Transcript 1 - RCRMC Family Medicine Residency

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 attentiondeficit/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 cognitive
impairment.
(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 the
following?
(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 the
first 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
the
carotid artery.
(A) True (B) False
Answer
• (A) True
The endothelial effects of statins
include:
1. Upregulation of nitric oxide
2. Reduced coagulation
3. Positive effects on oxidative stress
4. 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
and
affective 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 firstline therapy for treatment of SE
in an
emergency 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 in
pregnant 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
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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
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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
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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
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
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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
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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 highlevel acute treatment)
Background on acute treatment
of
migraines
• Migraine Disability Assessment Scale (MIDAS)—asks
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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 (MIGRAINEACT)—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
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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; angiotensinconverting 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
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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)
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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
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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
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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
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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 AD
Description
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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.
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Causes
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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.
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Symptoms
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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.
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Diagnosis
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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).
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Treatments
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Unfortunately, there is no known effective treatment for AD. A multidisciplinary, pain-managementoriented 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
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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
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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
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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
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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
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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
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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 2.4fold
• 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
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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
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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