NEUROLOGIC QUANDARIES
From the 32nd Annual Family Medicine Review Update 2006, sponsored by the University of Minnesota Medical
School, Minneapolis
| MIGRAINE PREVENTION —Frederick R. Taylor, MD, Adjunct Associate Professor of Neurology, University of Minnesota
Medical School, and Director, Park Nicollet Headache Clinic and Research Center, Minneapolis, MN
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| Introduction: 28 million Americans meet criteria for migraine, 30 million for probable migraine; according to World
Health Organization (WHO), migraine most frequent disabling condition in middle-aged women
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| Migraine pathophysiology: explosion model—altered neuronal hyperexcitability; triggers (ie, genetically mediated
and environmentally modifiable factors) lead to variable threshold neuronal maladaptation and pain dysmodulatory system;
preventive model—stabilize neuronal hyperexcitability; alter cortical spreading depression (CSD); alter membrane
pore hyperexcitability (with, eg, magnesium); restore abnormally low threshold; eliminate triggers; enhance neuronal adaptation
and pain inhibition; treatment model—1) prevention; reduce triggers, eg, sleep instability, sleep loss, lack of
exercise, stress, hormones; cognitive behavioral therapy; stress management therapy; medication; 2) acute therapy; enhance
neuronal adaptation system; increase threshold with prevention
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| Case presentation: woman 27 yr of age; nearly morbidly obese; complains about mixed headaches occurring 3 to 5 days
per month; describes alternating unilateral moderate pain lasting ≥12 hr; 50% of headaches start in neck, 30% in cheek, and
20% in frontal area; associated symptoms include nausea and light sensitivity (leading to missed work); takes ≈9 tablets per
day of over-the-counter (OTC) analgesics when needed; diagnosis—consider migraine, tension headache, and sinus headache;
management—offer migraine-specific therapy (eg, triptan agents) and hydrocodone; recognize migraine as mixed
headache syndrome (migraine with tension or sinus headache); allodynia occurs in ≥50% of patients with migraine and leads
to central sensitization phenomenon, decreasing likelihood of efficacy of therapy; limit acute treatment to <9 days per
month; treat early and avoid overuse of medication; identify triggers and counsel patient about modification; encourage prevention
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| Need for prevention: study of 19,000 patients with migraine identified need for prevention as ≥3 headaches per month
or 2 days with disability; determined nearly 40% of individuals needed prevention, but only 33% received prevention;
goals—reduce frequency of attacks; reduce cumulative impact on health-related quality of life; improve efficacy of
acute treatment; modify temporal profile of disease
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| Progression to migraine: intermittent headache—headaches present <9 days per month; general population has 3%
chance of progressing to headaches >15 days per month; patients under care of medical provider have nearly 15% chance
of progressing to daily headaches; yellow flags for progression include migraine, female sex, head trauma, and low educational
or socioeconomic status; modifiable factors include frequency of headache (greater risk for progression with
higher frequency), obesity, overuse of medication (>9 days per month), stressful life events, sleep disturbance, and caffeine
use; migraine chronification—headache begets headache; headache with drug overuse; increased frequency of
headache begets chronic migraine; important to reduce frequency of attacks; 16-fold increase in risk for cerebellar infarct
in patients with >1 attack per month
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| Preventing progression: address triggers; modify lifestyle; use symptomatic medications judiciously; indications for
rational drug prevention—>2 headache-days per month; disability lasting >3 days; overuse of acute medication (>2
days per week); acute medications fail or contraindicated (for, eg, uncommon migraine syndromes); indications for preemptive
prevention—increased frequency of attacks (may not be dramatic, but still require more drug); increased use of
acute medications (use of 12 triptan tablets per month by patients restricted to 9 days per month reasonable); anticipate
life events (eg, moving, starting new job, marriage, change of any kind) that can transform pain process from acute to
chronic; effective prevention involves proper diagnosis, assessing and addressing impact of disease and comorbidities,
and communicating openly with patient; communicating with patient—discuss optimal doses of drugs and optimal balance
between efficacy and side effects; stress harm of overuse of drugs; empower and support well-being of patients; patients
more likely to choose drugs with higher effectiveness, fewer side effects, and less frequent dosing; study found
patients preferred higher efficacy, even in presence of side effects and more frequent dosing
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| Behavioral prevention: address triggers; encourage participation; help patients prioritize management; ask about
needs, hopes, and fears; 90% of outcomes determined by patient factors rather than health system factors; encourage exercise
and tobacco smoking cessation; assess sleep—6 to 8 hr per night; biofeedback—stress management; cognitive
behavioral therapy; well-proven; caffeine—control substances; eliminate caffeine; do not skip meals—always eat
breakfast and lunch; meals should be eaten on time; exercise—maintain regular schedule (variability in sleeping, eating,
stress management, and exercise can increase risk for episodes); fluids—prevent dehydration; groups—promote social
interaction and connections (eg, mothers to daughters); goals—decrease risk factors; develop patient’s sense of control
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| Effects of behavioral management: effects of electromyographic (EMG) biofeedback—thermal biofeedback and
relaxation equivalent to drug therapy; cognitive behavior and stress management therapies with biofeedback considered
grade-A proven and complement drug therapy for synergistic effect
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| Drug therapy: “control is possible, cure is not”; use calendars to control drug overuse; goals—reduce frequency (more
treatable headaches can occur with acute drug); prevent progression
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| Pearls for implementing prevention: be aggressive; do no harm; start drug at lowest dose and increase slowly; be
persistent until patient improves by 50% (or develops side effects) and maintain for ≥8 wk; eliminate medication overuse
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| Medications: amitriptyline—therapeutic gain 21% greater than with placebo; side effects include drowsiness, weight
gain, and exacerbation of mania and bipolar disease; β-blockers—many side effects with propranolol, including fatigue;
high-dose β-blockers not recommended because depression major comorbidity of migraine; divalproex sodium
(Depakote)—therapeutic gain 34% with 1000 mg; 1500 mg shown to reduce headache (from baseline) as early as 2 wk;
consider side effects; topiramate—therapeutic gain 31%; slower efficacy (1-2 mo); side effects include cognitive effects
and weight loss
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| Cluster and tension headaches: cluster—diagnosis important; verapamil most effective; tension—amitriptyline
only proven agent
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| Other agents: meperidine (Demerol)—managing patients who demand Demerol institutional issue; proinflammatory
and vasodilatory agent; treats anxiety and expectations of patients; many patients who request Demerol have history of
use; intravenous (IV) options—1 g of IV magnesium over 10 min may terminate headache; hydration (2 L normal saline
unless contraindicated); IV steroids (eg, dexamethasone [Decadron] or hydrocortisone); IV therapy preferred over
intramuscular (IM) therapy; use ketorolac (Toradol) in appropriate patients; 50 mg of IV diphenhydramine (Benadryl)
can terminate migraine; prochlorperazine (Compazine); 10 mg IV of diphenhydramine and prochlorperazine; 10 mg IV
of metoclopramide (Reglan); valproate sodium (Depacon) IV—1 g or 30 mg/kg; package insert indicates 3 mg/kg per
minute; safety data (not in package insert) indicate 6 mg/kg per minute
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| Questions and answers: patent foramen ovale (PFO) and migraines—Migraine Intervention with STARFlex Technology
(MIST) trial found no difference in complete relief between control (“sham”) group and procedure (closure with
STARFlex device [septal repair implant; approved in England]) group; secondary variable looking at 50% reduction in
headache showed superiority of implant vs sham (therapeutic gain 21%); more data needed; patients who have migraine
with aura have ≤50% chance of having PFO; currently obtaining implants on humanitarian device exemptions; not always
most rational
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| BRAIN TUMORS —Walter A. Hall, MD, MBA, Professor of Neurosurgery, University of Minnesota Medical School, Minneapolis
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| Introduction: brain tumors constitute 1% of adult cancers, 21% of childhood cancers; 17,000 new cases per year of primary
brain tumors; 100,000 to 170,000 new cases per year of metastatic brain tumors
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| Low-grade gliomas: ≈9% astrocytomas; 3.5% oligodendrogliomas; gangliogliomas; juvenile pilocytic tumors; dysembryoplastic
tumors; 90% present with epilepsy; 10% present with head injury or severe headache; some tumors invisible
on computed tomography (CT); T2-weighted magnetic resonance imaging (MRI) shows changes in brain related to hydrogen
and water content; symptoms from some low-grade tumors may resemble stroke; anticonvulsants usually necessary,
especially at time of surgery (use for 6 mo after surgery); levetiracetam (Keppra) preferred drug (virtually no side
effects; do not measure levels); other useful drugs include Depakote, carbamazepine (Tegretol), and phenytoin (Dilantin)
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| Management: only following tumors can lead to delay in diagnosis (40% of tumors thought to be benign have malignant
features); chance for sampling error with biopsy alone, 5%; remove tumors when possible (“if I can get ≥80% of tumor
out, I’ll do that”); resection curative for oligodendrogliomas; study found patients with oligodendrogliomas or astrocytomas
who underwent complete surgical resection had 90% disease-specific survival at 10 yr; functional areas in brain (eg,
motor function, speech function, short-term memory) can be mapped; after ≥80% resection, follow patients with sequential
imaging and no adjuvant treatment; in patients who return with oligodendroglioma and genetic abnormality (1p/19q
deletion), tumor responds to chemotherapy (use oral temozolomide [Temodar] for 5 successive days, every month, for 1
yr); after 1 yr, follow patients; constipation only significant side effect; astrocytomas more concerning because 3 to 8 yr
after diagnosis, 33% to 50% of tumors become malignant; if large amount of astrocytoma left behind, use partial-brain irradiation
(5400 cGy for 6 wk)
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| High-grade tumors: glioblastomas—40% of primary brain tumors; usually in patients 55 to 65 yr of age; anaplastic
tumors—less common (≈11%); grow in 3 mo; take careful history (family members often notice changes in behavior,
headache complaints, or symptoms within previous 3 mo); ≈90% present with headaches; seizures occur in ≈75% of patients,
50% with hemiparesis; flare images best for viewing full extent of tumor; T1-weighted MRI shows enhancement;
use anticonvulsants and corticosteroids (consider side effects [eg, weight gain, diabetes, hypertension]); reserve mannitol
until time of surgery; Decadron does not prevent cerebral edema, but prevents more edema from occurring; never discharge
patients on lower dose than dose admitted on because “they will get worse neurologically”
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| Goals of surgery: primarily diagnosis; decompress neural structures; biopsy often performed on deep-seated lesions and
lesions adjacent to eloquent areas; better outcomes with resection of high-grade gliomas in patients with malignant tumors
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| Management of high-grade glioma: radiation therapy required; 60% to 70% of patients benefit from irradiation;
partial-brain irradiation with 2- to 3-cm margin (6000 cGy over 6 wk); 75 mg/m2 of Temodar given daily proven to increase
efficacy of radiation therapy; after radiation therapy, choose appropriate chemotherapy regimen; carmustine
(BCNU)—gold standard; myelosuppressive (lipophilic; enters bone marrow); causes severe pulmonary fibrosis in tobacco
smokers; procarbazine, lomustine (CCNU), and vincristine (PCV) ineffective and no longer used; disruption of
blood-brain barrier—with patient under general anesthesia, open barrier with 25% mannitol and give drug; barrier
stays open for 30 min; after barrier closes, drug trapped in brain; carboplatin or methotrexate used with cyclophosphamide
(Cytoxan) and etoposide IV; delivers 100 times concentration of drug to tumor; 1% risk for stroke; benefit rate of
conventional chemotherapy ≈30%, with blood-brain barrier disruption ≈80%; survival ≈49 mo for patients with anaplastic
tumor, 1 yr for patients with glioblastoma; causes of death—patients die from complications of treatment (eg, deep
venous thrombosis causing pulmonary embolus, urinary tract infection causing sepsis, neutropenia); radiation injury; radiation
necrosis; multifocal glioblastomas (may be genetic; occur 8% of time); new therapies—targeted toxins (protein
made in Escherichia coli) recognize marker on tumor cells and stop protein synthesis (cells do not have to be dividing);
also vaccine for gliobastoma
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| Brain metastases: 15% to 40% of cancer patients develop brain metastases; 11% false-positive diagnosis rate with MRI
(patients actually may have primary brain tumor, abscess, infarct, or hemorrhage; perform biopsy); most common symptoms
headache or altered mental status; patients commonly present with no symptoms; 50% have single brain metastasis
(survival rate better), 50% have multiple metastases; non–small cell lung cancer most common, followed by breast cancer
and small cell lung cancer (60% of brain metastases from lung); brain metastases also from melanoma, renal cell, and
gastrointestinal (GI) cancers; if single lesion amenable to surgical resection, survival 11 mo (vs 3 mo with no surgery);
speaker performs surgery on multiple lesions if lesions can be resected in single craniotomy; surgery effective, especially
if mass effect high, tumor too large for radiosurgery with gamma knife to be effective, or no time to wait 8 to 12 wk for
efficacy of radiosurgery; whole-brain radiation therapy—3000 cGy in 2 wk; focal radiotherapy boosts (ie, use of
coned-down field) ineffective; 11% of time, patients develop dementia 1 yr after whole-brain irradiation; does not extend
survival; prevents new foci from developing; maintains quality of life; gamma knife—can treat ≥1 lesion in 1 setting;
outpatient procedure; no risk for infection; disadvantages include longer time to efficacy and slight (1%) risk for radiation
injury
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Educational Objectives
| The goal of this program is to educate the listener about migraine prevention and the management of brain tumors. After
hearing and assimilating this program, the participant will be better able to:
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 | 1. Identify and reduce triggers of migraine.
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| 2. Select effective medications for treatment of migraine.
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| 3. Counsel patients on behavioral strategies to prevent migraine.
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| 4. Distinguish types and severity of brain tumors.
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| 5. Choose effective drug therapy and appropriate delivery route for treatment of brain tumors.
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Suggested Reading
Chang SD et al: Current treatment of patients with multiple brain metastases. Neurosurg Focus 9:e5, 2000; Cho KH
et al: The role of radiosurgery for multiple brain metastases. Neurosurg Focus 9:e2, 2000; Couch JR et al: Amitriptyline
in migraine prophylaxis. Arch Neurol 36:695, 1979; Dehdashti AR et al: New trends in the medical management
of glioblastoma multiforme: the role of temozolomide chemotherapy. Neurosurg Focus 20:E6, 2006; Fanciullacci M et
al: Preventing chronicity of migraine. J Headache Pain 6:331, 2005; Fogarty GB et al: The utility of magnetic resonance
imaging in the detection of brain metastases in the staging of cutaneous melanoma. Clin Oncol (R Coll Radiol)
18:360, 2006; Fox SW et al: Cognitive impairment in patients with brain tumors: assessment and intervention in the clinic
setting. Clin J Oncol Nurs 10:169, 2006; Giordana MT et al: Functional rehabilitation and brain tumour patients. A review
of outcome. Neurol Sci 27:240, 2006; Grier JT et al: Low-grade gliomas in adults. Oncologist 11:681, 2006; Hall
WA et al: Convection-enhanced delivery: targeted toxin treatment of malignant glioma. Neurosurg Focus 20:E10, 2006;
Hall WA et al: Osmotic blood-brain barrier disruption chemotherapy for diffuse pontine gliomas. J Neurooncol 77:279,
2006; Hall WA: Extending survival in gliomas: surgical resection or immunotherapy? Surg Neurol 61:145, 2004; Katsarava
Z et al: Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 62:788,
2004; Klapper J: Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia 17:103, 1997; Kruit
MC et al: Migraine as a risk factor for subclinical brain lesions. JAMA 291:427, 2004; Lipton RB et al: Migraine: epidemiology,
impact, and risk factors for progression. Headache 45 Suppl 1:S3, 2005; Ramadan NM: Migraine headache
prophylaxis: current options and advances on the horizon. Curr Neurol Neurosci Rep 6:95, 2006; Scher AI et al: Factors
associated with the onset and remission of chronic daily headache in a population-based study. Pain 106:81, 2003; Snow V
et al: Pharmacologic management of acute attacks of migraine and prevention of migraine headache. Ann Intern Med
137:840, 2002; Tfelt-Hansen P et al: Timolol vs propranolol vs placebo in common migraine prophylaxis: a double-
blind multicenter trial. Acta Neurol Scand 69:1, 1984; Wen PY et al: Medical management of patients with brain tumors.
J Neurooncol 80:313, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reported
nothing to disclose.
Drs. Taylor and Hall spoke in Minneapolis, MN, at the 32nd Annual Family Medicine Review, presented May 1-5, 2006,
by the University of Minnesota Medical School. The Audio-Digest Foundation thanks the speakers and the University of
Minnesota Medical School for their cooperation in the production of this program.
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