Neurology Issues

Study data suggest that increased levels of dietary _______ may

protect against dementia.(A) Coenzyme Q10

(B) Resveratrol (C) Selenium

(D) Iron

Answer

• (B) Resveratrol

Which of the following is characteristic of the behavioral

changes that occur with the onset of dementia?

(A) Difficulty learning new skills (B) Self-awareness of cognitive

deficits (C) Loss of long-term skills

(D) Loss of short-term memory

Answer

• (C) Loss of long-term skills

The differential diagnosis of mild cognitive impairment includes all

the following, except:(A) Depression

(B) Stress(C) Adult

attention-deficit/hyperactivity disorder

(D) Progressive supranuclear palsy

Answer

• (D) Progressive supranuclear palsy

All the following are psychosocial issues that must be addressed in dementia patients,

except:(A) Family education and support (B) Short and long term disability

(C) Driving privileges (D) Patient’s insight into his or

her disease

Answer

• (D) Patient’s insight into his or her disease

Identify the incorrect statement about structural imaging of the brain in the

diagnosis of mild cognitiveimpairment.

(A) Clearly indicated when there are focal neurologic findings

(B) Essential for making the diagnosis(C) Indicated in patients with risk factors for

cerebrovascular disease(D) Single-photon emission computed

tomography gives a functional assessment of brain activity

Answer

• (B) Essential for making the diagnosis

Which of the following may be the first symptom of an

underlying neurologic voice disorder?

(A) Hoarseness (B) Weak voice

(C) Fatigue during speech (D) Any of the above

Answer

• (D) Any of the above

Other concurrent symptoms that may support the diagnosis of a

neurologic voice disorder include which of thefollowing?

(A) Torticollis (B) Ptosis

(C) Fasciculations (D) Any of the above

Answer

• (D) Any of the above

Bowing of the vocal folds can be seen in the normal aging process.

(A) True (B) False

Answer

• (A) True

According to the Mayo Clinic classification, hypernasality is a

classic symptom of _______ dysarthria, while a

strained and strangled voice is characteristic of _______

dysarthria.(A) Flaccid; spastic (B) Spastic;

flaccid

Answer

• (A) Flaccid; spastic

Patients with _______ dysarthria are often perceived as being

angry.(A) Hyperkinetic

(B) Ataxic or cerebellar (C) Spastic

(D) Hypokinetic

Answer

• (C) Spastic

Patients with migraine headaches showed superior responses when:

(A) Stratified based on level of disability before treatment is

prescribed(B) Stepped through different

treatments before proceeding to migraine-specific therapies

Answer

• (A) Stratified based on level of disability before treatment is prescribed

Patients with infrequent headaches (10 headache days per

month) should attempt dosing with triptans _______ after thefirst symptoms of a migraine

appear.(A) <2 hr (B) <1 hr

(C) <30 min (D) <15 min

Answer

• (B) <1 hr

The peripheral pain associated with migraines is associated with inflammation and vasodilation in

the:(A) Dorsal raphe

(B) Sphenopalatine ganglion (C) Meninges

(D) All the above

Answer

• (C) Meninges

Chronic daily headaches may be prevented by:

(A) Selecting correct medications

(B) Reducing repeat dosing (C) Reducing medication

overuse (D) All the above

Answer

• (D) All the above

Prophylaxis of migraines requires a minimum of _______ of

treatment to produce benefit.(A) 1 yr

(B) 6 to 8 mo (C) 2 to 3 mo (D) 2 to 4 wk

Answer

• (C) 2 to 3 mo

Statins show the greatest benefits when treating patients at risk for:

(A) Atherosclerosis (B) Embolic stroke

(C) Hemorrhagic stroke (D) All the above

Answer

• (A) Atherosclerosis

Research supports lowering low density lipoprotein to _______ in patients with multiple risk factors

for stroke.(A) <130 mg/dL (B) <100 mg/dL (C) <70 mg/dL (D) <45 mg/dL

Answer

• (C) <70 mg/dL

Statins have been shown to reduce the thickness of arterial

plaques in patients with asymptomatic atherosclerosis of

thecarotid artery.

(A) True (B) False

Answer

• (A) True

The endothelial effects of statins include:

1. Upregulation of nitric oxide2. Reduced coagulation

3. Positive effects on oxidative stress4. Increased platelet function

5. Reduced inflammation after myocardial infarction and stroke

(A) 1,2,5 (B) 1,2,3,4 (C) 2,3,4,5 (D) 1,2,3,5

Answer

• (D) 1,2,3,5

Statins may improve outcomes in patients with subarachnoid hemorrhages by reducing:(A) Cerebral vasospasm

(B) Expression of endothelial nitric oxide synthase protein(C) Low density lipoprotein

levels(D) All the above

Answer

• (A) Cerebral vasospasm

Cluster headaches (CH) are extremely rare in patients

younger than:(A) 45 yr of age (B) 35 yr of age (C) 25 yr of age (D) 16 yr of age

Answer

• (D) 16 yr of age

Stimulation of the _______ mimics the clinical symptoms of

CH by activating autonomic structures connected to the eye

and nose.(A) Mandibular nerve

(B) Pterygopalatine ganglion (C) Descending palatine nerves

(D) Trigeminal ganglion

Answer

• (B) Pterygopalatine ganglion

Initiation of the pain process involved in CH:

(A) Relates to the dilation of blood vessels

(B) Is a hypothalamically mediated event

(C) Proceeds through the trigeminal system(D) All the above

Answer

• (D) All the above

Plasma levels of _______ increase rapidly during CH

attacks.(A) Endorphins (B) Enkephalins (C) Dynorphins

(D) A and B

Answer

• (D) A and B

Which of the following classes of medications may exacerbate the

biochemical irregularities seen in patients with CH?(A) Analgesics

(B) Opioids (C) Calcium channel antagonists

(D) beta-blockers

Answer

• (B) Opioids

The preferred preventive treatment for CH is:

(A) Prednisone (B) Methylergonovine

(C) Verapamil (D) Nimodipine

Answer

• (C) Verapamil

Hyperkalemic periodic paralysis (HPP) is classified as a disorder

of _______ channels.(A) Potassium

(B) Calcium (C) Sodium

(D) All the above

Answer

• (C) Sodium

Which of the following may prevent, forestall, or shorten

attacks of HPP?(A) Ingesting carbohydrates (B) beta-adrenergic inhalants

(C) Mild exercise (D) All the above

Answer

• (D) All the above

Unlike with HPP, patients with hypokalemic periodic paralysis

(HOPP) do not show:(A) Myotonic discharges

(B) Decreased compound muscle action potential amplitudes(C) Sensitivity to cooling

(D) Elevated creatine kinase levels

Answer

• (A) Myotonic discharges

Secondary HPP is most commonly caused by:

(A) Ingestion of exogenous potassium

(B) Diseases leading to hyporeninemic

hypoaldosteronism(C) Aldoesterone-producing tumors in the adrenal gland

(D) Thyrotoxicosis

Answer

• (B) Diseases leading to hyporeninemic hypoaldosteronism

What percentage of patients with transient ischemic attacks (TIA) will develop a stroke in 3 mo?

(A) 50% to 60% (B) 30% to 45% (C) 10% to 15% (D) 2% to 7%

Answer

• (C) 10% to 15%

For 90 days after assessment, patients with an age, blood pressure, clinical features,

symptom duration(ABCD2) score of _______ have

an 18% chance of stroke.(A) 6-7 (B) 4-5 (C) 1-3

Answer

• (A) 6-7

For assessment of patients for defects of the arch and septum or

valvular disease, _______echocardiography

shows greater sensitivity than _______ echocardiography.

(A) Transesophageal; transthoracic

(B) Transthoracic; transesophageal

Answer

• (A) Transesophageal; transthoracic

Hypercoagulation profiles are particularly useful in the work-up

of possible TIA in younger patients and those

without identifiable vascular risk factors.

(A) True (B) False

Answer

• (A) True

After a stroke, endogenous growth

factor levels decrease

dramatically.(A) True (B) False

Answer

• (B) False

Which of the following selective serotonin reuptake inhibitors has been shown to improve cognitive

andaffective outcomes when given within a few weeks after stroke.

(A) Sertraline (B) Fluoxetine

(C) Escitalopram (D) Paroxetine

Answer

• (C) Escitalopram

_______ given after infusions of -human chorionic gonadotropin

has(have) produced superior outcomes in

animal models of stroke.(A) Marrow stromal cells

(B) Erythropoietin (C) Granulocyte-colony

stimulating factor (D)Levodopa

Answer

• (B) Erythropoietin

Marrow stromal cells have been shown to assist brain repair after

stroke by:(A) Differentiating into new

neurons(B) Promoting myelination

(C) Increasing dendritic formation

(D) Elaborating beneficial growth factors

Answer

• (D) Elaborating beneficial growth factors

In patients 22 to 44 yr of age, the majority of strokes are

caused by:(A) Ischemia

(B) Subarachnoid hemorrhage (C) Intracerebral hemorrhage

(D) Arteriovenous malformation

Answer

• (A) Ischemia

Fibromuscular dysplasia affects the internal carotid

artery and _______ arteries.

(A) Vertebral (B) Renal

(C) Pulmonary (D) Coronary

Answer

• (B) Renal

American Heart Association guidelines endorse the use of tissue plasminogen activator

(tPA) up to_______after an acute ischemic stroke.

(A) 12 hr (B) 8 hr

(C) 4.5 hr (D) 3 hr

Answer

• (C) 4.5 hr

Studies show _______ of eligible patients receive treatment with

tPA after an acute ischemic stroke.

(A) 43% to 57% (B) 31% to 43% (C) 19% to 31%(D) 3% to 7%

Answer

• (D) 3% to 7%

The rigidity and extensor posturing seen during the initial

stage of a tonic-clonic seizure are caused by

activation of the:(A) Prefrontal motor cortex

(B) Brainstem (C) Hypothalamus (D) All the above

Answer

• (B) Brainstem

In the medical intensive care unit (ICU) setting, 40% of seizures

are caused by:(A) Substance abuse

(B) Anesthesia toxicity (C) Drug withdrawal

(D) Renal or hepatic dysfunction

Answer

• (C) Drug withdrawal

The majority of convulsive states seen in the ICU are diagnosed as:

(A) Tonic-clonic seizures (B) Complex partial seizures

(C) Simple partial seizures (D) Myoclonic seizures

Answer

• (A) Tonic-clonic seizures

Perioperative seizures caused by anesthesia toxicity are most often

associated with high doses of:(A) Lidocaine (B) Ketamine (C) Propofol (D) Fentanyl

Answer

• (A) Lidocaine

Status epilepticus (SE) is diagnosed when a patient cannot

coherently respond to questioning for:

(A) 1 hr (B) 30 min (C) 15 min (D) 5 min

Answer

• (D) 5 min

Status epilepticus begins to exacerbate baseline neurologic

injuries after:(A) 1 hr

(B) 30 min (C) 15 min (D) 5 min

Answer

• (B) 30 min

Periodic lateralizing epileptic discharges are most often a result

of:(A) Withdrawal

(B) Traumatic brain injury (C) Anoxic arrest

(D) Intracranial tumors

Answer

• (C) Anoxic arrest

Which of the following types of drugs are recommended as first-line therapy for treatment of SE

in anemergency setting?

(A) Benzodiazepines (B) Anticonvulsants

(C)General anesthetics (D) Antiarrhythmics

Answer

• (A) Benzodiazepines

Sleep deprivation may cause breakthrough seizures during the third trimester of pregnancy in

patients with:(A) Complex partial seizures

(B) Juvenile myoclonic epilepsy (C) Tonic-clonic seizures

(D) All the above

Answer

• (B) Juvenile myoclonic epilepsy

Of all commonly utilized antiepilepsy drugs, _______

produces the highest rate of fetal malformations inpregnant women.

(A) Valproate (B) Carbamazepine

(C) Phenytoin (D) Lamotrigine

Answer

• (A) Valproate

In utero exposure to _______ is associated with decreases in IQ

scores.(A) Valproate (B) Phenytoin

(C) Lamotrigine (D) Phenobarbital

Answer

• (A) Valproate

Which of the following drugs interfere(s) with the efficacy of

oral contraceptive pills:(A) Carbamazepine

(B) Phenytoin (C) Phenobarbital (D) All the above

Answer

• (D) All the above

_______ is the most common type of comorbid hemorrhage

found with subarachnoid hemorrhages (SAH).

(A) Intracranial bleeding (B) Intraventricular hemorrhage

(C) Subdural hematoma (D) None of the above

Answer

• (A) Intracranial bleeding

_______ may cause SAH in patients with or without

aneurysms.(A) Tobacco use

(B) Heavy alcohol use (C) Cocaine use

(D) Sickle cell anemia

Answer

• (C) Cocaine use

Which of the following aneurysms typically present with

SAH?(A) Fusiform (B) Saccular

(C) Dissecting (D) Hernial

Answer

• (B) Saccular

Which of the following is recommended as the primary

diagnostic tool when assessing aneurysms?

(A) Computed tomography (CT) (B) Magnetic resonance imaging

(MRI) (C) Transcranial Doppler (TCD)

(D) Lumbar puncture

Answer

• (A) Computed tomography (CT)

In CTs of patients with incidental carotid terminus aneurysms,

blood is most often visible in the:(A) Interhemispheric fissure

(B) Prepontine cistern (C) Lateral suprasellar cistern (D) Interpeduncular cistern

Answer

• (C) Lateral suprasellar cistern

To predict the occurrence of cerebral vasospasm, it is recommended that _______ imaging be performed at

least every other day, and preferably daily, after obtaining a baseline

image.(A) CT

(B) MRI (C) TCD transcranial Doppler

(D) Angiographic

Answer

• (C) TCD transcranial Doppler

Prevention• avoid extremes

• avoid excessive consumption of high glycemic index foods

• excessive drinking

• Substance abuse

• excessive stress

• doctors must exemplify this for their patients

• processed foods—foods that ars white, (eg white sugar, white flour) usually have high glycemic index

• glass of red wine with dinner may be helpful in vascular disease, myocardial infarction, and dementia

• diet should approximate Mediterranean diet

• (fish, olive oil, fruits and vegetables, whole grains)

Prevention• resveratrol—increased levels may be protective

• Found in skin of red grapes, pomegranate juice, red wine

• Resveratrol is a substance found in red wine, grapes, berries and dark chocolate

• Difficult to consume enough to adequately elevate this level

• alternatively, resveratrol levels increased by 33% reduction in caloric intake

Resveratrol• Doctors Philippe Marambaud, Haitian Zhao, and Peter Davies from 

the Litwin-Zucker Research Center for the Study of Alzheimer’s Disease and Memory Disorders at the North Shore-Long Island Jewish Institute for Medical Research in Manhasset, New York published a study in 2005 that found that resveratrol, a red wine ingredient, lowers the levels of an Alzheimer’s disease protein.

• Several studies show that moderate red wine consumption is associated with a lower risk of Alzheimer’s disease. Wine is full of antioxidant compounds that have potential nerve protection characteristics. In this study, resveratrol is shown to lower the levels of a specific protein that clumps in the brain as a result of a gene variation. This protein, called beta amyloid, can lead to memory loss and dementia, which are features of Alzheimer’s disease.

• Alzheimer’s disease is a disorder that leads to the most common form of dementia occurring in aging adults. These findings suggest resveratrol, a natural compound, has a therapeutic potential in Alzheimer’s disease. Studies have shown that moderate wine intake reduces the risk of developing Alzheimer’s disease. Resveratrol is suspected to have antioxidant and nerve protection properties. Therefore, resveratrol contributes to the beneficial effect of drinking red wine on the nerve degeneration process associated with aging.

Resveratrol• Their report, published electronically yesterday in Nature, implies that

very large daily doses of resveratrol could offset the unhealthy, high-calorie diet thought to underlie the rising toll ofobesity in the United States and elsewhere, if people respond to the drug as mice do.

• Resveratrol is found in the skin of grapes and in red wine and is conjectured to be a partial explanation for the French paradox, the puzzling fact that people in France enjoy a high-fat diet yet suffer less heart disease than Americans.

• The researchers fed one group of mice a diet in which 60 percent of calories came from fat. The diet started when the mice, all males, were a year old, which is middle-aged in mouse terms. As expected, the mice soon developed signs of impending diabetes, with grossly enlarged livers, and started to die much sooner than mice fed a standard diet.

Resveratrol• Another group of mice was fed the identical high-fat diet but with a large daily dose of resveratrol

(far larger than a human could get from drinking wine). The resveratrol did not stop them from putting on weight and growing as tubby as the other fat-eating mice. But it averted the high levels of glucose and insulin in the bloodstream, which are warning signs of diabetes, and it kept the mice’s livers at normal size.

• Even more striking, the substance sharply extended the mice’s lifetimes. Those fed resveratrol along with the high- fat diet died many months later than the mice on high fat alone, and at the same rate as mice on a standard healthy diet. They had all the pleasures of gluttony but paid none of the price.

• Scientists have long known that a moderate intake of alcohol, and red wine in particular, is associated with a lowered risk of heart disease and other benefits. More recently, scientists began to suspect resveratrol had particularly powerful effects and began investigating its role in lifespan.

• The researchers, led by David Sinclair and Joseph Baur at the Harvard Medical School and by Rafael de Cabo at the National Institute on Aging, also tried to estimate the effect of resveratrol on the mice’s physical quality of life. They gauged how well the mice could walk along a rotating rod before falling off, a test of their motor skills. The mice on resveratrol did better as they grew older, ending up with much the same staying power on the rod as mice fed a normal diet.

What I tell my patients• Consider

• Red wine one glass a day that has about 1.5 to 3 milligrams of resveratrol per liter

• Supplement that is 500 to 1,000 mg a day

• There have been impurities in supplements

• Fish oil high in DHA omega 3 Fatty Acids, try to get 2,000 mg of DHA and EPA Omega 3 fatty acids that may 4 to 5 fish oil tablets a day

Diagnosis• first warning signs—loss of long-term skills (eg,

carpenter loses ability to distinguish tools)• Difficulty learning new skills expected concomitant of

older age• patient unaware of changes in behavior• loss of insight (in Alzheimer, frontotemporal dementia,

and somewhat in Lewy body dementia)• comments on behavioral changes by friends and family• strong family history of same symptoms starting at same

age

Diagnosis• mild cognitive impairment (MCI) has no clear diagnostic criteria

• Mini-Mental Status Examination (MMSE) or Montreal Cognitive Assessment (MoCA) often not enough for clinical assessment

• SLUMS (Saint Louis University Mental Status Exam) test much better

• Neuroimaging may not be necessary

• differential diagnosis for MCI—depression, stress, adult attention-deficit/hyperactivity disorder (ADHD)

• findings on neurologic examination may indicate need for neurology

• Physical therapy, speech and language pathologist, or occupational therapy consultation

Diagnosis• MCI in parkinsonism—may be drug effect, but consider progressive

supranuclear palsy, corticobasal syndrome, or Parkinson disease• clumsiness in one hand—possible limb apraxia of corticobasal syndrome• limb atrophy, fasciculations, weakness, dysphonia—possible Huntington

disease or bulbar problem due to amyotrophic lateral sclerosis (ALS)• dysphagia—possible ALS• structural imaging—in 1999, indicated only in event of focal neurologic

finding (eg, asymmetric reflexes)• today, patients with risk factors for cerebrovascular disease should get

structural imaging (because of large role of cerebrovascular disease in dementia)

• obtain computed tomography (CT) of head without contrast

Imaging

• single-photon emission computed tomography (SPECT) scan of brain gives functional assessment (identifies involved areas not yet subject to atrophy

• location of these areas specific to type of dementia)

• Look for a decrease in SPECT signal above and beyond that expected from level of atrophy

Case study• 72-yr-old woman artist with premorbid eccentric personality presents with inappropriate

behavior (sexually inappropriate comments to grandchildren), irritability, suspiciousness, and new compulsions

• Family primarily noted memory loss

• husband primarily noted behavioral change

• memory worse for nonverbal items

• confabulation—fabrication of stories

• no perseveration

• intact visual constructive skills (patient with artistic background)

• MMSE score, 27

• Behavioral Neurology Assessment Short Form (BNAS) score, 72 of 114 (should have approximated 90)

• neuroimaging—to distinguish Alzheimer disease (AD) from frontotemporal dementia

• in frontotemporal dementia, typically see asymmetric regional atrophy

• AD may be asymmetric, but typically more bilateral and posteriorly based (parietal and medial temporal lobes)

Case study• MRI shows asymmetric atrophy in

temporal lobes, with thinned hippocampus

• right side worse (corresponds to sparing of verbal memory);

• speaker’s as diagnosis AD because anterior cingulate gyrus relatively spared (usually involved in frontotemporal dementia)

Treatment• depression—often comorbid with dementia

• cholinesterase inhibitor may help

• difficulty sleeping— when comorbid with depression, sedative antidepressant may help

• in case of resistance or intolerance to these medications

• psychosocial resources—connect patient with First Link at Alzheimer Society (provides family education and support)

• cerebrovascular risk factors—assess and advise one aspirin daily (further cardiac work-up)

• medication administration—should be supervised

Treatment• financial issues—establish power of attorney• safety—investigate presence of firearms in patient’s home• disability—assist in application for shortor long-term disability• laboratory—check vitamin B12 levels and thyroid function• activities of daily living— help patients by simplifying their day• Driving privileges—should probably be revoked if instrumental activities of daily living

impaired• no specific cognitive test score useful in determining driving ability (MMSE not helpful; formal

neuropsychologic testing by neuropsychologist may point to set of cognitive deficits that impair driving)

• medication management—• atypical antipsychotics (some studies show higher serious adverse event rate)• start at low dose and increase slowly• maintain regular follow-up• much evidence in favor of trazodone• selective serotonin reuptake inhibitors (SSRIs)

Treatment• target symptoms for medications should be explained to family

• early use of cholinesterase inhibitor (for MCI) off-label

• speaker delays use of cholinesterase inhibitor until patient meets criteria for dementia

• duration of use depends on patient response

• 3 available cholinesterase inhibitors have different mechanisms of action

• possible to discontinue one if ineffective and prescribe another (may not help)

• Memantine may be added to cholinesterase inhibitor or attempted after cholinesterase inhibitor failure (useful for agitated behavior)

Neurologic voice disorder• any dysphonia or abnormal voice quality not primarily due to

vocal fold abnormality that is caused by abnormal motor control such as weakness or spasticity

• seen in conjunction with other speech and swallowing problems

• dysphonia may be first symptom of underlying neurologic disorder

• First symptom may be hoarseness or weak voice or fatiguany dysphonia or abnormal voice quality not primarily due to vocal fold abnormality

• caused by abnormal motor control such as weakness or spasticity

• seen in conjunction with other speech and swallowing problems

• dysphonia may be first symptom of underlying neurologic disorder

Neurologic voice disorder• First symptom may be hoarseness or weak voice or

fatigue (can be mistakenly attributed to stress or reflux)

• Other symptoms that support diagnosis of neurologic voice disorder include dysphagia

• dystonia (eg, blepharospasm, torticollis)

• ocular symptoms (eg, ptosis, diplopia)

• fasciculations

• muscle weakness

• imbalance

Types of neurologic voice disorders

• movement disorders

• vocal cord paralysis or paresis

• unilateral or bilateral

• acquired or congenital

• spasmodic dysphonia

• essential voice tremor

• dysphonia as part of dysarthria

Speech production• requires respiration, phonation, articulation, resonance, and prosody• vocal folds generate sound that has to be resonated through cavity• respiration—breath support critical to voice production (breath support may be

abnormal, weak, dystonic, or spastic)• phonation—occurs when vocal folds vibrate• (due to steady flow of air from lungs; if flow of air not steady, voice tremulous)• vocal folds must be mobile and have adequate closure• without closure, speech breathy (males have complete closure females and

adolescents have normal small posterior gap)• symmetric tonus needed in vocal folds (unilateral vocal fold paralysis treated with

injection of synthetic material into paralyzed vocal fold to bulk up fold and allow better approximation)

• dysphonia frequently primary feature of dysarthria (differentiation can be difficult)

Mayo Clinic classification of dysarthrias

• Flaccid: lower motor neuron disease produces weakness of speech muscles and weakened abdominal support (results in low volume)

• fatigue common with speech

• seen in certain bulbar strokes and myasthenia gravis

• 75% of patients in speaker’s voice disorder clinic complain of fatigue with speech

• test by having patient count from 1 to 100 three times

• classic symptoms of flaccid dysarthria—imprecise articulation, hypernasality, reduced volume, breathy vocal quality, and dysprosody\

• 1978 study showed 27% of myasthenia gravis patients present with dysarthria as first symptom (another 60% develop dysarthria later)

• 2001 study showed 65% of myasthenia gravis patients present with hoarseness, and 53% present with vocal fatigue

• 1961 study found initial most common symptom ptosis, followed by dysarthria, dysphagia, and leg weakness

Speech production• vocal fold• weakness results in bowing of folds• folds should abduct for respiration and close for voice production• air escapes through center of bowed vocal folds (seen in normal aging process, Parkinson, congenital

conditions, and prolonged endotracheal intubation) • articulation— pronouncing• requires modifying shape of oral cavity• requires mobile tongue, lips, temporomandibular joint, and mandible (lack of movement produces

muted voice)• soft palate must elevate symmetrically• all structures must have adequate range of motion, strength, and flexibility• resonance—ability to close off area between oral and nasal cavities by soft palate elevation• this, combined with lateral pharyngeal wall compression, acts as sphincter• all English sounds except “n,” “m,” and “ng” require closure between oral and nasal cavities• acquired hypernasality (sudden or gradual, not iatrogenic) almost always indicative of neurologic

dysfunction• prosody —fluctuation of pitch and intensity by varying length of vocal folds and breath support

Background on acute treatment of migraines

• necessary in patients also receiving preventive therapy

• required for all patients with migraine headaches

• high-level (migraine-specific) vs low-level (nonspecific) treatments—choice dependent on whether patient disabled by headache pain or more affected by other associated migraine symptoms

• standard of care should provide sustained pain-free response within 2 hr (with limited

• recurrence), reduce disability, restore function, and minimize side effects and costs

• speaker recommends assessing disability, impact, or loss of time to determine optimal type of acute treatment

• strategies—1) start with low-level treatment (eg, over-the-counter medication, nonsteroidal anti-inflammatory drug, combination medicine), then gradually step up treatment before proceeding to migraine-specific therapies

• 2) stratify care (screen patients for features indicating need for high-level acute treatment)

Background on acute treatment of migraines

• Migraine Disability Assessment Scale (MIDAS)—asks patient, eg, “how many days in the last 3 mo were you 50% disabled?” (10 days equals moderate impairment, 20 days severe impairment)

• Lipton study— showed superior results when stratifying patients by level of disability before prescribing treatment

• patients progressed gradually through different types of therapies required many additional physician visits and more time before treatment success achieved

• disabling migraines—in speaker’s experience, present in majority of patients reporting episodic migraines

• triptans and ergots—recommended for most patients reporting episodic migraines (excluding patients with vascular contraindications)

• most migraine attacks progress to disabling migraines

Background on acute treatment of migraines

• patients with infrequent attacks (ie, 10 headache days per month) should take triptans soon (<60 min) after onset of attack, while pain remains mild monitor number of headache days per month (prevents overtreatment)

• Taking medication early reduces overall usage by preventing pain and recurrence

• Migraine Assessment of Current Therapy (MIGRAINE- ACT)—patient-developed tool for assessing outcomes of therapy

• assesses functioning and whether pain-free 2 hr after medication, consistency of treatment effects, and discomfort while planning activities

Agents for acute treatment of migraines• Triptans: group 1 triptans show rapid effects and high potency

• group 2 triptans show delayed effects (take twice as long compared to group 1)

• group 1 triptans—sumatriptan (Imitrex);

• sumatriptan and naproxen (Treximet); zolmitriptan (Zomig); rizatriptan (Maxalt); almotriptan (Axert); eletriptan (Relpax)

• group 2 triptans—naratriptan (Amerge): frovatriptan (Frova)

• sumatriptan—available in subcutaneous form (4 mg or 6 mg as brand name or generic)

• Optimal oral dose 100 mg

• also available as nasal spray (not well tolerated or consistently effective)

• zolmitriptan—available as pill or “melt” (orally dissolvable, but not sublingual)

• Nasal spray recommended by speaker

• rizatriptan—available as pill or melt

• formulation—all other triptans available only as pills

• melts still lost if patients vomits

Determining ideal triptan• consider whether patients require rapid effects (ie, when

headaches peak)

• patients with vomiting symptoms may require nonoral formulations

• Also check tier levels under patient’s insurance

• needle-free sumatriptan injection—nitrogen gas forces sumatriptan under skin

• superior ease of use (compared to subcutaneous formulations)

• but more expensive

New and future options• liquid diclofenac—sachet of medication dissolved in water

• relieves pain within 15 min (compared to 60 min for standard pills)

• headache relief comparable to triptans

• inhaled dihydroergotamine (DHE)—

• availability in near future; achieves blood

• concentrations similar to intravenous (IV) DHE without nausea

• sumatriptan iontophoretic patch—undergoing clinical trials

• electric current pushes sumatriptan under skin and provides continuous delivery over 4 hr

• telcagepant— calcitonin gene-related peptide (CGRP) antagonist

Pathophysiology of migraines

• migraines generated from area near periaqueductal grey or dorsal raphe

• signals travel along parasympathetic outflow pathway (from superior salivary nucleus to sphenopalatine ganglion, then through synapse out to meninges) and cause release of neuroinflammatory peptides (eg, CGRP) after reaching meninges

• inflammation and vasodilation in meninges create peripheral pain mechanism in migraines

• nociceptive pain signal returns to brain, travels to lower brainstem, becomes integrated, and then ascends to thalamus and cortex

Chronic daily headache• prevented by selecting correct medication

• typically evolves from episodic migraines

• Eliminating patient’s need for repeat dosing prevents rebound episodes

• majority of daily headaches associated with acute overuse of medication (may be triggered by dosing 10-15 days per month)

• preventing overuse—utilize acute treatments appropriately and provide preventive treatments to reduce number of headache days per month

Daily prophylaxis of migraines• indications—migraines interfering significantly with daily routines despite acute treatment

• contraindication for acute medications

• special circumstances (eg, migraines causing hemiplegia or increasing risk for stroke)

• migraine attacks showing increasing frequency

• Pregnancy endangered by severe vomiting associated with migraines

• goals—not focused on eliminating migraines

• intended to decrease frequency, severity, and duration of attacks

• preventive treatment should increase effectiveness of acute treatment, reduce disability, and prevent rebound

• Clinicbased study—patients with 6 to 9 headache days per month showed 6-fold increase in odds ratio for developing daily headaches, and those with 10 to 14 per month showed 20-fold increase (compared to patients with lower headache frequency)

• severity—with more significantly disabling headaches, lower number of headaches per month needed to indicate prophylaxis

• constantly evaluate degree of disability vs frequency of headaches

Agents for prophylaxis of migraines• agents with multiple randomized controlled trials (RCTs)

showing effectiveness—• amitriptyline; propranolol; timolol; divalproex; topiramate• agents with 1 RCT showing benefit—venlafaxine (150

mg); lisinopril (20 mg; angiotensin-converting enzyme); candesartan and telmisartan (angiotensin receptor blockers); butterbur root; coenzyme Q10

• recommended nonpharmacologic adjunctive therapies—biofeedback, relaxation therapy, and cognitive behavioral therapy (supported by quality data)

Principles for migraine prophylaxis• start with low dosages• escalate treatment gradually• long-acting formulations increase compliance• 2 to 3 mo of treatment required to see benefit• choose medication that maximizes treatment of comorbid illnesses• avoid contraindicated medications• assess progress with headache diary• risk factors for failure of prophylaxis—• selection of incorrect agent• excessive initial dosage• Inadequate final dosage• insufficient treatment duration• need for copharmacy• lack of adherence (reduced by use of headache diary)• patients with symptoms from medication overuse often show no benefit from prophylaxis

Future treatments for daily headaches• onabotulinumtoxin A— shown effective for reducing number of

migraines per month in 1 of 2 phase III trials• awaiting approval• Reformulated gabapentin—shows lower intestinal absorption

and more linear absorption• neurostimulators—eg, occipital nerve, sphenopalatine ganglion• pathophysiology of migraines shows numerous points at which

inhibitory or neuromodulating stimulators may block transmission of pain signals

• sphenopalatine ganglion stimulator study—properly located stimulators eliminated cluster and migraine headaches

Background on cluster headache (CH)• consistent characteristics and location

• severe pain and autonomic symptoms (sympathetic and parasympathetic ipsilateral to headache)

• autonomic symptoms—manifest during headaches (not premonitory)

• migraine-type auras infrequently reported (more common in women)

• duration—brief (15 min)

• frequency—from 1 every 48 hr to 8 per day

• etiology— rule out other pathologies

• rarely inherited

• course— majority of patients have repetitive episodes over lifetime

Background on cluster headache (CH)• triggers—no correlation with lifestyle factors

• however, CH may be induced

• alcohol—provokes CH episodes (only small quantities necessary)

• during cluster periods, patients often show extreme sensitivity that disappears when cluster period ends

• absence of sensitivities may indicate misdiagnosis

• onset—extremely rare in patients <16 yr of age

• commonly begin at 20 to 40 yr of age

• natural remission may occur at 60 to 80 yr of age

• Circannual patterns—bunches of CH occur in cycles

• patterns unique to individual patients, typically 1 to 2 cycles annually (lasting several weeks to months)

• attacks often remit suddenly and spontaneously

• remission periods of 1 to 2 yr typical

• some patients never enter remission

Pathophysiology• positron emission tomography (PET)— shows increased

metabolic activity in multiple areas of hypothalamus during attacks

• photoperiod process—may explain link between CH episodes and seasons

• alterations in sleepwake cycle—may lead to activation of hypothalamic areas associated with CH

• parasympathetic pathways—stimulation of pterygopalatine ganglion mimics clinical symptoms of CH by activating autonomic structures connected to eye and nose (confirms parasympathetic involvement)

Pathophysiology

• Sympathetic involvement—suggested by changes in carotid artery diameter seen on angiography during CH episodes

• cervical sympathetic processing involved

• initiation of pain process—related to dilation of blood vessels

• hypothalamically mediated event

• proceeds through trigeminal system

Periodicity and patient characteristics• circadian patterns—• majority of patients have attacks on regular basis (ie, at same time daily)• many attacks occur during nightly sleeping periods• however, sleep studies show no major anomalies in sleepwake cycle• correcting sleep apnea has no effect on periodicity• evidence suggests circadian patterns relate to physiologic phenomena in

hypothalamic areas (eg, changes in melatonin, testosterone, cortisol, prolactin)

• endorphins and enkephalins—plasma levels start to drop 2 wk before onset of CH cycle (nadirs coincide with onset of cycle)

• plasma levels increase rapidly during attack, decrease to subnormal immediately after attack, then return to normal when cycle remits

• (supports hypothesis that CH hypothalamically mediated)

Characteristics of attacks• reach peak intensity rapidly• boring, intense pain• patients often stand, pace, rock, engage in self-injurious behavior, or run• extreme pain behaviors (eg, threats of harm against self or others)• autonomic phenomena, eg, partial Horner syndrome —common during attacks• after years of CH, patients may show residual eyelid droop• hormonal factors— in women, CH phenomena more like those of migraine• chronic CH—10% of patients begin with or transition to chronic symptoms, ie,

periods of remission last <2 wk• many typical characteristics of CH disappear (eg, circadian patterns), and

attacks often increase in frequency• patients become resistant to therapy• (acute and preventive)

Horner's syndrome• Signs found in all patients on affected side of face include; ptosis (which is

drooping of the upper eyelid from loss of sympathetic innervation to the superior tarsal muscle, also known as Müller's muscle [1]), upside-down ptosis (slight elevation of the lower lid), and miosis (constricted pupil), and anhidrosis (decreased sweating on the affected side of the face), dilation lag (slow response of the pupil to light), Enophthalmos (the impression that the eye is sunk in) loss of ciliospinal reflex and bloodshot conjunctiva may occur depending on the site of lesion. Sometimes there is flushing of the face is on the affected side of the face due to dilation of blood vessels under the skin.

• The clinical features of Horner's syndrome can be remembered using the mnemonic, "Horny PAMELa" forPtosis, Anhydrosis, Miosis, Enophthalmos and Loss of ciliospinal reflex

Acute treatment• except for sumatriptan, all therapies off-label• oxygen—effective in terminating individual attacks• Typically given as 100% oxygen• recommends face mask with flow rate of 8 to 10 L per min• safe and effective• usable multiple times per day; sumatriptan—subcutaneous

(sc) and intra nasal formulations beneficial• 4 to 6 mg given sc shows significant efficacy• safety and cost issues;

Acute treatment• Dihydroergotamine mesylate (DHE 45)—sc and intranasal formulations effective• intranasal zolmitriptan—recent studies indicate efficacy• Oral and sublingual triptans no recommended (due to delayed onset of activity)• local anesthetic agents—4% solution of aqueous lidocaine most commonly used• technique for treating CH with lidocaine—soak elongated cotton pledget in

lidocaine• pass cotton down nasal septum• retract cotton by 1 inch after reaching posterior pharyngeal wall• flood area with lidocaine• treatment should anesthetize sphenopalatine ganglion• nasal formulation may be used (with appropriate sprayer)• analgesics and narcotics—not indicated; opioids may exacerbate endorphin and

enkephalin dysfunction

Prevention• corticosteroids—primary treatment (as injection or orally)

• 40 mg of prednisone may terminate cycle of CH in 4 to 12 hr

• works by modulating hypothalamic pituitary axis

• Attacks often recur after patients return to physiologic level (when used as sole treatment)

• methylergonovine—alternative to methysergide

• long-acting triptans—eg, naratriptan, frovatriptan

• frequent dosing costly

• verapamil—preferred preventive treatment

• calcium channel blocker

• typically given at initial dosage of 240 mg (before increasing to maximum of 720-960 mg)

• electrocardiography (ECG) recommended for patients receiving >480 mg (higher dosages may cause heart block)

• often shows results during first week of treatment

Prevention• nimodipine—cerebrovascular-specific calcium channel blocker• shows efficacy with CH• lithium carbonate— oldest preventive agent for CH• efficacious, but poorly tolerated• effects not dose dependent cyproheptadine—divided doses of 32 mg may be effective• antiepileptic agents—eg, divalproex and topiramate• often highly effective; rapid onset of activity• given in modest doses (eg, 500 mg daily for divalproex)• direct-acting (not extended release) formulation recommended• 15 mg of topiramate may be effective (without side effects seen in migraine suffers)• indomethacin—agent of choice for specific types of CH (eg, traditional episodic or chronic CH)• given in modest doses after remission, but high doses used during initiation (200-250 mg)• 12.5 mg of liquid formulation may be effective for long-term maintenance• melatonin—addresses hypothalamically-regulated circadian dysfunction• typically given in doses of 9 to 10 mg• Botulinum toxin—use reported• clonidine and tizanidine—reported useful

Refractory CH• histamine proven to induce remission• use intravenous (IV) formulation• surgical approaches—most studies of deep brain

stimulation halted due to recurrence of attacks and complications

• after surgery, similarly refractory CH may occur on opposite side

• surgical blocks may cause anesthesia dolorosa• (frequent cause of malpractice claims)

Anesthesia Dolorosa ADDescription• Anesthesia Dolorosa (AD) is one of the most dreaded complications of the treatment of trigeminal neuralgia.  It occurs when the

trigeminal nerve is damaged by surgery or physical trauma, resulting in numbness in the face, with pain present within the numb area.

• Causes• AD is caused by injury to the trigeminal nerve, either deliberately as during ablative treatment for trigeminal neuralgia, or

accidentally as during injury to the trigeminal nerve for some other reason.• Symptoms• The two main symptoms of AD are facial numbness (much like the numbness from a dental anesthetic injection) and constant

pain.  The pain is usually burning, pulling or stabbing but can also include a sharp, stinging, shooting or electrical component. Pressure and “heaviness” can also be part of the pain symptoms. Often there is eye pain.  Cold increases the feeling of numbness sometimes making the face feel frozen.

• Diagnosis• The diagnosis of AD is made when patients have an area of total numbness in the face that is also painful. Quantitative sensory

testing is a test that confirms that the affected area is, in fact, numb, but this test is not necessary to make the diagnosis. If the painful area of the face has partial sensation, then the correct diagnosis is trigeminal deafferentation pain (for patients whose injury occurs during treatment for trigeminal neuralgia) or trigeminal neuropathic pain (for patients without trigeminal neuralgia).

• Treatments• Unfortunately, there is no known effective treatment for AD.  A multidisciplinary, pain-management-oriented approach is most

appropriate. Some helpful strategies include anticonvulsants, antidepressants, opiates, psychological support, and complementary and alternative therapies. There are no good surgical options at this point, but motor cortex stimulation has shown some promise in preliminary studies.

Transient ischemic attack (TIA)• often regarded as benign, giving patients false sense of

security• TIA and stroke represent spectrum of ischemia• TIA gives opportunity for preventive intervention• pathophysiology—arterial occlusion causes symptoms that

disappear after occlusion clears• Patients show no residual injury and complete recovery• definition—brief episode of neurologic dysfunction resulting

from focal brain or retinal ischemia, typically lasting <1 hr, without evidence of acute infarction on magnetic resonance imaging (MRI)

Predicting TIA(ABCD2)

• age, blood pressure, clinical features, symptom duration (ABCD2)—robust standard for predicting stroke risk after TIA

• patients with scores of 6-7 have 18% chance of stroke during next 90 days

• 8% chance within first 2 days; scale also stratifies risk in hyperacute settings (6-12 hr after TIA)

• imaging results not included in scoring (new lesion on• MRI indicates increased risk for short-term stroke)

ABCD2 Score for TIA• Age ≥ 60? Yes +1• BP ≥ 140/90 mmHg at initial evaluation? Yes +1• Clinical Features of the TIA: • Unilateral Weakness +2

Speech Disturbance without Weakness +1• Duration of Symptoms? 10-59 minutes +1

≥ 60 minutes +2• Diabetes Mellitus in Patient's History? Yes +1

Management• patients with suspected TIAs should undergo immediate evaluation• however, patients may not present immediately after TIA• speaker’s recommendations—hospitalize patients with ABCD2 scores >3• admit emergency department (ED) patients with TIAs for full

assessment; patients reporting TIA symptoms 2 to 7 days after event should also visit ED

• For TIAs reported after 2 to 3 wk, outpatient assessment may be sufficient

• goals of work-up—determine if TIA of vascular origin• determine mechanism in cases with vascular origin (eg, large vessel,

cardioembolism, small vessel)• knowing mechanism allows customized treatment and prognostication

Neuroimaging• infarcts—determine whether visible infarcts occurred recently• determine relevance to TIA• determine origin (eg, cortical or in perforator territory)• computed tomography (CT)—effective for revealing new

clinically relevant strokes• TIAs with longer durations associated with greater incidence of

lesions on CT• CT angiography (CTA) and perfusion CT (CTP)—conducted

during basic CT• quick tests that provide additional information• issues with CT—exposure to radiation and contrast

Neuroimaging• MRI—diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) provide additional

information• however, significance of lesions found remains unclear• On DWI—TIA lesions appear smaller than those of strokes• however, TIA lesions important predictors of future stroke• Patients with DWI abnormalities (particularly multiple abnormalities) at much higher risk for recurrent

events• large vessel occlusion— diagnosed with CTA or MR angiography (MRA)• predictor of new vascular event• multiple lesions on DWI—may indicate large number of emboli (potentially from ipsilateral carotid

artery or cardiac source)• extracranial disease—evaluate neck area (eg, with carotid ultrasonography [CUS], MRA, CRA); ideal

method and protocol for assessing neck undetermined• choose tests based on institution’s strengths and patient’s health status• CUS and transcranial Doppler (TCD)—have prognostic significance• patients with history of TIA and severe intracranial or extracranial stenosis at increased risk for stroke• CTA— has excellent negative predicative value; requires contrast

Neuroimaging• MRA—performed during MRI• gadolinium-enhanced or contrast-enhanced MRA possibly superior• speaker’s recommendations—patients with abnormalities on CUS

should receive second noninvasive test and undergo CTA if results discordant

• imaging must ultimately determine if patient requires carotid endarterectomy or stenting

• TCD—realtime imaging• visualizes migrating emboli an microemboli• diagnostic cerebral angiography—gold standard for assessing

patients with TIA• made easier and safer by recent advances

Cardiac assessment• cardiac testing and electrocardiography— critical• further cardiac testing—in patients without history of cardiac findings, yields findings

in minority of patients• Recommended after excluding other causes; when compared to trans thoracic

echocardiography, transesophageal echocardiography shows superior sensitivity (eg, for assessing arch, septum, and valvular disease)

• Holter monitoring—prolonged cardiac monitoring; used in patients with cryptogenic stroke

• Paroxysmal atrial fibrillation (AF)—frequent cause of cryptogenic strokes• often missed by ECG and inpatient assessments• Holter monitoring for 2 to 4 wk improves diagnosis rates• blood tests— recommended to rule out TIA mimics and identify risk factors (eg,

unealthy lipid profiles, elevated hemoglobin A1C, hypercoagulation profiles [particularly useful in younger patients and those without identifiable vascular risk factors])

Background on statins and risk for stroke• statins lower risk associated with elevated cholesterol levels• risk factors for heart disease also implicated in neurovascular disease• Mechanism of action for statins—upregulation of low-density lipoprotein (LDL) receptors increases

metabolism and clearance of LDL cholesterol in liver• optimal dose of any statin eventually lowers LDL by 30%• statins also show anti-inflammatory, immunomodulatory, vascular, endothelial, antioxidant, and

antithrombotic activity• large risk factor study—includeing 500,000 patients• no correlation found between cholesterol levels and risk for stroke-related mortality• however, elevated lipid levels associated with increased risk for cardiac death• Results of study possibly affected by >80% survival rate seen in• patients with strokes, and choice of mortality (rather than morbidity)• as end point; cardiovascular vs neurovascular• mechanisms—most cardiovascular disease shows atherosclerotic• etiology; however, embolic and hemorrhagic strokes typically• occur independently from atherosclerosis• statins show greatest benefits when treating risk factors for atherosclerosis

Studies of statins, cholesterol, and risk reduction

• Cholesterol and stroke study—statins reduced incidence of first major vascular event (myocardial infarction [MI], recurrent stroke, or need for revascularization procedure) by 24%, and reduced stroke rate by 25%

• rates of composite end points decreased in patients with history of stroke (including patients without preexisting coronary heart disease [CHD])

• statins alsom showed benefits in patients with controlled cholesterol levels (130 mg/dL of LDL)

• meta-analysis of primary stroke prevention—statins showed protective benefit (39 mg/dL reduction in LDL correlated with relative risk reduction of 21%)

• however, no reduction in fatal strokes found (another example of inappropriateness of mortality as primary end point)

• statins also reduced risk for stroke in patients with history of previous stroke (less pronounced than effects on patients with CHD)

• study prompted Food and Drug Administration to include stroke in indications for treatment with statins (without LDL cutoff)

• stroke now seen as CHD equivalent

Statin recommendations

• initial recommendations—goal of reducing LDL to <100 mg/dL• patients with borderline LDL ranges receive dietary and lifestyle restrictions, and those

with elevated LDL level receive restrictions plus medication• Modification to initial recommendations—issued in response to studies showing risk

reductions in patients with lower levels of LDL• includes LDL of <70 mg/dL as therapeutic option• Recommended for patients at high risk (with 10-yr CHD risk of >20%, established

CHD, multiple major risk factors [eg, diabetes],• severe or poorly controlled risk factors, multiple risk factors for metabolic syndrome

[eg, abdominal obesity, elevation of triglycerides, depression of HDLs, elevated blood pressure, glucose intolerance; presence of 3 factors qualifies patients for treatment as high risk])

• carotid artery stenosis study—in patients with asymptomatic atherosclerosis of carotid artery

• statins reduced thickness of plaques

Pleiotropic effects of statins• endothelial effects—upregulation of nitric oxide• reduced coagulation (particularly in patients treated with tissue plasminogen

activator) • positive effect on oxidative stress• reduced platelet function• reduced inflammation after acute events (eg, MI, stroke); effect on stem cells• MI studies—patients who received high dose lipid therapy 1 to 4 days after

MI showed significant reduction in risk for recurrent symptomatic ischemia (compared to placebo group)

• Multiple studies found acute administration of statins reduced adverse events occurring immediately after initial MI

• however, benefits showed no correlation with reductions in LDL

Pleiotropic effects of statins• (indicating patients may benefit from pleiotropic effects before reductions in cholesterol appear)• patients receiving atorvastatin also showed reduced rate of stroke• high-dose vs lowdose therapy—some trials of low-dose statins failed to show• reduction in rate of stroke• higher dosages show more prominent pleiotropic effects• study showed that patients receiving high-dose statins had reductions in C-reactive protein,

serum amyloid A, and other inflammatory markers• Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study—included

5000 patients with history of stroke or transient ischemic attacks (TIAs) but without preexisting CHD

• treatment with high-dose atorvastatin associated with statistically significant reduction in incidence of fatal and nonfatal strokes

• profound reduction in TIAs also shown• however, overall benefits modest• placebo group showed significant off-label use of statins (possibly compromising accuracy of

study)

Subarachnoid hemorrhage• causes lingering ischemia due to cerebral vasospasms• pathophysiology of vasospasms—theory attributes to

imbalance between endothelial-dependent vasodilatation and vasoconstriction

• vascular adjustment mediated by nitric oxide and endothelial-derived constriction factors

• Imbalance in homeostasis manifested by changes in levels of endothelial nitric oxide synthase (ENOS) protein, messenger RNA, and immune activity which correlate with depletion of nitric oside

Subarachnoid hemorrhage• statin effects—improve endothelial function without changing lipid levels• upregulate ENOS protein expression 3-• fold in vascular endothelium

• prevent delayed ischemic neurologic deficits and vasospasms (in animal model)

• Vasospasm study—only 2% of patients receiving statin therapy (before incidence of subarachnoid hemorrhage) developed cerebral vasospasms

• statins during acute phase of subarachnoid hemorrhage—patients given 80 mg of simvastatin for 14 days after hospitalization showed reduced vasospasm and less elevation of middle cerebral artery velocity (compared to placebo group)

• possibly related to pleiotropic effects

Concerns about aggressive use of statins• pleiotropic effect on platelet function may predispose patients to bleeding

(seen in• patients with marked reductions in LDL)• SPARCL study found increased rates of nonfatal hemorrhagic stroke in

patients receiving statins• ischemic stroke study—statins did not increase risk for hemorrhagic stroke

(suggesting increased risk of bleeding seen in other trials may not be related to control of LDL)

• cerebral hemorrhage outcome and recurrence study—found no association between statin use before hemorrhage and larger hematomas, worsened functional outcomes (in patients with recurrent hemorrhage), or increased recurrence rates

• potential increase in risk for hemorrhagic stroke may be offset by reduced risk for ischemic stroke

Background on brain repair

• definition—spontaneous or therapeutically induced process restoring aspects of brain structure or functioning after insult

• tissue plasminogen activator (tPA)—only 2% to 3% of patients in United States receive tPA within 4.5-hr window after stroke

• 1 study found tPA failed to prevent significant disability in 50% of patients

Types of therapies• growth factors—large proteins with critical role in development and repair of

all human organs• Increase dramatically after stroke• studies show addition of exogenous growth factors further promotes spontaneous

brain repair• monoclonal antibodies—eg, anti-Nogo protein and antibodies against myelin-

associated glycoprotein (anti- MAG)• axons in central nervous system (CNS) normally incapable of regrowth (due to

presence of myelin inhibitory proteins)• coating inhibitory proteins with antibodies allows axon regrowth (associated with

improved behavioral outcomes)• catecholaminergic agents—promote brain repair after many types of insults• eg, amphetamines, levodopa; 2001 study found levodopa significantly superior

to placebo for improving outcomes after stroke

Types of therapies• selective serotonin reuptake inhibitors (SSRIs)—recent literature suggests

escitalopram may improve cognitive and affective outcomes when started soon after stroke (ie, few weeks)

• cell-based therapy—in early stages of development

• animal studies show efficacy even at 30 days after stroke

• intensive physiotherapy— content, intensity, duration, and intervals affect efficacy

• Experience of therapist also affects outcomes

• Neuroprosthetics and neurostimulators—focal electrical manipulation of brain may improve repair and behavioral status after stroke

• lasers—global and focal use may enhance brain repair

• Motor imagery—eg, imagining movement or speaking

• may assist recovery

Growth factors• basic fibroblast growth factor (FGF)— group that received FGF at 6

hr after stroke did better than group treated earlier, suggesting action to start repair

• granulocyte- colony stimulating factor (GCSF)—capable of entering brain and producing beneficial effects in animal models

• affects many organ systems (consistent with most other growth factors)

• study in humans under way• Erythropoietin (EPO)—studies of extremely large doses

(neuroprotective range) 5 to 8 hr after stroke showed poor results• Possibly beneficial when combined with other agents, given at lower

doses, and started later

Growth factors• sequential growth factors—during development, growth factors

trigger in sequences• Deciphering natural sequences may reveal effective treatments• Beta-human chorionic gonadotropin (Beta-hCG) animal study—

EPO given after Beta-hCG• animals receiving both agents showed superior outcomes• speaker’s Beta-hCG plus EPO human study— 3 doses of BHCG

given 24 to 48 hr after stroke• 3 doses of EPO given after 1 wk (with tPA cleared from patient’s

body)• found safe; efficacy data forthcoming

Physiotherapy

• constraint-induced therapy—constraint of unaffected body parts enhances rehabilitation of stroke-affected anatomy

• in study, found superior to usual care when given for 2 wk

• no side effects; significant gains last for 2 yr• however, 2009 study found overly aggressive

or early application harmed patients

Cell-based therapies• ideal delivery methods and long-term fate of deployed cells

remain uncertain• regulatory concerns over purity not yet addressed (cells do

not remain in static state when stored)• marrow stromal cells (MSC)— adult stem cells• when taken from bones, grown in culture, and introduced into

brain, MSC preferentially migrate to injured areas, transform, and elaborate growth factors capable of helping injured systems (viable alternative to replacing specific cell types)

• speaker’s protocol—small sample of patient’s bone marrow cultured, then intravenously reinfused after 20 days

Robotic therapy• hand-wrist assistive rehabilitation device—

• patients play virtual reality motor games

• if patients cannot complete movements, robots provide assistance

Principles of brain repair• sensitivity to time—treatments targeting repair-based biochemical or cellular events show

greatest efficacy during first month after stroke (“golden period”)

• early intervention synergizes with natural biologic recovery (peaking at 2-3 wk after stroke)

• earlier treatment also guarantees access to patient and bypasses “learned disuse”

• Dependence on experience—combinations of repair-based drugs with behavioral reinforcement (eg, through rehabilitation) provide superior benefits

• processes involved in brain repair after stroke mimic those occurring during childhood development

• patient selection—enroll only patients with sufficient biologic target for effective treatment

• measure injuries and CNS functioning to assist stratification of patients

• domain-specific end points—neurologic domains recover to different extents and at different rates

• assessments of stroke severity and recovery more accurate when broken down into specific areas (eg, language, motor skills)

Stroke in a “young adult”• Background: “young adult” typically defined as 15 to 45 yr of

age

• account for 3% to 4% of all ischemi strokes

• 50% independent after 1 yr, and 68% return to work

• distinct etiologies

• majority of survivors have residual emotional, social, and physical impairments interfering with employment or quality of life

• multiethnic first-stroke study—in patients 22 to 44 yr of age,

• 45% of strokes caused by ischemia

• (24% by subarachnoid hemorrhage [SAH

• 31% by intracerebral hemorrhages [ICH])

Etiologies of Stroke in Young

• Dissection: causes 10% to 20% of ischemic strokes in young adults

• spontaneous or traumatic

• causes—chiropractic manipulation

• Coughing

• Straining

• hyperextension or rotation of neck

• outdoor activities, genetic diseases affecting connective tissue

• carotid artery dissection

• brain or retinal ischemia

• unilateral pain in face, head, or neck

• Horner syndrome (ptosis, miosis, unilateral facial anhidrosis)

• Symptoms of vertebral dissection—pain in back of head

Pregnancy• risk for ischemic stroke and ICH increases 2.4-fold• greatest risk during third trimester, labor, delivery, and 3 wk

postpartum• causes of stroke during pregnancy—hypertension (eg, due to

preeclampsia)• Hemolysis• elevated liver enzymes• low platelet count (HELLP) syndrome• air embolism• Arterial dissection• amniotic fluid embolism

Cardioembolism• causes 5% to 25% of ischemic strokes in young adults• causes—AF• rheumatic heart disease (HD)• coronary artery disease• congenital HD• Endocarditis• Atrial myxoma (rare)• Cardiomyopathies• patent foramen ovale (PFO• found in 15%-25% of total population)

Vascular malformations• lifetime risk for hemorrhagic stroke (2%-32%

yearly)

• arteriovenous malformation (study)—38% of patients presented with hemorrhages or seizures

• 23% presented with other symptoms (eg, headache)

• highest risk for hemorrhage occurred during first year after presentation

• hemorrhagic presentation, aneurysm, and deep venous draining predicted increased risk for stroke

Vascular malformations• nonatherosclerotic vasculopathies—infectious causes include herpes zoster and

meningovascular syphilis• noninfectious causes include systemic lupus erythematosus, rheumatoid arthritis, Churg-

Strauss syndrome, periarteritis nodosa, Wegener granulomatosis, and Moyamoya• Disease• Moyamoya disease—progressive stenosis of internal carotid artery (ICA) and proximal

branches• Incidence peaks at 5 and 40 yr of age• rare in United States• clinical symptoms include ischemic stroke, TIA, seizures, and headaches• patients develop compensatory collateral vessels with unique appearance on angiography• Fibromuscular dysplasia—nonatherosclerotic and noninflammatory; cause unknown• affects ICA and renal arteries; 25% to 30% of patients show involvement of carotid and

vertebral arteries• 7% to 50% show associated intracranial aneurysm• areas of stenosis have unique appearance on angiography

Atherosclerosis• plaques may eventually rupture and embolize• thrombus formed at rupture site may break of and form distal

emboli• risk factors—obesity• hypertension• smoking and alcohol use (smoking associated with platelet

activation and SAH• doubles risk for cerebral infarction)• high cholesterol (10% of patients 12-19 yr of age have total

cholesterol >200 mg/dL)• metabolic syndrome

Genetic vasculopathies• Rare• cerebral autosomal-dominant arteriopathy and

subcortical ischemi leukoencephalopathy• caused by mutation in NOTCH-3 gene• patients have strokelike episodes• hemiplegic migraines• rapid cognitive decline• and possible dementia at 50 yr of age

Hematologic disorders• factor V Leiden mutations—most common

• other causes—factor VIII deficiency

• high homocysteine levels

• prothrombin gene mutations

• Anticardiolipin antibodies

• antithrombin III deficiency

• protein C deficiency

• protein S deficiency

Migraine headaches• 3.7% of patients with ischemic stroke have active

migraines• posterior circulation predominantly involved• risk factors—oral contraceptives (OCPs)• Smoking• hypertension;• OCP study—found all types of OCPs increased risk for

stroke 2-fold• risk increased with age >30 yr age, smoking, hypertension,

high cholesterol, diabetes, and obesity

Drug use• cocaine—may cause subcortical

hemorrhages and intraventricular hemorrhages

• amphetamines—may cause ischemic stroke, ICH, and SAH

Cryptogenic stroke• 30% to 40% of ischemic strokes

• causes— aortic arch atheroma

• interatrial septal abnormalities with mural thrombus formation

• PFO with paradoxic embolism

• AF

• Unknown genetic causes