Eric J. Ashman

Practice parameter: The usefulness of evoked potentials in identifying clinically silent lesions in patients with suspected multiple sclerosis (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology

The Quality Standards Subcommittee of the American Academy of Neurology (AAN) is charged with developing practice parameters for neurologists for diagnostic procedures, treatment modalities, and clinical disorders. The selection of topics for which practice parameters are used is based on prevalence, frequency of use, economic impact, membership involvement, controversy, urgency, external constraints, and resources required. This article addresses the usefulness of evoked potentials (EPs) in identifying clinically silent lesions in patients with suspected MS. The diagnosis of MS remains primarily clinical, requiring evidence of white matter lesions disseminated in space and time.1,2 Some patients with suspected MS not fulfilling clinical dissemination criteria (MS suspects) have abnormal EPs that identify clinically unsuspected lesions.3,4 Current diagnostic criteria allow MS suspects to be reclassified into definite MS categories if EPs identify clinically silent lesions.2,5 The identification of clinically unsuspected lesions is one major reason clinicians use EPs in MS suspects.4,6 Presumably, MS suspects with EP-identified clinically silent lesions are more likely to have MS and are at higher risk for developing MS-related disabilities. Accurately identifying these high-risk patients will become increasingly important if early therapies are demonstrated to be effective in preventing or delaying disability in patients with MS. To determine the effectiveness of EP-identified silent lesions in diagnosing MS, we performed a systematic review and analysis of the literature. Based on this review we propose practice parameters for the use of EPs in patients with suspected MS. Confirmation of the ability of EP-identified clinically silent lesions to diagnose MS requires a comparison with an independently verifiable gold standard.7 Potential gold standards include pathologic confirmation of MS lesions, brain MRI, or the eventual development of clinically definite MS (CDMS). Pathologic confirmation in MS suspects is not usually practical given the …

Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache Report of the Guideline Development Subcommittee of the American Academy of Neurology

Objective: To update the 2008 American Academy of Neurology (AAN) guidelines regarding botulinum neurotoxin for blepharospasm, cervical dystonia (CD), headache, and adult spasticity. Methods: We searched the literature for relevant articles and classified them using 2004 AAN criteria. Results and recommendations: Blepharospasm: OnabotulinumtoxinA (onaBoNT-A) and incobotulinumtoxinA (incoBoNT-A) are probably effective and should be considered (Level B). AbobotulinumtoxinA (aboBoNT-A) is possibly effective and may be considered (Level C). CD: AboBoNT-A and rimabotulinumtoxinB (rimaBoNT-B) are established as effective and should be offered (Level A), and onaBoNT-A and incoBoNT-A are probably effective and should be considered (Level B). Adult spasticity: AboBoNT-A, incoBoNT-A, and onaBoNT-A are established as effective and should be offered (Level A), and rimaBoNT-B is probably effective and should be considered (Level B), for upper limb spasticity. AboBoNT-A and onaBoNT-A are established as effective and should be offered (Level A) for lower-limb spasticity. Headache: OnaBoNT-A is established as effective and should be offered to increase headache-free days (Level A) and is probably effective and should be considered to improve health-related quality of life (Level B) in chronic migraine. OnaBoNT-A is established as ineffective and should not be offered for episodic migraine (Level A) and is probably ineffective for chronic tension-type headaches (Level B).

Level of evidence reviews: three years of progress.

Neurology® 2012;79:13–14

The AAN response to evidence-based medicine: promise and pitfalls

Beginning in January 2009,1 the journal Neurology has appended a level of evidence (LOE) statement to the abstract of all articles addressing the efficacy of therapies. The LOE statement is accompanied by a rating of the study on a 4-point ordinal scale—the Class of evidence. As of this writing over 170 articles have been rated—25% Class I, 20% Class II, 28% Class III, and 26% Class IV. Authors of rated articles are occasionally upset by the LOE designation.2 Incorrectly, some view the Class of evidence designation as a “grade” for the article. It is not. The purpose of the rating is not to give a pass or fail grade or to indicate the article’s importance.3 Rather, it is an indicator of the study’s risk of bias – primarily its internal validity. The LOE statement is intended to provide clinicians with a succinct statement indicating how much caution they should employ when applying the results of the paper to their patients. The Class of evidence designation is only one feature of the LOE statement that accompanies every therapeutic article in Neurology. The specific wording of the statement is designed to give the reader some idea of the generalizability–or external validity–of the study. It does so by enumerating as specifically as possible the patient population, intervention, and outcome addressed by the question the study attempts to answer. For example, the LOE statement will indicate whether a study used a surrogate outcome. The LOE statement regarding the vitamin D paper4 referred to by Drs. Goodin and Reder2 clearly indicates that the results were based upon a surrogate outcome—MRI lesions—and not a clinical outcome. Issues of statistical precision are also captured in the LOE statement (or abstract), with the description of the effect size accompanied, when possible, by confidence intervals. Two Neurology LOE reviewers independently rated the long-term follow-up (LTF) study of patients with multiple sclerosis (MS) who participated in the randomized controlled trial (RCT) of interferon-beta.5 Both assigned a Class of evidence rating of III on the basis of pre-specified criteria.6 The reason for the rating was unambiguous. Given the outcome was all-cause mortality, it was essential to ensure that patients in different treatment groups were substantially similar on characteristics that could affect allcause mortality (e.g., smoking and lipid status). Because the distribution of these baseline characteristics was not described, the study was assigned a Class III rating. Of course, randomization is performed to balance patients in different treatment groups on important prognostic baseline characteristics. However, important imbalances in confounding characteristics can occur despite randomization, especially when there is a large number of potential confounders. This is the reason the CONSORT group7 recommends a table describing the distribution of confounding baseline characteristics. It is important to make certain randomization worked. If important imbalances are found, it is sometimes possible to make statistical adjustments to compensate. Such adjustments were made in the LTF study using multivariate Cox regression for some baseline variables such as T2 burden of disease. It is impossible to adjust for imbalances in important baseline characteristics if they are not measured. Drs. Goodin and Reder state that most of the deaths of their patients were related to MS, and thus it was not important to look at confounders other than those that would affect MS-related mortality. Curiously, MS-related mortality was not mentioned at all in the original submitted draft of the manuscript. It is briefly mentioned in the published document. We agree, had MS-related deaths been the outcome of interest, the study would have arguably been known to be substantially balanced on potential confounders related to MS-related mortality. MS-related mortality, however, was not the outcome analyzed in the LTF study. If the LTF study had used MS-related mortality as the outcome, another potential bias would have affected the study’s LOE rating. All-cause mortality is an objective outcome unlikely to be affected by observer expectation. In contrast, assigning death to a specific cause, such as MS, requires considerable judgment. These judgments are prone to observer expectation bias. To be eligible for a Class I or Class II rating by the AAN system, the determination of a nonobjective outcome requires masked outcome assessment. The method for assigning the cause of death is not described in the LTF study. Other sources indicate that the cause of death in the LTF study was only determined in 75.3% of the patients.8 Additionally, we cannot find evidence that LTF study investigators used masked adjudication of the cause of death. Thus, even if authors had used The AAN response to evidence-based medicine: promise and pitfalls 448449 MSJ18710.1177/1352458512448449Gronseth and AshmanMultiple Sclerosis Journal 2012

Practice guideline: Cervical and ocular vestibular evoked myogenic potential testing: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

Objective: To systematically review the evidence and make recommendations with regard to diagnostic utility of cervical and ocular vestibular evoked myogenic potentials (cVEMP and oVEMP, respectively). Four questions were asked: Does cVEMP accurately identify superior canal dehiscence syndrome (SCDS)? Does oVEMP accurately identify SCDS? For suspected vestibular symptoms, does cVEMP/oVEMP accurately identify vestibular dysfunction related to the saccule/utricle? For vestibular symptoms, does cVEMP/oVEMP accurately and substantively aid diagnosis of any specific vestibular disorder besides SCDS? Methods: The guideline panel identified and classified relevant published studies (January 1980–December 2016) according to the 2004 American Academy of Neurology process. Results and Recommendations: Level C positive: Clinicians may use cVEMP stimulus threshold values to distinguish SCDS from controls (2 Class III studies) (sensitivity 86%–91%, specificity 90%–96%). Corrected cVEMP amplitude may be used to distinguish SCDS from controls (2 Class III studies) (sensitivity 100%, specificity 93%). Clinicians may use oVEMP amplitude to distinguish SCDS from normal controls (3 Class III studies) (sensitivity 77%–100%, specificity 98%–100%). oVEMP threshold may be used to aid in distinguishing SCDS from controls (3 Class III studies) (sensitivity 70%–100%, specificity 77%–100%). Level U: Evidence is insufficient to determine whether cVEMP and oVEMP can accurately identify vestibular function specifically related to the saccule/utricle, or whether cVEMP or oVEMP is useful in diagnosing vestibular neuritis or Ménière disease. Level C negative: It has not been demonstrated that cVEMP substantively aids in diagnosing benign paroxysmal positional vertigo, or that cVEMP or oVEMP aids in diagnosing/managing vestibular migraine.

Practice guideline update recommendations summary: Disorders of consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research

Objective To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition on minimally conscious state (MCS) and provide care recommendations for patients with prolonged disorders of consciousness (DoC). Methods Recommendations were based on systematic review evidence, related evidence, care principles, and inferences using a modified Delphi consensus process according to the AAN 2011 process manual, as amended. Recommendations Clinicians should identify and treat confounding conditions, optimize arousal, and perform serial standardized assessments to improve diagnostic accuracy in adults and children with prolonged DoC (Level B). Clinicians should counsel families that for adults, MCS (vs vegetative state [VS]/unresponsive wakefulness syndrome [UWS]) and traumatic (vs nontraumatic) etiology are associated with more favorable outcomes (Level B). When prognosis is poor, long-term care must be discussed (Level A), acknowledging that prognosis is not universally poor (Level B). Structural MRI, SPECT, and the Coma Recovery Scale–Revised can assist prognostication in adults (Level B); no tests are shown to improve prognostic accuracy in children. Pain always should be assessed and treated (Level B) and evidence supporting treatment approaches discussed (Level B). Clinicians should prescribe amantadine (100–200 mg bid) for adults with traumatic VS/UWS or MCS (4–16 weeks post injury) to hasten functional recovery and reduce disability early in recovery (Level B). Family counseling concerning children should acknowledge that natural history of recovery, prognosis, and treatment are not established (Level B). Recent evidence indicates that the term chronic VS/UWS should replace permanent VS, with duration specified (Level B). Additional recommendations are included.

Practice Guideline Update Recommendations Summary: Disorders of Consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research

OBJECTIVE To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition on minimally conscious state (MCS) and provide care recommendations for patients with prolonged disorders of consciousness (DoC). METHODS Recommendations were based on systematic review evidence, related evidence, care principles, and inferences using a modified Delphi consensus process according to the AAN 2011 process manual, as amended. RECOMMENDATIONS Clinicians should identify and treat confounding conditions, optimize arousal, and perform serial standardized assessments to improve diagnostic accuracy in adults and children with prolonged DoC (Level B). Clinicians should counsel families that for adults, MCS (vs vegetative state [VS]/ unresponsive wakefulness syndrome [UWS]) and traumatic (vs nontraumatic) etiology are associated with more favorable outcomes (Level B). When prognosis is poor, long-term care must be discussed (Level A), acknowledging that prognosis is not universally poor (Level B). Structural MRI, SPECT, and the Coma Recovery Scale-Revised can assist prognostication in adults (Level B); no tests are shown to improve prognostic accuracy in children. Pain always should be assessed and treated (Level B) and evidence supporting treatment approaches discussed (Level B). Clinicians should prescribe amantadine (100-200 mg bid) for adults with traumatic VS/UWS or MCS (4-16 weeks post injury) to hasten functional recovery and reduce disability early in recovery (Level B). Family counseling concerning children should acknowledge that natural history of recovery, prognosis, and treatment are not established (Level B). Recent evidence indicates that the term chronic VS/UWS should replace permanent VS, with duration specified (Level B). Additional recommendations are included.

Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society

Objective To update the 2004 American Academy of Neurology (AAN) guideline for treating new-onset focal or generalized epilepsy with second- and third-generation antiepileptic drugs (AEDs). Methods The 2004 AAN criteria were used to systematically review literature (January 2003–November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength. Results Several second-generation AEDs are effective for new-onset focal epilepsy. Data are lacking on efficacy in new-onset generalized tonic-clonic seizures, juvenile myoclonic epilepsy, or juvenile absence epilepsy, and on efficacy of third-generation AEDs in new-onset epilepsy. Recommendations Lamotrigine (LTG) should (Level B) and levetiracetam (LEV) and zonisamide (ZNS) may (Level C) be considered in decreasing seizure frequency in adults with new-onset focal epilepsy. LTG should (Level B) and gabapentin (GBP) may (Level C) be considered in decreasing seizure frequency in patients ≥60 years of age with new-onset focal epilepsy. Unless there are compelling adverse effect–related concerns, ethosuximide or valproic acid should be considered before LTG to decrease seizure frequency in treating absence seizures in childhood absence epilepsy (level B). No high-quality studies suggest clobazam, eslicarbazepine, ezogabine, felbamate, GBP, lacosamide, LEV, LTG, oxcarbazepine, perampanel, pregabalin, rufinamide, tiagabine, topiramate, vigabatrin, or ZNS is effective in treating new-onset epilepsy because no high-quality studies exist in adults of various ages. A recent Food and Drug Administration (FDA) strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years old and perampanel as monotherapy received FDA approval.

Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy: Report of the American Epilepsy Society and the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

Objective: To update the 2004 American Academy of Neurology (AAN) guideline for treating new-onset focal or generalized epilepsy (GE) with second- and third-generation antiepileptic drugs (AEDs). Methods: The 2004 AAN criteria was used to systematically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength. Results: Several second-generation AEDs are effective for new-onset focal epilepsy. Data are lacking on efficacy in new-onset generalized tonic–clonic seizures, juvenile myoclonic epilepsy, or juvenile absence epilepsy, and on efficacy of third-generation AEDs in new-onset epilepsy. Recommendations: Lamotrigine (LTG) should (Level B) and levetiracetam (LEV) and zonisamide (ZNS) may (Level C) be considered in decreasing seizure frequency in adults with new-onset focal epilepsy. LTG should (Level B) and gabapentin (GBP) may (Level C) be considered in decreasing seizure frequency in patients ≥60 years with new-onset focal epilepsy. Unless there are compelling adverse-effect–related concerns, ethosuximide (ETS) or valproic acid (VPA) should be considered before LTG to decrease seizure frequency in treating absence seizures in childhood absence epilepsy (Level B). No high-quality studies suggest clobazam, eslicarbazepine, ezogabine, felbamate, GBP, lacosamide, LEV, LTG, oxcarbazepine, perampanel, pregabalin, rufinamide, tiagabine, topiramate, vigabatrin, or ZNS is effective in treating new-onset epilepsy because no high-quality studies exist in adults of various ages. A recent FDA strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years old and perampanel as monotherapy received FDA approval.

Comprehensive Systematic Review Update Summary: Disorders of Consciousness

OBJECTIVE To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition for the minimally conscious state (MCS) by reviewing the literature on the diagnosis, natural history, prognosis, and treatment of disorders of consciousness lasting at least 28 days. METHODS Articles were classified per the AAN evidence-based classification system. Evidence synthesis occurred through a modified Grading of Recommendations Assessment, Development and Evaluation process. Recommendations were based on evidence, related evidence, care principles, and inferences according to the AAN 2011 process manual, as amended. RESULTS No diagnostic assessment procedure had moderate or strong evidence for use. It is possible that a positive EMG response to command, EEG reactivity to sensory stimuli, laser-evoked potentials, and the Perturbational Complexity Index can distinguish MCS from vegetative state/unresponsive wakefulness syndrome (VS/UWS). The natural history of recovery from prolonged VS/UWS is better in traumatic than nontraumatic cases. MCS is generally associated with a better prognosis than VS (conclusions of low to moderate confidence in adult populations), and traumatic injury is generally associated with a better prognosis than nontraumatic injury (conclusions of low to moderate confidence in adult and pediatric populations). Findings concerning other prognostic features are stratified by etiology of injury (traumatic vs nontraumatic) and diagnosis (VS/UWS vs MCS) with low to moderate degrees of confidence. Therapeutic evidence is sparse. Amantadine probably hastens functional recovery in patients with MCS or VS/UWS secondary to severe traumatic brain injury over 4 weeks of treatment. Recommendations are presented separately.