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Stephen D. Silberstein, MD, FACP
Primary Psychiatry. 2003;10(10):64-71

Dr. Silberstein is professor of neurology and director of the Jefferson Headache Center at Thomas Jefferson University Hospital in Philadelphia, Pennsylvania.

Disclosure: Dr. Silberstein is a consultant for Eli Lilly; has received research support and/or unrestricted educational grants from Abbott, Allergan, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Johnson & Johnson, Merck, Ortho-McNeil, Parke Davis, Pfizer, Robert Wood Johnson, UCB Pharma, and Vernalis; and is on the advisory panel and/or speaker’s bureau of Abbot, Allergan, AstraZeneca, Elan, GlaxoSmithKline, Johnson & Johnson, and Merck.

Please direct all correspondence to: Stephen D. Silberstein, MD, FACP, Jefferson Headache Center, Thomas Jefferson University Hospital; 111 South 11th St; Gibbon Building, Suite 8130; Philadelphia, PA 19107; Tel: 215-955-2243; Fax: 215-955-1960; E-mail: stephen.silberstein@jefferson.edu.


Focus Points

Migraine is associated with several neurologic and psychiatric disorders which produce changes in mood, thought, and behavior attributed to poorly-specified alterations of brain function.
A bidirectional causal influence occurs between migraine and depression, suggesting that migraine and psychiatric comorbidities may share overlapping etiologies.
Pharmacologic treatment of migraine may be acute (abortive, symptomatic) and administered 2–3 days/week, or preventive (prophylactic) and given on a daily basis.
 

Many psychiatric drugs, including antiepileptics and antipsychotics, may be effective in the treatment of migraine headaches, especially in patients with comorbid disorders.

Abstract

How can the clinician best recognize and treat migraine while taking into account the high prevalence of comorbid illness? A migraine is an episodic headache disorder typically experienced in multiple phases, with warning signs coming hours or even days before the migraine itself. Migraine severity ranges from moderate to marked and the pain is often aggravated by routine physical activity or simple head movement. Migraine is associated with a number of comorbid neurologic and psychiatric disorders, and is linked to traditional psychiatric conditions on many levels. A bidirectional causal influence occurs between migraine and depression. The relationship is due to the presence of the disorder, not attack frequency. Migraines and psychiatric conditions may in fact share underlying neural mechanisms. Pharmacologic treatment of migraine may be acute (abortive, symptomatic) or preventive (prophylactic); patients experiencing frequent severe headaches often require both approaches. Medications used in acute headache treatment include analgesics, antiemetics, anxiolytics, nonsteroidal antiinflammatory drugs, ergots, steroids, major tranquilizers, narcotics, and, more recently, selective serotonin agonists (triptans). Preventive medications with the best documented efficacy are β-blockers, divalproex, topiramate, and amitriptyline. Treatment choice is made based on a drug’s proven efficacy and tolerability, the physician’s knowledge and experience, the patient’s preferences and headache profile, and the presence or absence of coexisting disorders.
 

Introduction

Both headache and psychopathology can be divided into primary and secondary disorders. For the primary headaches (migraine, cluster, tension-type headache [TTH]), the headache disorder itself is the problem. These disorders are analogous to the major idiopathic psychiatric disorders.1 In secondary headache the symptoms are due to an underlying condition, such as a metabolic derangement, a brain tumor, a stroke, or other forms of structural brain disease. Secondary headache disorders are therefore analogous to the organic psychiatric syndromes.
 

Migraine

Migraine is an episodic headache disorder often accompanied by neurologic, gastrointestinal, autonomic, and psychologic changes. The International Headache Society (IHS)distinguishes seven categories of migraine, the most important of which are migraine without aura, formerly referred to as common migraine (Table 1) and migraine with aura, formerly referred to as classic migraine (Table 2). The aura is the complex of focal neurologic symptoms that initiates or accompanies an attack.2 An individual patient may have headache without aura, headache with aura, and aura without headache. The migraine attack can be divided into four phases: the premonitory phase, the aura, the headache phase, and the postdrome.3


 

Premonitory Phase

Premonitory (prodromal) phenomena occur in approximately 60% of migraineurs, often hours to days before the onset of headache. These phenomena include psychologic, neurologic, constitutional, and autonomic features.3 Psychologic symptoms include depression, euphoria, irritability, restlessness, mental slowness, hyperactivity, fatigue, and drowsiness. Neurologic phenomena include photophobia, phonophobia, and hyperosmia. Constitutional symptoms include a stiff neck, a cold feeling, sluggishness, increased thirst, increased urination, anorexia, diarrhea, constipation, fluid retention, and food cravings. According to Griffin and colleagues4 some patients report a poorly characterized feeling that a migraine attack is coming. Migraineurs who reported premonitory symptoms were able to accurately predict their full-blown headaches 72% of the time. The most common premonitory symptoms were feeling tired/weary (72%), difficulty concentrating (51%), and stiff neck (50%). Poor functioning commonly predicted headache.

Aura

The migraine aura is characterized by focal neurologic symptoms that typically precede but sometimes accompany an attack. Approximately 20% of migraine sufferers experience auras. Most aura symptoms evolve slowly over 5–20 minutes and usually <60 minutes. The aura can be characterized by visual, sensory, or motor phenomena, alone or in combination. Auras may also involve language or brainstem disturbances. Headache usually occurs within 60 minutes of the end of the aura.
 

The most common migraine aura is visual. The visual aura often has a hemianoptic distribution and includes both positive (scintillations, fortification spectra, photopsia) and negative (scotomata) visual features that often occur together. Elementary visual disturbances can occur; these include colorless scotomata or positive visual phenomena, such as photopsia (the sensation of unformed flashes of light or sparkles before the eyes) or phosphenes (an objective visual sensation that appears with the eyes closed and in the absence of light). Simple flashes, specks, or crude or uniform pseudohallucinations of geometric forms (points, stars, lines, curves, circles, sparks, flashes, or flames) may occur and may be single or number in the hundreds. They may move rapidly across the visual field, sometimes crossing the midline and often preceding a scotoma. More complicated pseudohallucinations include the teichopsia or fortification spectrum, which is the most characteristic visual aura and is almost diagnostic of migraine. An arc of scintillating lights often begins in central vision, sometimes forms a herringbone-like pattern, and may expand to encompass an increasing portion of a visual hemifield. Other complex positive features, such as bright geometric lights, may occur. Objects may occasionally appear to change in size or shape.5,6

Numbness or tingling (paresthesias) over one side of the face and in the ipsilateral hand or arm are the most common of the somatosensory phenomena. Hemiparesis may occur, and, if the dominant hemisphere is involved, dysphasia or aphasia may develop. Olfactory hallucinations have been reported. Odors tend to be unpleasant and can last from 5 minutes to 24 hours. This may be preceded or followed by other aura symptoms. Anxiety, deja vu, and jamais vu have been reported and are presumably of temporal lobe origin.3 Auras may occur repeatedly, even many times an hour, for several months. In cases where persistent auras are present, they are documented and referred to as the “migraine aura status.”6

Headache Phase

The typical migraine headache is unilateral and throbbing. The severity ranges from moderate to marked and the pain is often aggravated by routine physical activity or simple head movement. The pain may be bilateral at its onset (which it is in 40% of patients); it may remain bilateral throughout the attack or begin on one side and become generalized.7 The headache can occur at any time of the day or night, but it occurs most frequently upon arising.7 The onset is usually gradual; the pain peaks and then subsides, lasting usually between 4 and 72 hours in adults and 2 and 48 hours in children.5
 

The pain of migraine is invariably accompanied by other features. Anorexia is common, although food cravings can occur. Nausea occurs in as many as 90% of migraineurs and vomiting occurs in about one third.8,9 Many patients experience sensory hyperexcitability manifested by photophobia, phonophobia, and osmophobia, and seek a dark, quiet environment.7,10 Other systemic symptoms, including blurry vision, nasal stuffiness, anorexia, hunger, tenesmus, diarrhea, abdominal cramps, polyuria (followed by decreased urinary output after the attack), facial pallor (or, less commonly, redness), sweating, and sensations of heat or cold, may be noted during the headache phase. Impaired concentration is common; memory impairment occurs less frequently. Depression, fatigue, anxiety, nervousness, and irritability are common.

Postdrome

The headache of migraine is often followed by the postdrome. During the postdrome, patients may have many of the symptoms that occurred during the prodrome. The patient may feel tired, washed out, irritable, and listless, and may have impaired concentration, scalp tenderness, or mood changes. Some people feel unusually refreshed or euphoric after an attack, whereas others note depression and malaise. Recurrent psychosis has been reported, with the so-called migraine madness lasting up to 4 weeks and manifested by morbid visual hallucinations and delusions, including the belief that homes or people have been replaced by exact doubles (reduplicative paramnesia or Capgras syndrome).6
 

Unusual Migraine Auras

The visions of Hildegard of Bingen, an 11th century mystic, have been attributed in part to her migrainous scintillating scotomata. Characteristic of the visions that she and other visionary prophets saw were working, boiling, or fermenting lights. Hildegard indicates that her visions often contained elements of blinding lights in the following manner11:
 

I saw a great star most splendid and beautiful, and with it an exceeding multitude of falling sparks which with the star followed southward… But sometimes I behold within this light another light which I name “the living light itself

In addition, in the book of the prophet Ezekiel, Ezekiel describes his vision thus12:
 

I saw a storm wind coming from the north, a vast cloud with flashes of fire and brilliant light about it; and within was a radiance like brass, glowing in the heart of the flames… As I looked at the living creatures, I saw wheels on the ground, one beside each of the four. The wheels sparkled like topaz, and they were all alike: in form and working they were like a wheel inside a wheel, and when they moved in any of the four directions they never swerved in their course.

Epidemiology

Migraine prevalence is similar and stable in Western countries and the United States.13 In the US, 17.6% of women and 6% of men had experienced one migraine attack in the previous year.14 Migraine prevalence varies by age, gender, race, and income. Before puberty, migraine prevalence is approximately 4%.15 After puberty, prevalence increases more rapidly in girls than in boys. In the US, migraine prevalence decreases as household income increases.14,16,17
 

Comorbidity of Migraine

Migraine is associated with a number of neurologic diseases (epilepsy, stroke) and psychiatric disorders (depression, mania, anxiety, and panic). The term comorbidity, coined by Feinstein,18 originally referred to coexistent conditions in clinical trials. For the purpose of this article, comorbidity refers to an association between two disorders that is more than coincidental.19
 

Migraine comorbidity is important for a number of reasons.19 Co-occurring diseases can complicate diagnosis, influence treatment choices, and give clues about pathophysiology. For example, depression, anxiety disorders, or epilepsy, can all cause headaches, while headaches can change mood and behavior.20,21 However, comorbidity is more than a problem of differential diagnosis; the real challenge for the neuropsychiatrist is recognizing that more than one disease is present.19 Because of the high rate of comorbid disorders in migraine, the principle of diagnostic parsimony (attributing all symptoms to one diagnosis)does not apply. The presence of migraine should increase the suspicion that another disorder may be present. Conversely, patients with depressive disorders often have medically undiagnosed migraine, and there may be a tendency to attribute the migrainous manifestations to the depressive disorder.22

Antidepressants can be used to treat both migraine and depression.23,24 When migraine occurs with manic depressive illness or epilepsy, topiramate or divalproex sodium can be used to treat both conditions.3 However, comorbid illnesses may impose therapeutic limitations. Some treatments may be relatively contraindicated in individuals who have more than one disease. For example, β-blockers may be a less desirable option when treating a migraine patient who also has depression.
 

Psychopathology and Psychiatric Disorders

A number of studies have examined the relationship between migraine and specific psychiatric disorders.9 Several clinic-based studies have reported an increased prevalence of migraine in patients with major depressive disorder (MDD) and an increased prevalence of MDD in patients with migraine.25-27 Three population-based studies have examined a wide range of psychiatric disorders in addition to MDD.9,24,28-30
 

Merikangas and colleagues24 reported on the association of migraine with specific psychiatric disorders in a random sample of 457 adults 27–28 years of age in Zurich, Switzerland. Persons with migraine (n=61) were found to have increased 1-year rates of affective and anxiety disorders. Specifically, the odds ratio for MDD (2.2, 95% CI 1.1-4.8), bipolar spectrum disorders (2.9, 95% CI 1.1-8.6), generalized anxiety disorder (2.7, 95% CI 1.5-5.1), panic disorder (3.3, 95% CI 0.8-13.8), simple phobia (2.4, 95% CI 1.1-5.1), and social phobia (3.4, 95% CI 1.1-10.9), were significantly higher in persons with migraine compared to those without migraine.

Migraine with MDD was frequently complicated by an anxiety disorder. Merikangas and colleagues24 suggest that in persons with all three disorders, the onset of anxiety generally precedes the onset of migraine, whereas the onset of MDD most often follows the onset of migraine.
 

Epidemiologic studies support the association between migraine and MDD previously reported in clinic-based studies. The prospective data indicate that the observed cross-sectional or lifetime association between migraine and MDD could result from a bidirectional influence, from migraine to subsequent onset of MDD and from MDD to first migraine attack (Table 3). Furthermore, these epidemiologic studies indicate that persons with migraine have increased prevalence of bipolar disorder, panic disorder, and one or more anxiety disorders.9,16,23,31

It has been proposed that MDD in patients with migraine might represent a psychologic reaction to repeated, disabling migraine attacks. Migraine generally has an earlier mean age of onset than MDD in the normal population and in patients with comorbid disease. Nonetheless, the bidirectional influence of each condition on the risk for the onset of the other is incompatible with the simple causal model.9 Furthermore, Breslau and Davis31 reported that the increased risk for first episode of MDD (and/or panic disorder) did not vary by the proximity of prior migraine attacks. These findings lessen the plausibility that the migraine-depression association results from the demoralizing experience of recurrent and disabling headaches, suggesting instead that their association might reflect shared etiologies.

Breslau and colleagues32 recently examined migraine and depression comorbidity in a large-scale epidemiologic study, the Detroit Area Study of Headache. The study comprised three groups: persons with migraine (n=536), persons with other severe headaches of comparable pain severity and disability (n=162), and matched controls with no history of severe headache (n=586).
 

The results suggest the possibility that different causal pathways might account for the comorbidity of MDD in these two headache categories. The results for migraine suggest shared causes, whereas those for other headaches of comparable severity suggest a causal effect of headache on depression.

Another line of evidence comes from a study of a biologic marker of depression in migraineurs. Jarman and colleagues33 administered the tyramine test to 40 migraine patients, 16 of whom had a lifetime history of MDD. Low tyramine conjugation, a trait marker for endogenous depression, was strongly associated with a lifetime history of MDD in subjects with comorbid disease, regardless of their current psychiatric status. The authors argue that the association of the trait marker with MDD in migraineurs rules out the possibility that the depression is a psychologic reaction to migraine attacks.9
 

Personality Characteristics and Psychopathology

The relationship between migraine and psychopathology has been discussed far more often than it has been systematically studied.9 Over the years, many studies have focused on particular personality traits of migraineurs. The basic assumptions are: (1) migraineurs share common personality traits; (2) these traits are enduring and measurable; and (3) these traits differentiate migraineurs from controls.34
 

The notion of a migraine personality first grew out of clinical observations of the highly selected patients seen in subspecialty clinics.9 In 1934, Touraine and Draper35 reported that migraineurs were deliberate, hesitant, insecure, detailed, perfectionistic, sensitive to criticism, and deeply frustrated emotionally. They were said to lack warmth and to have difficulty making social contacts. Wolff36 found migraineurs to be rigid, compulsive, perfectionistic, ambitious, competitive, chronically resentful, and unable to delegate responsibility.

Most investigations have used psychometric instruments, such as the Minnesota Multiphasic Personality Inventory (MMPI) or the Eysenck Personality Questionnaire (EPQ). The EPQ is a well-standardized measure which includes four scales: psychoticism, extroversion, neuroticism, and lie.
 

Brandt and colleagues37 used the Washington County Migraine Prevalence Study to conduct the first population-based case-control study of personality in migraine (Table 4).6,30,37,38 Over 10,000 subjects 12–29 years of age were selected using random-digit dialing and received a diagnostic telephone interview. A sample of subjects who met the criteria for migraine with or without aura [n=162] were compared with subjects without migraine. Each subject received the EPQ, the 28-item version of the General Health Questionnaire, and a question about headache laterality. Migraineurs scored significantly higher than controls on the neuroticism scale of the EPQ scale, indicating that they were more tense, anxious, and depressed than the control group. In addition, women with migraine scored significantly higher than controls on the psychoticism scale of the EPQ, indicating that they were more hostile, less interpersonally sensitive, and out of step with their peers. Overall, studies that used the EPQ or similar personality measures and compared migraineurs to nonmigraine controls have generally reported an association between migraine and neuroticism.9,38-41

Many investigators42-45 have used the MMPI to investigate the migraine personality. These studies have been limited by several factors.1 MMPI studies have usually been clinic-based, limiting their generalizability and creating opportunities for selection bias. Most have not used control groups, relying instead on historical norms. Many have not used explicit diagnostic criteria for migraine. Despite these limitations, most studies show elevation of the neurotic triad, although this is not statistically significant (Table 5).9,42,43,45-50

 

Studies of migraine and personality have generally not controlled for drug use, headache frequency, and headache-related disability. Furthermore, they have not controlled for major psychiatric disorders (such as MDD or panic disorder), which occur more commonly in migraineurs. The association between major psychiatric disorders and personality disorders may confound the assessment of the relationships between these disorders and migraine. Neuroticism, in particular, is associated with depression and anxiety, which occur with increased prevalence in migraineurs. Differences in neuroticism across studies might reflect variations in the role of comorbid psychiatric disease. The available data suggest that migraineurs may be more neurotic than nonmigraineurs. The stereotypical rigid, obsessional migraine personality might reflect the selection bias of a distinct subtype of migraine that is more likely to be seen in the clinic.

Breslau and Andreski51 examined the association between migraine and personality, taking into account history of co-occurring psychiatric disorders. The results suggest that migraine sufferers might be more vulnerable to psychopathology and poor adjustment to their medical condition. This also suggests that the association between migraine and neuroticism is not attributable to comorbid depression or anxiety disorders.
 

In a later report, Breslau and colleagues52 presented findings from prospective data on the migraine-neuroticism association from their epidemiologic study of young adults. Controlling for MDD and anxiety disorders at baseline, women scoring in the highest quartile of the neuroticism scale were nearly three times more likely to develop migraine than those scoring in the lowest quartile during a 5-year follow-up. In men, neuroticism did not predict migraine, although the small number of incidence cases in men precluded reliable estimates of the risk for migraine associated with neuroticism.

Treatment

Pharmacologic treatment of migraine may be acute (abortive, symptomatic) or preventive (prophylactic). Patients experiencing frequent severe headaches often require both approaches. Symptomatic treatment attempts to abort (stop the progression of) or reverse a headache once it has started. Preventive therapy is given on a daily basis, even in the absence of a headache, to reduce the frequency and severity of anticipated attacks. Symptomatic treatment is appropriate for most acute attacks and should be used no more than 2–3 days/week. If attacks occur more frequently, treatment strategies should focus on decreasing the attack frequency.
 

Medications used in acute headache treatment include analgesics, antiemetics, anxiolytics, NSAIDs, ergots, steroids, major tranquilizers, narcotics, and, more recently, selective serotonin agonists (triptans). One or more of these medications can be used for headaches of differing severities.5 Preventive treatments include a broad range of medications, most notably b-blockers, calcium channel blockers, antidepressants, and antiepileptic drugs (AEDs) (Table 6).

Preventive Treatment

Preventive medications are meant to reduce attack frequency, duration, or severity.5,53 According to the US Headache Consortium Guidelines,54

indications for preventive treatment include:

• Migraine that significantly interferes with the patient’s daily routine despite acute treatment
 

• Failure of, contraindication to, or troublesome adverse events from acute medications

• Acute medication overuse
 

• Very frequent headaches (>2/week), indicating risk of medication overuse

• Patient preference
 

• Special circumstances, such as hemiplegic migraine or attacks with a risk of permanent neurologic injury

Preventive medication groups include β-adrenergic blockers, antidepressants, calcium-channel antagonists, serotonin antagonists, AEDs, and nonsteroidal antiinflammatory drugs. Choice is based on efficacy, adverse events, and coexistent and comorbid conditions (Table 6).55 The medication should be started at a low dose and increased slowly until therapeutic effects develop or the ceiling dose is reached. A full therapeutic trial may take 2–6 months. Acute headache medications should not be overused. If headaches are well controlled, medication can be tapered and discontinued, but dose reduction may provide a better risk:benefit ratio. Women of childbearing potential should be on adequate contraception.
 

Behavioral and psychological interventions used for prevention include relaxation training, thermal biofeedback combined with relaxation training, electromyography biofeedback, and cognitive-behavioral therapy.56 These measures are effective as monotherapy, but they are more effective when used in conjunction with pharmacologic management.

Medication

β-Blockers
Propranolol, nadolol, atenolol, metoprolol, and timolol are effective pharmacologic treatments of migraine.57 As their relative efficacy has not been established, choice is based on b-selectivity, convenience, adverse events, and patients’ tolerability.5 b-blockers can produce behavioral adverse events, such as drowsiness, fatigue, lethargy, sleep disorders, nightmares, depression, memory disturbance, and hallucinations, and should be avoided when patients are depressed. Decreased exercise tolerance limits their use by athletes. Less common adverse events include impotence, orthostatic hypotension, and bradycardia. β-blockers are relatively contraindicated for patients with congestive heart failure, asthma, Raynaud’s disease, and insulin-dependent diabetes.
 

Antidepressants

 

The tricyclic antidepressant amitriptyline is the only antidepressant with fairly consistent support for efficacy in the treatment of migraine,57 although there is one positive trial for fluoxetine.58 Adverse events associated with antidepressants include increased appetite, weight gain, dry mouth, sedation, and sexual dysfunction59; cardiac toxicity and orthostatic hypotension occur occasionally.58 Antidepressants are especially useful for patients with comorbid depression and anxiety disorders.

Antiepileptics
 

Divalproex sodium and sodium valproate, in both immediate and extended release formulations, are effective in the treatment of migraine.57 The most frequent adverse events associated with their use are nausea (42%), alopecia (31%), tremor (28%), asthenia (25%), dyspepsia (25%), somnolence (25%), and weight gain (19%).60 Hepatotoxicity and pancreatitis are the most serious adverse events, but irreversible hepatic dysfunction is extremely rare in adults. Baseline liver function studies should be obtained, but follow-up studies of adults on AED monotherapy for headaches are probably not necessary.61 Divalproex carries a high risk of congenital abnormality.

Gabapentin was shown to be effective in a placebo-controlled, double-blind trial.62 Migraine attack frequency was reduced by 50% in about one-third of patients. The most common adverse events were dizziness or giddiness and drowsiness.
 

Topiramate, a D-fructose derivative, has been associated with weight loss. In two large, double-blind, placebo-controlled, multicenter trials, topiramate, both 100 and 200 mg, was effective in reducing migraine attack frequency by 50% in half of the patients.63,64 Dropouts due to adverse events were common in the topiramate groups, but did not affect statistical significance.

To circumvent the contraindications to β-blockers, divalproex and topiramate may be useful in migraine patients with comorbid epilepsy, anxiety disorder, bipolar disorder, depression, Raynaud’s disease, asthma, and diabetes.

Setting Treatment Priorities

The goals of treatment are to relieve or prevent the pain and associated symptoms of migraine and to optimize the patient’s ability to function normally (Table 6). The preventive medications with the best documented efficacy are β-blockers, amitriptyline (some believe its efficacy is less documented), divalproex, and topiramate. Medication choice is made based on a drug’s proven efficacy, the physician’s informed belief about medications not yet evaluated in controlled trials, the drug’s adverse events, the patient’s preferences and headache profile, and the presence or absence of coexisting disorders.6
 

Conclusion

The primary headache disorders are linked to traditional psychiatric diseases on many levels. Diagnosis depends upon self-reported symptoms and other clinical features. Both families of disorders produce changes in mood, thought, and behavior attributed to poorly-specified alterations of brain function. Epidemiologic studies show that migraine and mood disorders are powerfully associated. The bidirectionality of risk is incompatible with simple causal models; depression cannot merely be a response to pain, since the onset of depression may precede the onset of migraine. Comorbidity is most likely, at least in part, a consequence of overlapping neural mechanisms. This notion is supported by the many drugs that are effective in the treatment of both headache and psychiatric disease. Antidepressants, AEDs, lithium carbonate, and neuroleptics, are part of the shared therapeutic armamentarium. Many of the drugs developed in psychiatry may find application in the treatment of headache, especially in patients with comorbid disease. PP
 

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