesis may occur as a migraine aura, and sometimes, particularly in younger patients, aphasia and or confusion may usher in the headache. Silberstein SD, Saper JR, Freitag FG. Migraine: diagnosis and treatment. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolff’s Headache And Other Head Pain . 7th ed. New York: Oxford University Press; 2001:121-237.

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)

Migraine with aura clinical criteria At least 2 attacks fulfilling criteria B & C at least three of the following four characteristics One or more fully reversible aura symptoms indicating focal nature At least one aura symptom develops gradually over > 4minutes, or two or more symptoms occur in succession No aura symptoms lasts >60 minutes (or diagnosis is migraine with prolonged aura). Duration increased if more than one aura symptom is present Headache follows aura with free interval of less than 60 minutes (may also begin before or simultaneously with aura History, physical and neurologic examinations, and, if appropriate, diagnostic tests exclude related organic disease or headache not temporally related to organic disorder Other less common types of migraine Hemiplegic -With hemiplegic migraines, the aura is much more severe and can cause temporary paralysis or numbness on one side of the body, or a loss of motor control. Individuals who have experienced a hemiplegic headache say they also endured dizziness, visual disturbances, involuntary eye movement, attention deficits and memory loss. Status Migrainosus -A debilitating Migraine attack lasting for more than 72 hours. Treat fast-risk of stroke! Menstrual

Very severe migraine attack / status migrainosus: Triptan (sumatriptan 6 mg s.c.) Lysine acetylsalicylate 1,000 mg i.v. Metamizol (NSAID) 500-1,000 mg i.v. Antiemetics i.v. Steroids i.v. Status migrainosus:Attack treatment in emergency

IMPORTANT TO KNOW! MIGRAINE WITH AURA IS A RISK FACTOR FOR ISCHAEMIC STROKE THEREFORE PATIENTS SUFFERING FROM MIGRAINE WITH AURA SHOULD NOT SMOKE!!! SHOULD NOT USE ORAL CONTRACEPTIVE DRUGS!!! THE PROPO R TION OF PATENT FORAMEN ( for-a-men ) OVALE IN PATIENTS WITH MIGRAINE WITH AURA IS ABOUT 50-55% . A trial septal defect, a form of congenital heart defect that enables blood flow between the left and right atria via the interatrial septum.

Material to read later- Is there a relationship between aura and patent foramen ovale ? Shunting of venous blood to the arterial side could be the reason  no breakdown of certain neurotransmitters (5HT) in the lung! Comorbidity could be also an explanation. However, closure of patent foramen ovale decreases the frequency of migraine attacks. BUT! Migraine is a benign disease. Please do not indicate closure of patent foramen ovale just because of migraine with aura! 

Diagnostic criteria for migraine without aura : Normal physical examination No other reasonable cause for headache 5 attacks ; each lasting 4- 72 hrs (2–48 h in children) each attack to be accompanied by one of the following: nausea or vomiting phonophobia photophobia 2 of the 4 pain characteristics unilateral location Pulsating/throbbing quality moderate to severe intensity aggravation by physical activity

Cluster headache Short, excruciating (15 min-3 hrs) Usually occur in the middle of the night unilateral pain behind eye occur daily for 2-3mths then remit for months-years Red, watering eyes, blocked nose Tension headache diffuse pain in tight head-band pattern bilateral, non-pulsating no prodrome/aura No nausea and vomiting 10 attacks lasting 30 min–7 days 2 of the following 4 Bilateral Not pulsating Mild or moderate intensity Not aggravated by routine physical activity No nausea or vomiting One or neither photophobia or phonophobia Not attributable to another disorder Sinus headache Evidence of purulent discharge from the nose constant dull ache in cheek area accompanied by sinusitis worsens with bending over or blowing nose Differential diagnosis of primary headaches

Chronic Paroxysmal Hemicrania The pain is unilateral, always affects the same side, and is generally oculofrontotemporal in location. The pain is usually most severe in the oculotemporal area, the forehead, and above or behind the ear. Occasionally, pain can radiate and involve the ipsilateral shoulder, arm, and neck. Headache can appear at any time in patients with CPH, in contrast to CH in which the headache usually occurs at night. During severe attacks, excruciating pain with throbbing, boring, pulsating, or clawlike character has been described. In contrast to patients with CH, patients with CPH usually sit quietly or may curl up in bed between attacks. The attack frequency usually is 10-20 attacks per day and may range from 2-50 attacks per day. Attacks usually last 2-25 minutes, but they may last as long as 60 minutes. CPH can be triggered by various stimuli, including neck movement, external pressure to neck, or other factors. CPH attacks are accompanied by autonomic symptoms, mostly on the same side as the pain, such as red eyes, tearing, nasal congestion, and sometimes rhinorrhea. Occasionally, photophobia may be present, but gastrointestinal symptoms are very rare. Recognizing the various stages and different patterns of CPH is important. For example, during severe frequent attacks, patients may describe a constant headache or persisting tenderness on the symptomatic side. IHS diagnostic criteria for CPH include the following (slightly modified from the Headache Classification Committee, 1988): At least 50 attacks fulfilling the criteria mentioned below: Attacks of severe unilateral orbital, supraorbital, and/or temporal pain always on the same side lasting 2-45 minutes Attack frequency more than 5 per day for more than half of the time (periods with lower frequency may occur) Pain associated with at least one of the following signs/symptoms on the symptomatic side: Conjunctival injection Lacrimation Nasal congestion Rhinorrhea Ptosis Eyelid edema Absolute effectiveness of indomethacin (150 mg/d or less)

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

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

Material to read later: Migraine phases 4 Phases: Prodrome, Aura, Headache and Resolution/postdrome 1. Prodrome Occur in 20-60% of pts Hours to days before onset May include: psychological neurological constitutional or autonomic features Most common are: feeling tired or weary, difficulty concentrating, a stiff neck and poor functioning Originate in hypothalamus and frontal lobes

2. Aura A sensation that precedes the development of the migraine headache occurs in ~30% of cases Usually develops over 5-20 minutes lasts for less than 60 minutes Can be visual, sensory, motor or involve language disturbances May have multiple aura types Vary in complexity Simple auras include: Scotomata, Simple flashes, specks, geometric forms and shimmering Complex auras include: Teichopsia, fortification specra, metamorphosia, micropsia, macropsia, zoom vision, mosaic vision May include numbness or tingling Material to read later: Migraine phases

3. Headache Median frequency is 1.5 attacks per month Typical headache is unilateral, throbbing with gradual onset Moderate to marked in severity Aggravated by movement Headache can sometime be bilateral or begin unilaterally and become generalised Lasts 4-72 hours in adults and 1-72 hours in children Anorexia is common Nausea occurs in almost 90%, vomiting in ~30% Wide range of other sensations occur ( diarrhoea, fatigue, facial pallor, cramps, irritability, etc) Material to read later: Migraine phases

4. Postdrome After headache has resolved Patient feels tired, washed out, irritable or listless Can have impaired concentration, scalp tenderness or mood changes Some patients feel refreshed or euphoric after attack, others feel depressed Occurs in 90% patients Symptoms can persist for several days lethargy exhaustion impaired concentration irritability sluggishness diminished appetite euphoria Material to read later: Migraine phases

Migraine Diagnosis The cause or type of most headaches can be determined by a careful history and physical examination . The clinical imperative is to recognize the warning signals that raise red flags and prompt further diagnostic testing. If atypical features are present or the patient does not respond to conventional therapy, the diagnosis should be questioned and the possibility of a secondary headache disorder should be revisited . Because migraine and tension-type headache (TTH) account for over 90% of the primary headache disorders in clinical practice, this discussion will focus on their clinical features, the warning signals of serious secondary headaches, and the role of diagnostic testing in the evaluation of headache .

Positive diagnosis if attack history fulfils criteria for migraine Organic disease must be excluded Detailed History and Examination Primary Headache? Preliminary Diagnosis NO Secondary Headache Diagnostic Testing Atypical Features YES

HISTORY AND EXAMINATIONS SHOULD CLARIFY IF THE PATIENT HAS PRIMARY OR SECONDARY HEADACHE IS THERE ANY URGENCY IN CASE OF PRIMARY HEADACHE ONLY THE HEADACHE ATTACKS SHOULD BE TREATED ( ATTACK THERAPY ), OR PROPHYLACTIC THERAPY IS ALSO NECESSARY ( PREVENTIVE THERAPY )

History : Profile of HA time from onset to peak usual time of onset (week , month, season, hour of day) frequency & duration change over lifetime description : pulsating, pressing, sharp location : unilateral or bilateral or changing severity precipitating factors Aggravating factors factors that relieve the headache effectiveness of pharmacological or non-pharmacological treatments Aura

Migraine Diagnosis: Questions for headache patients Age, occupation –past history How old was the patients when the headaches began? Are the headaches in attacks? How frequent are they? What is the nature of the pain? Is it throbbing? Is it worse with exercise? Is there any associated nausea or vomiting? Are there any other symptoms sensory or speech changes related to the headache? What treatment has been tried? Is the headache a throbbing, pulsating pain? Is the headache located on one side of the head at any stage Does headache last between 3hrs and 4 days? Do you feel well between attacks? Do you see wavy lines or flashed of light or similar that affects your vision before the headache? Do you feel sick or vomit during the headache? Do you feel like you want to avoid light/ noise during the headache? Do you usually sit or lie quietly during the headache? Are you prevented from, or have difficulty, conducting normal activity during the headache? Yes to all or most of these indicates migraine-type headache

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.

IMPORTANT DIAGNOSTIC CONSIDERATIONS Although research demonstrates that some criteria are more predictive of migraine than others, no single criterion is sufficient. Likewise, no single criterion is essential to confirm a diagnosis of migraine. A common misconception is that aura is the telltale sign of migraine . Eighty-five percent of migraine patients do not experience aura. Many, but not all, patients have other symptoms that they recognize as premonitory. Common amongst these are: tiredness, stiff neck, craving for sweets, and yawning. Although nausea is very common in migraine patients, vomiting occurs much less frequently. Most migraine patients experience nausea with a large proportion of their headaches, vomiting with a few of their headaches, and neither symptom with some of their headaches. Many migraine patients report never having vomited in association with their headaches. Unilateral pain is a common characteristic of migraine and can be a key symptom in making the diagnosis. However, many (41%) migraine patients report headaches that begin bilaterally and then settle on one side or headaches that remain bilateral throughout, but nonetheless meet the other criteria for migraine. Similarly, pulsating or throbbing pain is a common characteristic of migraine but just as many migraine patients will report a penetrating, boring, or stabbing pain. Because approximately 80% of migraine patients also have other headaches and may have more than one headache type at the same time, parsing out migraine symptoms can be challenging. Headache specialists widely believe that moderate to severe, recurrent headache is migraine until proven otherwise. Pryse-Phillips WEM, Dodick DW, Edmeads JG, et al. Guidelines for the diagnosis and management of migraine in clinical practice. Can Med Assoc J . 1997;156(9):1273-1287. Russell MB, Rasmussen BK, Fenger K, Olesen J. Migraine without aura and migraine with aura are distinct clinical entities: a study of four hundred and eighty-four male and female migraineurs from the general population. Cephalalgia . 1996;16(4):239-245.

Headache ‘red flags’ An attempt to elicit these worrisome features should be part of every new headache evaluation because their presence may signify an underlying pathological condition for which diagnostic testing is obligatory. Systemic symptoms, such as fever, malaise, or weight loss, should suggest an underlying infectious or systemic inflammatory disorder. Newly acquired neurologic signs or symptoms should always raise concern. The mode of onset is perhaps the most important characteristic of a headache to be delineated. Those patients who have a sudden or abrupt headache that peaks in seconds or minutes require careful assessment to exclude causes such as subarachnoid hemorrhage (SAH) venous sinus thrombosis, arterial dissection, or raised intracranial pressure . Any new or progressive headache that begins in middle age or any headache that deviates significantly from a previous pattern should be investigated further. If these features are addressed, the chance of overlooking a sinister cause for headache are greatly diminished. Silberstein SD, Lipton RB, Dalessio DJ. Overview, diagnosis, and classification. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolff’s Headache And Other Head Pain . 7th ed. Oxford, England: Oxford University Press; 2001:20.

No longer fulfils IHS criteria New onset headache in middle age or later ; and progressive headache, especially in middle-age >50 (giant cell arteritis) New or progressive headache that lasts for days Headache with extremely abrupt onset Progressively worsening headaches rapidly increasing frequency or severity of headache Significant change from previous headache pattern : Different type of headache-change in headache clinical features (change in attack frequency, severity, or clinical features) First or “worst-ever” headache- headaches that reach maximal severity at onset Onset of headache with exertion- Precipitation of headache by coughing/sneezing/ bending down Headache with neurologic symptoms dizziness, numbness or tingling abnormal pupils Clumsiness or weakness Other signs do not resolve when headache resolves ( cf phases) Systemic symptoms such as myalgia, fever, malaise, weight loss, scalp tenderness, jaw claudication Focal symptoms, seizures , confusion, impaired conciousness, physical examination abnormalities Systemic symptoms (f neck stiffness, f ever, weight loss) or Secondary risk factors (HIV, systemic cancer) Abnormal signs (confusion, impaired alertness, or consciousness) Headache ‘red flags’

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.

Migraine Disability Assessment Score (MIDAS) I Minimal or infrequent disability 0-5 II Mild or infrequent disability 6-10 III Moderate disability 11-20 IV Severe disability 21+

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.

Bousser MG et al. In: Wolff’s Headache And Other Head Pain . 2001 . The complex relationship between migraine and stroke has challenged clinicians for centuries. Not only can the migraine aura mimic a TIA, but headache may occur as a pre-ictal, ictal, or post-ictal feature of stroke. Moreover, casual relationships between migraine and stroke can occur at several levels: The two may coexist by coincidence or by some unknown associated mechanism. Migraine-induced stroke, although rare and always a diagnosis of exclusion, is a well-recognized phenomenon. Stroke may result from a condition that is comorbid with migraine, such as mitral valve prolapse, carotid dissection, or antiphospholipid antibody syndrome. The two conditions may result from an underlying metabolic or hereditary condition, such as MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like syndromes) and CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy).

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.

Consensus expert opinion MRI is more sensitive Role of CT or MRI in patients with nonmigraine headache is unclear In patients with recurrent migraine, neither CT nor MRI is warranted except in cases where: Recent substantial change in headache pattern History of seizures Focal neurologic symptoms or signs Report of Quality Standards Subcommittee of AAN. Neurology . 1994.

EEG may be useful in those patients with Alteration or loss of consciousness Residual focal neurologic defects or encephalopathy Atypical migrainous aura EEG is not useful In the routine evaluation of patients with headache to exclude structural cause Report of Quality Standards Subcommittee of AAN. Neurology . 1995.

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

Common Theories of Migraine Pathogenesis Theories on the pathogenesis of migraine include: The vascular theory The cortical spreading depression theory The neurovascular hypothesis The serotonergic abnormalities hypothesis The integrated hypothesis. Activation of trigeminovascular pathways

Migraine Pathogenesis: The vascular theory H. Wolff developed the vascular theory of migraine pathogenesis during the 1940s and 1950s. According to this theory, migraine is a vasospastic disorder that is initiated by when blood vessels in the brain contract and expand inappropriately . The vasoconstriction stage appears to be associated with migraine aura. This may start in the occipital lobe , in the back of the brain, as arteries spasm. The reduced flow of blood from the occipital lobe triggers the aura that some individuals who have migraines experience because the visual cortex is in the occipital area. Following the early vasoconstrictive stage, intracranial or extracranial blood vessels dilate. The once solid walls of the blood vessels become permeable and some fluid leaks out. This leakage is recognized by pain receptors in the blood vessels of surrounding tissue. In response, the body supplies the area with chemicals which cause inflammation. Whereas most of the brain is insensitive to pain, meningeal blood vessels show a high level of innervation. Thus, blood vessel dilation activates the trigeminal sensory nerves that surround the meningeal blood vessels, causing pain . Activation of trigeminal nerves also causes the release of vasoactive neuropeptides that further contribute to dilation and worsen pain. The vascular theory of migraines is now considered secondary to the other theories.

Migraine Pathogenesis: The cortical spreading depression theory Cortical spreading depression (CSD) is a relatively short-lasting wave of depolarization (electrical change) that spreads across the surface of the brain, moving from the back (occipital region) of the cerebral cortex toward the front at about 3-5 mm/minute. Neurological activity is depressed over an area of the cortex of the brain. This situation results in the release of inflammatory mediators leading to irritation of trigeminal nerve roots, which conveys the sensory information for the face and much of the head. It has been suggested that migraine aura results from this spreading depression that suppresses neuronal activity as it passes forward over the cerebral cortex. Although CSD has been demonstrated only in animals, support for the CSD theory comes from observations that, in patients who have migraine with aura, a gradual spread of reduced cerebral blood flow that mimics the rate of progression of CSD in animals can be measured during the aura phase.

Migraine Pathogenesis: The Neurovascular theory Fibers from the trigeminal nerve innervate blood vessels in the meninges , the extracranial arteries, and those in the circle of Willis. These nerve fibers contain nociceptors that are capable of generating pain impulses , and the endings of these nerve fibers contain peptide neurotransmitters . The neurovascular hypothesis proposes that either migraine triggers or CSD can activate trigeminal nerve axons, which then release neuropeptides (such as substance P, neurokinin A, and CGRP) from axon terminals near the meningeal and other blood vessels. Substance P and neurokinin A cause vasodilation and promote the extravasation of plasma proteins and fluid from nearby meningeal blood vessels. Although CGRP does not promote plasma extravasation, it is a potent vasodilator. Together, these neuropeptides produce an inflammatory response in the area around the innervated blood vessels. This response is termed sterile neurogenic perivascular inflammation. The neuropeptides may also sensitize nerve endings, providing a mechanism for sustaining the headache . When activated, the trigeminal nerve also transmits pain impulses to the trigeminal nucleus caudalis, which relays pain impulses to higher centers of the brain. According to the neurovascular theory, vasodilation is not the cause of migraine headaches but is an accompanying phenomenon attributable to trigeminal nerve activation. Although the cause of this activation is not known, it may be due to ionic and metabolic disturbances in brain function, such as those associated with CSD. It has also been proposed that abnormal activity in brain stem sensory nuclei may cause antidromic activation of trigeminal sensory pathways.

Migraine Pathogenesis: The Serotonergic Abnormalities theory Observations that both plasma and platelet levels of serotonin fluctuate during a migraine attack suggest that serotonin may be involved in the pathogenesis of migraine. When platelets are activated, they aggregate and release serotonin, thus increasing the plasma serotonin level. An increase in plasma serotonin level would be expected to cause vasoconstriction, whereas a decrease in serotonin would promote vasodilation. Platelet serotonin levels may drop precipitously during the headache phase of migraine. Also, urine levels of serotonin and its metabolites rise during headaches, suggesting that there is a large release of serotonin during such attacks. Moreover, drugs such as reserpine that cause the release and depletion of serotonin from tissue storage sites may precipitate migraine headaches. An initial surge in plasma serotonin levels may cause constriction of cerebral blood vessels and a reduction in cerebral blood flow. If the blood flow is sufficiently reduced, migraine aura may result. A subsequent depletion and drop in serotonin levels may then lead to a marked dilation of extracranial and intracranial arteries, precipitating migraine pain. Triptans activate serotonin receptors to stop a migraine attack. Several questions regarding the serotonin abnormalities hypothesis remain unanswered. It seems unlikely that changes in blood serotonin levels are solely responsible for the development of migraine. For instance, global changes in plasma serotonin levels do not explain the unilateral nature of migraine pain, and serotonin levels in patients with migraine may remain depressed long after the headache has resolved. It may be, however, that changes in plasma serotonin levels reflect more important disturbances in brain serotonin levels. One brain stem structure that has a high concentration of serotonin receptors is the dorsal raphe nucleus. This nucleus contains many serotonin-secreting neurons that terminate on cerebral blood vessels and various other brain areas that are involved in the production of migraine symptoms. It has been suggested that the raphe nucleus, which is responsive to changes in serotonin levels, may serve as a "migraine generator."

Migraine Pathogenesis: The integrated hypothesis Both vascular and neural influences cause migraines. 1. Stress triggers changes in the brain 2. These changes cause serotonin to be released 3. Blood vessels constrict and dilate 4. Chemicals including substance P irritate trigeminal nerve endings and blood vessels causing neurogenic inflammation and pain The integrated hypothesis of migraine pathogenesis is an attempt to consolidate various theories and explain several observations related to migraine pain. According to this theory, triggers such as stress, glare, noise, the patient's internal clock, the dilation of the internal or external carotid arteries, or other factors may activate specific centers in the brain stem. One such center, the locus ceruleus, causes changes in epinephrine levels. Another center, the dorsal raphe nucleus, affects serotonin levels in the brain. Constriction of cerebral blood vessels may cause a localized deficiency in blood flow, provoking CSD, which may, in turn, stimulate trigeminovascular fibers, eliciting neurogenic inflammation and headache pain. Nerve fibers from the locus ceruleus, the dorsal raphe nucleus, and the trigeminal nerve cause a stimulation of cranial nerves that dilate both cerebral and extracranial blood vessels. The dilation of meningeal vessels contributes to pain generation. The locus ceruleus also sends fibers to higher centers of the cerebral cortex, where it influences a person’s state of arousal and awareness, and descending projections interact with the body’s pain control mechanisms. Likewise, the dorsal raphe nucleus sends multiple fibers to blood vessels and upward toward the cerebral cortex. These serotonin-secreting fibers help regulate sleep and neuroendocrine functions. Other connections are made with lower brain stem areas and with the hypothalamus. A disruption in the normal function of the hypothalamus may be responsible for prodromal signs and symptoms of migraine such as mood changes, food cravings, drowsiness, thirst, and yawning. These signs and symptoms may occur several hours, or even as long as 1 day, before headache pain begins.

Migraine Pathophysiology: videos http://www.youtube.com/watch?v=yZr9Joe85wg http://www.youtube.com/watch?v=hGgDho_qPZ0&feature=related http://www.youtube.com/watch?v=cnath-Oe5Ds&feature=related

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 .

Mechanism of current pharmacological migraine treatments

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.

Goals of acute migraine therapy Establish diagnosis Discuss findings Establish reasonable expectations Involve patient in decisions  Encourage Pt to avoid triggers Choose the best treatment (tailoring) Create treatment plan Reduce attack frequency, severity, and disability Reduce reliance on poorly tolerated, ineffective, or unwanted acute pharmacotherapies. Have minimal or no adverse side effects. Avoid acute headache medication escalation Educate and enable patients to manage their disease to enhance personal control of their migraine Reduce headache-related distress and psychological symptoms Treat attacks rapidly and consistently without recurrence. Restore the patient’s ability to function. .

Mechanisms to meet acute treatment goals Use of migraine-specific therapy (eg triptans) in patients who respond poorly to NSAIDs Failure to use treatment promptly may increase pain, disability and duration of headache Do not use aspirin in children <15 yrs Select non-oral route if severe nausea or vomiting Nausea is one of the most disabling symptoms  treat with Anti-emetics Rescue medication may be required in some patients who do not respond Guard against overuse headache ( rebound headache ) Caused by frequent use of medication Limit acute therapy to 2 days per week Patients with medication overuse should use preventive therapy

Nonspecific NSAIDs Combination analgesics Opioids Neuroleptics/anti-emetics Corticosteroids Misc. (divalprolex=sodium valproate and valproic acid in a 1:1), magnesium, lidocaine, propofol) Specific Triptans Ergotamine/DHE

Strategy of acute treatment of migraine attacks Step care accross or within attacks 1: NSAID 2:triptan 3: e rgot Stratified care do not go through all the steps, but drug can be chosen depending on the severity of the attack

Nonspecific Prescription Medications Butorphanol IN (opioid analgesic Ibuprofen/Naproxen sodium Prochlorperazine IV (phenothiazine class of antipsychotic) GROUP 1a: Substantial empirical evidence and pronounced clinical benefit in migraine Silberstein SD. Neurology . 2000. Migraine-Specific Medications Triptans DHE SC, IM, IN, IV (plus antiemetic)

GROUP 2: Moderate empirical evidence and clinical benefit Opioids  Others Over-the-Counter Analgesics Aspirin Acetaminophen, aspirin, plus caffeine Silberstein SD. Neurology . 2000. GROUP 1b: Substantial empirical evidence of clinical benefit in restricted populations

Rebound: Recurring headache induced by repetitive and chronic overuse of acute headache medication Recurrence: Return of episodic headache during the same attack following acute treatment Prevention: Treat early, add NSAID. Use long duration triptan or DHE Treatment: Repeat initial acute headache drug; almost always effective Tfelt-Hansen P et al. Drugs . 2000; Capobianco DJ et al. Headache . 2001.

Antimigraine agents: analgesics Useful in early stages or for mild-moderate migraine Only if patient can tolerate oral medication Effervescent or fast acting formulation where possible Aspirin –agent of choice Needs to be given in adequate dosage (900mg) NSAIDs Ibuprofen has established effectiveness Recommended for children and adolescents <15 yrs; women naproxen/ naproxen sodium, diclofenac Side Effects GI bleeding renal dysfunction Paracetamol plus codeine, metoclopramide or domperidone Less evidence for effectiveness as monotherapy

Antimigraine agents: Triptans serotonin (5HT 1B/1D/1F ) receptor agonists sumatriptan (oral, nasal spray, sc inj) [*Imigran] naratriptan (oral) [*Naramig] zolmitriptan (oral, dispersible) [*Zomig] rizatriptan [*Maxalt TGA approved] – not PBS almotriptan (*Axert- not yet available) eletriptan (*Relpax TGA approved) – not PBS frovatriptan (*Frovelan –not yet available) TGA= Therapeutic Goods Administration

Proven efficacy Improvement in 70% in 1 hour, 85% in 2 hours Regardless of cost –generally very effective and safe. Generally well tolerated Avoid with MAO-A inhibitors Avoid in pts with ischemic heart disease (IHD), angina, myocardial infarction (MI), uncontrolled hypertension (HT) Failure with one triptan does not preclude use of another Patients respond variably to different drugs Do not combine with ergot agents Favorable side effect profile-In the majority of patients, the intensity of adverse effects is mild and of short duration. Adverse effects can include chest pressure, flushing, dizziness, drowsiness, and nausea. Patients who are at risk for coronary heart disease, diabetes, obesity, severe uncontrolled hypertension, or hypercholesterolemia should be screened prior to administration of triptans. Antimigraine agents: Triptans

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

Comparison of Triptans Sumatriptan First agent introduced, flexible dose administration Highest potency (injection), quickest onset (nasal spray and injection formulations) Headache may recur in 40% - usually responds to second dose $ Since its introduction in the early 1990s, over 400 million doses of sumatriptan have been given $ ! Naratriptan Slow onset, gentle adverse effect profile, lower headache recurrence, proven effectiveness in preventing menstrual migraine Longer half-life than sumatriptan, and lower recurrence rate Lowest incidence of side effects Has lower efficacy than sumatriptan Zolmitriptan Highest consistency in open-label studies, can be successfully used in persistent headache Well tolerated Has a longer half-life than sumatriptan. Rizatriptan Fast-acting orally, has orally disintegrating (wafer) formulation, greatest likelihood of 2- hour pain-free response Almotriptan Highest oral bioavailability, favourable adverse effect profile Eletriptan Steep dose response curve, therefore good dose titration, higher likelihood of drug-drug interactions (metabolised by CYP 3A4 ) Frovatriptan Slow onset of action, but extremely long half –life (26 hours) Low rate of adverse events, and a low recurrence rate.

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

Material to read later- Triptans dosing

Triptans - advantages & disadvantages Useful in established migraine Headache recurrence headache may recur within 24 hrs of treatment occurs in about 1/3 patients taking triptans may take second dose (but not more than recommended dose) Side-effects all have some vasoconstrictive action on coronary circulation rate of serious vascular events is low chest & throat tightness (not cardiac in origin)

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.

Antimigraine agents: Ergot Alkaloids Serotonin (5HT1B/1D)receptor agonists Ergotamin tartarate 2-4 mg per os, sublingual (wafer) or rectal 1 mg nasal spray Dihydrergotamin (DHE) (oral & parenteral, nasal spray) Should not be used in patients with vascular disease, ischemic heart disease or hypertension Used with caution in patients with vascular risk factors or prolonged or severe aura Should not be combined Avoid ergotamine if triptan used in previous 6 hrs Avoid triptan if ergotamine used in previous 24 hrs Dihydrergotamin Ergotamin

Ergot Alkaloids: Advantages & disadvantages Used for >80years, Efficacy 50-70 % No longer first-line, superseeded by triptans Side-effects: Ergotamine nausea, vomiting, drowsiness, fatigue ischaemia rebound headache (>3-4 doses per week) Dihydroergotamine not useful orally only nasal delivery, IM or IV less likely to cause rebound headache Low rate of headache recurrence (~17%) due to long duration of action does not prolong aura role of caffeine ? the concurrent administration of caffeine improves both the rate and extent of absorption of ergotamine

Antiemetics (Anti-nauseants) Nausea and vomiting are common in migraine Gastroprokinetic agents may also relieve gastric stasis May improve absorption of simple analgesics Metoclopramide increased gastric motility may increase bioavailability of analgesics by increasing GI absorption 10-20 mg per oral 20 mg rectal, Parenteral IV, IM High dose in children-Drug induced dystonia, tardive dyskinesia Available in combination with paracetamol Domperidon 10-20 mg per oral Also used to stimulate lactation. Domperidone is excreted in breast milk-may be increased risk of seizures to neonates of mothers taking oral domperidone. Can be used in patients with Parkinson's disease because, unlike metoclopramide, domperidone does not cross the blood-brain barrier (both drugs are dopamine receptor antagonists). Metoclopranide ampule

Treatment Migraine and pregnancy Migraine without aura in >70% of women less frequent or absent (prognostic factor: menstrual migraine) Significantly more manifestation of migraine with aura Acute treatment: paracetamol; NSAIDs in second trimenon Triptans not allowed Prophylaxis: magnesium, metoprolol, (fluoxetine)

Treatment Migraine in childhood Acute treatment: First choice: ibuprofen 10 mg/kg Second choice: paracetamol 15 mg/kg Third choice: sumatriptan nasal spray 10-20 mg Prophylaxis: Flunarizine (calcium channel blocker) 5-10 mg Propranolol 80 mg Non-drug therapy very effective

Medication overuse headache Rebound headache occur with regular use of any migraine medication (except dihydroergotamine) increased frequency of headaches associated with withdrawal of migraine therapy Headaches are refractory, daily or nearly daily limit use: Triptans 12 doses per month Withdrawal symptoms last from 2-10 days Symptoms include: Headache Nausea Vomiting Arterial hypotension Tachycardia Sleep disturbances Restlessness Anxiety and nervousness Valproate, amitriptyline, neuroleptics, IV DHE, & oxygen may be effective in acute withdrawal Prognosis 72% success at 6 months

These are some difficult headache problems. Some account for patients’ dissatisfaction with their medications. Migraine sufferers have high expectations for treatment. They want medications that provide complete pain relief, lack of recurrence, and rapid onset of pain relief. If a patient is not responding to the current medication and is using an analgesic, treat earlier, consider adding metoclopramide or switch to an oral triptan. If the patient is taking an oral triptan treat earlier, increase the dose, or add a NSAID. Change formulations (nasal spray or injection) or consider switching to another triptan. Add a preventive medication. If pain recurrence is frequent and the patient is taking an oral triptan, treat earlier, increase dose, or consider switching to a long-acting triptan (naratriptan or frovatriptan) or DHE nasal spray. Treating when the pain is mild may lead to more complete relief with less recurrence. Specialists sometimes add a long-acting nonsteroidal agent to the triptan. If there is an inconsistent response to the medication, try increasing the dose of the therapeutic agent or administering the drug earlier in the course of treatment. Another alternative is to choose a medication with higher bioavailability. In cases in which patients experience significant adverse effects, options include switching to naratriptan or to a different class of agents altogether. In the elderly, use acetaminophen, COX 2 inhibitors, opioids, and atypical neuroleptics. Try to avoid ergots, DHE, triptans, and NSAIDS. During pregnancy use acetaminophen, opioids, corticosteroids, and neuroleptics. Avoid ergots, DHE, and triptans. Limit aspirin and NSAIDS during the third trimester. Silberstein SD, Saper JR, Freitag FG. Migraine diagnosis and treatment. In: Silberstein SD, Lipton RB, Dalessio DE, eds. Wolff’s Headache and Other Head Pain . 7th ed. Oxford, England: Oxford University Press; 2001:121-237. Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice . Oxford, England: Isis Medical Media; 1998.

Migraine Prophylaxis Aims: Reduce attack frequency, duration or severity Optimize the patient's ability to function normally usually aim for 50% reduction in headache severity &/or frequency Preventive therapy may be more appropriately guided by one or more of the following circumstances: >2 attacks per week prolonged attacks (>48hrs) severe and disruptive (patient cannot function) Regular, predicted attacks (menstrual migraine) Patient preference or special circumstances Adverse events, contraindication to or ineffectiveness Cost of both acute and preventive therapies The presence of uncommon migraine conditions, including hemiplegic migraine, basilar migraine, migraine with prolonged aura, and migrainous infarction Use of acute treatment more than twice per week also may warrant initiation of preventive therapy.

Prophylaxis Management guide Educate patient about migraine & plan Pt to keep diary of headaches & medication use Use one prophylactic agent at a time (generally). Use long-acting formulation if compliance an issue Use low dose first and gradually increase dose Continue trial for several months before withdrawing slowly to avoid rebound headaches Avoid interfering, overused, and contraindicated medications If no response to a trial of combination of agents from different classes – need neurologist!

Pharmacological Prophylactic treatment of migraine The major medication groups for preventive migraine treatment include: Beta-receptor-blockers (propranolol) Calcium channel blockers (flunarizine) Antiepileptics (valproic acid) Tricyclic antidepressants (amitriptyline) Calcium channel antagonists Anticonvulsants ( Topiramate ) Serotonin antagonists NSAID s Others (including riboflavin, minerals, herbs, and botulinum toxin A) If preventive medication is indicated, the agent preferentially should be chosen from one of the first-line categories, based on the drug’s side effect profile and the patient’s coexistent and comorbid conditions. Silberstein SD. Preventive treatment of migraine: an overview. Cephalalgia. 1997;17(2):67-72.

Ranking of migraine preventative therapies US Headache consortium Group 1 –medium/high efficacy, good evidence, mild/moderate side effects propranolol, timolol, amitriptyline, sod. valproate, topiramate Group 2 – lower efficacy or limited evidence, mild/moderate side effects Betablockers (atenolol,metoprolol), Calcium channel blockers (verapamil, flunarizine), NSAIDs (aspirin, ketoprofen, naproxen sod., mefenamic acid), others (gabapentin,etc.)

Ranking of migraine preventative therapies Group 3 – clinically effective, no scientific evidence Antidepressants (doxepin, fluvoxamine, imipramine, mirtazepine, venlafaxine, paroxetine, sertraline, trazodone) Others (cyproheptadine, diltiazem, ibuprofen, tiagabine, topiramate) Group 4 – medium/high efficacy, good evidence, side-effect concerns Methysergide Group 5 - evidence showing no benefit over placebo Carbamazepine, clomipramine, clonazepam, indomethacin, nifedipine, pindolol

Material to read latter-Prophylactic drugs b-blockers (not all are effective) propranolol, timolol, metoprolol, atenolol Those with intrinsic sympathomimetic activity are not effective (pindolol) Failure with one b-blocker does not preclude use of another Reduce dose when migraines are controlled Adverse effects include drowsiness, lethargy, sleep disorders, nightmares, depression, etc. Decreased exercise tolerance restricts their use by athletes Useful for patients with angina or hypertension Contra-indicated in pts with: asthma, COPD, IDDM, heart failure, PVD

Tricyclic antidepressants less-sedating (protriptyline, desipramine) sedating (amitriptyline, doxepin, nortriptyline, imipramine) Useful for patients with co-morbid depression and anxiety disorders Calcium channel blockers May work by neurotransmitter modulation and cytoprotection verapamil, flunarizine (most effective in this class), diltiazem Serotonin antagonist methysergide, pizotifen High rate of severe adverse effects Other agents sodium valproate, gabapentin, topiramate,, clonidine, cyproheptadine, NSAIDs, phenelzine, feverfew (effectiveness not established) Material to read latter-Prophylactic drugs

Prophylactic treatment of the chronic tension type of headache Tricyclic antidepressants Guidelines: Start with low dose (10-25 mg) and increase the dose if no beneficial effect after 1-2 weeks Maximal dose should not be more than 75 mg/day Change to other tricyclic antidepressant only after 6-8 weeks Ask the patient to use headache diary Use the tricyclic antidepressant for 6-9 months Decrease the dose gradually

Prophylactic treatment of the chronic tension type of headache First choice of drug: Amitryptiline or Mirtazapine 1st week: 25 mg in the evening 2nd week: 50 mg in the evening 3rd week: 75 mg in the evening continuously Change to other drug (e.g. clomipramine) if no beneficial effect within 6 weeks

Prophylactic treatment of the episodic form of cluster headache Epi s odic form: prednisolon e Treatment: 1-5. days 40 mg 6-10. days daily 30 mg 10-15. days daily 20 mg 16-20. days daily 15 mg 21-25. days daily 10 mg 26-30. days daily 5 mg Nothing Intravenous magnesium sulfate relieves cluster headaches in about 40% of patients with low serum ionized magnesium levels. Melatonin has also been demonstrated to bring significant improvement in approximately half of episodic patients

Prophylactic treatment of the chronic form of cluster headache Lithium carbonate Daily 600-700 mg Can be decreased after 2 weeks remission Control of serum level is necessary (0,4 - 0,8 mmol/l) Methysergide (synthetic ergot alkaloid), and the anticonvulsant topiramate are alternative treatments.

GENERAL PRINCIPLES OF PROPHYLACTIC TREATMENT Take into account the presence of coexisting diseases. Some comorbid conditions are more common in persons with migraine. These conditions include Stroke Myocardial infarction Raynaud’s phenomenon Epilepsy Affective disorders Anxiety disorders Coexisting diseases present both treatment opportunities and limitations. Once the coexistent condition has been identified, select a pharmacologic agent that will treat both disorders . Establish that the coexistent disease is not a contraindication for the selected migraine therapies (eg,  -blockers are contraindicated in patients with asthma) . Ensure that treatments being used for coexistent conditions do not exacerbate migraine . Beware of interactions between pharmacologic agents used for migraine and those used for other conditions. Special attention should be directed to women who are pregnant or want to become pregnant. Preventive migraine medications may have teratogenic effects. If treatment is absolutely necessary, select a treatment with the lowest risk of adverse effects to the fetus. Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice . 2nd ed. London, England: Martin Dunitz; 2002.

COMORBID AND COEXISTENT CONDITIONS Coexistent disorders are commonly present Therapeutic limitations Avoid  -blockers with depression, asthma, or hypotension Silberstein SD et al. Headache in Clinical Practice . 2nd ed. 2002. Therapeutic opportunities Treat two disorders with a single drug Hypertension or angina — use  -blocker Depression — use TCAs or SSRIs Epilepsy or mania — use divalproex or topiramate

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

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

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.

PROPHYLACTIC TREATMENT: USE OF ACUTE MEDICATION Can use acute and preventive treatment together Limit acute drug use to prevent drug-induced headache Certain drugs require caution or cannot be used together Acute medications may have more benefit Breakthrough attacks need treatment Silberstein SD. Cephalalgia . 1997. Preventive treatment does not eliminate all attacks

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

Common Reasons for Prophylactic Treatment failure Analgesic or ergot overuse Inadequate trial duration 8 weeks at effective doses Inadequate trial of non-pharmacological regimens DI interactions Inaccurate diagnosis

Material to read latter-Migraine prophylaxis Summary Drugs include: B-blockers, antidepressants, calcium channel antagonists, serotonin antagonists, anticonvulsants, NSAIDs. Choice based on effectiveness, adverse effects and co-existent conditions 4-6 weeks minimum trial (maybe longer 2-6 months) discontinue if not effective Prophylactic therapy in children is more difficult as often insufficient evidence is available to either establish efficacy or safety

Effective > 50% Diet, education re: Strategies for identifying and avoiding triggers ,relaxation Cognitive behavioral therapy Moderately effective 30-50% Stop smoking, exercise, riboflavin Ineffective <30% Avoiding tyramine, aspartame, chocolate Acupuncture Cervical manipulation Hyperbaric oxygen Hypnosis Non-pharmacoligical prophylactic treatment of migraine

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

Acute Migraine Management Begins with accurate diagnosis Headache diary/calendars may be helpful Record frequency, features, duration, severity and response to treatment Early treatment is critical - “window of opportunity” Medication Tailor treatment to individual patient severity of migraine co-existing conditions previous response Choice of treatment depends on: severity of attack, associated symptoms, co-existent disorders, previous treatment response the drug’s efficacy, potential for overuse and adverse effects A non-oral route should be considered for severe nausea and vomiting

The general principles of acute migraine care include the following: Initiate therapy with the lowest effective dose. Begin with a low dose of the chosen pharmacological agent and increase the dose slowly until clinical benefits are achieved in the absence of adverse events or until limited by adverse events. Give each treatment an adequate trial. A clinical benefit may take as long as two to three months to manifest itself. Avoid interfering medications e.g., overuse of certain acute medications such as ergotamine Treat the headache as early as possible in the attack to reduce the intensity and duration of the attack as well as the accompanying features. Failure to use effective therapy early may increase the pain, disability, and impact of the headache. Tailor the treatment to both the individual and the individual attack. Use the correct dose and formulation. The route of administration is especially important in patients experiencing severe nausea and vomiting. Generally, the use of acute therapy should be restricted to a maximum of 2–3 days per week to avoid rebound. Everyone needs acute treatment in addition to patient education and, in many cases, nonpharmacologic intervention. Consider the addition of preventive therapy for selected patients.

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

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.

CADASIL ( c erebral a utosomal d ominant a rteriopathy with s ubcortical i nfarcts and l eukoencephalopathy) is the most common form of hereditary stroke disorder, and is thought to be caused by mutations of the Notch 3 gene on chromosome 19. The underlying pathology of CADASIL is progressive degeneration of the smooth muscle cells in blood vessels. The most common clinical manifestations are migraine headaches and transient ischemic attacks or strokes, which usually occur between 40 and 50 years of age, although MRI is able to detect signs of the disease years prior to clinical manifestation of disease. Migraine is often the first clinical manifestation of this syndrome, usually presenting at the age of 30 years, approximately 15 years before the first ischemic stroke. Migraine is present in approximately 40 percent of families with CADASIL. Often these patients have migraine with aura and sometimes basilar or hemiplegic migraine . Some patients with migraine-associated confusion or coma have been described. Prior to developing attacks of migraine with aura, these patients often have a presymptomatic phase during which the MRI is abnormal. Bousser MG, Good J, Kittner SJ, Silberstein SD. Headache associated with vascular disorders. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolff’s Headache And Other Head Pain . 7th ed. New York: Oxford University Press; 2001:349-392. CADASIL

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

Giant cell arteritis (GCA or temporal arteritis) is an autoimmune disease, granulomatose inflammation of branches of External Carotid Artery that supply the head eyes, and optic nerves . It is a form of vasculitis. The name (giant cell arteritis) reflects the type of inflammatory cell that is involved (as seen on biopsy). The terms " giant cell arteritis " and "temporal arteritis" are sometimes used interchangeably, because of the frequent involvement of the temporal artery. Epidemiology: It is more common in females than males by a ratio of 3:1. The mean age of onset is about 70 years, and it is rare in those less than 50 years of age. The incidence is 24.2 per 100,000 women over 50 and 8.2 per 100,000 men over 50

Clinical Presentation: Unilateral headache, pulsating pain more sever at night Fever Tenderness and sensitivity on the scalp Jaw claudication (pain in jaw when chewing)  inflammation of internal maxillary artery Tongue claudication (pain in tongue when chewing) and necrosis Reduced visual acuity (blurred vision) Acute visual loss (sudden blindness) Diplopia (double vision) Acute tinnitus (ringing in the ears) Approximately 50% of GCA patients also have polymyalgia rhematica (PMR), which is characterized by muscle pain and stiffness. The inflammation may affect blood supply to the eye and blurred vision or sudden blindness may occur. In 76% of cases involving the eye, the ophthalmic artery is involved causing anterior ischemic optic neuropathy . Loss of vision in both eyes may occur very abruptly and this disease is therefore a medical emergency. Amaurosis fugax may precede the blindness Anterior ischemic optic neuropathy resulting from giant cell arteritis. The optic nerve is swollen, and there are surrounding hemorrhages.

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.

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

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).

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

Material to read later-Case Study 17 yr old female L-sided pulsatile headache recurring 3-4x monthly headache preceded by loss of visual fields headache is accompanied by nausea, vomiting and photophobia headache lasts all day unless able to lie in a dark room & sleep affects ability to work/study past medical history unremarkable - no other medical problems general physical & neurologic exam -normal

Other information needed? How long has she had the headaches? About 3months Is the headache the same as before? Yes, has vision change then onset of headache that gradually worsens Is it triggered by anything? May be precipitated by fatigue, lack of sleep or stress Any associated drowsiness/confusion? No Taking any medication? OCP

What makes this migraine? Recurring, pulsatile headache preceding aura accompanied by nausea, vomiting, photophobia worsened by activity relieved by sleep trigger factors -maybe including OCP NO OTHER ABNORMALITIES

Acute treatment Diagnosis according to IHS criteria Stepwise approach to care Initiate with low end therapies Simple analgesics Anti-emetics Migraine-specific therapies used only when other therapies have failed Triptans Ergotamine (not as widely used)

Treatment Initial Aspirin /ibuprofen take immediately experience aura -don’t wait for headache! Metoclopramide Subsequent triptan choice may depend on headache duration (long duration naratriptan may be good choice) maybe sumatriptan (varying methods of admin.) DHE ergotamine

Prophylactic treatment? Not at this stage full trial of therapeutic agents may need to change or cease OCP only if fulfils criteria >2-6 attacks per month prolonged attacks (>48hrs) severe and disruptive (pt cannot function) failure of, or contraindications to, abortive therapy needs 4-6 week trial

Total Recall- What you need to know Understand the models of migraine pathophysiology Understand the clinical presentation of headaches Revise drugs used in acute therapy and their application Revise drugs used in preventive therapy and when they are indicated To be able to apply that knowledge in a clinical situation to determine rational therapy

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