February 2013 Vol. 15 No.

2
From the publishers of
The New England Journal of Medicine

Time to Rethink Our
Assumptions About ICP
Monitoring for TBI
A randomized trial finds no benefit from
therapy guided by intracranial pressure
monitoring rather than clinical and
radiographic signs.
Guidelines recommend intracranial pres-
sure (ICP) monitoring in the acute man-
agement of severe traumatic brain injury
(TBI). However, only observational data
support this recommendation, and not all
clinicians follow it. Investigators have now
performed the first randomized trial of ICP
monitoring in patients with severe TBI.
Taking advantage of widespread equi-
poise in South America regarding the ben-
efits of ICP monitoring, the trial involved
six Bolivian and Ecuadorian hospitals with
intensivist-staffed ICUs, 24-hour comput-
ed tomography availability, and neurosur-
gical coverage. Investigators enrolled pa-
tients older than 12 years with a Glasgow
Coma Scale (GCS) score of 38, excluding
those with unsurvivable injuries or a GCS
score of 3 and bilateral fixed and dilated
pupils. Those randomized to ICP monitor-
ing received an intraparenchymal monitor
CONTENTS
Time to Rethink Our Assumptions About
ICP Monitoring for TBI............................................... 9
Teamwork and Expertise
Can Be Powerful Medicines .................................... 9
Citicoline for Traumatic Brain Injury:
Time for Other Options............................................. 10
Indicators for Prognosis
in Mild Traumatic Brain Injury................................ 10
Simplifying Acute Stroke Prognostication.............. 11
Alzheimer Disease Risk Variant Discovered .......... 11
Low-Dose Aspirin and Dementia
in Older Women ........................................................ 12
Better Cognitive Functioning in Elders
Linked to More-Intense Physical Activity ........... 12
Neurologists as Neurohospitalists........................... 13
NEUROLOGY
and treatment to keep ICP <20 mm Hg. after TBI can be guided appropriately by
The other half of patients received treat- either ICP monitoring or the clinical
ment triggered by signs of increased ICP on approach outlined in the trial protocol.
clinical examination or imaging. Hooman Kamel, MD
The 324 enrolled patients had charac- Chesnut RM et al. A trial of intracranial-pressure
teristics of severe TBI, with a median GCS monitoring in traumatic brain injury. N Engl J Med
score of 4 and midline shift in about one 2012 Dec 27; 367:2471.
third. Six months after their injury, pa-
tients in both groups had similar scores on Teamwork and Expertise
a composite measure of functional status Can Be Powerful Medicines
and cognition, and similar cumulative
Implementation of a coordinated, protocol-
mortality (39% in the ICP-monitoring driven pediatric neurocritical care program
group vs. 41% in the imaging-examination improved outcomes after traumatic brain
group, a nonsignificant difference). Pa- injury.
tients who underwent ICP monitoring Patients with traumatic brain injury (TBI)
received fewer specific treatments for face a high risk for secondary brain injury
cerebral edema. from potentially reversible complications
COMMENT that affect many different organ systems.
This impressive study requires us to re- Other similarly complex disease states ap-
think how we define and measure intra- pear to benefit from closely coordinated,
cranial hypertension. In the meantime, it specialized care. Therefore, investigators
should be noted that this trial did not test at a childrens hospital hypothesized that
whether we should treat intracranial hy- outcomes of pediatric TBI could be im-
pertension, which was treated aggressively proved through a program to facilitate
in both groups. Instead, the authors found cross-disciplinary communication
no benefit to ICP monitoring in guiding and consistent implementation of best
this treatment. These results indicate that practices in monitoring and treatment.
the treatment of intracranial hypertension In 2005, these investigators initiated
a pediatric neurocritical care program
(PNCP) that coordinated efforts among
providers in critical care, neurosurgery,
Additional Emergency Department Staff surgery, anesthesia, and radiology. Provid-
Training and Physical Therapy Provide ers received specific training for the pro-
No Long-Term Benet for Whiplash .................... 13
gram, supported by ongoing feedback and
A New Treatment for Tumors
in Tuberous Sclerosis Complex? ........................... 13 quality improvement. To assess the pro-
Pallidal DBS in Primary Dystonia: grams effects, the researchers compared
5-Year Findings ......................................................... 14 discharge outcomes during about 6 years
Early Resection Better Than Biopsy before PNCP implementation with those
in Adult Low-Grade Glioma .................................... 14
during 6 years after implementation.
Migraine and School Performance
in Elementary School Children............................... 15 The study included 123 patients with
Painful Diabetic Neuropathy: severe TBI (Glasgow Coma Scale [GCS]
A Three-Drug Comparison ..................................... 15 score 8), excluding patients with abuse-
Measuring the Inner Retinal Layer related head trauma, cardiac arrest before
in Multiple Sclerosis ................................................ 16
admission, or a GCS score of 3 with fixed,

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
10
EDITORS-IN-CHIEF
S. Claiborne Johnston, MD, PhD, Professor of
Neurology, and Epidemiology and Biostatistics;
Associate Vice Chancellor, Research; Director,
Clinical and Translational Science Institute,
University of California, San Francisco
S. Andrew Josephson, MD, Associate Professor
of Neurology; Director, Neurohospitalist Program;
Medical Director, Inpatient Neurology, University
of California, San Francisco
EXECUTIVE EDITOR
Christine Sadlowski, MS
Massachusetts Medical Society
ASSOCIATE EDITORS
Peter J. Goadsby, MD, PhD, DSc, Professor of
Neurology, University of California, San Francisco
Hooman Kamel, MD, Assistant Professor of
Neurology and Neuroscience, Weill Cornell Medical
College, New York City
Robert C. Knowlton, MD, MSPH, Associate Professor
of Neurology, University of Alabama at Birmingham
(UAB); Acting Director, UAB Epilepsy Center
Brandy R. Matthews, MD, Assistant Professor,
Clinical Neurology; Associate Director, Neurology
Residency Training Program, Alzheimer Disease
Center, Indiana University School of Medicine
Robert T. Naismith, MD, Assistant Professor of
Neurology, Washington University, St. Louis
Jaime Toro, MD, Chief, Section of Neurology,
Fundacin Santa Fe de Bogot; Professor and
Director of the Program of Neurology, University
of El Bosque, Santa Fe de Bogot, Colombia
CONTRIBUTING EDITORS
Michael Benatar, MD, MS, PhD, Walter Bradley
Chair in ALS Research; Associate Professor,
Neurology; Chief, Neuromuscular Division,
University of Miami
Seemant Chaturvedi, MD, Professor of Neurology,
Wayne State University School of Medicine,
and Director, WSU/Detroit Medical Center
Comprehensive Stroke Program, Detroit
Michael S. Okun, MD, Co-Director, Center for
Movement Disorders and Neurorestoration,
University of Florida McKnight Brain Institute
Thomas R. Swift, MD, Professor and former Chair,
Department of Neurology, Medical College of Georgia
MASSACHUSETTS MEDICAL SOCIETY
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NEUROLOGY
dilated pupils. Rates of favorable disposi-
tion (discharge to home) increased from
48% in the pre-PNCP period to 67% after-
ward, a significant difference. In multivari-
able models accounting for demographic
characteristics and initial injury severity,
PNCP implementation remained signifi-
cantly associated with improved rates of fa-
vorable disposition. Confirmatory analyses
showed no changes over time in discharge
decision making for patients with similar
neurological function. Nationwide secular
trends during the study period did not ac-
count for the improved outcomes after
PNCP implementation.
COMMENT
This study is limited by its reliance on dis-
charge rather than long-term outcomes
data. Nevertheless, the investigators found
no changes over time in discharge decision
making for patients with similar neurologi-
cal function. This finding supports the as-
sumption that the higher rate of discharge
to home after PNCP implementation re-
flects better long-term neurological out-
comes. These results indicate that special-
ized teams working in close coordination
can improve the outcomes of complex ill-
ness even in the absence of specific thera-
peutic advances such as new medicines or
surgical procedures.
Hooman Kamel, MD
Pineda JA et al. Effect of implementation of a paedi-
atric neurocritical care programme on outcomes
after severe traumatic brain injury: A retrospective
cohort study. Lancet Neurol 2013 Jan; 12:45.
Citicoline for Traumatic Brain
Injury: Time for Other Options
This well-designed study showed no benefit.
Despite the high prevalence of traumatic
brain injury (TBI), few controlled, ran-
domized, medication trials have been suffi-
ciently powered to provide definitive re-
sults. These researchers assessed the effects
of citicoline (an intermediate element in
phosphatidylcholine synthesis) in 1213 pa-
tients hospitalized with TBI at eight Level I
trauma centers.
TBI was complicated mild (basically,
having computerized tomography evi-
dence of lesions), moderate, or severe.
Approximately two thirds of patients
had complicated mild injuries; one fourth
had post-traumatic amnesia lasting less
Vol. 15 No. 2
than 24 hours. Participants were random-
ized to 90 days of manufacturer-supplied
citicoline 2000 mg/day or placebo starting
within 24 hours of injury.
The study was stopped early because of
futility, although a sample size of 1426, pre-
determined as necessary for adequate pow-
er, had not yet been reached. The primary
outcome (functional and cognitive status at
90 days) did not differ between the groups
(improvement: citicoline, 35.4%; placebo,
35.6%). Secondary outcomes also did not
differ between groups, except that among
patients with complicated mild TBI, pla-
cebo was associated with better cognitive
performance at the 180-day evaluation
than citicoline.
COMMENT
The best studies give us guidance for treat-
ment, and negative studies are important
telling us that we need to explore other op-
tions. As the editorialists note, studies may
need to control for post-trauma rehabilita-
tion or the mechanism of injury, and one
could argue that other patients (e.g., those
with uncomplicated mild TBI) might re-
spond differently to citicoline. Nonetheless,
the total lack of response must be taken seri-
ously. Other studies have demonstrated effi-
cacy of amantadine, methylphenidate, and
cholinesterase inhibitors. With the publica-
tion of this study, there is no indication for
citicoline after TBI.
Jonathan Silver, MD,
Journal Watch Psychiatry
Zafonte RD et al. Effect of citicoline on functional
and cognitive status among patients with traumatic
brain injury: Citicoline Brain Injury Treatment Trial
(COBRIT). JAMA 2012 Nov 21; 308:1993.
Ruff RL and Riechers RG. Effective treatment of
traumatic brain injury: Learning from experience.
JAMA 2012 Nov 21; 308:2032.
Indicators for Prognosis
in Mild Traumatic Brain Injury
MRI results and initial symptoms buoy
prediction of outcomes in studies of athletes
and emergency department patients.
Some individuals with mild traumatic brain
injuries (mTBIs) suffer persistent symp-
toms. Two studies have now examined
predictive factors for prolonged recovery.
Yuh and colleagues analyzed prognostic
information from 3T magnetic resonance
imaging (MRI) scans performed at a
February 2013
mean of 12 days postinjury and computed
tomography (CT) scans performed in the
emergency department among participants
who had presented for evaluation of an
mTBI. Of 1023 screened patients, 135 met
study criteria and completed the study
(mean age, 40 years; 80% with loss of con-
sciousness [LOC] or posttraumatic amne-
sia). Of 98 patients with normal CT, 28%
had abnormal MRIs (hemorrhagic axonal
injury, 23 patients; extraaxial hematomas,
4; contusions, 3). Historical and demo-
graphic features (TBI history, educational
background, and employment status) ex-
plained only 9.5% to 10.2% of outcome
variability. The strongest predictor of worse
3-month outcomes was presence of one or
more contusions on MRI (odds ratio, 4.5).
CT evidence of subarachnoid hemorrhage
correlated with MRI evidence of contu-
sions.
McCrea and colleagues examined pro-
spective data on recovery for 45 or 90 days
in 570 concussed athletes who had pre-
season evaluations. Immediate memory
scores were significantly lower at day 6 or
7 in 57 prolonged-recovery patients than
in 513 typical-recovery patients (recovery,
1 week), but were similar at day 45/90.
Self-reported mTBI symptoms persisted
through day 45/90, but objective assess-
ments did not differ among the TBI groups
or a control group of 166 nonconcussed
athletes. Factors most strongly associated
with prolonged recovery were LOC (few
seconds), posttraumatic amnesia (maxi-
mum, several minutes), retrograde amne-
sia, and symptom severity within first
24 hours; LOC had the highest odds ratio
(OR, 4.15).
COMMENT
Both studies provide additional avenues for
improved understanding of poor outcomes
in patients with mild TBI. Lesions visible
on 3T MRI are associated with poorer
mTBI outcome. In sports mTBI, indicators
of a more severe concussion (loss of con-
sciousness, worse initial symptoms, and
memory problems) are associated with
prolonged recovery. Would MRIs of these
athletes also show abnormalities?
Jonathan Silver, MD,
Journal Watch Psychiatry
JWatch.org
Yuh EL et al. MRI improves 3-month outcome pre-
diction in mild traumatic brain injury. Ann Neurol
2012 Oct 11; [e-pub ahead of print]. (http://dx.doi
.org/10.1002/ana.23783)
McCrea M et al. Incidence, clinical course, and
predictors of prolonged recovery time following
sport-related concussion in high school and college
athletes. J Int Neuropsychol Soc 2013 Jan; 19:22.
Simplifying Acute Stroke
Prognostication
A combination of age and NIH Stroke Scale
score may reliably identify patients who are
unlikely to have a good outcome after stroke.
For clinicians who treat acute stroke, sever-
al clinical prediction scores are available
for prognosticating long-term outcomes,
but such scores are used infrequently for
decision making. Investigators have now
created a highly simplified rule based on
just two clinical factors. The Stroke Prog-
nostication using Age and NIH Stroke
Scale score (SPAN) index comprises a pa-
tients age in years added to the NIH Stroke
Scale score on admission. Scores are di-
chotomized at 100; patients are thereby la-
beled SPAN-100positive or SPAN-100
negative. The utility of this dichotomized
SPAN index was tested by applying it retro-
spectively to patients enrolled in the Na-
tional Institute of Neurological Disorders
and Stroke (NINDS) trials of tissue plas-
minogen activator (TPA) for acute stroke.
Unlike other major acute stroke thrombol-
ysis trials, the NINDS TPA trials did not
exclude patients based on age or stroke
severity.
Among 624 patients enrolled in these
TPA trials, 62 (9.9%) were SPAN-100
positive. In this subset, TPA (used in 36
of these patients) did not significantly in-
crease the rate of good functional outcomes
at 3 months (5.6% with TPA vs. 3.9% with
placebo). Instead, the benefit of TPA ac-
crued to SPAN-100negative patients
(55.4% had good 3-month outcomes with
TPA vs. 40.2% with placebo, a significant
difference). Significantly more SPAN-100
positive than SPAN-100negative patients
had intracerebral hemorrhage. Rates of
symptomatic intracerebral hemorrhage
were higher with TPA than with placebo in
both SPAN-100negative patients (6.9%
vs. 0.7%) and SPAN-100positive patients
(16.7% vs. 7.6%).
11
COMMENT
Advanced age and severe stroke should not
be used reflexively to withhold intravenous
TPA from clearly eligible patients. However,
such baseline characteristics should be tak-
en into account in patients for whom the
risks and benefits of TPA are less clear,
such as those with relative contraindica-
tions (e.g., recent surgery) or a question-
able likelihood of benefit (e.g., approaching
4.5 hours since stroke onset). Although
several acute stroke prognostication scores
have already been developed and validated,
the SPAN-100 scores simplicity would
make it an attractive tool for medical deci-
sion making in acute stroke, provided that
it is validated in other populations.
Hooman Kamel, MD
Saposnik G et al. Stroke Prognostication using
Age and NIH stroke scale: SPAN-100. Neurology
2013 Jan; 80:21.
Dr. Johnston is a study author but was not involved in
the selection or editing of this Journal Watch article.
Alzheimer Disease Risk
Variant Discovered
An anti-inflammatory gene is linked to
increased risk for Alzheimer disease.
Most cases of Alzheimer disease (AD) af-
fect people after age 65 and do not involve
clear autosomal-dominant genetics. Clini-
cians are generally aware of the increased
risk for late-onset AD conferred by the 4
allele of apolipoprotein E (APOE 4). Now,
two groups report a new, rare variant in the
gene encoding the triggering receptor ex-
pressed on myeloid cells 2 (TREM2) that
results in an odds ratio for AD that is simi-
lar to the odds with APOE 4. TREM2 is
expressed throughout the central nervous
system, particularly in the white matter. Its
protein is related to immunoglobulin and
acts as a phagocytic receptor for bacteria
and as a control of the inflammatory re-
sponse. On microglia, the protein is impor-
tant for the clearance of neural debris.
The two research teams each used a
complicated series of genetics methods,
including direct sequencing of DNA from
AD patients and controls, genome-wide
association studies with imputation, and
assays of gene expression across regions
of the human brain and in mouse models.
Jonsson and colleagues found that the
R47H variant of TREM2 was associated
with a significantly increased risk for AD
12
in a relatively homogenous Icelandic group
(odds ratio, 2.92), and in other, more het-
erogenous, populations. Similarly, among
people of European and North American
ancestry, Guerreiro and colleagues found a
significantly increased risk for AD associ-
ated with the R47H variant (OR, 4.5).
COMMENT
Because the R47H variant is rare, these
findings are unlikely to affect current clini-
cal care. However, the further implication
of neuroinflammation in the pathogenesis
of AD supports rapid and extensive explo-
ration of therapeutics in this domain. Like-
wise, as editorialists note, the associations
of the TREM2 gene with other neurode-
generative illnesses that lead to leukoen-
cephalopathy (polycystic lipomembranous
osteodysplasia with sclerosing leukoen-
cephalopathy, and hereditary diffuse leu-
koencephalopathy with spheroids) provide
a unique opportunity to explore overlap in
the pathophysiology of different forms of
neurodegeneration and the potential treat-
ment implications therein.
Brandy R. Matthews, MD
Jonsson T et al. Variant of TREM2 associated with
the risk of Alzheimers disease. N Engl J Med 2013
Jan 10; 368:107.
Guerreiro R et al. TREM2 variants in Alzheimers
disease. N Engl J Med 2013 Jan 10; 368:117.
Neumann H and Daly MJ. Variant TREM2 as risk
factor for Alzheimers disease. N Engl J Med 2013
Jan 10; 368:182.
Low-Dose Aspirin and
Dementia in Older Women
Does low-dose acetylsalicylic acid prevent
cognitive decline in women with high
cardiovascular risk?
Several studies have examined the effect
of nonsteroidal anti-inflammatory drugs
(NSAIDs) on the development of dementia
(JAMA 2003; 289:2819 and BMJ 2003;
327:128). Now, researchers have conducted
a prospective, observational study to exam-
ine whether low-dose aspirin could prevent
cognitive decline. The Swedish population-
based cohort included 681 women aged 70
to 92 at baseline. Comprehensive examina-
tions at baseline and 5 years later included
cognitive testing with the Mini-Mental
State Exam (MMSE), category fluency,
naming ability, and word memory tests.
Dementia was diagnosed according to the
NEUROLOGY
Diagnostic and Statistical Manual of Mental
Disorders, Third edition, revised, criteria.
Of the 681 women, 129 used low-dose
aspirin at baseline (75160 mg daily).
Overall, 95% of the participants had a car-
diovascular risk higher than 10%. The
mean Framingham score (indicating 10-
year cardiovascular risk) was significantly
higher in the aspirin group. After 5 years,
women taking regular low-dose aspirin
had significantly less cognitive decline
than those not taking aspirin, even after
adjustments for age, APOE status, other
NSAID use, and cardiovascular risk score.
Development of dementia did not differ be-
tween the groups. The authors speculate
that the thromboxane A inhibition of aspi-
rin may produce an anticoagulant and
anti-inflammatory effect, which other re-
search suggests is a major component of
neuritic plaques in Alzheimer disease.
They concluded that low-dose aspirin
treatment may have a neuroprotective
effect in older women with high cardio-
vascular risk.
COMMENT
The strengths of this study include the
population-based sample, the comprehen-
sive exams, and the longitudinal design.
However, the authors themselves indicate
there may be a selection bias, as individuals
with early cognitive dysfunction are less
likely to take aspirin. In addition, the
MMSE is not designed to detect small
changes in mental function.
This intriguing study adds to the po-
tential salutary effect of daily low-dose as-
pirin. Given aspirins low cost and relative
lack of side effects, those who tend to be-
lieve that low-dose aspirin may prevent de-
mentia will take it. However, with all re-
spect, it requires a leap of faith to believe
this is so. Jon Brillman, MD, FRCPI
Dr. Brillman is Chairman Emeritus, Department of
Neurology, Allegheny General Hospital, and Professor
of Neurology, Drexel University College of Medicine,
Allegheny Campus, Pittsburgh.
Kern S et al. Does low-dose acetylsalicylic acid
prevent cognitive decline in women with high car-
diovascular risk? A 5-year follow-up of a non-
demented population-based cohort of Swedish
elderly women. BMJ Open 2012 Oct 3; 2:e001288.
(http://dx.doi.org/10.1136/bmjopen-2012-001288)
Vol. 15 No. 2
Better Cognitive Functioning
in Elders Linked to More-
Intense Physical Activity
In a community sample of well-functioning
adults over age 60, peak intensity of physical
activity, rather than overall quantity, was
the better predictor of higher levels of
cognitive performance.
The association of physical exercise
with better general health is well known,
and exercise has increasingly been advo-
cated as an adjunct in the treatment of
psychiatric conditions. In this Australian,
partially industry-supported study of
physical activity and cognitive perfor-
mance, 217 community-dwelling, cogni-
tively healthy individuals over age 60
(mean age, 69.5; 54% female), researchers
used actigraphy devices for 7 days to moni-
tor the quantity and peak intensity of par-
ticipants physical activities. Participants
removed the wrist-worn devices only for
water activities, for showering, and in bed
if the device interfered with sleep.
Participants in the two tertiles with
higher intensity of physical activity (based
on peak activity level) were younger, leaner,
and less likely to have diabetes. After adjust-
ment for age, sex, and education, the highest
tertile of intensity was associated with better
scores than the lowest tertile on digit span,
digit symbol coding, and visuospatial func-
tioning and recall. After adjustment for po-
tential confounders, total activity level was
not associated with better cognitive func-
tioning, unlike previous studies.
COMMENT
The authors translated the peak activity
counts in the highest tercile into moderate-
intensity Metabolic Equivalent of Task
(MET) values, which have been described
elsewhere as walking at approximately
3 miles per hour, bicycling on flat ground,
or dancing. This cross-sectional study did
not specifically control for individuals
medical status and instead used age as a
proxy so that the potential impact of con-
current physical illness, medication use,
and other related factors on cognitive per-
formance cannot be determined. Presum-
ably, individuals with worse general health,
including cognitive health, have less capaci-
ty for physically intense activities. Never-
theless, these findings are consistent with
the view that intense physical activity, not
just overall quantity of activity, is associated
February 2013
with better cognitive functioning. These re-
sults support clinicians recommendations
for higher intensity of physical activity for
patients of all ages. Joel Yager, MD,
Journal Watch Psychiatry
Brown BM et al. Intense physical activity is
associated with cognitive performance in the
elderly. Transl Psychiatry 2012 Nov 20; 2:e191.
(http://dx.doi.org/10.1038/tp.2012.118)
Neurologists as
Neurohospitalists
A neurohospitalist service shortened length
of stay and lowered direct costs compared
with a traditional neurology service.
Does the value of hospital medicine on
length of stay, cost, quality of care, and pa-
tient use extend to its equivalent in neurol-
ogy? To find out, investigators retrospec-
tively examined patient outcomes 2 years
before (343 patients) and 2 years after
(436 patients) introduction of a neurohos-
pitalist service at an academic medical cen-
ter in California. Stroke patients belonged
to a separate neurovascular service and
therefore were excluded.
Before implementation of the neurohos-
pitalist service, the general neurology ser-
vice was managed by 11 attending neurolo-
gists who provided both primary and consult
services for 1 month annually. After imple-
mentation, the general service was separated
into primary and consult teams with a neu-
rohospitalist assigned to each. Neurohospi-
talists attended for at least 2 months annual-
ly and were responsible for case management
of patients on the primary service.
Average length of stay was significantly
shortened from 6.3 days before to 4.6 days
after introduction of the neurohospitalist
service. Median direct cost per patient was
also lower (US$10,132 vs. $8742), but the
difference was statistically significant only
after adjustment for confounders in multi-
variable analysis. During the neurohospi-
talist period, neurology patients appeared
to be more complex and were transferred
from other hospitals more often. Rates of
readmission and in-hospital mortality as
well as patient and resident satisfaction did
not change.
COMMENT
Whether the benefit of the neurohospitalist
service was derived from the divided work-
load, having an attending dedicated to the
primary service, extended inpatient experi-
JWatch.org
ence for physicians, or improved case man-
agement is unclear. Personnel costs were
not reported. Further, the findings are dif-
ficult to generalize given the scarcity of
stroke patients. Nevertheless, the neuro-
hospitalist service was associated with low-
er costs and shortened length of stay dur-
ing a period when overall patient costs and
length of stay in the hospital actually had
risen. Grace C. Huang, MD,
Journal Watch Hospital Medicine
Douglas VC et al. Effect of a neurohospitalist
service on outcomes at an academic medical center.
Neurology 2012 Sep 4; 79:988. (http://dx.doi.org/
10.1212/WNL.0b013e31826846cb)
Dr. Josephson is a study author but was not involved in
the selection or editing of this Journal Watch article.
Additional Emergency
Department Staff Training
and Physical Therapy Provide No
Long-Term Benefit for Whiplash
Usual care remains the best approach.
Clinical guidelines recommending physical
therapy for whiplash are not evidence-
based. To assess the benefit of additional
staff training and early physical therapy, re-
searchers performed a two-step pragmatic
study of 3851 patients presenting to 15
emergency departments (EDs) in the U.K.
with acute whiplash injuries, primarily after
motor vehicle collisions. The active man-
agement training group (>500 clinicians)
provided patients with reassurance, encour-
agement to return to regular activities, ad-
vice on consistent use of analgesia, and di-
rection that a neck collar should be avoided.
In step one, the EDs were randomized
to provide usual care (1598 patients) or ac-
tive management (2253 patients). Among
the 70% of patients who participated in
12-month follow-up, Neck Disability Index
(NDI) scores were similar between the two
treatment groups. In step two, 599 patients
who had persistent symptoms after 3 weeks
were randomized to a single physical thera-
py advice session or a package of up to six
physical therapy sessions. A modest benefit
in NDI scores was seen in the package group
at 4 months, but not at 8 or 12 months. Ac-
tive management consultations and physi-
cal therapy sessions were more expensive
than standard care.
COMMENT
In addition to causing patient discomfort,
whiplash injuries have a major economic
13
impact in terms of lost productivity and in-
surance costs. Although physical therapy
had a modest effect on early recovery, it
provided no long-term benefit in this
study. We should continue our current
practice of providing patient education, an-
algesia, and reassurance once the presence
of serious injury is eliminated.
Kristi L. Koenig, MD, FACEP, FIFEM,
Journal Watch Emergency Medicine
Lamb SE et al. Emergency department treatments
and physiotherapy for acute whiplash: A pragmatic,
two-step, randomised controlled trial. Lancet 2012
Dec 18; [e-pub ahead of print]. (http://dx.doi
.org/10.1016/S0140-6736(12)61304-X).
A New Treatment for Tumors
in Tuberous Sclerosis Complex?
The mTOR inhibitor everolimus appears
effective in reducing the size of subependymal
giant cell astrocytomas in TSC.
The tumor and tumor-like neurocutane-
ous lesions of tuberous sclerosis complex
(TSC) result from inappropriate constitu-
tive activation of the mammalian target of
rapamycin (mTOR), a protein kinase that
regulates protein synthesis and cell growth
and proliferation. Mutations in either the
TSC1 or TSC2 gene result in defective func-
tion of the hamartin-tuberin tumor sup-
pressor complex, which restricts mTOR ac-
tivation. Small preliminary studies suggest
efficacy of mTOR inhibition in decreasing
the size and number of TSC lesions.
This multicenter, manufacturer-
funded study aimed to establish efficacy
of an mTOR inhibitor, everolimus, in
reducing the volume of subependymal
giant cell astrocytomas (SEGAs), a slow-
growing type of tumor common in TSC
that increases the risk for potentially life-
threatening hydrocephalus. Researchers
randomized 117 patients (median age,
9.5 years) 2:1 to everolimus or placebo. Eli-
gible patients had a target SEGA of at least
1 cm in greatest diameter. The primary
endpoint was the proportion of patients
with target SEGA size reduction 50% (re-
sponse rate) without other signs of worsen-
ing. Secondary endpoints included (1)
change in seizure frequency between base-
line and 24 weeks, (2) time to progression
of SEGAs, (3) skin lesion response rate,
and (4) and angiomyolipoma response
rate. A blinded treatment phase ran until
the last patient was treated for 6 months.
14
At a median of 9.7 months, the re-
sponse rates were 35% with everolimus
versus none with placebo. SEGA response
to everolimus was present in all subgroups
TSC1 (50%), TSC2 (29%), and no
mutation (45%). Disease progression was
the main reason for discontinuation, and
was seen only with placebo (n=6). No ef-
fect on seizure frequency was apparent;
however, the baseline frequency was higher
in the placebo group. Time to progression
was not reached. Skin lesion response rates
were 42% with everolimus and 11% with
placebo; renal angiomyolipomas response
rates were 53% with everolimus and none
with placebo.
COMMENT
This important clinical trial is an excellent
example of the culmination of bench-to-
bedside research. Once the mechanisms
of defects in TSC gene products were eluci-
dated, the steps to discovering a potential
pharmacological treatment came relatively
quickly, with an existing drug. Now, Level
1 evidence is available to support the use
of everolimus to treat TSC patients with
SEGAs. This trial should encourage studies
of mTOR inhibitors to treat other TSC le-
sions and neurological disorders that in-
volve excessive activation of protein syn-
thesis and cell growth and proliferation.
Robert C. Knowlton, MD, MSPH
Franz DN et al. Efficacy and safety of everolimus for
subependymal giant cell astrocytomas associated with
tuberous sclerosis complex (EXIST-1): A multicentre,
randomised, placebo-controlled phase 3 trial. Lancet
2012 Nov 14; [e-pub ahead of print]. (http://dx.doi
.org/10.1016/S0140-6736(12)61134-9)
CASE DISCUSSION
SERIES ON THE WEB
Do you have an
interesting neurological
case?
Cases can be completed or still
evolving. E-mail a 100-word
description of the case to us at
jwneuro@mms.org.
We will publish both
the case and, when relevant,
an experts comments
on our website
neurology.jwatch.org.
NEUROLOGY
Pallidal DBS in Primary
Dystonia: 5-Year Findings
The first large randomized trial of pallidal
deep brain stimulation in primary general-
ized or segmental dystonia shows long-term
benefit in the open-label extension trial out
to 5 years.
Primary dystonia is an idiopathic movement
disorder characterized by sustained muscle
contractions, repetitive twisting movements,
or abnormal postures. When dystonia is se-
vere and medications or botulinum toxin
injections provide insufficient relief, deep
brain stimulation (DBS) is considered an ef-
fective treatment option. Several studies
have shown remarkable improvement
(50%80%) in motor symptoms within the
first 6 to 12 months after surgery, but few
studies (with mixed results) have demon-
strated the long-term effect of globus palli-
dus internus (GPi) DBS in primary dysto-
nia. To address the long-term effect of this
therapy on motor symptoms, disability, and
adverse events, researchers followed patients
for 5 years who had participated in a pro-
spective, blinded, sham-controlled trial of
neurostimulation in primary dystonia (JW
Neurol Feb 2007, p. 13, and N Engl J Med
2006; 355:1978). Uniquely, this study in-
cluded both generalized dystonia (typically
juvenile-onset, with spread of dystonia from
a limb to most body regions) and segmental
dystonia (typically adult-onset, with pre-
dominately cervical involvement). The pri-
mary outcome was dystonia severity (mea-
sured using the Burke-Fahn-Marsden
dystonia rating scale) at 3 and 5 years after
surgery compared with both before surgery
and after 6 months of stimulation.
Intent-to-treat analyses showed signifi-
cant improvements in dystonia severity
from baseline to 3 years (61.1%) and 5 years
(57.8%). Significant improvements also
occurred from 6 months to 3 and 5 years.
Typical device-related adverse effects in-
cluded infection, lead dislodgement, and
breakage, all of which were more common
in the generalized dystonia patients. Dysar-
thria was the most frequent nonsurgery-
related adverse effect and was more com-
mon in the segmental dystonia group.
Long-term patient disability and quality
of life also improved significantly.
COMMENT
These results provide further evidence that
pallidal DBS should be considered in
Vol. 15 No. 2
patients with severe, medically intractable
primary dystonia. Although device-related
complications can occur in some patients,
the overall benefit for most patients with
either generalized or segmental dystonia,
even 5 years after surgery, is remarkable.
Jill L. Ostrem, MD
Dr. Ostrem is Associate Professor of Clinical Neurology,
University of California, San Francisco, School of Medicine.
Volkmann J et al. Pallidal deep brain stimulation
in patients with primary generalised or segmental
dystonia: 5-year follow-up of a randomised trial.
Lancet Neurol 2012 Dec; 11:1029.
Early Resection
Better Than Biopsy
in Adult Low-Grade Glioma
A comparative population-based analysis
of adult low-grade glioma favors early
resection over biopsy.
In adults, low-grade gliomas are infiltrative
brain tumors that tend to grow more slowly
than their high-grade histologic counter-
parts. Initial treatment consists of biopsy or
surgical resection followed by close surveil-
lance, chemotherapy, or radiation, with no
universally accepted standard of care. Re-
gardless of the initial surgical or medical
management, low-grade gliomas virtually
always recur. Whether or not early surgical
resection provides survival benefit and
outweighs surgical risk in low-grade glio-
mas has been debated. Retrospective stud-
ies that have compared biopsy versus resec-
tion have produced mixed results with a
trend in favor of resection, but the benefit
of resection in these studies may have been
overestimated due to selection bias.
To address this limitation, researchers
performed a retrospective, population-
based comparison of regional cohorts in
Norway from two medical systems with
distinctly different approaches to initial
treatment. One system consistently favored
surgical resection, while the other tended
toward biopsy and surveillance. The pa-
tient populations were similar in both re-
gions, with minimal geographic crossover.
One study author reported having a small
stock holding with the manufacturer of the
surgical imaging system used in the study.
During a 7-year median follow-up of
153 patients, the median overall survival
was 5.9 years in the biopsy-only group
and was significantly longer, but not yet
reached, in the resection group. Expected
February 2013
7-year survival was lower in the biopsy-
only group than in the early-resection
group (44% vs. 68%). The rate of malignant
transformation was higher in the biopsy-
only group than in the early-resection
group (56% vs. 37%), and surgical compli-
cation rates were similar in the biopsy and
resection groups (9% and 8%).
COMMENT
These results support maximal safe surgi-
cal resection as the preferred initial treat-
ment for low-grade glioma. They demon-
strate an increasing survival benefit from
early resection, over a prolonged follow-up
period, without increased surgical risk. The
study design reduced the confounding ef-
fects of surgical selection bias that may
have affected results of previous studies,
but it did not eliminate other potential con-
founders, including variation in surgical
technique and other institutional differ-
ences that may contribute to the effect on
survival. Brian J. Scott, MD
Dr. Scott is Clinical Instructor of Neurohospitalist
Medicine and Neuro-oncology, Department of Medicine,
University of California, San Francisco.
Jakola AS et al. Comparison of a strategy favoring
early surgical resection vs a strategy favoring watch-
ful waiting in low-grade gliomas. JAMA 2012
Nov 14; 308:1881.
Migraine and School
Performance in Elementary
School Children
An observational study shows that migraine
is associated with poor school performance
in preadolescent children.
Migraine is a common and often disabling
neurological condition that affects both
children and adults (Cephalalgia 2010;
30:1065). To describe the school perfor-
mance of children with migraine compared
with the performance of those without
headache, researchers invited teachers of
Brazilian public school children aged 5 to
12 years to provide information and inter-
view mothers of the children. They used a
validated survey following International
Classification of Headache Disorders II
criteria to provide data for migraine diag-
nostic assignment by a study author. The
teachers categorized childrens school per-
formance as below, matching, or above ex-
pectations for grade level, and reported
school absences due to headache. (One
study author is an employee of Merck &
Co., Inc.)
JWatch.org
Parents of 75% of the children partici-
pated. Episodic migraine was diagnosed in
9.0% of children, probable migraine in
17.6%, and chronic migraine in 0.6%.
Chronic migraine was significantly more
common in children of low socioeconomic
status than in those of upper or high-middle
status (odds ratio, 4.16). Children with any
migraine type were more likely to have
below-average school performance than
headache-free children. By contrast, chil-
dren with episodic tension-type headache
performed no differently than children
without headache. Poor school performance
was significantly predicted by the duration,
frequency, and severity of migraine attacks
and by the presence of nausea with attacks,
use of analgesics, female sex, and abnormal
score on a mental health assessment instru-
ment. Children with migraine were also
more likely to miss school and to leave
school early than children with tension-type
headache. Predictors of school absence in-
cluded duration and severity of migraine at-
tacks, use of analgesics, and nausea.
COMMENT
This study provides important information
about the impact of migraine on the school
performance of elementary schoolaged
children. Although this study was observa-
tional, the association of poor school per-
formance with severity of migraine attacks
and presence of nausea suggests a causal
relationship. The study does not include in-
formation on history of migraine diagnosis
or use of migraine-specific treatment. Giv-
en that migraine is highly treatable and
highly prevalent even in young children,
future studies should focus on whether
treating migraine in children improves
school performance and learning. If it does,
screening for migraine in school children
may lead to improved school performance
in a large number of children. The associa-
tion between lower socioeconomic status
and chronic migraine suggests that under-
privileged children may benefit the most
from increased attention to migraine diag-
nosis and treatment. Amy Gelfand, MD
Dr. Gelfand is Clinical Instructor, Department of
Neurology, Division of Child Neurology, University
of California, San Francisco.
Arruda MA and Bigal ME. Migraine and migraine
subtypes in preadolescent children: Association with
school performance. Neurology 2012 Oct 30;
79:1881.
15
Painful Diabetic Neuropathy:
A Three-Drug Comparison
Amitriptyline, duloxetine, and pregabalin
reduced pain to a similar extent.
Head-to-head comparisons of drugs com-
monly prescribed for painful diabetic neu-
ropathy are scarce. In this double-blind
trial, funded by a maker of pregabalin (an
anticonvulsant; Lyrica), 83 patients (mean
age, 65) with painful diabetic neuropathy
were randomized to receive amitriptyline
(a tricyclic antidepressant), duloxetine (a
serotonin-norepinephrine reuptake inhibi-
tor; Cymbalta), or pregabalin. Patients
were treated for 4 weeks; total daily doses
were titrated to a maximum of 75 mg of
amitriptyline, 120 mg of duloxetine, and
600 mg of pregabalin.
At 4 weeks, mean pain scores had im-
proved in all three groups, with no signifi-
cant differences among groups. Duloxetine
lessened sleep efficiency compared with the
other two drugs, whereas pregabalin was
associated with slightly worse cognitive
function than the other two drugs. Adverse
effects (particularly fatigue, dizziness, and
somnolence) were most common with pre-
gabalin. Premature withdrawal from the
study due to adverse events occurred in six
pregabalin recipients, three duloxetine re-
cipients, and one amitriptyline recipient.
COMMENT
These three drugs had similar effects on
painful diabetic neuropathy. Pregabalin
was the least well tolerated, perhaps be-
cause of the high dose (note that target
doses for duloxetine and pregabalin in this
study were twice that of the FDA-approved
maximal doses for diabetic neuropathy).
Amitriptyline by far the least expensive
alternative seems to be the winner here;
however, many patients cant tolerate its
anticholinergic side effects, and tricyclics
are contraindicated in some patients with
cardiac disease. Allan S. Brett, MD,
Journal Watch General Medicine
Boyle J et al. Randomized, placebo-controlled com-
parison of amitriptyline, duloxetine, and pregabalin
in patients with chronic diabetic peripheral neuro-
pathic pain: Impact on pain, polysomnographic
sleep, daytime functioning, and quality of life.
Diabetes Care 2012 Dec; 35:2451.
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16 NEUROLOGY Vol. 15 No. 2

Measuring the Inner Retinal
Layer in Multiple Sclerosis
Thinning of the inner retinal layer occurs
relatively rapidly in early and active MS,
and its measurement is superior to that of
the retinal nerve fiber layer for assessing
neuroaxonal damage.
Optic nerve involvement in multiple sclero-
sis (MS) is common, and noninvasive mea-
sures of axonal degeneration are needed.
Optical coherence tomography (OCT) can
quantify both the peripapillary retinal
nerve fiber layer (RNFL) thickness and the
ganglion cell and inner plexiform (GCIP)
layer of the macula.
Participants were 164 patients with
MS who had at least 6 months of follow-up
after baseline OCT measurements and
59 healthy controls. Mean follow-up was
21.1 months. Baseline RNFL and GCIP
thinning were greatest in secondary
progressive MS, followed by relapsing
remitting MS, clinically isolated syndrome,
and primary progressive MS. During
follow-up, GCIP thinning occurred 46%
faster in patients than in controls. Rates
of GCIP thinning were faster for patients
with nonocular relapses (42% faster), new
gadolinium-enhancing lesions (54% fast-
er), new T2 lesions (36% faster), and dis-
ability progression (37% faster) than for
those without these factors. Patients with
disease duration <5 years had 43% faster
thinning than those with longer duration.
Patients with the combination of new
gadolinium-enhancing lesions, new T2
lesions, and disease duration <5 years
had 70% faster GCIP thinning than
those without these factors.
COMMENT
Axonal loss in MS is thought to begin early,
as a direct result of inflammatory plaques
that transect axons and expose demyelinat-
ed axons to degeneration. OCT has been
proposed as a surrogate of axonal injury in
MS clinical trials of neural protective and
reparative therapies. OCT is readily avail-
able, inexpensive, and fast. This study
shows that measurement of the GCIP layer
over time is more sensitive than similar
RNFL measurements. Atrophy was most
pronounced in early and active disease. Pa-
tients with secondary progressive disease
had lower baseline thickness than other
MS patients, but longitudinal thinning in
progressive disease was less pronounced.
GCIP measurement has advantages over
the more commonly measured RNFL
thickness in that it appears more sensitive
to change, does not fluctuate with transient
edema, and correlates well with clinical
function. GCIP measurement may become
a feasible surrogate marker of axonal pres-
ervation in clinical trials of therapeutics for
early MS. Robert T. Naismith, MD
Ratchford JN et al. Active MS is associated with
accelerated retinal ganglion cell/inner plexiform
layer thinning. Neurology 2013 Jan 1; 80:47.