Treatment of Neurocritical Care Emergencies in Pregnancy
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- Sheth, S.S. & Sheth, K.N. Curr Treat Options Neurol (2012) 14: 197. doi:10.1007/s11940-011-0161-6
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Neurologic emergencies are a major cause of morbidity and mortality in pregnant women. In part because the patient population is young, the nihilistic approach that often accompanies neurologically devastating disorders in other contexts is largely absent. A number of studies have demonstrated improved patient outcomes in the setting of aggressive care delivered by neurointensivists in a specialty-specific environment. It stands to reason that young, pregnant women who suffer from neurologically devastating disorders and who have a wide range of prognosis may also benefit from such specialized care. Close collaboration between obstetricians and neurointensivists is critical in this context. A number of unique considerations in diagnosis and management present dilemmas in the context of pregnancy, such as radiation dose from diagnostic neuroimaging, choice of pharmacotherapy for seizures, anticoagulation, and the method of delivery in the context of cerebral mass lesions and elevated intracranial pressure. Patients and their physicians are often faced with the additional challenge of balancing the relative risks and benefits of the impact of a management approach on both mother and fetus. In general, this balance tends to favor the interests of the mother, but the impact on the fetus becomes more relevant over the course of the pregnancy, especially in the third trimester. A low threshold for admission to an intensive care unit (ideally one that specializes in neurointensive care) should be used for pregnant patients. Because of the limited information regarding long-term outcomes in this population, rigid prognosis formation and early care limitations should be deferred in the immediate period. After the patient is stabilized and a plan has been charted for the remainder of the pregnancy, every effort should be made to engage patients in aggressive, urgent neurologic rehabilitation.
KeywordsPregnancyWomenNeurointensive careNeuroimagingDiagnosisDeliveryPreeclampsiaEclampsiaSeizuresIntracranial neoplasmsIntracranial pressureMedical managementTreatmentStrokeCerebral venous sinus thrombosisSubarachnoid hemorrhageAnticoagulationAntenatal corticosteroids
Significant neurologic events during pregnancy are rare, but pregnant women are at an increased risk for several conditions commonly seen in the neurointensive care setting. Symptoms of altered mental status, seizures, headaches, or vision changes in pregnancy require prompt recognition and diagnosis, as the associated conditions can become life-threatening. One study of obstetric admissions to an intensive care unit over a 10-year period showed that 26% presented with symptoms of altered mental status or seizures and 36% experienced some type of neurologic dysfunction [1, Class III]. The extent of neurologic dysfunction as determined by the Glasgow Coma Scale (GCS) has been shown to be an independent predictor of maternal mortality: the odds of death in a woman with a GCS score ≤8 is 4.7 times that of a woman with a GCS score >8 [2, Class III].
Neurointensive management may be required with obstetric conditions that have neurologic manifestations, such as preeclampsia (PEC) or eclampsia; preexisting neurologic diseases that may worsen during pregnancy, such as epilepsy or myasthenia gravis; and cerebrovascular conditions to which women are predisposed in pregnancy, such as ischemic or hemorrhagic stroke and cerebral venous thrombosis.
Hypertensive disorders, including PEC and eclampsia, are directly responsible for 17.6% of maternal deaths in the United States. PEC continues to affect 5–8% of pregnancies. Although eclampsia has declined to 0.04% to 0.1% of pregnancies in developed countries, it remains high in developing countries and accounts for 5,000 maternal deaths worldwide each year .
PEC is defined by new-onset hypertension with associated proteinuria (≥0.3 g of protein, as measured with a 24-hour urine specimen) occurring after 20 weeks gestation. Eclampsia is defined as new-onset grand mal seizures occurring during pregnancy or postpartum (up to 6 weeks after delivery) in patients with PEC. Though it is difficult to predict who will develop eclampsia, occipital or frontal headache precedes seizures in 50–75% of patients with PEC, and visual symptoms are noted in 20–30% [3, Class IV]. Additional sequelae of PEC and eclampsia may include HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), placental abruption, disseminated intravascular coagulation, acute pulmonary edema, renal failure, intracerebral hemorrhage (ICH), and aspiration pneumonia.
In patients presenting with seizures before 20 weeks gestation or more than 48 h after delivery, other causes must be considered, especially if there are accompanying focal deficits . The differential diagnosis includes cerebral parenchymal disorders, metabolic derangements, brain neoplasms, and cerebrovascular conditions.
Epilepsy is the most common cause of seizures in pregnancy. Status epilepticus, defined as recurrent seizures without return of consciousness or a prolonged seizure lasting for more than 30 min, is considered a neurologic emergency. In pregnancy, it typically occurs in women with prior epilepsy who have discontinued antiepileptic drugs owing to fear of teratogenicity or in whom levels of medication become subtherapeutic with pregnancy-associated changes in metabolism and absorption [4, Class IV].
Intracranial neoplasms may manifest for the first time during pregnancy because considerable tumor expansion and edema can develop with intracellular and extracellular fluid compartment expansion during pregnancy. Additionally, pregnancy may promote tumor growth through hormonal regulation, as meningiomas often express high-affinity progesterone receptors and both meningiomas and acoustic neuromas can express estrogen receptors. The incidence of primary brain tumors of various histologic types have been shown to be the same among pregnant and age-matched nonpregnant women, with gliomas being the most common, followed by meningiomas and acoustic neuromas [5, Class IV]. Pituitary macroadenomas may compress the optic nerve or chiasm as they enlarge.
Pituitary apoplexy resulting from sudden hemorrhage in the pituitary gland is seen in 2% of people with pituitary adenomas [6, Class IV]. In pregnancy, Sheehan’s syndrome has been described as infarction of the pituitary gland following postpartum hemorrhage and resulting hypotension. Pituitary failure is potentially life-threatening, as hypopituitarism can cause severe hypotension. Other symptoms include tachycardia, hypoglycemia, and lactation failure.
Several risk factors for cerebrovascular diseases are associated with pregnancy: hypertensive disorders, infection, thrombophilia, hyperemesis gravidarum, and perioperative factors with cesarean section. Stroke has been found to be more common in pregnant women (11 to 34 per 100,000 deliveries) than in age-matched nonpregnant women (10.7 per 100,000 women of reproductive age) [7, 8, Class II; 9, Class IV]. Furthermore, recent reports indicate that pregnancy-related hospitalizations with stroke have been rising in the United States, especially in the postpartum period. Antepartum hospitalizations for cerebral venous thrombosis doubled from 1994 to 1995 to 2006–2007, while postpartum hemorrhagic stroke rates quadrupled [10•, Class II].
Intracerebral hemorrhage is more common in pregnancy, with a relative risk compared with nonpregnant women of 2.5 during pregnancy and 18.2 immediately postpartum [11, Class I]. ICH in pregnancy is most often caused by ruptured berry aneurysms (75%) in pregnant patients or an arteriovenous malformation (25–50%), although hypertensive hemorrhage, PEC/eclampsia, anticoagulant toxicity, coagulopathies, and cocaine use can also lead to ICH. The risk of subarachnoid hemorrhage triples in pregnancy, with over 85% occurring in the second or third trimesters [12, Class IV].
Diagnostic Imaging in Pregnancy
The management of acute neurologic events in pregnancy should be focused on prompt diagnosis and treatment of symptoms and the underlying condition in order to stabilize the patient and thus the pregnancy. Radiologic imaging is a critical part of neurologic decision making and should be pursued as necessary to achieve an accurate diagnosis.
No evidence of pregnancy loss or fetal anomalies have been noted at ionizing radiation doses <0.05 Gy (5 rads). Typical diagnostic imaging techniques expose patients to less than this dose, and the exposure is fractionated over time [13–15, Class IV]. Guidelines recommended by the American Congress of Obstetricians and Gynecologists (ACOG) state that concern for the effects of ionizing radiation should not prevent medically indicated diagnostic procedures from being performed on a pregnant woman [15, Class IV].
Iodinated contrast material has been shown to cross the placenta and may produce transient effects on the fetal thyroid, but no clinical sequelae resulting from brief exposures have been noted. Gadolinium also crosses the placenta and is excreted by the fetus into the amniotic fluid, which the fetus swallows [15, 16, Class IV]. No adverse fetal or pregnancy effects have been observed in human pregnancies, based on limited data [17, Class III]. ACOG guidelines also recommend that radiopaque and paramagnetic agents may be used in pregnancy if the potential benefits outweigh the potential risk to the fetus, as they are unlikely to cause harm and may be of diagnostic benefit. Gadolinium and iodinated intravenous contrast are also considered safe during breastfeeding. Women have the option of pumping and discarding breast milk for 24 h after receiving contrast, if they desire [18, Class IV].
Seizures and eclampsia
The prevention and treatment of seizures during pregnancy is important, given the morbidity seizures pose to both mother and fetus. Maternal seizures can lead to severe lactic acidosis and increased cardiac output causing elevated blood pressures. This leads to increased intra-abdominal pressures and a shunting of blood flow to the brain and muscles and away from visceral organs, including the uterus. As in all patients acutely experiencing seizures, the first priority is securing an airway, preventing injury, and providing supportive measures. Reversible causes such as infection, electrolyte abnormalities, and medications or other drugs should be investigated and treated accordingly.
- General considerations for the treatment of seizures in pregnancy:
∘ Padded bedside rails should be used, with physical restraints as needed .
∘ Suctioning of secretions and emesis should be performed as needed .
For tonic-clonic seizures, 2 mg of intravenous (IV) lorazepam should be administered and repeated every 5 min if necessary. Diazepam boluses of 5 to 10 mg IV may be used as an alternative. [4, 21, Class IV].
An IV phenytoin loading dose should simultaneously be started at 18 mg/kg (rate not to exceed 50 mg/min) if the patient is not already taking oral phenytoin .
If seizures persist, intubation, addition of a midazolam infusion, and EEG monitoring may be required.
Meperidine should be avoided, as it can lower the seizure threshold .
The Eclampsia Trial Collaborative Group conducted a randomized control trial of 1,687 women assigned to receive magnesium sulfate versus diazepam or magnesium sulfate versus phenytoin. Women treated with IV magnesium sulfate had a 53% lower incidence of recurrent seizures than those on diazepam and a 67% lower incidence than those on phenytoin. [22, Class II].
Alternatively, magnesium sulfate may be administered via an intramuscular (IM) route: an IV loading dose of 4 g magnesium sulfate is administered as a 20% solution at 1 g/minute, followed by 10 g of 50% magnesium sulfate administered as 5 g IM in the upper outer quadrant of each buttock, followed by 5 g IM every 4 h [19, 25, Class IV].
Magnesium toxicity should be suspected if patellar reflexes are diminished or absent or if respiratory depression occurs. Treatment includes holding any further magnesium sulfate, administering 10 cc of 10% calcium gluconate infused over 3 min, and prompt use of endotracheal intubation and mechanical ventilation for patients with severe respiratory compromise [3, 19, 21, 25].
Blood pressure management
Blood pressure control is warranted in patients with PEC or eclampsia in order to prevent left ventricular failure or ICH, but it must be done without causing hypotension, which would reduce uterine blood flow and cerebral perfusion [3, 21].
Significant hypertension may be treated with IV hydralazine (5–10 mg for a maximum dose of 30 mg), IV labetalol (20–40 mg every 15 min for a maximum dose of 220 mg), or oral nifedipine (10–20 mg every 30 min for a maximum dose of 50 mg) [26–28, Class IV].
Regional anesthesia is the preferred method of intrapartum pain control in women with PEC/eclampsia and the absence of a coagulopathy; it is considered to be safe and effective [3, 26, 28, 29, Class IV].
General anesthesia in a woman with PEC/eclampsia has increased risks of failed intubation and aspiration due to airway edema and is associated with significant increases in systemic and cerebral pressures during intubation and extubation [25, 26, 28].
Fetal bradycardia acutely following a seizure is not an indication of emergent cesarean section. The fetus benefits from in utero resuscitation. Fetal recovery is typically noted within 10 min once seizures are controlled and maternal hypoxemia is treated. Should fetal bradycardia or persistent late decelerations continue despite aggressive resuscitation efforts beyond 15 min, placental abruption or nonreassuring fetal status should be considered .
A retrospective study of women with severe PEC/eclampsia remote from term showed that induction of labor was not harmful to low birth weight infants [32, Class III].
For women with severe PEC, successful induction of labor was noted in 62% at gestational age >32 weeks and 31% for women at 24–28 weeks gestation. The Bishop score was the best predictor of success [33, Class III].
Some recommend cesarean section in women with eclampsia before 30 weeks gestational age if the patient is not in labor and the Bishop score is <5 .
Labor induction is initiated with prostaglandins for ripening, if the Bishop score indicates an unfavorable cervix, or with IV oxytocin.
Seizure prophylaxis with anticonvulsants should be considered, using a single agent at the lowest effective dose. For a woman already taking an anticonvulsant, medication changes should be avoided during pregnancy .
For symptomatic treatment of elevated intracranial pressure or compression of adjacent structures, dexamethasone or prednisone are recommended to reduce tumor edema .
Corticosteroids also should be considered in patients with pituitary apoplexy, to avoid an Addisonian crisis and electrolyte disturbances.
Bromocriptine (1.25–2.5 mg/day starting dose, titrated to achieve a normal prolactin level without adverse effects) may decrease pituitary macroadenomas by up to 50% and is safe to use in pregnancy . Bromocriptine may also be used in the setting of pituitary apoplexy if the patient is neurologically stable, without visual loss [34, Class IV].
Most prolactinomas decrease in size following delivery, and treatment should be planned postpartum accordingly .
Surgical excision may be deferred until after delivery for symptomatic benign tumors such as meningiomas or acoustic neuromas or for slow-growing tumors with low malignant potential, such as gliomas [5, 21].
Surgical excision of hemorrhagic or necrotic tumor is indicated if pituitary apoplexy results in acute, severe vision loss or progression of neurologic symptoms [35, Class IV].
Preexisting elevations in intracranial pressure in pregnant patients with intracranial neoplasms should be considered in regard to the additional risks with Valsalva effects during the second stage of labor due to uterine contractions and pushing. Intracranial pressure can increase to as high as 70 cm H2O (normal, 20 cm H2O) during this stage of labor, placing the patient at risk of cerebral herniation. A passive second stage of labor with delivery assistance using vacuum or forceps may be indicated .
The management of pregnant women with stroke must focus on four goals: protecting salvageable brain tissue, preventing additional complications such as aspiration, controlling factors such as blood pressure, and facilitating physical rehabilitation .
Diagnosis of cerebrovascular disorders should include a history, physical examination, and relevant laboratory testing, which may include a complete blood count, complete metabolic profile, erythrocyte sedimentation rate, coagulation profile, HIV test, and urine drug screen. Additional tests may include electrocardiogram, echocardiogram, carotid Doppler studies, and lumbar puncture.
Diagnosis and management are also significantly aided by imaging studies, which should not be delayed or deferred because of pregnancy. Imaging may start with a noncontrast CT scan, a faster and less expensive option than MRI, which is optimal for mass lesions and acute hemorrhage. The CT scan may be followed by MRI and MR angiography, which are optimal for evaluating the posterior fossa and brainstem and for acute identification of ischemic changes.
Supportive therapy should include anticonvulsant medications, blood pressure control, reduction of intracranial pressure, and intravenous fluid hydration as needed.
Cerebral venous sinus thrombosis
Cerebral venous sinus thrombosis (CVT) is treated with anticoagulation therapy using intravenous heparin or subcutaneous low molecular weight heparin (LMWH). Anticoagulation treatment for CVT (with or without hemorrhagic infarction) is considered safe and effective in pregnancy . (See additional details below.) The 2011 American Heart Association/American Stroke Association guidelines recommend full anticoagulation doses with LMWH for CVT throughout pregnancy and LMWH or warfarin for at least 6 weeks postpartum, for a total minimum treatment duration of 6 months [38••, Class I].
Early administration of aspirin (within 48 h of symptom onset) remains a priority in pregnant women experiencing ischemic stroke if they are not receiving IV thrombolysis or IV heparin [39, 40, Class I].
Thrombotic stroke can be treated with anticoagulation therapy, which should be continued throughout the remainder of pregnancy and the postpartum period.
Recombinant tissue plasminogen activator (rtPA) is known to be beneficial in selected patients with acute ischemic stroke if they are treated within 4.5 h of symptom onset; its efficacy and safety in pregnancy are unknown. The only rtPA approved by the US Food and Drug Administration (FDA) for acute ischemic stroke is Alteplase, which is considered a pregnancy category C medication (no data on teratogenicity in humans but no risk found in animal studies).
The risks of thrombolysis in pregnancy may include maternal or fetal hemorrhagic complications, preterm labor, placental abruption, and fetal demise. Hemorrhage may also occur if labor ensues or delivery is required following thrombolysis [41, Class III].
In one review of off-label thrombolysis for acute ischemic stroke, 11 pregnant women were treated with IV tPA or intraarterial thrombolysis, and ICH was noted in 1 patient [42, Class IV]. In another review of 172 pregnant women treated with thrombolytics for a variety of conditions, the overall hemorrhagic complication rate was 8% [43, Class IV].
The guidelines are inconsistent with regards to the use of thrombolysis for acute ischemic stroke in pregnancy. The 2008 guidelines of the American College of Chest Physicians (ACCP) consider pregnancy an exclusion from tPA therapy , but the 2007 guidelines of the American Heart Association/American Stroke Association (AHA/ASA) do not . The Alteplase package insert also does not list pregnancy as an exclusion criterion, but it does note that the risk of therapy may be increased in pregnancy and the potential benefits should outweigh the potential risks.
Some clinicians will consider thrombolysis in pregnant patients with acute ischemic stroke if they otherwise meet eligibility criteria. Discussion with the patient and family about risks and benefits is important [44, 45, Class IV].
Cerebral venous sinus thrombosis
In the setting of rapid deterioration, decompressive craniectomy can be life-saving for patients with venous thrombosis and edema [47•, Class IV].
Intracerebral or subarachnoid hemorrhage
Early surgical clipping is recommended for ICH or SAH caused by a bleeding aneurysm. One study found that patients treated with early surgery had better maternal and fetal outcomes than those treated conservatively [48, Class III].
Conscious patients with less than severe deficits (Hunt and Hess scale I to III) are typically treated with early aneurysm clipping in the first 4 days of the bleeding [48, 49, Class III]. Intraoperative management should include placing the woman in the lateral decubitus position to prevent compression of the inferior vena cava and avoiding the use of perioperative mannitol, which can cause fetal and amniotic dehydration .
Postoperative cerebral vasospasm can be treated with volume expansion and induced hypertension following clipping . Central venous pressure should be maintained at ≥8 mm. Transcranial Doppler studies may be used to follow mean and peak velocities in major branches of the anterior and posterior circulation .
Patients who are comatose, severely obtunded, or experiencing other severe neurologic deficits (Hunt and Hess scale IV and V), however, should be treated with supportive therapy until their condition improves, as operative morbidity and mortality are very high in these patients [36, 49]. A ventricular drain may be considered to improve the patient’s level of consciousness .
In nonemergent settings, the second trimester is typically the optimal time to operate, as organogenesis is complete and the risk of preterm labor is low .
Endovascular coiling of aneurysms by interventional radiology may also be a treatment option, although its use in pregnant patients is limited because of fetal exposure to radiation.
Definitive surgical management of arteriovenous malformations (AVMs) includes surgical clipping or endovascular embolization. There is a high risk of AVM rebleeding in pregnancy, making surgical treatment important [46, 50, Class IV].
Comatose patients with large hematomas may benefit from urgent surgical intervention, whereas those with smaller hematomas may be considered for conservative management until delivery .
Emergent surgical evacuation of clot may be required in patients experiencing significant supratentorial or cerebellar mass effect .
Ventriculostomy may be indicated in patients with obstructive hydrocephalus caused by intraventricular clot .
In pre-viable pregnancies (<24 weeks gestation), treatment should focus on maternal well-being, with protection of brain tissue, management of factors such as blood pressure and edema, and prevention of complications .
Women with strokes who are between 24 and 34 weeks gestation must be stabilized, and consideration should be given to administering antenatal corticosteroids to support fetal lung maturation and facilitate early delivery if necessary for maternal or fetal indications. If maternal and fetal status remains stable, a scheduled controlled delivery may be planned for between 34 and 39 weeks gestation, as clinically indicated .
Beyond 34 weeks gestation, corticosteroids are no longer indicated; delivery may occur for maternal instability, nonreassuring fetal status, labor, rupture of membranes, or other obstetric indications .
Vaginal delivery should be attempted unless there is an obstetric indication for cesarean section. A passive second stage of labor may be necessary, with forceps-assisted delivery .
Intracerebral or subarachnoid hemorrhage
The method of delivery for women with aneurysms or AVMs that have not been definitively treated remains controversial . Data do not support improved maternal or fetal outcomes with cesarean delivery for women with unclipped aneurysms or AVMs , suggesting that cesarean sections should be performed only for obstetric indications. However, prophylactic cesarean section or forceps-assisted vaginal delivery under regional anesthesia remain valid options. Significant cerebral hemodynamic variations should be avoided.
Anticoagulation in pregnancy
Based on ACCP and AHA/ASA guidelines, options for anticoagulation therapy in women with CVT or ischemic stroke include aggressive, adjusted-dose unfractionated heparin (UH) or adjusted-dose LMWH in pregnancy. Vitamin K antagonists are contraindicated because of associated teratogenicity.
UH and LMWH do not cross the placenta [51, Class IV], and there is no known teratogenic risk to the fetus, so both are considered safe in pregnancy . Higher and more frequent doses of both are required during pregnancy to maintain therapeutic levels.
Advantages of LMWH over UH include a more predictable anticoagulant response with fixed doses, given better bioavailability and longer plasma half-life, lower risk of thrombocytopenia, and less bone mineral density loss with long-term use [51, 52, Class IV]. Additionally, LMWH is more convenient, as frequent monitoring of the activated partial thromboplastin time (aPTT) is not required. For these reasons, the ACCP considers LMWH to be the preferred option for anticoagulation .
Given its shorter half-life, UH is preferable closer to delivery, with respect to administration of regional anesthesia and decreased risk of postpartum hemorrhage .
Therapeutic UH dosing should be initiated with 10,000 units subcutaneously every 12 h, with doses adjusted to a target mid-interval aPTT (6 h after injection) in the therapeutic range (1.5–2.5) [51, 52].
Therapeutic LMWH dosing is weight-adjusted, with full treatment doses given once or twice daily: dalteparin 200 U/kg or tinzaparin 175 U/kg daily, dalteparin 100 U/kg every 12 h, or enoxaparin 1 mg/kg every 12 h. Some argue for intermittent weight-based dosing changes of LMWH with periodic monitoring (every 1 to 3 months) of anti–factor Xa (anti-Xa) LMWH levels 4 to 6 h after a dose, using a goal of 0.6 to 1.0 U/mL with twice-daily regimen (slightly higher with once-daily dosing) [51, 52].
AHA/ASA recommends LMWH or warfarin anticoagulation therapy in the postpartum period. Both LMWH and warfarin may be used by a breastfeeding patient. Warfarin dosing should be adjusted to a target INR of 2.0 to 3.0, with initial UH or LMWH overlap until the INR is at least 2.0. Treatment should be continued for at least 6 weeks after delivery, for a minimum therapy duration of 6 months [38••, 52].
For patients managed on LMWH during pregnancy, a switch to UH should be planned at 36 weeks gestation (or sooner if delivery is expected earlier) and should be continued until delivery.
Patients remaining on LMWH must wait 24 h following the last dose before they can receive regional anesthesia because of the longer half-life of LMWH and the risk of an epidural hematoma .
Patients on UH may receive regional anesthesia upon confirmation of a normal aPTT .
LMWH or UH therapy may be resumed 6 h after vaginal delivery and 12 h after cesarean delivery .
Antenatal corticosteroid use
Antenatal corticosteroid administration to induce fetal lung maturity is well established in reducing the risk of neonatal respiratory distress syndrome, resulting in decreased need for surfactant therapy, lower concentrations of supplemental oxygen, and less need for prolonged mechanical ventilation. Additionally, there is a lower risk of intraventricular hemorrhage and necrotizing enterocolitis. The optimal benefits are noted 24 h after initiation of therapy and last for 7 days. A 1994 NIH Consensus Development Conference recommended administering a single course of corticosteroids to all pregnant women between 24 weeks and 34 weeks gestation if they were at risk of preterm delivery within 7 days, unless immediate delivery (within 1 to 2 h) was anticipated [53, Class IV].
This therapy can be administered as two doses of betamethasone (12 mg) given intramuscularly 24 h apart or four doses of dexamethasone (6 mg) given intramuscularly every 12 h .
Dr. Kevin Sheth has received funding from an American Academy of Neurology Clinical Research Award.
No potential conflicts of interest relevant to this article were reported.