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March 2013 Vol. 15 No.

3
From the publishers of
The New England Journal of Medicine

NEUROLOGY
Neurodegeneration in CTE was identified in 68 of the men disorder. Ongoing research is likely to help
Athletes and Veterans (mean age at death, 60), 25 of whom had identify risk-modification targets.
The long-term effects of repetitive mild concomitant AD, dementia with Lewy Brandy R. Matthews, MD
traumatic brain injury may not be so mild. bodies, motor-neuron disease (MND), or Disclosure: I, an American football fan and behavioral
frontotemporal lobar degeneration. CTE neurologist, write this review with a vague sense of
Traumatic brain injury (TBI) and related hypocrisy while donning apparel to support my local
was not associated with the 4 allele of apo- National Football League franchise in its upcoming
neurodegeneration among athletes and
lipoprotein E, known to be linked with AD wildcard playoff game.
military personnel is garnering more atten-
risk. Among the 34 men who had played McKee AC et al. The spectrum of disease in chronic
tion from the media, from the American
American football professionally, the stage traumatic encephalopathy. Brain 2013 Jan; 136:43.
Academy of Neurology (see its position
of CTE (I through IV) correlated positively
statement on sports that involve intentional
with increased duration of play, longer
trauma to the brain [http://viajwat.ch/ No Benefit from Memantine
duration of survival after playing football,
UXYugn]) and from neuroscientists who for Frontotemporal Lobar
and older age at death. Among 51 men
study chronic traumatic encephalopathy Degeneration
with both CTE and MND, 26% had either
(CTE; JW Neurol Apr 2012, p. 31, and Memantine fared no better than placebo
expressed suicidal ideation or completed
Cephalalgia 2011; 31:1618). CTE, a hetero- in a double-blind, randomized trial.
suicide.
geneous clinical syndrome characterized
Frontotemporal lobar degeneration
by changes in cognition and behavior, is a COMMENT (FTLD) is a pathologically and clinically
progressive tauopathy with neurofibrillary This study is limited by autopsy-related heterogeneous dementing disorder charac-
tangles like those in Alzheimer disease selection bias, recall bias in retrospective terized by progressive decline in behavioral
(AD), albeit distinct in their cellular and clinical histories, and a lack of formal cog- and language function. No FDA-approved
regional distribution in the nervous system. nitive data. Nevertheless, the compelling disease-specific medications or disease-
To better characterize CTE, research- findings demand the attention of neurosci- modifying therapies for FTLD are currently
ers conducted autopsy studies of 84 men entists, athletes, veterans, and the lay pub- available. Acetylcholinesterase inhibitors,
and 1 woman who had histories of repeti- lic. Accumulating evidence about CTE has approved to treat symptomatic Alzheimer
tive mild TBI; nearly all had been injured already prompted scientists to study the disease, are not recommended for FTLD. In
during contact sports, military service, or conditions potential associations with clinical practice, the N-methyl-d-aspartate
both. Brains of 18 matched controls with- seemingly disparate topics ranging from receptor antagonist memantine is often
out TBI were analyzed for comparison. prion disease to posttraumatic stress prescribed for FTLD on the basis of anec-
dotal evidence and open-label trial find-
CONTENTS ings of a modest benefit in mitigating
behavioral symptoms (e.g., Alzheimer Dis
Neurodegeneration in Athletes and Veterans....... 17 EEG for Cardiac Arrest Patients Treated Assoc Disord 2009; 23:211).
No Benet from Memantine with Hypothermia ..................................................... 20
In a new, manufacturer-funded,
for Frontotemporal Lobar Degeneration .............. 17 Newer Is Not Always Better ..................................... 21
double-blind trial, researchers randomized
Depression and Cognitive Impairment Prehospital Thrombolysis
in Older Adults........................................................... 18 for Stroke Is Possible............................................... 21 81 patients (age range, 4080) who met
Cognitive-Behavioral Therapy for Patients Predictors of Responsiveness Recovery criteria for behavioral-variant FTLD or
with Treatment-Resistant Depression ................. 18 in Prolonged Anoxic Vegetative State ................. 22 semantic dementia to receive memantine
Concussion Healing in Children Is Vesicular Monoamine Transporter 2 and (20 mg daily) or placebo for 26 weeks.
Slower Than We Thought ....................................... 19 Treatment of a DopamineSerotonin Disorder .... 22
Spinal Cord Imaging in Clinically Uncertain Role for Diaphragm Pacing Among the 76 patients who completed
Isolated Syndrome ................................................... 19 in Patients with ALS ................................................. 22 the trial, improvements in the total
Assisted Reproduction Treatment The Challenge of Diagnosing Migraine Neuropsychiatric Inventory score and
Increases Disease Activity in MS ......................... 19 Headache in Children and Adolescents .............. 23
Clinical Global Impression of Change score
Extremely Obese Girls at Increased Can Patients with Central Field Loss
Risk for Pediatric Multiple Sclerosis .................... 20 Drive Safely?.............................................................. 24
did not differ significantly between the me-
mantine and placebo groups. The drug was

JOURNAL WATCH (AND ITS DESIGN) IS A REGISTERED TRADEMARK OF THE MASSACHUSETTS MEDICAL SOCIETY.
AN EDITORIALLY INDEPENDENT LITERATURE-SURVEILLANCE NEWSLETTER SUMMARIZING ARTICLES FROM MAJOR MEDICAL JOURNALS. 2013 MASSACHUSETTS MEDICAL SOCIETY.
ALL RIGHTS RESERVED. DISCLOSURE INFORMATION ABOUT OUR AUTHORS CAN BE FOUND AT http://neurology.jwatch.org/misc/board_disclosures.dtl
18 NEUROLOGY Vol. 15 No. 3

well tolerated, although significantly more In cross-sectional analyses, baseline


EDITORS-IN-CHIEF
S. Claiborne Johnston, MD, PhD, Professor of memantine recipients than placebo recipi- depression increased the odds for prevalent
Neurology, and Epidemiology and Biostatistics; ents experienced adverse cognitive events. MCI (odds ratio, 1.4) and dementia (OR,
Associate Vice Chancellor, Research; Director,
Clinical and Translational Science Institute,
2.2). In longitudinal analyses with mean
COMMENT
University of California, San Francisco follow-up of 5 years, baseline depression
S. Andrew Josephson, MD, Associate Professor The authors note that recruitment chal-
increased the odds for incident dementia
of Neurology; Director, Neurohospitalist Program; lenges may have affected their study.
Medical Director, Inpatient Neurology, University (hazard ratio, 1.7) but not MCI (HR, 0.9).
of California, San Francisco
Families of patients with FTLD are often
Patients with both depression and MCI at
EXECUTIVE EDITOR
desperate to find relief for these typically
baseline were more likely than those with-
Christine Sadlowski, MS young-onset dementias. Many prefer that
Massachusetts Medical Society
out either diagnosis to develop vascular
clinicians prescribe memantine or an ace-
ASSOCIATE EDITORS dementia (HR, 4.3).
Peter J. Goadsby, MD, PhD, DSc, Professor of
tylcholinesterase inhibitor off-label, with-
Neurology, University of California, San Francisco out clear evidence of benefit, rather than COMMENT
Hooman Kamel, MD, Assistant Professor of participate in a clinical trial. Nevertheless, As the authors note, their results suggest
Neurology and Neuroscience, Weill Cornell Medical
College, New York City
the current findings do not justify the ex- that depression is more common with in-
Robert C. Knowlton, MD, MSPH, Associate Professor pense of memantine treatment for FTLD. creasing cognitive impairment and more
of Neurology, University of Alabama at Birmingham Brandy R. Matthews, MD likely in patients diagnosed with VaD.
(UAB); Acting Director, UAB Epilepsy Center
These results do not help clarify causal re-
Brandy R. Matthews, MD, Assistant Professor, Boxer AL et al. Memantine in patients with fronto-
Clinical Neurology; Associate Director, Neurology temporal lobar degeneration: A multicentre, ran- lationships, given the lack of increase in in-
Residency Training Program, Alzheimer Disease domised, double-blind, placebo-controlled trial. cident MCI in depressed patients and the
Center, Indiana University School of Medicine
Lancet Neurol 2013 Feb; 12:149. lack of neuroimaging evidence to support
Robert T. Naismith, MD, Assistant Professor of
Neurology, Washington University, St. Louis the reported vascular burden. However, the
Jaime Toro, MD, Chief, Section of Neurology, findings highlight the importance of ag-
Fundacin Santa Fe de Bogot; Professor and Depression and Cognitive
gressively treating depression and vascular
Director of the Program of Neurology, University Impairment in Older Adults
of El Bosque, Santa Fe de Bogot, Colombia risk factors in elders, especially those with
Depression was commonly associated with,
CONTRIBUTING EDITORS or at increased risk for cognitive decline.
Michael Benatar, MD, MS, PhD, Walter Bradley but not necessarily antecedent to, both mild
Brandy R. Matthews, MD
Chair in ALS Research; Associate Professor, cognitive impairment and dementia in a
Neurology; Chief, Neuromuscular Division, cohort study. Richard E et al. Late-life depression, mild cognitive
University of Miami
Performance on tasks intended to assess impairment, and dementia. Arch Neurol 2012
Seemant Chaturvedi, MD, Professor of Neurology,
Wayne State University School of Medicine, Dec 31; [e-pub ahead of print]. (http://dx.doi
cognition and measures of mood symp- .org/10.1001/jamaneurol.2013.603)
and Director, WSU/Detroit Medical Center
Comprehensive Stroke Program, Detroit toms are related. At least half of patients di-
Michael S. Okun, MD, Co-Director, Center for agnosed with Alzheimer disease (AD), and
Movement Disorders and Neurorestoration, perhaps a higher proportion of those with Cognitive-Behavioral Therapy
University of Florida McKnight Brain Institute
Thomas R. Swift, MD, Professor and former Chair,
vascular dementia (VaD), experience de- for Patients with Treatment-
Department of Neurology, Medical College of Georgia pressive symptoms. The association be- Resistant Depression
MASSACHUSETTS MEDICAL SOCIETY tween depression and dementia remains CBT added to antidepressant drugs was
Christopher R. Lynch, Vice President, Publishing;
Jonathan Adler, MD, Publisher; Robert Dall,
unclear: They may both be symptoms of beneficial in primary care practices.
Editorial Director; Anne Russ, Business Manager; common pathology, depression might be a Primary care physicians (PCPs) often pre-
Sharon S. Salinger, Editorial Operations; reaction to cognitive and functional status
Betty Barrer, Kristin Odmark, Staff Editors; scribe antidepressant medications, but only
Kara OHalloran, Copy Editor; Misty Horten, Layout; changes, or depression may contribute to about a third of patients will respond fully to
Art Wilschek, Corrie Bridgeman, Christine Miller, the emergence and progression of cognitive
Lew Wetzel, Ad Sales; Bette Clancy, Customer initial pharmacotherapy. When initial phar-
Service symptoms. To examine the relationship, macotherapy fails, options include dose es-
Published 12 times a year. Subscription rates per year: researchers assessed a community cohort calation, changing agents, or psychotherapy.
$129 (U.S.), C$176.19 (Canada), US$169 (Intl); Residents/ of more than 2000 individuals aged 65
Students/Nurses/PAs: $69 (U.S.), C$96.19 (Canada), Brief cognitive-behavioral therapy (CBT) is
US$80 (Intl); Institutions: $239 (U.S.), C$284.76 (Canada), and older, in both cross-sectional and effective for patients with previously un-
US$259 (Intl); individual print only: $99 (U.S.). Prices longitudinal analyses. The researchers
do not include GST, HST, or VAT. In Canada remit to: treated depression, but its role as second-
Massachusetts Medical Society C/O #B9162, P.O. Box identified depression using the Center line therapy, added to antidepressant medi-
9100, Postal Station F, Toronto, Ontario, M4Y 3A5. All for Epidemiological Studies Depression
others remit to: Journal Watch Neurology, P.O. Box 9085, cations, has not been studied well.
Waltham, MA 02454-9085 or call 1-800-843-6356. E-mail scale (CES-D; scores 4 out of 10 indicate
inquiries or comments via the Contact Us page at Researchers in the U.K. identified
depression). They consensus-diagnosed
JWatch.org. Information on our conflict-of-interest 469 depressed adults who had failed to
policy can be found at JWatch.org/misc/conflict.dtl mild cognitive impairment (MCI; amnestic
respond to a minimum of 6 weeks of anti-
and nonamnestic) using Petersen criteria
depressant therapy. Patients continued to
and dementia (AD and VaD) using Na-
receive usual care by their PCPs (including
tional Institute of Neurological Disorders
antidepressants) and were randomized to
and Stroke criteria, and they assessed
receive or to not receive 12 to 18 sessions
Journal Watch is a publication of NEJM Group, progression from MCI to dementia.
a division of the Massachusetts Medical Society. of CBT delivered in or near their PCPs
March 2013 JWatch.org 19

offices. Usual-care participants could be Compared with controls, patients imaging included sagittal T2-weighted and
referred for counseling, CBT, or secondary showed deficits in attention and processing proton-density sequences of the entire cord.
care, when such treatment was deemed to speed and had greater fractional anisotropy At baseline, 82 patients (67.8%) had focal le-
be clinically appropriate. (FA) in multiple white-matter structures sions in the spinal cord; 31 of these patients
After 6 months, significantly more pa- bilaterally (i.e., white-matter integrity was had a nonspinal CIS. Mean follow-up was
tients in the CBT group than in the usual disrupted). Patients and controls could be 5 years (range, 210 years).
carealone group (46% vs. 22%) reached distinguished with 90% accuracy by the At initial presentation, 36 patients
the primary endpoint of 50% decline in number and volume of clusters with high fulfilled 2010 McDonald criteria for MS
depressive symptoms, as measured by FA. At the second scan, FA was still elevat- (JW Neurol March 2011, p. 17, and Ann
the 63-point Beck Depression Inventory ed in patients, even though their cognitive Neurol 2011; 69:292). Six additional pa-
(BDI). Patients who received CBT also deficits had resolved. tients with nonspinal presentations would
had significantly higher rates of remission COMMENT meet McDonald criteria if spinal cord im-
(BDI <10) after 6 months. Differences Other studies have similarly found that aging were included. The odds ratio for
in these outcomes remained significant post-concussive cognitive impairment re- conversion from CIS to clinically definite
after 12 months of follow-up. mits within a few months. White-matter MS (CDMS) was 3.53 for patients with ver-
injuries may result from influx of extracel- sus those without baseline spinal cord le-
COMMENT
lular water due to altered gating of ion flow, sions, and the time to conversion was signif-
This study will support the growing inter-
stretching of axons and oligodendrocytes, icantly shorter for those with spinal cord
est in integrating behavioral health services
and other effects of axonal shear. That such lesions. In the nonspinal presentation sub-
into primary care practices, where psychi-
white-matter injuries do not resolve at the group, the odds ratio for CDMS conversion
atric and somatic morbidities commonly
same speed as cognitive impairment has at was 6.48 with versus without spinal cord
coexist and interact. New clinical and fi-
least one important implication: Children lesions.
nancial models will be required, but the
payoff for patients health and productivity who return to sports such as football, hock- COMMENT
could be substantial. ey, and soccer after postconcussive symp- Diagnosis of CDMS requires dissemination
Bruce Soloway, MD, toms have resolved may be vulnerable to in space and time, which can sometimes be
Journal Watch General Medicine more-profound effects of a second head in- based on a single MRI if there are simulta-
jury if white matter has not yet recovered. neous enhancing and nonenhancing le-
Wiles N et al. Cognitive behavioural therapy as an Although this may be more likely to be an
adjunct to pharmacotherapy for primary care based sions in an asymptomatic location. Many
patients with treatment resistant depression: Results
issue with moderate TBI, it may apply even neurologists are comfortable recommend-
of the CoBalT randomised controlled trial. Lancet to some patients with mild TBI. ing treatment for a patient with CIS, with-
2013 Feb 2; 381:375. Steven Dubovsky, MD, out additional spinal cord imaging to meet
Journal Watch Psychiatry criteria for CDMS. For those reluctant to
Concussion Healing in Children Mayer AR et al. Diffusion abnormalities in pediatric begin treatment early, cord imaging can
mild traumatic brain injury. J Neurosci 2012 lead to more definite diagnosis and prog-
Is Slower Than We Thought
Dec 12; 32:17961. nosis for a second event.
Even after cognitive impairment has resolved,
white-matter injuries linger. Robert T. Naismith, MD

Mild head injury in children is increasingly Spinal Cord Imaging in Sombekke MH et al. Spinal cord lesions in patients
seen as different from adult traumatic Clinically Isolated Syndrome with clinically isolated syndrome: A powerful tool
in diagnosis and prognosis. Neurology 2013 Jan 1;
brain injury (TBI) in its likely causes and Spinal cord imaging for nonspinal demye-
80:69.
in childrens lesser skull thickness and neck linating presentations will allow diagnosis
strength, susceptibility to white-matter of multiple sclerosis in one out of seven
patients. Assisted Reproduction
injury, and immature excitatory amino-
acid neurotransmission. These investiga- Spinal cord imaging is typically routine in Treatment Increases Disease
tors gave diffusion tensor imaging (DTI) demyelinating syndromes when symptoms Activity in MS
and neuropsychological testing to 15 pa- and signs indicate spinal cord disease. How- Hormonal manipulation for infertility
tients (14 boys; mean age, 13.5) with a mild ever, spinal cord imaging is less frequently may enhance immune function and result
TBI (defined as brief loss of consciousness; included for clinically isolated syndromes in MS relapse.
Glasgow Coma Score, 1315; altered men- (CIS) of the cerebrum, optic nerve, or brain- Assisted reproduction treatment (ART)
tal status at time of injury; and brief post- stem and cerebellum. To determine the im- involving stimulation of ovulation is being
traumatic amnesia). Evaluations occurred pact of cord imaging on diagnosis of multi- used increasingly as a treatment for infertili-
about 2 weeks after injury. Fifteen age- ple sclerosis (MS), investigators recruited ty. The effects on immune function in pa-
and education-matched healthy controls 121 patients with monofocal CIS (63 refer- tients with multiple sclerosis (MS) have
also underwent DTI. Eleven patients and able to the spinal cord, 58 with nonspinal not been determined for gonadotropin-
12 controls had a second evaluation at an presentations), at least 24 months of follow- releasing hormone (GnRH), follicle-
average of 128 days later. up, and both brain and spinal cord magnetic stimulating hormone (FSH), progesterone,
resonance imaging (MRI) at baseline. Spine
20 NEUROLOGY Vol. 15 No. 3

and estradiol at the concentrations involved Extremely Obese Girls inflammatory mediators associated with
in ART. To study these effects, investigators at Increased Risk for adipocytes and obesity. Future studies
prospectively recruited 16 patients with Pediatric Multiple Sclerosis might seek to determine whether weight
relapsingremitting MS who had been A population-based study reveals a poten- loss can be a beneficial modifier of
trying to conceive naturally for at least tially modifiable environmental trigger. MS once it is diagnosed.
12 months. Disease-modifying therapy had Robert T. Naismith, MD
To examine whether childhood obesity is
been stopped for at least 15 months. ART in-
associated with risk for pediatric multiple Langer-Gould A et al. Childhood obesity and
cluded 26 treatments. If a given cycle did not risk of pediatric multiple sclerosis and clinically
sclerosis (MS) or clinically isolated syn-
result in a pregnancy, an additional ART cy- isolated syndrome. Neurology 2013 Feb 5; 80:548.
drome (CIS), researchers reviewed data
cle could be performed after 4 to 6 months.
from more than 900,000 children (aged
No patient had relapses or activity on 18 years or younger) from one private EEG for Cardiac Arrest Patients
imaging within 9 months before ART. Southern California healthcare system. The Treated with Hypothermia
Within the 3-month risk period after ART, authors categorized body-mass index (BMI) A grading system for continuous electro-
the annual exacerbation rate was 3.28 (rate as underweight (<5th percentile), normal encephalography readings correlated
ratio compared with unexposed periods, (5th to <85th percentile), overweight with outcomes.
6.93). Rate ratios were 8.70 for new T2 (85th percentile or BMI 25 kg/m2), The main goal of this study was to deter-
lesions and 8.82 for new gadolinium- moderately obese (95th percentile or mine the prognostic significance of contin-
enhancing lesions. ART was associated BMI 30 kg/m2), or extremely obese uous electroencephalography (cEEG) find-
with a Th1 shift in lymphocytes, with (95th percentile or BMI 35 kg/m2). ings in patients treated with hypothermia
increased interleukin (IL)-8, IL-12, Logistic regression adjusted for sex, age, (HT) after cardiac arrest (CA). Toward
interferon-, transforming growth factor and race/ethnicity. this goal, the authors conducted prelimi-
beta, vascular endothelial growth factor,
Of the children, 75 had a new diagnosis nary validation of an EEG grading system
and CXCL-12. Cells secreting antimyelin
of CIS or MS. Many of the children with and determined the benefit of treating sei-
oligodendrocyte glycoprotein immuno-
MS or CIS were Hispanic (52%), and chil- zures detected with cEEG in this clinical
globulin G were increased after ART.
dren with MS or CIS were more likely than setting. They reviewed case records from a
GnRH-induced CXCL-12 secretion in-
the other children to be categorized as time when all patients with out-of-hospital
creased mononuclear cell transmigration
overweight or obese (51%). The three fea- CA with ventricular fibrillation were treat-
in ex vivo Boyden chambers, demonstrat-
tures associated with MS or CIS were age ed with a consistent protocol of HT and
ing enhanced chemoattractant effects
12 to 18 years, African-American ethnicity, mild sedation. Blinded experts reviewed
associated with transmigration across
and weight class; sex and education were cEEG findings during HT, rewarming, and
the bloodbrain barrier.
no different compared with controls. In a normothermia (NT). The EEG scoring sys-
COMMENT subset analysis stratified by sex, extremely tem included multiple well-established pat-
MS is more common in women of child- obese girls were 3.76 times more likely to terns that were graded as mild, moderate,
bearing age. Sex hormones have been impli- have CIS or MS than girls who were under- or severe (based on the most severe find-
cated in the disease initiation, and a relative weight or normal weight; no such associa- ing). Outcomes of CA were scored accord-
remission is often seen during pregnancy. tion was found among boys. Girls in the ing to the Cerebral Performance Category
Sex hormones have pleomorphic effects on overweight and moderately obese categories (1=mild; 5=dead or declared brain dead),
immunologic function. This study demon- did not have significant risks for MS, but with scores of 1 or 2 considered good and
strated that patients who were stable off dis- an increasing trend confirmed the elevated 3 to 5 considered poor.
ease-modifying therapies for 12 months risk with increasing weight in girls. Of 54 cases reviewed, 51 had all data
while trying to conceive had a dramatic in- points. Change in EEG grade between HT
COMMENT
crease in disease activity associated with and NT was observed in only 25% of cases.
The findings of this population-based
ART. The number of patients is small, but A grade 3 EEG was strongly associated with
study suggest that teenage girls with BMI
the finding is strengthened by immunologic poor outcome. A grade 1 EEG during HT
35 kg/m2 are almost four times more likely
assay findings demonstrating upregulation uniformly predicted a good outcome. Treat-
to develop MS or CIS during childhood
of both T- and B-cell function. For our pa- ing seizures detected with cEEG did not af-
than those who are underweight or normal
tients choosing to undergo ART, they fect outcome (all patients with seizures had
weight. These findings need to be replicat-
should be counseled on the potential in- poor outcomes), and treating myoclonus in
ed in other populations, as the demograph-
creased risk for an MS relapse. For women patients with generalized periodic epilepti-
ics of this Southern California population
whose MS has been active or aggressive, form discharges had no effect either (all pa-
are different from many other countries or
ART should be pursued cautiously. tients with myoclonus died in hospital).
other parts of the U.S. Similarly, evaluating
Robert T. Naismith, MD
whether other pediatric autoimmune dis- COMMENT
Correale J et al. Increase in multiple sclerosis activity orders interact with obesity could prove in- These findings are clinically important.
after assisted reproduction technology. Ann Neurol sightful. Weight may contribute to disease
2012 Nov; 72:682. They show an association of EEG patterns
initiation by elevating sex hormones and with prognosis in cardiac arrest patients
March 2013 JWatch.org 21

treated with hypothermia, they reinforce agents to choose from, deriving random- Prehospital Thrombolysis
prior observations regarding prognosis, and ized, head-to-head, comparative data is for Stroke Is Possible
they further our understanding of the role impossible. Fortunately, epilepsy syn- The second published report on a dedicated
EEG should have after severe postanoxic drome, the presence of comorbidities and stroke ambulance shows that prehospital
brain injury. Patients with postanoxic myoc- comedications, and other factors narrow imaging and thrombolysis are feasible in
lonus (with or without generalized periodic the choice of AED to a manageable number the right healthcare setting.
epileptiform discharges) do not recover. The for most individual patients. Nevertheless, Few patients receive intravenous tissue
value of EEG in this clinical scenario is in randomized, controlled trial data that ad- plasminogen activator (TPA) within the
providing prognostic information only. Ag- dress AED choice in the setting of clinical optimal period of 90 minutes after stroke.
gressive monitoring measures and treatment equipoise remain important. Most efforts to speed treatment have fo-
with antiseizure medications are futile and The current findings are understand- cused on events after hospital arrival, but
waste resources. As the authors note, the use able considering that the study design German investigators recently showed that
of cEEG (expensive and resource intensive) involved switching not only AEDs, but TPA may be administered safely in the field
should be used judiciously. One may argue also AED classes. As more is known about by a mobile stroke unit. Now, another Ger-
that three routine EEGs one each during the neurobiological bases of AED action man group has reported its experience with
HT, rewarming, and NT are sufficient for and adverse effects (Neurology 2009; prehospital thrombolysis.
optimal care of these patients. 72:1223), it makes little sense to switch, In 2011, investigators at Berlins emer-
Robert C. Knowlton, MD, MSPH say, a PHT-intolerant patient to another gency medical services system piloted the
Crepeau AZ et al. Continuous EEG in therapeutic sodium-channel blocker (e.g., CBZ); con- stroke emergency mobile unit (STEMO).
hypothermia after cardiac arrest: Prognostic and sidering another AED class altogether is An ambulance with portable computed to-
clinical value. Neurology 2013 Jan 22; 80:339. wiser. Assuming the sodium and nonsodi- mography (CT) capability, a point-of-care
um drug classes are equally effective at sei- laboratory, and telemedicine equipment
Newer Is Not Always Better zure control, one expects what the authors was staffed by a physician certified in neu-
When used as substitution monotherapy
observed an equivalent improvement in- rology and emergency medicine, a para-
in epilepsy patients who had failed initial dependent of precise choice of replacement medic, and a radiology technician. Dis-
anticonvulsant monotherapy, either of two AED. patchers used a validated algorithm to
older drugs (valproate and carbamazepine) A significant (though necessary) direct the STEMO to potential stroke pa-
is as tolerable and effective as a newer drug study shortcoming is the consideration tients. Strokes were diagnosed clinically by
(levetiracetam). the STEMO physician, and patients under-
of the cohort as a homogeneous group.
The past 20 years have witnessed an explo- Patient characteristics heavily influence went CT imaging that was viewed remotely
sion in available prescription antiepileptic AED choice: Would I really switch a by a radiologist. Eligible patients were then
drugs (AEDs) and a concomitant lack VPA-intolerant patient with juvenile myo- administered TPA at the scene.
of systematic comparative evidence to clonic epilepsy to CBZ? Or a CBZ-intoler- Of 152 patients treated during the pilot
guide prescribing habits. Debate is ongoing ant woman of childbearing age to VPA? study period, 77 patients completed in-
regarding the merits of AEDs introduced (No, in both cases.) In addition, the lack of formed consent for study inclusion. Of
in the early 1990s and later versus older drug interactions with newer AEDs signifi- these patients, 56 received a diagnosis of
drugs. cantly favors their use in a patient taking stroke (45 were confirmed in hospital),
To provide such comparative data, re- medication for other conditions. The cur- and 23 received TPA. The mean call-to-
searchers equally randomized 99 patients rent study adds valuable Class I evidence needle time was 62 minutes, compared
with epilepsy who had already failed initial regarding the use of a newer AED versus with 98 minutes in historical controls
AED monotherapy with phenytoin (PHT), two older AEDs. But, as ever, such evidence treated after hospital arrival. Symptomatic
carbamazepine (CBZ) or valproate (VPA), is no substitute for sound clinical judgment intracranial hemorrhage occurred in two
to levetiracetam (LEV) or to one of the in the individual patient. TPA-treated patients (9%).
older AEDs (VPA or CBZ). Psychosocial Giridhar P. Kalamangalam, MD,
variables (quality of life and depression DPhil, FRCP COMMENT
scores) and several secondary outcome Dr. Kalamangalam is Assistant Professor of Neurology, This is the second report of impressively
measures (seizure response, AED adverse University of Texas Health Science Center, Houston. fast treatment times with a mobile stroke
effects, neurocognitive performance) were Hakami T et al. Substitution monotherapy with unit. Whether this approach can improve
levetiracetam vs older antiepileptic drugs: A ran- long-term outcomes cost-effectively re-
assessed during the subsequent 12 months.
domized comparative trial. Arch Neurol 2012 mains unknown, but these preliminary
No outcome showed superiority of Dec; 69:1563.
data suggest that mobile stroke units may
LEV over the older drugs.
be worth investigating in the right health-
COMMENT care settings. Envisioning these units in the
Which AED? and Which AED next? U.S. is difficult, given our decentralized
remain real and important questions in emergency medical services, physician
epilepsy practice. With >20 FDA-approved shortages, and unsuitable reimbursement
22 NEUROLOGY Vol. 15 No. 3

systems (issues discussed in an editorial COMMENT COMMENT


that accompanies the article). For now, SEP measurement, and also more advanced Neurologists are taught to have a low
U.S. stroke centers should continue to focus procedures such as positron emission to- threshold to use levodopa to treat any child
on improving door-to-needle times after mography, functional magnetic resonance with a parkinsonian or dystonic presenta-
hospital arrival. Hooman Kamel, MD imaging, and magnetoencephalography, are tion, in case the patient has a dopa-respon-
providing exiting new opportunities in the sive dystonia syndrome. Some specialists
Weber JE et al. Prehospital thrombolysis in acute
stroke: Results of the PHANTOM-S pilot study. assessment of patients with severe brain may also be on the lookout for dopamine
Neurology 2013 Jan 8; 80:163. damage. I would now use evoked potentials transporter issues, tetrahydrobiopterin de-
Schwamm LH and Starkman S. Have CT will in addition to clinical assessment. However, ficiencies, tyrosine hydroxylase deficiency,
travel: To boldly go where no scan has gone before. all these procedures will never replace, but and aromatic l-amino acid decarboxylase
Neurology 2013 Jan 8; 80:130. rather will complement, standardized, re- (AADC) deficiency (which has been asso-
peated clinical assessments by experienced ciated with a strong family history of de-
Predictors of Responsiveness and appropriately qualified personnel. pression, similar to the current case pa-
Jaime Toro, MD tients). AADC cases somewhat resemble
Recovery in Prolonged
those of VMAT2 cases in that they respond
Anoxic Vegetative State Estraneo A et al. Predictors of recovery of respon-
siveness in prolonged anoxic vegetative state. to dopamine agonists. However, AADC
Clinical features and evoked potentials
Neurology 2013 Jan 29; 80:464. usually neither improves nor worsens with
are useful predictors of recovery of
responsiveness. levodopa. Additionally, AADC improves
with vitamin B6, and it worsens in the
Patients in a vegetative state (VS) have a Vesicular Monoamine
evening, possibly due to neurotransmitter
very poor prognosis; even when some kind Transporter 2 and Treatment of depletion.
of recovery is achieved, quality of life is a DopamineSerotonin Disorder
very poor. Foremost is the concern that the Depending on the particular enzyme
Identification of a novel mutation led to
prognosis be made accurately, as treatment or transporter deficiency, patients with
symptom improvement with dopamine
decisions include the possibility of with- agonist therapy in affected family members. these symptoms may respond to dopamine
drawal of life support. In this prospective agonists (especially if there are presynaptic
The biogenic amine mediatorrelated syn-
clinical study, researchers aimed to identify issues) and may not respond to levodopa.
dromes are well-described neurological
prognostic markers, recorded in the chron- Worsening with levodopa in VMAT2 defi-
disorders that include nine enzyme defi-
ic phase, that are useful in predicting re- ciency was consistent in this reported fam-
ciencies and one transporter disorder. Now,
covery of responsiveness in a cohort of pa- ily. The authors suggest that urine testing
researchers report the identification of a
tients in postanoxic VS. and gene sequencing may be sufficient to
novel disease in this category, in eight chil-
allow diagnosis and appropriate treatment.
The analysis included 43 inpatients in dren of a consanguineous Saudi Arabian
This idea must be confirmed by future
prolonged anoxic VS (>1 month; 23 women; family.
studies. Clinicians should be keen to try
age range, 1283). The authors collected The patients had an infantile-onset dopamine agonists if levodopa has no ef-
data about medical history, clinical find- neurological disorder characterized by de- fect or causes worsening in children with
ings, and neurophysiologic assessments at layed ambulation or failure to ambulate, de- this clinical presentation.
study entry. At 24 months, patients were velopmental delay, parkinsonism, dystonia,
classified as responsive or unresponsive on These findings may also have implica-
oculogyric crises, mood disorder, and auto-
the basis of clinical criteria and the Coma tions for clinical depression in which
nomic instability. Five parents of the chil-
Recovery ScaleRevised (CRS-R). VMAT might play a key role and tardive
dren had histories of depression. The inves-
dyskinesia and Tourette syndrome for
Twelve patients remained in VS, and tigators discovered that the patients were
which VMAT has been suggested as a target
22 died in VS. Nine patients recovered re- homozygous for a mutation in SLC18A2,
for drug therapy. Michael S. Okun, MD
sponsiveness, but two of them died after which is known to encode vesicular mono-
entering a minimally conscious state amine transporter 2 (VMAT2). Unaffected Rilstone JJ et al. Brain dopamineserotonin
family members were not homozygous. vesicular transport disease and its treatment.
(MCS). Of the other seven who were re-
N Engl J Med 2013 Feb 7; 368:543.
sponsive, five were in MCS and two VMAT2 presynaptically moves dopamine
emerged from MCS and were conscious but and serotonin into synaptic vesicles; it is
severely disabled. Patients who recovered thought to be important to motor, mood, Uncertain Role for Diaphragm
responsiveness were significantly younger and autonomic function. Treatment with Pacing in Patients with ALS
than those who did not and had higher levodopa worsened the condition in this A small study suggests lack of benefit, but its
CRS-R total scores and lower Disability family; however, treatment with a dopa- methods are flawed.
Rating Scale scores. Somatosensory evoked mine agonist (pramipexole) resulted in Amyotrophic lateral sclerosis (ALS) is
potentials (SEPs) were significantly more dramatic benefit, including ambulation a neurodegenerative disorder that pro-
common in those who regained respon- within 1 week in three patients previously duces progressive weakness of limb, axial,
siveness (all of whom had SEPs) than in unable to walk. bulbar, and respiratory muscles, with
those who did not. death typically occurring 3 to 5 years after
March 2013 JWatch.org 23

symptom onset. Noninvasive ventilation at some point, and only half the DP pa- confirmed by the study clinician. Com-
(NIV) prolongs survival and improves qual- tients had multiple VC measurements. pared with the neurologists diagnosis, the
ity of life. Direct intramuscular electrical Unfortunately, this study adds little sensitivity of the DIHS-C was 98% and
stimulation of the diaphragm, or diaphrag- to our understanding of DP in ALS. Well- the specificity was 61%.
matic pacing (DP), has emerged as a poten- designed prospective studies with large COMMENT
tial therapy despite the absence of support- numbers of adequately characterized pa- Although the sensitivity of the Diagnostic
ive randomized, controlled trial data. To tients receiving regimented follow-up are Interview of Headache SyndromesChild
determine whether DP slows the rate of vital under way that we hope will provide more Version was high compared with expert
capacity (VC) decline or prolongs ventila- answers regarding the utility of this costly clinical assessment, the duration of the
tor-free survival compared with NIV alone, intervention. Richard S. Bedlack, MD, interview (2040 minutes) renders it not
researchers retrospectively reviewed data PhD, and Michael Benatar, MD, MS, PhD applicable to the primary care setting. In
from a cohort of 354 patients who did not
Dr. Bedlack is Associate Professor of Medicine/ contrast, a recently published 44-item
undergo DP and 8 patients who received DP. Neurology, Duke University Medical Center, Durham, NC.
questionnaire for adolescents that can be
Among the NIV-only group, the rate Mahajan KR et al. Diaphragm pacing and noninva-
completed in 10 minutes had a reported
of VC decline was 5.1% per month before sive respiratory management of amyotrophic lateral
sclerosis/motor neuron disease. Muscle Nerve 2012 sensitivity of 76% and a specificity of
NIV use and 2.5% per month with NIV Dec; 46:851. 100%, compared with diagnosis by a spe-
use (in 216 patients). By contrast, the mean cialist (Headache 2009; 49:202), but that
monthly VC decline for four DP patients questionnaire is only available in Italian.
was 10.5% (4 others discontinued DP use). The Challenge of Diagnosing
Unfortunately, samples of the DIHS-C
The authors conclude that DP may actually Migraine Headache in Children questions were not included in the valida-
accelerate VC decline and does not prolong and Adolescents tion study. An adjunct to an interview for
ventilator-free survival, and that wide- A new structured diagnostic interview is migraine is to ask the child to draw a pic-
spread public funding of DP systems in sensitive but too time-consuming to be used ture of how the headache felt. Drawings
ALS may be premature. in primary care settings. that include features consistent with mi-
Migraine and tension headaches are the graine (e.g., artistic depiction of pounding
COMMENT
most common forms of headaches in chil- pain, nausea/vomiting, desire to lie down,
This study addresses an important issue in
dren and adolescents. Clinicians rely on periorbital pain, photophobia, visual scoto-
ALS treatment (Muscle Nerve 2012; 46:1).
patient and parent interviews to differenti- ma) are reported to be highly predictive of
However, it is confusing and highly flawed
ate the two subtypes and to provide appro- migraine (Pediatrics 2002; 109:460).
and does not adequately test the authors
priate treatment. Researchers at the Na- Martin T. Stein, MD,
hypotheses, much less justify changes in
tional Institute of Mental Health assessed Journal Watch Pediatrics and
healthcare policy. Although ventilator-free
the validity of the structured Diagnostic Adolescent Medicine
survival was one of the primary outcome
Interview of Headache SyndromesChild
measures, comparative data for the two Lateef T et al. Validation of a migraine interview
Version (DIHS-C). The interview consists for children and adolescents. Pediatrics 2013 Jan;
treatment groups were not clearly reported.
of an open-ended clinical history and 131:e96. (http://dx.doi.org/10.1542/peds
Moreover, nonrandomized trials require
questions to assess symptoms of each ma- .2012-1008)
careful matching of treatment and control
jor headache subtype, impairment, dura-
groups, but the study population (rapidly
tion, frequency, course, and treatment.
progressive ALS/motor neuron disease)
Parents are the primary informants for
is poorly characterized according to
children younger than 12 years.
El Escorial criteria and well-known ALS
prognostic factors (age, site of onset). The The DIHS-C was conducted in 104
one important baseline prognostic factor children and adolescents (51% boys; age
identified (time from symptom onset to range, 717 years) who were either en- Save time and stay informed
diagnosis) is not reported in a comparable rolled in a community-based health study with a FREE daily e-mail alert.
way for the treatment and control groups. or were patients in a hospital headache Relevant information and
Therefore, differences in outcomes be- clinic. Among 40 participants who had practical intelligence you can use
tween groups may simply result from de- previously received migraine diagnoses by Brief reviews of the medical news
mographics and not from treatment. To a clinician, all were found to have migraine that affects your practice
their credit, the authors acknowledge their according to the DIHS-C. Among 79 par-
Gleaned from government
small sample size, but this limitation is far ticipants who underwent neurological eval- agencies, journals, and other
worse than they admit: Three quarters of uation and ascertainment of headache by a key sources
their DP patients had to turn the DP down neurologist, 43 were diagnosed with mi-
Delivered to your e-mail box each
or off because of pain (an extraordinarily graine and only 1 patient did not have
weekday by 7:30 a.m. ET
poor postoperative outcome in our experi- migraine according to the DIHS-C. The
ence), half discontinued DP permanently DIHS-C identified 14 patients as having Visit JWatch.org to sign up FREE
migraine who were not subsequently
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JWatch.org

24 NEUROLOGY Vol. 15 No. 3

Can Patients with Central Field termine the size of the central scotoma and and use other tests that help detect visual
Loss Drive Safely? the location of the lateral preferred retinal field defects, such as color perception
Patients with central scotomas and lateral locus (PRL). Participants completed a sim- assessment and the Amsler grid.
preferred retinal locus did poorly at identi- ulated driving test with reaction times to Jaime Toro, MD
fying pedestrians in a simulator test. pedestrian sightings recorded.
Bronstad PM et al. Driving with central field loss I:
As the population ages, impaired vision Compared with controls, participants Effect of central scotomas on responses to hazards.
caused by both aging and macular degen- with CFL responded significantly more JAMA Ophthalmol 2013 Jan 17; [e-pub ahead of
print]. (http://viajwat.ch/12w0DnK)
eration is growing. A substantial number slowly to virtual pedestrians (reaction
of patients with macular degeneration times, 3.35 vs. 1.27 seconds) and missed
and other conditions develop irreversible
CASE DISCUSSION
seeing more virtual pedestrians (29% vs.
SERIES ON THE WEB
central field loss (CFL). Visual field is 3%), particularly those presented in their
of great importance in motion detection blind areas and during highway versus city
Do you have an
and safe driving. However, in many coun- driving simulations.
tries including the U.S., visual acuity is
interesting neurological
the visual criterion for determining
COMMENT case?
One of the most important functions of
licensure. Cases can be completed or still
peripheral vision during driving is motion
To test the effect of CFL on driving detection. Patients with CFL probably can- evolving. E-mail a 100-word
ability, researchers screened 28 patients description of the case to us at
not drive safely. The results of this study
with CFL; 11 with binocular CFL (7 with jwneuro@mms.org.
show that the configuration of PRL and We will publish both
age-related macular degeneration; 1 with scotoma affect driving performance more the case and, when relevant,
Stargardt disease) completed the study, as than visual acuity does. Neurologists and an experts comments
did 11 age-matched controls with normal ophthalmologists, who increasingly see on our website
vision. Prior to driving tests, each patient older patients, must master the techniques neurology.jwatch.org.
with CFL had a visual field mapped to de- of confrontation visual field examination

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